Beruflich Dokumente
Kultur Dokumente
Metabolism
Sumit Kumar
Tomas Berl
T
he maintenance of the tonicity of body fluids within a very nar-
row physiologic range is made possible by homeostatic mecha-
nisms that control the intake and excretion of water. Critical to
this process are the osmoreceptors in the hypothalamus that control
the secretion of antidiuretic hormone (ADH) in response to changes in
tonicity. In turn, ADH governs the excretion of water by its end-organ
effect on the various segments of the renal collecting system. The
unique anatomic and physiologic arrangement of the nephrons brings
about either urinary concentration or dilution, depending on prevail-
ing physiologic needs. In the first section of this chapter, the physiol-
ogy of urine formation and water balance is described.
The kidney plays a pivotal role in the maintenance of normal water
homeostasis, as it conserves water in states of water deprivation, and
excretes water in states of water excess. When water homeostasis is
deranged, alterations in serum sodium ensue. Disorders of urine dilu-
tion cause hyponatremia. The pathogenesis, causes, and management
strategies are described in the second part of this chapter.
When any of the components of the urinary concentration mecha-
nism is disrupted, hypernatremia may ensue, which is universally
characterized by a hyperosmolar state. In the third section of this
chapter, the pathogenesis, causes, and clinical settings for hyperna-
tremia and management strategies are described.
CHAPTER
1
1.2 Disorders of Water, Electrolytes, and Acid-Base
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Normal medullary blood flow
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NaCl
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H 2O
GFR
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H 2O
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ADH
ADH
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NaCl
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NaCl H 2O
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Determinants of delivery of NaCl NaCl
H 2O
NaCl to distal tubule:
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GFR ADH
NaCl
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Proximal tubular fluid and
H 2O
solute (NaCl) reabsorption H 2O
H 2O
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NaCl
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H 2O
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;;; Collecting system water
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Water delivery
permeability determined by
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NaCl movement Presence of arginine vasopressin
Solute concentration Normal collecting system
FIGURE 1-2
Determinants of the renal concentrating mechanism. Human kidneys have two popula-
tions of nephrons, superficial and juxtamedullary. This anatomic arrangement has impor-
tant bearing on the formation of urine by the countercurrent mechanism. The unique
anatomy of the nephron [1] lays the groundwork for a complex yet logical physiologic
arrangement that facilitates the urine concentration and dilution mechanism, leading to the
formation of either concentrated or dilute urine, as appropriate to the person’s needs and
dictated by the plasma osmolality. After two thirds of the filtered load (180 L/d) is isotoni-
cally reabsorbed in the proximal convoluted tubule, water is handled by three interrelated
processes: 1) the delivery of fluid to the diluting segments; 2) the separation of solute and
water (H2O) in the diluting segment; and 3) variable reabsorption of water in the collect-
ing duct. These processes participate in the renal concentrating mechanism [2].
1. Delivery of sodium chloride (NaCl) to the diluting segments of the nephron (thick
ascending limb of the loop of Henle and the distal convoluted tubule) is determined by
glomerular filtration rate (GFR) and proximal tubule function.
2. Generation of medullary interstitial hypertonicity, is determined by normal functioning
of the thick ascending limb of the loop of Henle, urea delivery from the medullary col-
lecting duct, and medullary blood flow.
3. Collecting duct permeability is determined by the presence of antidiuretic hormone
(ADH) and normal anatomy of the collecting system, leading to the formation of a
concentrated urine.
1.4 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 1-3
Normal functioning of Determinants of the urinary dilution mech-
Thick ascending limb of loop of Henle anism include 1) delivery of water to the
Cortical diluting segment
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thick ascending limb of the loop of Henle,
distal convoluted tubule, and collecting sys-
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tem of the nephron; 2) generation of maxi-
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mally hypotonic fluid in the diluting seg-
ments (ie, normal thick ascending limb of
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the loop of Henle and cortical diluting seg-
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NaCl
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H 2O
ment); 3) maintenance of water imperme-
ability of the collecting system as deter-
mined by the absence of antidiuretic
GFR
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hormone (ADH) or its action and other
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NaCl collecting filtration rate; NaCl—sodium chloride;
duct H2O—water.
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Determinants of delivery of H2O NaCl H 2O
to distal parts of the nephron
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GFR NaCl
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Proximal tubular H2O and
NaCl reabsorption H 2O
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NaCl
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H 2O
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Collecting duct impermeability depends on
Absence of ADH
H 2O
FIGURE 1-4
Distal tubule Mechanism of urine concentration:
Urea
overview of the passive model. Several
models of urine concentration have been
2 put forth by investigators. The passive
Cortex H 2O model of urine concentration described by
H 2O
Kokko and Rector [3] is based on perme-
Na+ Na+ ability characteristics of different parts of
K+ K+ 1
2Cl2– 2Cl2– the nephron to solute and water and on the
Urea Outer medullary fact that the active transport is limited to
NaCl
Na+ Na+ collecting duct the thick ascending limb. 1) Through the
K+ K+ Na+, K+, 2 Cl cotransporter, the thick
2Cl2– 2Cl2–
ascending limb actively transports sodium
Urea chloride (NaCl), increasing the interstitial
H 2O
Outer medulla tonicity, resulting in tubular fluid dilution
with no net movement of water and urea
on account of their low permeability. 2)
H 2O Inner medullary The hypotonic fluid under antidiuretic hor-
4 collecting duct mone action undergoes osmotic equilibra-
3 H 2O tion with the interstitium in the late distal
Urea
tubule and cortical and outer medullary
collecting duct, resulting in water removal.
NaCl NaCl Urea concentration in the tubular fluid rises
Urea
5 on account of low urea permeability. 3) At
the inner medullary collecting duct, which
is highly permeable to urea and water, espe-
NaCl
cially in response to antidiuretic hormone,
Inner medulla Loop of Henle Collecting tubule the urea enters the interstitium down its
concentration gradient, preserving intersti-
tial hypertonicity and generating high urea
concentration in the interstitium.
(Legend continued on next page)
Diseases of Water Metabolism 1.5
FIGURE 1-5
Pathways for urea recycling. Urea plays an important role in the
Cortex generation of medullary interstitial hypertonicity. A recycling mech-
anism operates to minimize urea loss. The urea that is reabsorbed
Urea
into the inner medullary stripe from the terminal inner medullary
Urea
collecting duct (step 3 in Fig. 1-4) is carried out of this region by
the ascending vasa recta, which deposits urea into the adjacent
descending thin limbs of a short loop of Henle, thus recycling the
Urea
urea to the inner medullary collecting tubule (pathway A).
Some of the urea enters the descending limb of the loop of Henle
and the thin ascending limb of the loop of Henle. It is then carried
Urea
through to the thick ascending limb of the loop of Henle, the distal
Outer collecting tubule, and the collecting duct, before it reaches the
stripe Outer inner medullary collecting duct (pathway B). This process is facili-
Inner
Urea medulla tated by the close anatomic relationship that the hairpin loop of
stripe Henle and the vasa recta share [4].
Urea
Collecting
duct
Urea
Urea
Ascending vasa recta Pathway B
FIGURE 1-6
1500 Changes in the volume and osmolality of
20 mL 0.3 mL tubular fluid along the nephron in diuresis
and antidiuresis. The osmolality of the tubu-
1200 lar fluid undergoes several changes as it pass-
es through different segments of the tubules.
Tubular fluid undergoes marked reduction in
Osmolality, mOsm/kg H2O
FIGURE 1-7
Paraventricular neurons Osmoreceptors Pathways of antidiuretic hormone release. Antidiuretic hormone is
Pineal responsible for augmenting the water permeability of the cortical
Baroreceptors Third ventricle and medullary collecting tubules, thus promoting water reabsorp-
VP,NP tion via osmotic equilibration with the isotonic and hypertonic
Supraoptic neuron
interstitium, respecively. The hormone is formed in the supraoptic
Tanycyte
and paraventricular nuclei, under the stimulus of osmoreceptors
SON
and baroreceptors (see Fig. 1-11), transported along their axons
Optic chiasm and secreted at three sites: the posterior pituitary gland, the portal
Superior hypophysial capillaries of the median eminence, and the cerebrospinal fluid of
artery the third ventricle. It is from the posterior pituitary that the antidi-
Portal capillaries uretic hormone is released into the systemic circulation [6].
in zona externa of Mammilary body SON—supraoptic nucleus; VP—vasopressin; NP—neurophysin.
median eminence VP,NP
Posterior pituitary
Long portal vein
Systemic venous system
Anterior pituitary
Short portal vein VP,NP
FIGURE 1-8
Exon 1 Exon 2 Exon 3 Structure of the human arginine vasopressin
(AVP/antidiuretic hormone) gene and the
prohormone. Antidiuretic hormone (ADH)
is a cyclic hexapeptide (mol. wt. 1099) with
Pre-pro-vasopressin AVP Gly Lys Arg Neurophysin II Arg Glycopeptide a tail of three amino acids. The biologically
(164 AA) (Cleavage site) inactive macromolecule, pre-pro-vaso-
pressin is cleaved into the smaller, biologi-
Signal
peptide cally active protein. The protein of vaso-
pressin is translated through a series of sig-
nal transduction pathways and intracellular
Pro-vasopressin AVP Gly Lys Arg Neurophysin II Arg Glycopeptide
cleaving. Vasopressin, along with its bind-
ing protein, neurophysin II, and the glyco-
protein, are secreted in the form of neurose-
cretory granules down the axons and stored
Products of AVP NH2 + Neurophysin II + Glycopeptide in nerve terminals of the posterior lobe of
pro-vasopressin
the pituitary [7]. ADH has a short half-life
of about 15 to 20 minutes and is rapidly
metabolized in the liver and kidneys.
Gly—glycine; Lys—lysine; Arg—arginine.
Diseases of Water Metabolism 1.7
FIGURE 1-9
Intracellular action of antidiuretic hormone. The multiple actions
AQP-3 of vasopressin can be accounted for by its interaction with the V2
receptor found in the kidney. After stimulation, vasopressin binds
to the V2 receptor on the basolateral membrane of the collecting
Recycling vesicle
duct cell. This interaction of vasopressin with the V2 receptor leads
to increased adenylate cyclase activity via the stimulatory G protein
Endocytic (Gs), which catalyzes the formation of cyclic adenosine 3’, 5’-
cAMP retrieval
monophosphate (cAMP) from adenosine triphosphate (ATP). In
ATP AQP-2
turn, cAMP activates a serine threonine kinase, protein kinase A
AQP-2 (PKA). Cytoplasmic vesicles carrying the water channel proteins
migrate through the cell in response to this phosphorylation
PKA H 2O process and fuse with the apical membrane in response to increas-
ing vasopressin binding, thus increasing water permeability of the
Gαs AQP-2 collecting duct cells. These water channels are recyled by endocyto-
sis once the vasopressin is removed. The water channel responsible
Gαs
for the high water permeability of the luminal membrane in
Exocytic
insertion response to vasopressin has recently been cloned and designated as
aquaporin-2 (AQP-2) [8]. The other members of the aquaporin
AVP Recycling vesicle family, AQP-3 and AQP-4 are located on the basolateral mem-
branes and are probably involved in water exit from the cell. The
molecular biology of these channels and of receptors responsible
AQP-4 for vasopressin action have contributed to the understanding of the
syndromes of genetically transmitted and acquired forms of vaso-
Basolateral Luminal
pressin resistance. AVP—arginine vasopressin.
FIGURE 1-10
Aquaporins and their characteristics. An ever growing family of different channels have been cloned and characterized; however,
aquaporin (AQP) channels are being described. So far, about seven only four have been found to have any definite physiologic role.
1.8 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 1-11
Isotonic volume depletion Osmotic and nonosmotic regulation of antidiuretic hormone (ADH) secretion. ADH is
Isovolemic osmotic increase secreted in response to changes in osmolality and in circulating arterial volume. The
50
“osmoreceptor” cells are located in the anterior hypothalamus close to the supraoptic
45 nuclei. Aquaporin-4 (AQP-4), a candidate osmoreceptor, is a member of the water channel
40 family that was recently cloned and characterized and is found in abundance in these neu-
Plasma AVP, pg/mL
35 rons. The osmoreceptors are sensitive to changes in plasma osmolality of as little as 1%.
In humans, the osmotic threshold for ADH release is 280 to 290 mOsm/kg. This system is
30
so efficient that the plasma osmolality usually does not vary by more than 1% to 2%
25 despite wide fluctuations in water intake [9]. There are several other nonosmotic stimuli
20 for ADH secretion. In conditions of decreased arterial circulating volume (eg, heart failure,
15 cirrhosis, vomiting), decrease in inhibitory parasympathetic afferents in the carotid sinus
baroreceptors affects ADH secretion. Other nonosmotic stimuli include nausea, which can
10
lead to a 500-fold rise in circulating ADH levels, postoperative pain, and pregnancy. Much
5 higher ADH levels can be achieved with hypovolemia than with hyperosmolarity, although
0 a large fall in blood volume is required before this response is initiated. In the maintenance
of tonicity the interplay of these homeostatic mechanisms also involves the thirst mecha-
0 5 10 15 20 nism, that under normal conditions, causes either intake or exclusion of water in an effort
Change, % to restore serum osmolality to normal.
Increased thirst Increased ADH release Decreased thirst Decreased ADH release
Decreased ADH release and thirst Increased ADH release and thirst
A B
FIGURE 1-12
Pathways of water balance (conservation, A, and excretion, B). In anatomically distinct. Between the limits imposed by the osmotic
humans and other terrestrial animals, the thirst mechanism plays thresholds for thirst and ADH release, plasma osmolality may be
an important role in water (H2O) balance. Hypertonicity is the regulated still more precisely by small osmoregulated adjustments
most potent stimulus for thirst: only 2% to 3 % changes in plasma in urine flow and water intake. The exact level at which balance
osmolality produce a strong desire to drink water. This absolute occurs depends on various factors such as insensible losses through
level of osmolality at which the sensation of thirst arises in healthy skin and lungs, and the gains incurred from eating, normal drink-
persons, called the osmotic threshold for thirst, usually averages ing, and fat metabolism. In general, overall intake and output come
about 290 to 295 mOsm/kg H2O (approximately 10 mOsm/kg into balance at a plasma osmolality of 288 mOsm/kg, roughly
H2O above that of antidiuretic hormone [ADH] release). The so- halfway between the thresholds for ADH release and thirst [10].
called thirst center is located close to the osmoreceptors but is
Diseases of Water Metabolism 1.9
FIGURE 1-13
Plasma osmolality Pathogenesis of dysnatremias. The countercurrent mechanism of
280 to 290 mOsm/kg H2O the kidneys in concert with the hypothalamic osmoreceptors via
antidiuretic hormone (ADH) secretion maintain a very finely tuned
Decrease Increase balance of water (H2O). A defect in the urine-diluting capacity
with continued H2O intake results in hyponatremia. Conversely, a
defect in urine concentration with inadequate H2O intake culmi-
Supression Supression Stimulation Stimulation nates in hypernatremia. Hyponatremia reflects a disturbance in
of thirst of ADH release of thirst of ADH release
homeostatic mechanisms characterized by excess total body H2O
relative to total body sodium, and hypernatremia reflects a defi-
ciency of total body H2O relative to total body sodium [11].
(From Halterman and Berl [12]; with permission.)
Dilute urine Concentrated urine
Hyponatremia Hypernatremia
FIGURE 1-15
Pathogenesis of hyponatremia. The
↓ Reabsorption of sodium chloride
in distal convoluted tubule normal components of the renal diluting
Thiazide diuretics mechanism are depicted in Figure 1-3.
Hyponatremia results from disorders of
this diluting capacity of the kidney in the
following situations:
1. Intrarenal factors such as a dimin-
ished glomerular filtration rate
↓ Reabsorption of sodium (GFR), or an increase in proximal
chloride in thick ascending tubule fluid and sodium reabsorp-
limb of loop of Henle
tion, or both, which decrease distal
Loop diuretics
GFR diminished Osmotic diuretics delivery to the diluting segments of
Age Interstitial disease the nephron, as in volume depletion,
Renal disease
congestive heart failure, cirrhosis, or
Congestive heart failure
Cirrhosis nephrotic syndrome.
Nephrotic syndrome 2. A defect in sodium chloride transport
Volume depletion out of the water-impermeable seg-
NaCl ments of the nephrons (ie, in the thick
ascending limb of the loop of Henle).
This may occur in patients with inter-
stitial renal disease and administra-
tion of thiazide or loop diuretics.
↑ ADH release or action 3. Continued secretion of antidiuretic
Drugs hormone (ADH) despite the presence
Syndrome of inappropriate of serum hypo-osmolality mostly
antidiuretic hormone
secretion, etc. stimulated by nonosmotic mecha-
nisms [12].
NaCl—sodium chloride.
UNa >20 UNa <20 UNa >20 UNa >20 UNa <20
Renal losses Extrarenal losses Glucocorticoid deficiency Acute or chronic Nephrotic syndrome
Diuretic excess Vomiting Hypothyroidism renal failure Cirrhosis
Mineralcorticoid deficiency Diarrhea Stress Cardiac failure
Salt-losing deficiency Third spacing of fluids Drugs
Bicarbonaturia with Burns Syndrome of inappropriate
renal tubal acidosis and Pancreatitis antidiuretic hormone
metabolic alkalosis Trauma secretion
Ketonuria
Osmotic diuresis
FIGURE 1-16
Diagnostic algorithm for hyponatremia. The next step in the evalua- increased but total body water is increased even more than sodium,
tion of a hyponatremic patient is to assess volume status and identify causing hyponatremia. These syndromes include congestive heart
it as hypovolemic, euvolemic or hypervolemic. The patient with failure, nephrotic syndrome, and cirrhosis. They are all associated
hypovolemic hyponatremia has both total body sodium and water with impaired water excretion. Euvolemic hyponatremia is the most
deficits, with the sodium deficit exceeding the water deficit. This common dysnatremia in hospitalized patients. In these patients, by
occurs with large gastrointestinal and renal losses of water and definition, no physical signs of increased total body sodium are
solute when accompanied by free water or hypotonic fluid intake. detected. They may have a slight excess of volume but no edema
In patients with hypervolemic hyponatremia, total body sodium is [12]. (Modified from Halterman and Berl [12]; with permission.)
Diseases of Water Metabolism 1.11
FIGURE 1-19
DIAGNOSTIC CRITERIA FOR THE SYNDROME OF Diagnostic criteria for the syndrome of inappropriate antidiuretic
INAPPROPRIATE ANTIDIURETIC HORMONE hormone secretion (SIADH). Clinically, SIADH is characterized by
SECRETION a decrease in the effective extracellular fluid osmolality, with inap-
propriately concentrated urine. Patients with SIADH are clinically
euvolemic and are consuming normal amounts of sodium and
Essential water (H2O). They have elevated urinary sodium excretion. In the
Decreased extracellular fluid effective osmolality (< 270 mOsm/kg H2O) evaluation of these patients, it is important to exclude adrenal, thy-
Inappropriate urinary concentration (> 100 mOsm/kg H2O) roid, pituitary, and renal disease and diuretic use. Patients with
Clinical euvolemia clinically suspected SIADH can be tested with a water load. Upon
Elevated urinary sodium concentration (U[Na]), with normal salt and H2O intake administration of 20 mL/kg of H2O, patients with SIADH are
Absence of adrenal, thyroid, pituitary, or renal insufficiency or diuretic use unable to excrete 90% of the H2O load and are unable to dilute
Supplemental their urine to an osmolality less than 100 mOsm/kg [15]. (Modified
Abnormal H2O load test (inability to excrete at least 90% of a 20–mL/kg H2O load from Verbalis [15]; with permission.)
in 4 hrs or failure to dilute urinary osmolality to < 100 mOsm/kg)
Plasma antidiuretic hormone level inappropriately elevated relative to plasma osmolal-
ity
No significant correction of plasma sodium with volume expansion, but improvement
after fluid restriction
1.12 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 1-20
SIGNS AND SYMPTOMS OF HYPONATREMIA Signs and symptoms of hyponatremia. In evaluating hyponatremic
patients, it is important to assess whether or not the patient is
symptomatic, because symptoms are a better determinant of thera-
Central Nervous System Gastrointestinal System py than the absolute value itself. Most patients with serum sodium
values above 125 mEq/L are asymptomatic. The rapidity with
Mild Anorexia
which hyponatremia develops is critical in the initial evaluation of
Apathy Nausea
such patients. In the range of 125 to 130 mEq/L, the predominant
Headache Vomiting
symptoms are gastrointestinal ones, including nausea and vomiting.
Lethargy
Musculoskeletal System Neuropsychiatric symptoms dominate the picture once the serum
Moderate
Cramps sodium level drops below 125 mEq/L, mostly because of cerebral
Agitation edema secondary to hypotonicity. These include headache, lethargy,
Diminished deep tendon reflexes
Ataxia reversible ataxia, psychosis, seizures, and coma. Severe manifesta-
Confusion tions of cerebral edema include increased intracerebral pressure,
Disorientation tentorial herniation, respiratory depression and death.
Psychosis Hyponatremia-induced cerebral edema occurs principally with
Severe rapid development of hyponatremia, typically in patients managed
Stupor with hypotonic fluids in the postoperative setting or those receiving
Coma diuretics, as discussed previously. The mortality rate can be as
Pseudobulbar palsy great as 50%. Fortunately, this rarely occurs. Nevertheless, neuro-
Tentorial herniation logic symptoms in a hyponatremic patient call for prompt and
Cheyne-Stokes respiration immediate attention and treatment [16,17].
Death
FIGURE 1-21
1 Cerebral adaptation to hyponatremia.
Na+/H2O ↓Na+/↑H2O 3 ↓Na+/↑H2O A, Decreases in extracellular osmolality
2 cause movement of water (H2O) into the
cells, increasing intracellular volume and
K+, Na+ K+, Na+ ↓K+, ↓Na+ thus causing tissue edema. This cellular
H 2O ↑H2O H 2O
osmolytes osmolytes ↓osmolytes edema within the fixed confines of the cra-
nium causes increased intracranial pressure,
leading to neurologic symptoms. To prevent
this from happening, mechanisms geared
Normonatremia Acute hyponatremia Chronic hyponatremia toward volume regulation come into opera-
A tion, to prevent cerebral edema from devel-
oping in the vast majority of patients with
hyponatremia.
After induction of extracellular fluid hypo-osmolality, H2O moves into the brain in
response to osmotic gradients, producing cerebral edema (middle panel, 1). However,
K+ within 1 to 3 hours, a decrease in cerebral extracellular volume occurs by movement of
fluid into the cerebrospinal fluid, which is then shunted back into the systemic circulation.
Glutamate
This happens very promptly and is evident by the loss of extracellular and intracellular
solutes (sodium and chloride ions) as early as 30 minutes after the onset of hyponatremia.
Na+ As H2O losses accompany the losses of brain solute (middle panel, 2), the expanded brain
Urea
volume decreases back toward normal (middle panel, 3) [15]. B, Relative decreases in indi-
vidual osmolytes during adaptation to chronic hyponatremia. Thereafter, if hyponatremia
Inositol persists, other organic osmolytes such as phosphocreatine, myoinositol, and amino acids
Cl– like glutamine, and taurine are lost. The loss of these solutes markedly decreases cerebral
Taurine swelling. Patients who have had a slower onset of hyponatremia (over 72 to 96 hours or
B Other
longer), the risk for osmotic demyelination rises if hyponatremia is corrected too rapidly
[18,19]. Na+—sodium; K+—potassium; Cl-—chloride.
Diseases of Water Metabolism 1.13
Initial symptoms
Complication Persons at Risk Mutism
Dysarthria
Acute cerebral edema Postoperative menstruant females Lethargy and affective changes
Elderly women taking thiazides
Classic symptoms
Children Spastic quadriparesis
Psychiatric polydipsic patients Pseudobulbar palsy
Hypoxemic patients
Lesions in the midbrain, medulla oblongata, and pontine tegmentum
Osmotic demyelination syndrome Alcoholics Pupillary and oculomotor abnormalities
Malnourished patients Altered sensorium
Hypokalemic patients Cranial neuropathies
Extrapontine myelinolysis
Burn victims
Ataxia
Elderly women taking thiazide diuretics Behavioral abnormalities
Parkinsonism
Dystonia
FIGURE 1-22
Hyponatremic patients at risk for neurologic complications. Those
at risk for cerebral edema include postoperative menstruant FIGURE 1-23
women, elderly women taking thiazide diuretics, children, psychi- Symptoms of central pontine myelinolysis. This condition has been
atric patients with polydipsia, and hypoxic patients. In women, described all over the world, in all age groups, and can follow cor-
and, in particular, menstruant ones, the risk for developing neuro- rection of hyponatremia of any cause. The risk for development of
logic complications is 25 times greater than that for nonmenstruant central pontine myelinolysis is related to the severity and chronicity
women or men. The increased risk was independent of the rate of of the hyponatremia. Initial symptoms include mutism and
development, or the magnitude of the hyponatremia [21]. The dysarthria. More than 90% of patients exhibit the classic symptoms
osmotic demyelination syndrome or central pontine myelinolysis of myelinolysis (ie, spastic quadriparesis and pseudobulbar palsy),
seems to occur when there is rapid correction of low osmolality reflecting damage to the corticospinal and corticobulbar tracts in
(hyponatremia) in a brain already chronically adapted (more than the basis pontis. Other symptoms occur on account of extension of
72 to 96 hours). It is rarely seen in patients with a serum sodium the lesion to other parts of the midbrain. This syndrome follows a
value greater than 120 mEq/L or in those who have hyponatremia biphasic course. Initially, a generalized encephalopathy, associated
of less than 48 hours’ duration [20,21]. (Adapted from Lauriat and with a rapid rise in serum sodium, occurs. This is followed by the
Berl [21]; with permission.) classic symptoms 2 to 3 days after correction of hyponatremia,
however, this pattern does not always occur [22]. (Adapted from
Laureno and Karp [22]; with permission.)
A B
FIGURE 1-24
A, Imaging of central pontine myelinolysis. Brain imaging is the images, hypointense. These lesions do not enhance with gadolinium.
most useful diagnostic technique for central pontine myelinolysis. They may not be apparent on imaging until 2 weeks into the illness.
Magnetic resonance imaging (MRI) is more sensitive than computed Other diagnostic tests are brainstem auditory evoked potentials,
tomography (CT). On CT, central pontine and extrapontine lesions electroencephalography, and cerebrospinal fluid protein and myelin
appear as symmetric areas of hypodensity (not shown). On T2 basic proteins [22]. B, Gross appearance of the pons in central pon-
images of MRI, the lesions appear as hyperintense and on T1 tine myelinolysis. (From Laureno and Karp [22]; with permission.)
1.14 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 1-25
Severe hyponatremia (<125 mmol/L) Treatment of severe euvolemic hyponatrem-
ia (<125 mmol/L). The evaluation of a
hyponatremic patient involves an assessment
Symptomatic Asymptomatic
of whether the patient is symptomatic, and
if so, the duration of hyponatremia should
Acute Chronic Chronic be ascertained. The therapeutic approach
Duration <48 h Duration >48 h Rarely <48 h to the hyponatremic patient is determined
more by the presence or absence of symp-
toms than by the absolute level of serum
Emergency correction needed Some immediate correction needed No immediate sodium. Acutely hyponatremic patients
Hypertonic saline 1–2 mL/kg/h Hypertonic saline 1–2 mL/kg/h correction needed are at great risk for permanent neurologic
Coadministration of furosemide Coadministration of furosemide
Change to water restriction upon sequelae from cerebral edema if the hypona-
10% increase of sodium or if tremia is not promptly corrected. On the
symptoms resolve other hand, chronic hyponatremia carries
Perform frequent measurement the risk of osmotic demyelination syndrome
of serum and urine electrolytes if corrected too rapidly. The next step
Do not exceed 1.5 mmol/L/hr
or 20 mmol/d involves a determination of whether the
patient has any risk factors for development
of neurologic complications.
The commonest setting for acute, sympto-
matic hyponatremia is hospitalized, postop-
Long-term management
Identification and treatment of
erative patients who are receiving hypotonic
reversible causes fluids. In these patients, the risk of cerebral
Water restriction edema outweighs the risk for osmotic
Demeclocycline, 300–600 mg bid demyelination. In the presence of seizures,
Urea, 15–60 g/d obtundation, and coma, rapid infusion of
V2 receptor antagonists
3% sodium chloride (4 to 6 mL/kg/h) or
even 50 mL of 29.2% sodium chloride has
been used safely. Ongoing careful neurolog-
ic monitoring is imperative [20].
Acute hyponatremia (duration < 48 hrs) Calculate the net water loss needed to raise the serum sodium (SNa) from 110 mEq/L
Increase serum sodium rapidly by approximately 2 mmol/L/h until symptoms resolve to 120 mEq/L in a 50 kg person.
Full correction probably safe but not necessary Example
Chronic hyponatremia (duration > 48 hrs) Current SNa Total body water (TBW) = Desired SNa New TBW
Initial increase in serum sodium by 10% or 10 mmol/L Assume that TBW = 60% of body weight
Perform frequent neurologic evaluations; correction rate may be reduced with Therefore TBW of patient = 50 0.6 = 30 L
improvement in symptoms 110 mEq/L 30 L
New TBW = = 27.5 L
At no time should correction exceed rate of 1.5 mmol/L/h, or increments of 120 mEq/L
15 mmol/d Thus the electrolyte-free water loss needed to raise the SNa to
Measure serum and urine electrolytes every 1–2 h 120 mEq/L = Present TBW New TBW = 2.5 L
Calculate the time course in which to achieve the desired correction (1 mEq/h)—in
*The sum of urinary cations (UNa + UK) should be less than the concentration of this case, 250 mL/h
infused sodium, to ensure excretion of electrolyte-free water. Administer furosemide, monitor urine output, and replace sodium, potassium, and
excess free water lost in the urine
Continue to monitor urine output and replace sodium, potassium, and excess free
FIGURE 1-26 water lost in the urine
General guidelines for the treatment of symptomatic hyponatremia,
A. Included herein are general guidelines for treatment of patients
with acute and chronic symptomatic hyponatremia. In the treat-
ment of chronic symptomatic hyponatremia, since cerebral water is exceed 1.0 to 1.5 mEq/L/h, and the total increment in 24 hours
increased by approximately 10%, a prompt increase in serum sodi- should not exceed 15 mmol/d [12]. A specific example as to how
um by 10% or 10 mEq/L is permissible. Thereafter, the patient’s to increase a patient’s serum sodium is illustrated in B.
fluids should be restricted. The total correction rate should not
Diseases of Water Metabolism 1.15
FIGURE 1-27
Management options for patients with chronic asymptomatic antidiuretic hormone (ADH) secretion, it must be treated as a
hyponatremia. If the patient has chronic hyponatremia and is chronic disorder. As summarized here, the treatment strategies
asymptomatic, treatment need not be intensive or emergent. involve fluid restriction, pharmacologic inhibition of ADH action,
Careful scrutiny of likely causes should be followed by treatment. and increased solute intake. Fluid restriction is frequently success-
If the cause is determined to be the syndrome of inappropriate ful in normalizing serum sodium and preventing symptoms [23].
FIGURE 1-28
MANAGEMENT OF NONEUVOLEMIC Management of noneuvolemic hyponatremia. Hypovolemic
HYPONATREMIA hyponatremia results from the loss of both water and solute, with
relatively greater loss of solute. The nonosmotic release of antidi-
uretic hormone stimulated by decreased arterial circulating blood
Hypovolemic hyponatremia volume causes antidiuresis and perpetuates the hyponatremia.
Volume restoration with isotonic saline Most of these patients are asymptomatic. The keystone of therapy
Identify and correct causes of water and sodium losses
is isotonic saline administration, which corrects the hypovolemia
and removes the stimulus of antidiuretic hormone to retain fluid.
Hypervolemic hyponatremia Hypervolemic hyponatremia occurs when both solute and water
Water restriction are increased, but water more than solute. This occurs with heart
Sodium restriction failure, cirrhosis and nephrotic syndrome. The cornerstones of
Substitiute loop diuretics for thiazide diurectics treatment include fluid restriction, salt restriction, and loop diuret-
Treatment of timulus for sodium and water retention ics [20]. (Adapted from Lauriat and Berl [20]; with permission.)
V2-receptor antagonist
1.16 Disorders of Water, Electrolytes, and Acid-Base
Renal losses Extrarenal losses Renal losses Extrarenal losses Sodium gains
Osmotic or loop diuretic Excessive sweating Diabetes insipidus Insensible losses Primary
Postobstruction Burns Hypodipsia Respiratory Hyperaldosteronism
Intrinsic renal disease Diarrhea Dermal Cushing's sydrome
Fistulas Hypertonic dialysis
Hypertonic sodium bicarbonate
Sodium chloride tablets
FIGURE 1-30
Diagnostic algorithm for hypernatremia. As for hyponatremia, the ini- and respiratory tract, in febrile or other hypermetabolic states. Very
tial evaluation of the patient with hypernatremia involves assessment of high urine osmolality reflects an intact osmoreceptor–antidiuretic
volume status. Patients with hypovolemic hypernatremia lose both hormone–renal response. Thus, the defense against the development
sodium and water, but relatively more water. On physical examination, of hyperosmolality requires appropriate stimulation of thirst and the
they exhibit signs of hypovolemia. The causes listed reflect principally ability to respond by drinking water. The urine sodium (UNa) value
hypotonic water losses from the kidneys or the gastrointestinal tract. varies with the sodium intake. The renal water losses that lead to
Euvolemic hyponatremia reflects water losses accompanied by inad- euvolemic hypernatremia are a consequence of either a defect in
equate water intake. Since such hypodipsia is uncommon, hyperna- vasopressin production or release (central diabetes insipidus) or
tremia usually supervenes in persons who have no access to water or failure of the collecting duct to respond to the hormone (nephrogenic
who have a neurologic deficit that impairs thirst perception—the very diabetes insipidus) [23]. (Modified from Halterman and Berl [12];
young and the very old. Extrarenal water loss occurs from the skin with permission.)
Diseases of Water Metabolism 1.17
FIGURE 1-31
Urine volume = CH2O + COsm Physiologic approach to polyuric disorders. Among euvolemic hyper-
natremic patients, those affected by polyuric disorders are an impor-
tant subcategory. Polyuria is arbitrarily defined as urine output of
more than 3 L/d. Urine volume can be conceived of as having two
COsm CH2O
Isotonic or hypertonic urine Hypotonic urine components: the volume needed to excrete solutes at the concentration
of solutes in plasma (called the osmolar clearance) and the other being
the free water clearance, which is the volume of solute-free water that
Polyuria due to increased Polyuria due to increased has been added to (positive free water clearance [CH2O]) or subtract-
solute excretion free water clearance ed (negative CH2O) from the isotonic portion of the urine osmolar
Sodium chloride Excessive water intake clearance (Cosm) to create either a hypotonic or hypertonic urine.
Diuretics Psychogenic polydipsia
Consumption of an average American diet requires the kidneys to
Renal sodium wasting Defect in thirst
Excessive salt intake Hyper-reninemia excrete 600 to 800 mOsm of solute each day. The urine volume in
Bicarbonate Potassium depletion which this solute is excreted is determined by fluid intake. If the
Vomiting/metabolic alkalosis Renal vascular disease urine is maximally diluted to 60 mOsm/kg of water, the 600 mOsm
Alkali administration Renal tumors will need 10 L of urine for effective osmotic clearance. If the concen-
Mannitol Renal hypoperfusion
trating mechanism is maximally stimulated to 1200 mOsm/kg of
Diuretics Increased renal water excretion
Bladder lavage Impaired renal water concentrating water, osmotic clearance will occur in a minimum of 500 mL of
Treatment of cerebral edema mechanism urine. This flexibility is affected when drugs or diseases alter the
Decreased ADH secretion renal concentrating mechanism.
Increased ADH degradation Polyuric disorders can be secondary to an increase in solute clear-
Resistance to ADH action
ance, free water clearance, or a combination of both. ADH—antidi-
uretic hormone.
* Water intake is restricted until the patient loses 3%–5% of weight or until three consecutive hourly determinations of
urinary osmolality are within 10% of each other. (Caution must be exercised to ensure that the patient does not
become excessively dehydrated.) Aqueous AVP (5 U subcutaneous) is given, and urine osmolality is measured after FIGURE 1-33
60 minutes. The expected responses are given above. Clinical features of diabetes insipidus.
Other clinical features can distinguish com-
FIGURE 1-32 pulsive water drinkers from patients with
central diabetes insipidus. The latter usually
Water deprivation test. Along with nephrogenic diabetes insipidus and primary polydipsia,
has abrupt onset, whereas compulsive water
patients with central diabetes insipius present with polyuria and polydipsia. Differentiating
drinkers may give a vague history of the
between these entities can be accomplished by measuring vasopressin levels and determin-
onset. Unlike compulsive water drinkers,
ing the response to water deprivation followed by vasopressin administration [25]. (From
patients with central diabetes insipidus have
Lanese and Teitelbaum [26]; with permission.)
a constant need for water. Compulsive
water drinkers exhibit large variations in
water intake and urine output. Nocturia
is common with central diabetes insipidus
and unusual in compulsive water drinkers.
Finally, patients with central diabetes
insipidus have a predilection for drinking
cold water. Plasma osmolality above
295 mOsm/kg suggests central diabetes
insipidus and below 270 mOsm/kg suggests
compulsive water drinking [23].
1.18 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 1-34
CAUSES OF DIABETES INSIPIDUS Causes of diabetes insipidus. The causes of diabetes insipidus can
be divided into central and nephrogenic. Most (about 50%) of the
central causes are idiopathic; the rest are caused by central nervous
Central diabetes insipidus Nephrogenic diabetes insipidus system involvement with infection, tumors, granuloma, or trauma.
The nephrogenic causes can be congenital or acquired [23].
Congenital Congenital
Autosomal-dominant X-linked
Autosomal-recessive Autosomal-recessive
Acquired Acquired
Post-traumatic Renal diseases (medullary cystic disease,
Iatrogenic polycystic disease, analgesic nephropathy,
Tumors (metastatic from breast, sickle cell nephropathy, obstructive uro-
craniopharyngioma, pinealoma) pathy, chronic pyelonephritis, multiple
myeloma, amyloidosis, sarcoidosis)
Cysts
Hypercalcemia
Histiocytosis
Hypokalemia
Granuloma (tuberculosis, sarcoid)
Drugs (lithium compounds, demeclocycline,
Aneurysms
methoxyflurane, amphotericin, foscarnet)
Meningitis
Encephalitis
Guillain-Barré syndrome
Idiopathic
FIGURE 1-35
Congenital central diabetes insipidus (DI),
autosomal-dominant form. This condition
has been described in many families in
Europe and North America. It is an autoso-
mal dominant inherited disease associated
SP VP NP NP NP CP with marked loss of cells in the supraoptic
nuclei. Molecular biology techniques have
Exon 1 Exon 2 Exon 3 revealed multiple point mutations in the
vasopressin-neurophysin II gene. This con-
83 dition usually presents early in life [25].
–19..–16 47 A rare autosomal-recessive form of central
79 87 DI has been described that is characterized
50 by DI, diabetes mellitus (DM), optic atro-
14 phy (OA), and deafness (DIDMOAD or
Wolfram’s syndrome). This has been linked
17 to a defect in chromosome-4 and involves
57 abnormalities in mitochondrial DNA [27].
20
SP—signal peptide; VP—vasopressin;
61 NP—neurophysin; GP—glycoprotein.
–3 24 62 67
–1 65
Missense mutation Stop codon Deletion
Diseases of Water Metabolism 1.19
FIGURE 1-36
TREATMENT OF CENTRAL DIABETES INSIPIDUS Treatment of central diabetes insipidus (DI). Central DI may be
treated with hormone replacement or drugs. In acute settings when
renal water losses are extensive, aqueous vasopressin (pitressin) is
Condition Drug Dose useful. It has a short duration of action that allows for careful mon-
itoring and avoiding complications like water intoxication. This
Complete central DI dDAVP 10–20 (g intranasally q 12–24 h drug should be used with caution in patients with underlying coro-
Partial central DI Vasopressin tannate 2–5 U IM q 24–48 h nary artery disease and peripheral vascular disease, as it can cause
Aqueous vasopressin 5–10 U SC q 4–6 h vascular spasm and prolonged vasoconstriction. For the patient
Chlorpropamide 250–500 mg/d with established central DI, desmopressin acetate (dDAVP) is the
Clofibrate 500 mg tid–qid agent of choice. It has a long half-life and does not have significant
Carbamazepine 400–600 mg/d vasoconstrictive effects like those of aqueous vasopressin. It can be
conveniently administered intranasally every 12 to 24 hours. It is
usually tolerated well. It is safe to use in pregnancy and resists
degradation by circulating vasopressinase. In patients with partial
DI, agents that potentiate release of antidiuretic hormone can be
used. These include chlorpropamide, clofibrate, and carbamazepine.
They work effectively only if combined with hormone therapy,
decreased solute intake, or diuretic administration [23].
FIGURE 1-37
T T S A M Extracellular Congenital nephrogenic diabetes insipidus,
P *
A
S L M –NH2
S H
S
P
L L G
P
V 1
X-linked–recessive form. This is a rare dis-
N S P
S
ease of male patients who do not concen-
S trate their urine after administration of
Q R F
E
R
D R antidiuretic hormone. The pedigrees of
T G
P A P A E P W affected families have been linked to a
L P L F
L D D
K D C G
R group of Ulster Scots who emigrated to
R T W A A S G G P E
A P
A
R A L W G E R
T D L Halifax, Nova Scotia in 1761 aboard the
C V V
A L C
D T N
Y * W E ship called “Hopewell.” According to
E Q R R V A G
L L P Q A A Q F T W W A A P F
the Hopewell hypothesis, most North
* L A V V K
A L I Q L V
F S I L A L F V
Y
V
L Q
M L F P Q
I
F V
M V F F
L V L L M
L * American patients with this disease are
L A A A P L
A V A V G M L A C W
A S
L D
C L H
A Y S L L T L P
V L N L descendants of a common ancestor with a
G S V L M
S S
Y S L A F A A
G I V Y
S C
T
A L V N F I G I L
A A W C Q V I
V V N P W
I single gene defect. Recent studies, howev-
A
L L H V M T
V L
V V L
I F M T
L Y A
*
*
A
I
P
L
D P
S
er, disproved this hypothesis [28]. The
R E R R S F C C
R A
R
H R H
I V
V
S S L A
R
gene defect has now been traced to 87 dif-
W L
R N
G H A
W
A T
K
S
S E L R
S G ferent mutations in the gene for the vaso-
R R G I S R
C
H L V S A
T
pressin receptor (AVP-R2) in 106 presum-
A H A V
R
G *
V
A
A P ably unrelated families [29]. (From Bichet,
P P P
M S G G C S E D Q P G L
S et al. [29]; with permission.)
L G E
A P T
Y R H G P S
S G T
E T A
R S
R * S S
P G R L A K 371
G R R R G D T S
S –COOH
Intracellular
1.20 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 1-38
Urinary lumen L A P A Congenital nephrogenic diabetes insipidus (NDI), autosomal-
S 11 V
L A V 9,12 R V recessive form. In the autosomal recessive form of NDI, mutations
D N A T
G A 8 P G have been found in the gene for the antiiuretic hormone (ADH)–
R L
I S
N K sensitive water channel, AQP-2. This form of NDI is exceedingly
M F
D N S D rare as compared with the X-linked form of NDI [30]. Thus far, a
A S
P T
13 C D total of 15 AQP-2 mutations have been described in total of 13
G H
T 6 T T W families [31]. The acquired form of NDI occurs in various kidney
I A V
Q A L P S H
E G
Y
H F
diseases and in association with various drugs, such as lithium
L Q I W
P
W L
V
A
L A
T
V G
L
L I
G and amphotericin B. (From Canfield et al. [31]; with permission.)
N I Q M A A G 4 E V G H L
P
A L S A V
A
F
L A
L
G
V
G F G A G V A
G L L L L
L T
S I
V F F I G T G Q
L
Q G
F
G
L
F A L I S 12 S
L 13 V L A V L L
T L Q V L L
A Y F C A Y
A A I P T N
F L G L A
A
F
P
G V
Y
E L
H R S 7
A N F
F I L T E P
S V D G
V E R R P
A 1 G S A
R A V K
S H H S
F I L
C P Q
A S S L S
2 N G H P E
I L 11 R
P V G R
M S E L
W E L R A L T
V K A
3 V C A V
T V A S
Q L
R K
R
Principal cell V E
R E
G
L
-intracellular E W D T D P E
Defect in Generation
of Medullary Defect in cAMP Downregulation Elders and infants
Disease State Interstitial Tonicity Generation of AQP-2 Other Hospitalized patients receiving
Chronic renal failure ✔ ✔ ✔ Downregulation of V2 Hypertonic infusions
receptor message Tube feedings
Hypokalemia ✔ ✔ ✔ Osmotic diuretics
Hypercalcemia ✔ ✔ Lactulose
Sickle cell disease ✔ Mechanical ventilation
Protein malnutrition ✔ ✔ Altered mental status
Demeclocycline ✔ Uncontrolled diabetes mellitus
Lithium ✔ ✔ Underlying polyuria
Pregnancy Placental secretion of
vasopressinase
FIGURE 1-40
Patient groups at increased risk for severe
FIGURE 1-39 hypernatremia. Hypernatremia always
Causes and mechanisms of acquired nephrogenic diabetes insidpidus. Acquired nephrogenic reflects a hyperosmolar state. It usually
diabetes insipidus occurs in chronic renal failure, electrolyte imbalances, with certain drugs, occurs in a hospital setting (reported inci-
in sickle cell disease and pregnancy. The exact mechanism involved has been the subject of dence 0.65% to 2.23% of all hospitalized
extensive investigation over the past decade and has now been carefully elucidated for most patients) with very high morbidity and mor-
of the etiologies. tality (estimates of 42% to over 70%) [12].
Diseases of Water Metabolism 1.21
FIGURE 1-43
GUIDELINES FOR THE TREATMENT OF Guidelines for the treatment of symptomatic hypernatremia.
SYMPTOMATIC HYPERNATREMIA* Patients with severe symptomatic hypernatremia are at high risk of
dying and should be treated aggressively. An initial step is estimat-
ing the total body free water deficit, based on the weight (in kilo-
Correct at a rate of 2 mmol/L/h grams) and the serum sodium. During correction of the water
Replace half of the calculated water deficit over the first 12–24 hrs deficit, it is important to perform serial neurologic examinations.
Replace the remaining deficit over the next 24–36 hrs
Perform serial neurologic examinations (prescribed rate of correction can be
decreased as symptoms improve)
Measure serum and urine electrolytes every 1–2 hrs
*If UNa + U K is less than the concentration of PNa, then water loss is ongoing and
needs to be replaced.
1.22 Disorders of Water, Electrolytes, and Acid-Base
References
1. Jacobson HR: Functional segmentation of the mammalian nephron. 16. Berl T, Schrier RW: Disorders of water metabolism. In Renal and
Am J Physiol 1981, 241:F203. Electrolyte Disorders, edn. 4. Edited by Schrier RW. Philadelphia:
2. Goldberg M: Water control and the dysnatremias. In The Sea Within Lippincott-Raven, 1997:54.
Us. Edited by Bricker NS. New York: Science and Medicine 17. Berl T, Anderson RJ, McDonald KM, Schreir RW: Clinical Disorders
Publishing Co., 1975:20. of water metabolism. Kidney Int 1976, 10:117.
3. Kokko J, Rector F: Countercurrent multiplication system without 18. Gullans SR, Verbalis JG: Control of brain volume during hyperosmo-
active transport in inner medulla. Kidney Int 1972, 114. lar and hypoosmolar conditions. Annu Rev Med 1993, 44:289.
4. Knepper MA, Roch-Ramel F: Pathways of urea transport in the mam- 19. Zarinetchi F, Berl T: Evaluation and management of severe hypona-
tremia. Adv Intern Med 1996, 41:251.
malian kidney. Kidney Int 1987, 31:629.
20. Lauriat SM, Berl T: The Hyponatremic Patient: Practical focus on
5. Vander A: In Renal Physiology. New York: McGraw Hill, 1980:89.
therapy. J Am Soc Nephrol 1997, 8(11):1599.
6. Zimmerman E, Robertson AG: Hypothalamic neurons secreting vaso- 21. Ayus JC, Wheeler JM, Arieff AI: Postoperative hyponatremic
pressin and neurophysin. Kidney Int 1976, 10(1):12. encephalopathy in menstruant women. Ann Intern Med
7. Bichet DG: Nephrogenic and central diabetes insipidus. In Diseases of 1992,117:891.
the Kidney, edn. 6. Edited by Schrier RW, Gottschalk CW. Boston: 22. Laureno R, Karp BI: Myelinolysis after correction of hyponatremia.
Little, Brown, and Co., 1997:2430 Ann Intern Med 1997, 126:57.
8. Bichet DG : Vasopressin receptors in health and disease. Kidney Int 23. Kumar S, Berl T: Disorders of serum sodium concentration. Lancet
1996, 49:1706. 1998. in press.
9. Dunn FL, Brennan TJ, Nelson AE, Robertson GL: The role of blood 24. Cogan MG: Normal water homeostasis. In Fluid & Electrolytes,
osmolality and volume in regulating vasopressin secretion in the rat. Physiology and Pathophysiology. Edited by Cogan MG. Norwalk:
J Clin Invest 1973, 52:3212. Appleton & Lange, 1991:94.
10. Rose BD: Antidiuretic hormone and water balance. In Clinical 25. Rittig S, Robertson G, Siggaard C, et al.: Identification of 13 new
Physiology of Acid Base and Electrolyte Disorders, edn. 4. New York: mutations in the vasopressin-neurophysin II gene in 17 kindreds with
McGraw Hill, 1994. familial autosomal dominant neurohypophyseal diabetes insipidus.
Am J Hum Genet 1996, 58:107.
11. Cogan MG: Normal water homeostasis. In Fluid & Electrolytes,
26. Lanese D, Teitelbaum I: Hypernatremia. In The Principles and
Physiology and Pathophysiology. Edited by Cogan MG. Norwalk:
Practice of Nephrology, edn. 2. Edited by Jacobson HR, Striker GE,
Appleton & Lange, 1991:98.
Klahr S. St. Louis: Mosby, 1995:895.
12. Halterman R, Berl T: Therapy of dysnatremic disorders. In Therapy in 27. Barrett T, Bundey S: Wolfram (DIDMOAD) syndrome. J Med Genet
Nephrology and Hypertension. Edited by Brady H, Wilcox C. 1997, 29:1237.
Philadelphia: WB Saunders, 1998, in press.
28. Holtzman EJ, Ausiello DA: Nephrogenic Diabetes insipidus: Causes
13. Veis JH, Berl T, Hyponatremia: In The Principles and Practice of revealed. Hosp Pract 1994, Mar 15:89–104.
Nephrology, edn. 2. Edited by Jacobson HR, Striker GE, Klahr S.
29. Bichet D, Oksche A, Rosenthal W: Congential Nephrogenic Diabetes
St.Louis: Mosby, 1995:890. Insipidus. J Am Soc Nephrol 1997, 8:1951.
14. Berl T, Schrier RW: Disorders of water metabolism. In Renal and 30. Lieburg van, Verdjik M, Knoers N, et al.: Patients with autosomal
Electrolyte Disorders, edn 4. Philadelphia: Lippincott-Raven, nephrogenic diabetes insipidus homozygous for mutations in the
1997:52. aquaporin 2 water channel. Am J Hum Genet 1994, 55:648.
15. Verbalis JG: The syndrome of ianappropriate diuretic hormone secre- 31. Canfield MC, Tamarappoo BK, Moses AM, et al.: Identification and
tion and other hypoosmolar disorders. In Diseases of the Kidney, edn. characterization of aquaporin-2 water channel mutations causing
6. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown, and nephrogenic diabetes insipidus with partial vasopressin response.
Co., 1997:2393. Hum Mol Genet 1997, 6(11):1865.
Disorders of
Sodium Balance
David H. Ellison
S
odium is the predominant cation in extracellular fluid (ECF); the
volume of ECF is directly proportional to the content of sodium
in the body. Disorders of sodium balance, therefore, may be
viewed as disorders of ECF volume. The body must maintain ECF vol-
ume within acceptable limits to maintain tissue perfusion because
plasma volume is directly proportional to ECF volume. The plasma
volume is a crucial component of the blood volume that determines
rates of organ perfusion. Many authors suggest that ECF volume is
maintained within narrow limits despite wide variations in dietary
sodium intake. However, ECF volume may increase as much as 18%
when dietary sodium intake is increased from very low to moderately
high levels [1,2]. Such variation in ECF volume usually is well toler-
ated and leads to few short-term consequences. In contrast, the same
change in dietary sodium intake causes only a 1% change in mean
arterial pressure (MAP) in normal persons [3]. The body behaves as if
the MAP, rather than the ECF volume, is tightly regulated. Under
chronic conditions, the effect of MAP on urinary sodium excretion
displays a remarkable gain; an increase in MAP of 1 mm Hg is asso-
ciated with increases in daily sodium excretion of 200 mmol [4].
Guyton [4] demonstrated the importance of the kidney in control
of arterial pressure. Endogenous regulators of vascular tone, hormon-
al vasoconstrictors, neural inputs, and other nonrenal mechanisms are
important participants in short-term pressure homeostasis. Over the
long term, blood pressure is controlled by renal volume excretion,
which is adjusted to a set point. Increases in arterial pressure lead to
natriuresis (called pressure natriuresis), which reduces blood volume.
A decrease in blood volume reduces venous return to the heart and
cardiac output. Urinary volume excretion exceeds dietary intake until
CHAPTER
the blood volume decreases sufficiently to return the blood pressure to
2
the set point.
Disorders of sodium balance resulting from primary renal sodium
retention lead only to modest volume expansion without edema
because increases in MAP quickly return sodium excretion to baseline
2.2 Disorders of Water, Electrolytes, and Acid-Base
levels. Examples of these disorders include chronic renal failure (see Chapter 1). Disorders of sodium balance are disorders of
and states of mineralocorticoid excess. In this case, the price of ECF volume. This construct has a physiologic basis because
a return to sodium balance is hypertension. Disorders of sodi- water balance and sodium balance can be controlled separately
um balance that result from secondary renal sodium retention, and by distinct hormonal systems. It should be emphasized,
as in congestive heart failure, lead to more profound volume however, that disorders of sodium balance frequently lead to or
expansion owing to hypotension. In mild to moderates cases, are associated with disorders of water balance. This is evident
volume expansion eventually returns the MAP to its set point; from Figure 2-24 in which hyponatremia is noted to be a sign
the price of sodium balance in this case is edema. In more severe of either ECF volume expansion or contraction. Thus, the dis-
cases, volume expansion never returns blood pressure to nor- tinction between disorders of sodium and water balance is use-
mal, and renal sodium retention is unremitting. In still other sit- ful in constructing differential diagnoses; however, the close
uations, such as nephrotic syndrome, volume expansion results interrelationships between factors that control sodium and
from changes in both the renal set point and body volume dis- water balance should be kept in mind.
tribution. In this case, the price of sodium balance may be both The figures herein describe characteristics of sodium home-
edema and hypertension. In each of these cases, renal sodium ostasis in normal persons and also describe several of the regu-
(and chloride) retention results from a discrepancy between the latory systems that are important participants in controlling
existing MAP and the renal set point. renal sodium excretion. Next, mechanisms of sodium transport
The examples listed previously emphasize that disorders of along the nephron are presented, followed by examples of dis-
sodium balance do not necessarily abrogate the ability to orders of sodium balance that illuminate current understanding
achieve sodium balance. When balance is defined as the equa- of their pathophysiology. Recently, rapid progress has been
tion of sodium intake and output, most patients with ECF made in unraveling mechanisms of renal volume homeostasis.
expansion (and edema or hypertension) or ECF volume deple- Most of the hormones that regulate sodium balance have been
tion achieve sodium balance. They do so, however, at the cloned and sequenced. Intracellular signaling mechanisms
expense of expanded or contracted ECF volume. The failure to responsible for their effects have been characterized. The renal
achieve sodium balance at normal ECF volumes characterizes transport proteins that mediate sodium reabsorption also have
these disorders. been cloned and sequenced. The remaining challenges are to
Frequently, distinguishing disorders of sodium balance from integrate this information into models that describe systemic
disorders of water balance is useful. According to this scheme, dis- volume homeostasis and to determine how alterations in one or
orders of water balance are disorders of body osmolality and usu- more of the well-characterized systems lead to volume expan-
ally are manifested by alterations in serum sodium concentration sion or contraction.
FIGURE 2-2
14 10 Effects of changes in dietary sodium (Na) intake on extracellular fluid (ECF) volume. The
13
7 ship between dietary Na intake (dashed line) and ECF volume (solid line) is derived from
6 the model of Walser [1]. In this model the rate of Na excretion is assumed to be propor-
12 5
4 tional to the content of Na in the body (At) above a zero point (A0) at which Na excretion
11 3 ceases. This relation can be expressed as dAt/dt = I - k(At - A0), where I is the dietary Na
2
1 intake and t is time. The ECF volume is approximated as the total body Na content divid-
10 0 ed by the plasma Na concentration. (This assumption is strictly incorrect because approxi-
0 5 10 15 20 25 mately 25% of Na is tightly bound in bone; however, this amount is nearly invariant and
Days can be ignored in the current analysis.) According to this construct, when dietary Na
intake changes from level 1 to level 2, the ECF volume approaches a new steady state
exponentially with a time constant of k according to the following equation:
I I I
A2 A1 = 2 + 1 2 ekt
k k
17 98
96
16
Mean arterial pressure, mmHg
94
15
ECF volume, L
92
14 90
88
13
86
12
∆≈ 18% ∆≈ 1%
84
11
82
10 80
0 1 2 3 4 5 6 0 1 2 3 4 5 6
A Sodium intake, g/d B Sodium intake, g/d
FIGURE 2-3
Relation between dietary sodium (Na), extracellular fluid (ECF) vol- intake when consuming a “no added salt” diet. The light blue bar
ume, and mean arterial pressure (MAP). A, Relation between the indicates that a “low-salt” diet generally contains about 2 g/d of Na.
dietary intake of Na, ECF volume, and urinary Na excretion at Note that increasing the dietary intake of Na from very low to nor-
steady state in a normal person. Note that 1 g of Na equals 43 mmol mal levels leads to an 18% increase in ECF volume. B, Relation
(43 mEq) of Na. At steady state, urinary Na excretion essentially is between the dietary intake of Na and MAP in normal persons. MAP
identical to the dietary intake of Na. As discussed in Figure 2-2, ECF is linearly dependent on Na intake; however, increasing dietary Na
volume increases linearly as the dietary intake of Na increases. At an intake from very low to normal levels increases the MAP by only
ECF volume of under about 12 L, urinary Na excretion ceases. The 1%. Thus, arterial pressure is regulated much more tightly than is
gray bar indicates a normal dietary intake of Na when consuming a ECF volume. (A, Data from Walser [1]; B, Data from Luft and
typical Western diet. The dark blue bar indicates the range of Na coworkers [3].)
2.4 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 2-5
Lumen Blood
Sodium (Na) reabsorption along the mammalian nephron. About
Na
DCT 25 moles of Na in 180 L of fluid daily is delivered into the
Cl 5-7% glomerular filtrate of a normal person. About 60% of this load is
reabsorbed along the proximal tubule (PROX), indicated in dark
blue; about 25% along the loop of Henle (LOH), including the
CD
3-5% thick ascending limb indicated in light blue; about 5% to 7%
along the distal convoluted tubule (DCT), indicated in dark gray;
PROX
60% – + and 3% to 5% along the collecting duct (CD) system, indicated in
Na light gray. All Na transporting cells along the nephron express the
Lumen Blood
ouabain-inhibitable sodium-potassium adenosine triphosphatase
Lumen H 2O Blood K (Na-K ATPase) pump at their basolateral (blood) cell surface. (The
Na pump is not shown here for clarity.) Unique pathways are
HCO3
H H+ expressed at the luminal membrane that permit Na to enter cells.
OH Lumen Blood
CO2 + – The most quantitatively important of these luminal Na entry path-
Na
H2CO3 K ways are shown here. These pathways are discussed in more detail
HCO3
CA Cl in Figures 2-15 to 2-19. CA—carbonic anhydrase; Cl—chloride;
H 2O CO2 K
CO2—carbon dioxide; H—hydrogen; H2CO3—carbonic acid;
Na HCO3—bicarbonate; K—potassium; OH—hydroxyl ion.
LOH
25%
Disorders of Sodium Balance 2.5
Mechanisms of Extracellular
Fluid Volume Control
FIGURE 2-6
↑ Renal tubular sodium reabsoption Integrated response of the kidneys to changes in extracellular fluid
(ECF) volume. This composite figure illustrates natriuretic and
antinatriuretic mechanisms. For simplicity, the systems are shown
↑ ERSNA ↑ Angiotensin II ↑ Aldosterone ↑ FF operating only in one direction and not all pathways are shown.
The major antinatriuretic systems are the renin-angiotensin-aldos-
↑ Activation of terone axis and increased efferent renal sympathetic nerve activity
↑ Renin (ERSNA). The most important natriuretic mechanism is pressure
baroreceptors
natriuresis, because the level of renal perfusion pressure (RPP)
determines the magnitude of the response to all other natriuretic
↓ Arterial pressure systems. Renal interstitial hydrostatic pressure (RIHP) is a link
between the circulation and renal tubular sodium reabsorption.
Atrial natriuretic peptide (ANP) is the major systemic natriuretic
ECFV contraction
hormone. Within the kidney, kinins and renomedullary
prostaglandins are important modulators of the natriuretic
response of the kidney. AVP—arginine vasopressin; FF—filtration
Normal ECF volume
fraction. (Modified from Gonzalez-Campoy and Knox [7].)
ECFV expansion
↑ RIHP ↑ Prostaglandins
FIGURE 2-7
Overview of the renin-angiotensin-aldosterone system [8,9].
Angiotensinogen (or renin substrate) is a 56-kD glycoprotein
produced and secreted by the liver. Renin is produced by the
ACE
juxtaglomerular apparatus of the kidney, as shown in Figures 2-8
and 2-9. Renin cleaves the 10 N-terminal amino acids from
SVR angiotensinogen. This decapeptide (angiotensin I) is cleaved by
angiotensin converting enzyme (ACE). The resulting angiotensin II
+
+ comprises the 8 N-terminal amino acids of angiotensin I. The pri-
Angiotensinogen mary amino acid structures of angiotensins I and II are shown in
DRVYIHPFHL DRVYIHPF
single letter codes. Angiotensin II increases systemic vascular resis-
Angiotensin I Angiotensin II tance (SVR), stimulates aldosterone secretion from the adrenal
gland (indicated in gray), and increases sodium (Na) absorption by
+
+ renal tubules, as shown in Figures 2-15 and 2-17. These effects
Aldo decrease urinary Na (and chloride excretion; UNaV).
Renin –
–
UNaV
2.6 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 2-8
The juxtaglomerular (JG) apparatus. This apparatus brings into close apposition the afferent
B (A) and efferent (E) arterioles with the macula densa (MD), a specialized region of the thick
ascending limb (TAL). The extraglomerular mesangium (EM), or lacis “Goormaghtigh appa-
N ratus (cells),” forms at the interface of these components. MD cells express the Na-K-2Cl
JG (sodium-potassium-chloride) cotransporter (NKCC2) at the apical membrane [10,11]. By
N
A way of the action of this transporter, MD cells sense the sodium chloride concentration of
luminal fluid. By way of mechanisms that are unclear, this message is communicated to JG
cells located in and near the arterioles (especially the afferent arteriole). These JG cells
IM increase renin secretion when the NaCl concentration in the lumen is low [12]. Cells in the
G MD afferent arteriole also sense vascular pressure directly, by way of the mechanisms discussed in
Figure 2-9. Both the vascular and tubular components are innervated by sympathetic nerves
(N). B—Bowman’s space, G—glomerular capillary; IM—intraglomerular mesangium. (From
G JG E Barajas [13]; with permission.)
FIGURE 2-9
ANP
Schematic view of a (granular) juxtaglomerular cell showing secre-
tion mechanisms of renin [8]. Renin is generated from prorenin.
– Prorenin Renin secretion is inhibited by increases in and stimulated by
β1 decreases in intracellular calcium (Ca) concentrations. Voltage-sen-
Renin Sympathetic sitive Ca channels in the plasma membrane are activated by mem-
Renin AC nerves brane stretch, which correlates with arterial pressure and is
assumed to mediate baroreceptor-sensitive renin secretion. Renin
↑cAMP AT1 All secretion is also stimulated when the concentration of sodium (Na)
+ and chloride (Cl) at the macula densa (MD) decreases [12,14]. The
– – +
NO mediators of this effect are less well characterized; however, some
↑Ca ↑Ca
studies suggest that the effect of Na and Cl in the lumen is more
–
potent than is the baroreceptor mechanism [15]. Many other fac-
PGE2 +
PGI2
tors affect rates of renin release and contribute to the physiologic
Membrane
depolarization regulation of renin. Renal nerves, by way of receptors coupled
+ + to adenylyl cyclase (AC), stimulate renin release by increasing the
Membrane production of cyclic adenosine monophosphate (cAMP), which
stretch reduces Ca release. Angiotensin II (AII) receptors (AT1 receptors)
+
inhibit renin release, as least in vitro. Prostaglandins E2 and I2
MD NaCl (PGE2 and PGI2, respectively) strongly stimulate renin release
Arterial through mechanisms that remain unclear. Atrial natriuretic peptide
pressure (ANP) strongly inhibits renin secretion. Constitutive nitric oxide
(NO) synthase is expressed by macula densa (MD) cells [16]. NO
appears to stimulate renin secretion, an effect that may counteract
inhibition of the renin gene by AII [17,18].
Disorders of Sodium Balance 2.7
FIGURE 2-10
AME or Licorice
Basolateral Apical Mechanism of aldosterone action in the distal nephron [19]. Aldosterone, the predominant
human mineralocorticoid hormone, enters distal nephron cells through the plasma mem-
Cortisone brane and interacts with its receptor (the mineralocorticoid receptor [MR], or Type I
receptor). Interaction between aldosterone and this receptor initiates induction of new
11β HSD
proteins that, by way of mechanisms that remain unclear, increase the number of sodium
Cortisol Cortisol GR channels (ENaC) and sodium-potassium adenosine triphosphatase (Na-K ATPase) pumps
at the cell surface. This increases transepithelial Na (and potassium) transport. Cortisol,
↑ ENaC the predominant human glucocorticoid hormone, also enters cells through the plasma
Cortisone ↑ Na/K ATPase membrane and interacts with its receptor (the glucocorticoid receptor [GR]). Cortisol,
11β HSD however, also interacts with mineralocorticoid receptors; the affinity of cortisol and aldos-
Cortisol terone for mineralocorticoid receptors is approximately equal. In distal nephron cells, this
MR interaction also stimulates electrogenic Na transport [20]. Cortisol normally circulates at
concentrations 100 to 1000 times higher than the circulating concentration of aldosterone.
Aldo Aldo In aldosterone-responsive tissues, such as the distal nephron, expression of the enzyme
MR 11-hydroxysteroid dehydrogenase (11-HSD) permits rapid metabolism of cortisol so
that only aldosterone can stimulate Na transport in these cells. An inherited deficiency of
the enzyme 11-HSD (the syndrome of apparent mineralocorticoid excess, AME), or inhi-
Distal nephron cell bition of the enzyme by ingestion of licorice, leads to hypertension owing to chronic stim-
ulation of distal Na transport by endogenous glucocorticoids [21].
FIGURE 2-11
↑ Preload Control of systemic hemodynamics by the atrial natriuretic peptide
(ANP) system. Increases in atrial stretch (PRELOAD) increase ANP
SLRRSSCFGGRLDRIGAQSGLGCNSFRY
+ secretion by cardiac atria. The primary amino acid sequence of
ANP is shown in single letter code with its disulfide bond indicated
Plasma ANP by the lines. The amino acids highlighted in blue are conserved
+ – between ANP, brain natriuretic peptide, and C-type natriuretic pep-
+ – –
tide. ANP has diverse functions that include but are not limited to
Vagal afferent Capillary Renal NaCl Renin Arteriolar the following: stimulating vagal afferent activity, increasing capillary
activity permeability reabsoption secretion contraction permeability, inhibiting renal sodium (Na) and water reabsorption,
+ inhibiting renin release, and inhibiting arteriolar contraction. These
– + +
+
effects reduce sympathetic nervous activity, reduce angiotensin II
+ Angiotensin II
+ + generation, reduce aldosterone secretion, reduce total peripheral
Sympathetic Aldosterone + resistance, and shift fluid out of the vasculature into the intersti-
efferent Fluid shift – tium. The net effect of these actions is to decrease cardiac output,
activity into vascular volume, and peripheral resistance, thereby returning pre-
+ interstitium Vascular load toward baseline. Many effects of ANP (indicated by solid
volume Peripheral
vascular arrows) are diminished in patients with edematous disorders (there
Cardiac – + resistance is an apparent resistance to ANP). Effects indicated by dashed
output arrows may not be diminished in edematous disorders; these effects
↓ Preload contribute to shifting fluid from vascular to extravascular tissue,
+ + + leading to edema. This observation may help explain the association
between elevated right-sided filling pressures and the tendency for
Blood
Na retention [22]. (Modified from Brenner and coworkers [23].)
pressure
2.8 Disorders of Water, Electrolytes, and Acid-Base
20 Afferent Efferent
Wild type
18 Cerebral cortex
Knockout Carotid
16 sinus Hypothalamus
ANP infusion
UNAV, mmol/min/g body wt
14 IX Medulla
12 X
Carotid X
10 bodies
8
6
Thoracic
4
2
0
15 30 45 60 75 90 105 120 135 150 165 180
Time, min Blood vessel
Lumbar
Adrenal
FIGURE 2-12
Mechanism of atrial natriuretic peptide (ANP) action on the kid-
ney. Animals with disruption of the particulate form of guanylyl Kidney
cyclase (GC) manifest increased mean arterial pressure that is inde- Other somatic
(eg, muscle, splanchnic
pendent of dietary intake of sodium chloride. To test whether ANP
viscera, joint receptors)
mediates its renal effects by way of the action of GC, ANP was
Sacral
Spinal
infused into wild-type and GC-A–deficient mice. In wild-type ani- cord
mals, ANP led to prompt natriuresis. In GC-A–deficient mice, no
effect was observed. UNaV—urinary sodium excretion volume. Splanchnic
(Modified from Kishimoto [24].) viscera
FIGURE 2-13
Schematic diagram of neural connections important in circulatory
control. Although the system is bilaterally symmetric, afferent fibers
are shown to the left and efferent fibers to the right. Sympathetic
fibers are shown as solid lines and parasympathetic fibers as dashed
lines. The heart receives both sympathetic and parasympathetic
innervation. Sympathetic fibers lead to vasoconstriction and renal
sodium chloride retention. X indicates the vagus nerve; IX indicates
glossopharyngeal. (From Korner [25]; with permission.)
FIGURE 2-14
Normal effective Low effective Cellular mechanisms of increased solute
arterial volume arterial volume
and water reabsorption by the proximal
GFR =Filtration fraction ↓GFR =↑Filtration fraction tubule in patients with “effective” arterial
RPF ↓↓RPF volume depletion. A, Normal effective arte-
rial volume in normal persons. B, Low
Filtration Filtration effective arterial volume in patients with
both decreased glomerular filtration rates
A E A E
(GFR) and renal plasma flow (RPF). In con-
trast to normal persons, patients with low
effective arterial volume have decreased
GFR and RPF, yet the filtration fraction is
increased because the RPF decreases more
onc onc than does the GFR. The increased filtration
Reabsorption Reabsorption fraction concentrates the plasma protein
(indicated by the dots) in the peritubular
capillaries leading to increased plasma
Pt Pi Pt Pi
oncotic pressure (onc). Increased plasma
oncotic pressure reduces the amount of
Backleak ↓ Backleak backleak from the peritubular capillaries.
A B Simultaneously, the increase in filtration
fraction reduces volume delivery to the
(Legend continued on next page)
Disorders of Sodium Balance 2.9
FIGURE 2-16
Lumen Cellular mechanisms and regulation of sodium (Na) and chloride
(Cl) transport by thick ascending limb (TAL) cells. Na, Cl, and
cAMP ? potassium (K) enter cells by way of the bumetanide-sensitive Na-K-
Na +
2Cl cotransporter (NKCC2) at the apical membrane. K recycles back
V2 AVP through apical membrane K channels (ROMK) to permit continued
2Cl – operation of the transporter. In this nephron segment, the asymmet-
K –
ric operations of the luminal K channel and the basolateral chloride
– PR PGE2 channel generate a transepithelial voltage, oriented with the lumen
K positive. This voltage drives paracellular Na absorption. Although
Cl
20-HETE arginine vasopressin (AVP) is known to stimulate Na reabsorption by
20-COOH-AA TAL cells in some species, data from studies in human subjects sug-
c-P450 gest AVP has minimal or no effect [31,32]. The effect of AVP is
Arachidonic ~ mediated by way of production of cyclic adenosine monophosphate
acid 3Na+ 2K+ (cAMP). Prostaglandin E2 (PGE2) and cytochrome P450 (c-P450)
metabolites of arachidonic acid (20-HETE [hydroxy-eicosatetraenoic
+ – acid] and 20-COOH-AA) inhibit transepithelial NaCl transport, at
Na least in part by inhibiting the Na-K-2Cl cotransporter [33–35]. PGE2
also inhibits vasopressin-stimulated Na transport, in part by activat-
ing Gi and inhibiting adenylyl cyclase [36]. Increases in medullary
Interstitum
NaCl concentration may activate transepithelial Na transport by
increasing production of PGE2. Inset A, Regulation of NKCC2 by
chronic Na delivery. Animals were treated with 0.16 mol NaCl
or water as drinking fluid for 2 weeks. The Western blot shows
A 0.16 mol NaCl H 2O upregulation of NKCC2 in the group treated with saline [37].
kD
Gi—inhibitory G protein; PR—prostaglandin receptor; V2— AVP
199-
receptors. (Modified from Ecelbarger [37].)
120-
87-
48-
FIGURE 2-17
Lumen Mechanisms and regulation of sodium (Na) and chloride (Cl)
transport by the distal nephron. As in other nephron segments,
Aldo receptor + Aldo intracellular Na concentration is maintained low by the action of
+
Na See figure Y the Na-K ATPase (sodium-potassium adenosine triphosphatase)
pump at the basolateral cell membrane. Na enters distal convolut-
+ ed tubule (DCT) cells across the luminal membrane coupled direct-
Cl α ly to chloride by way of the thiazide-sensitive Na-Cl cotransporter.
+ Activity of the Na-Cl cotransporter appears to be stimulated by
both aldosterone and angiotensin II (AII) [38–40]. Transepithelial
+ ~ Na transport in this segment is also stimulated by sympathetic
3Na+ 2K+
nerves acting by way of receptors [41,42]. The DCT is imperme-
able to water.
AT1 All
See figure 2-7
DCT
– + Interstitum
Disorders of Sodium Balance 2.11
Na Na
Aldo receptor + Aldo Na Na cGMP
Na + Na Na – AR ANP
+ Na GC
~
+ 3Na+ 2K+
K PGE2 –
cAMP
R Lumen
α PGE2 ~
+
Gi 3Na+ 2K+
AC
H 2O
Gs + V2 AVP
ATP H 2O
V2 AVP
CCT –
MCT
+
FIGURE 2-18
Principal cortical collecting tubule (CCT) cells. In these cells, sodi- FIGURE 2-19
um (Na) enters across the luminal membrane through Na channels Cellular mechanism of the medullary collecting tubule (MCT).
(ENaC). The movement of cationic Na from lumen to cell depolar- Sodium (Na) and water are reabsorbed along the MCT. Atrial natri-
izes the luminal membrane, generating a transepithelial electrical uretic peptide (ANP) is the best-characterized hormone that affects
gradient oriented with the lumen negative with respect to intersti- Na absorption along this segment [22]. Data on the effects of argi-
tium. This electrical gradient permits cationic potassium (K) to dif- nine vasopressin (AVP) and aldosterone are not as consistent
fuse preferentially from cell to lumen through K channels [46,49]. Prostaglandin E2 (PGE2) inhibits Na transport by inner
(ROMK). Na transport is stimulated when aldosterone interacts medullary collecting duct cells and may be an important intracellu-
with its intracellular receptor [43]. This effect involves both lar mediator for the actions of endothelin and interleukin-1 [50,51].
increases in the number of Na channels at the luminal membrane ANP inhibits medullary Na transport by interacting with a G-pro-
and increases in the number of Na-K ATPase (Sodium-potassium tein–coupled receptor that generates cyclic guanosine monophos-
adenosine triphosphatase) pumps at the basolateral cell membrane. phate (cGMP). This second messenger inhibits a luminal Na channel
Arginine vasopressin (AVP) stimulates both Na absorption (by that is distinct from the Na channel expressed by the principal cells
interacting with V2 receptors and, perhaps, V1 receptors) and of the cortical collecting tubule, as shown in Figure 2-18 [52,53].
water transport (by interacting with V2 receptors) [44–46]. V2 Under normal circumstances, ANP also increases the glomerular fil-
receptor stimulation leads to insertion of water channels (aquapor- tration rate (GFR) and inhibits Na transport by way of the effects
in 2) into the luminal membrane [47]. V2 receptor stimulation is on the renin-angiotensin-aldosterone axis, as shown in Figures 2-7
modified by PGE2 and 2 agonists that interact with a receptor to 2-10. These effects increase Na delivery to the MCT. The combi-
that stimulates Gi [48]. AC—adenylyl cyclase; ATP—adenosine nation of increased distal Na delivery and inhibited distal reabsorp-
triphosphate; cAMP—cyclic adenosine monophosphate; CCT—cor- tion leads to natriuresis. In patients with congestive heart failure,
tical collecting tubule; Gi—inhibitory G protein; Gs—stimulatory distal Na delivery remains depressed despite high levels of circulat-
G protein; R—Ri receptor. ing ANP. Thus, inhibition of apical Na entry does not lead to natri-
uresis, despite high levels of MCT cGMP. AR—ANP receptor;
GC—guanylyl cyclase; K—potassium; V2—receptors.
2.12 Disorders of Water, Electrolytes, and Acid-Base
Primary renal sodium retention (with hypertension but without edema) Extrarenal losses (urine sodium concentration low)
Hyperaldosteronism (Conn’s syndrome) Gastrointestinal salt losses
Cushing’s syndrome Vomiting
Inherited hypertension (Liddle’s syndrome, glucocorticoid remediable hyperaldo- Diarrhea
steronism, pseudohypoaldosteronism Type II, others) Nasogastric or small bowel aspiration
Renal failure Intestinal fistulae or ostomies
Nephrotic syndrome (mixed disorder) Gastrointestinal bleeding
Secondary renal sodium retention Skin and respiratory tract losses
Hypoproteinemia Burns
Nephrotic syndrome Heat exposure
Protein-losing enteropathy Adrenal insufficiency
Cirrhosis with ascites Extensive dermatologic lesions
Cystic fibrosis
Low cardiac output
Pulmonary bronchorrhea
Hemodynamically significant pericardial effusion
Drainage of large pleural effusion
Constrictive pericarditis
Valvular heart disease with congestive heart failure Renal losses (urine sodium concentration normal or elevated)
Severe pulmonary disease Extrinsic
Cardiomyopathies Solute diuresis (glucose, bicarbonate, urea, mannitol, dextran, contrast dye)
Peripheral vasodilation Diuretic agents
Pregnancy Adrenal insufficiency
Gram-negative sepsis Selective aldosterone deficiency
Anaphylaxis Intrinsic
Arteriovenous fistula Diuretic phase of oliguric acute renal failure
Trauma Postobstructive diuresis
Cirrhosis Nonoliguric acute renal failure
Idiopathic edema (?) Salt-wasting nephropathy
Drugs: minoxidil, diazoxide, calcium channel blockers (?) Medullary cystic disease
Increased capillary permeability Tubulointerstitial disease
Idiopathic edema (?) Nephrocalcinosis
Burns
Allergic reactions, including certain forms of angioedema
Adult respiratory distress syndrome
Interleukin-2 therapy
Malignant ascites FIGURE 2-21
Sequestration of fluid (“3rd spacing,” urine sodium concentration low) In volume depletion, total body sodium is decreased.
Peritonitis
Pancreatitis
Small bowel obstruction
Rhabdomyolysis, crush injury
Bleeding into tissues
Venous occlusion
FIGURE 2-20
In volume expansion, total body sodium (Na) content is increased.
In primary renal Na retention, volume expansion is modest and
edema does not develop because blood pressure increases until Na
excretion matches intake. In secondary Na retention, blood pres-
sure may not increase sufficiently to increase urinary Na excretion
until edema develops.
Disorders of Sodium Balance 2.13
FIGURE 2-22
Clinical signs of volume expansion. FIGURE 2-23 FIGURE 2-24
Clinical signs of volume depletion. Note that laboratory test results for volume
expansion and contraction are similar.
Serum sodium (Na) concentration may be
increased or decreased in either volume
expansion or contraction, depending on the
cause and intake of free water (see Chapter
1). Acid-base disturbances, such as metabol-
ic alkalosis, and hypokalemia are common
in both conditions. The similarity of the lab-
oratory test results of volume depletion and
expansion results from the fact that the
“effective” arterial volume is depleted in
both states despite dramatic expansion of
the extracellular fluid volume in one.
Unifying Hypothesis of
Renal Sodium Excretion
from a reduction in mean arterial pressure
Myocardial ↓ Extracellular (MAP). Some disorders decrease cardiac
dysfunction fluid volume output, such as congestive heart failure
owing to myocardial dysfunction; others
– – High output decrease systemic vascular resistance, such
AV fistula Cirrhosis Pregnancy
failure as high-output cardiac failure, atriovenous
– – – fistulas, and cirrhosis. Because MAP is the
– product of systemic vascular resistance and
cardiac output, all causes lead to the same
Cardiac output × Systemic vascular resistance = Mean arterial pressure
result. As shown in Figures 2-3 and 2-4,
small changes in MAP lead to large changes
+ in urinary Na excretion. Although edema-
tous disorders usually are characterized as
Sodium excretion resulting from contraction of the effective
(pressure natriuresis) arterial volume, the MAP, as a determinant
of renal perfusion pressure, may be the cru-
cial variable (Figs. 2-26 and 2-28 provide
FIGURE 2-25 supportive data). The mechanisms of edema
Summary of mechanisms of sodium (Na) retention in volume contraction and in depletion in nephrotic syndrome are more complex
of the “effective” arterial volume. In secondary Na retention, Na retention results primarily and are discussed in Figures 2-36 to 2-39.
2.14 Disorders of Water, Electrolytes, and Acid-Base
130 130
MI J Lab Clin Med 1978
125 125
AVF Am J Physiol 1977
120 120
Mean arterial pressure, mmHg
110 110
105 105
100 100
95 95
90 90
Control Small MI Large MI Control Balance Na Ret. Ascites
A AVF B Cirrhosis
FIGURE 2-26
Role of renal perfusion pressure in sodium (Na) retention. A, Results which experimental cirrhosis was induced in dogs by sporadic feeding
from studies in rats that had undergone myocardial infarction (MI) or with dimethylnitrosamine. Three cirrhotic stages were identified based
placement of an arteriovenous fistula (AVF) [54]. Rats with small and on the pattern of Na retention. In the first, dietary Na intake was bal-
large MIs were identified. Both small and large MIs induced signifi- anced by Na excretion. In the second, renal Na retention began, but
cant Na retention when challenged with Na loads. Renal Na retention still without evidence of ascites or edema. In the last, ascites were
occurred in the setting of mild hypotension. AVF also induced signifi- detected. Because Na was retained before the appearance of ascites,
cant Na retention, which was associated with a decrease in mean arte- “primary” renal Na retention was inferred. An alternative interpreta-
rial pressure (MAP) [55,56]. Figure 2-3 has shown that Na excretion tion of these data suggests that the modest decrease in MAP is respon-
decreases greatly for each mm Hg decrease in MAP. B, Results of two sible for Na retention in this model. Note that in both heart failure
groups of experiments performed by Levy and Allotey [57,58] in and cirrhosis, Na retention correlates with a decline in MAP.
FIGURE 2-27
600 10 Mechanism of sodium (Na) retention in high-output cardiac failure.
UNaV
UNaV, mmol/d or plasma ANP, pg/mL or MAP, mmHg;
400
line) declined modestly. After day 5, the plasma atrial natriuretic
6 peptide concentration (ANP; dashed line) increased because of vol-
300 ume expansion, returning urinary Na excretion to baseline levels.
Thus, Na retention, mediated in part by the renin-angiotensin-aldos-
4 terone system, led to volume expansion. The volume expansion sup-
200 pressed the renin-angiotensin-aldosterone system and stimulated
ANP secretion, thereby returning Na excretion to normal. These
experiments suggest that ANP secretion plays an important role in
2 maintaining Na excretion in compensated congestive heart failure.
100
This effect of ANP has been confirmed directly in experiments using
anti-ANP antibodies [60]. AI—angiotensin I.
0 0
-5 0 5 10 15 20 25 30 35 40
Days
Disorders of Sodium Balance 2.15
FIGURE 2-28
400
ANP Mechanism of renal resistance to atrial natriuretic peptide (ANP) in experimental low-out-
UNaV, µmol/min
300 ANP & SAR put heart failure. Low-output heart failure was induced in dogs by thoracic inferior vena
ANP & AII caval constriction (TIVCC), which also led to a significant decrease in renal perfusion
200 ANP & AII & SAR pressure (RPP) (from 127 to 120 mm Hg). ANP infusion into dogs with TIVCC did not
AII & SAR increase urinary sodium (Na) excretion (UNaV, ANP group). In contrast, when the RPP
100 was returned to baseline by infusing angiotensin II (AII), urinary Na excretion increased
greatly (ANP + AII). To exclude a direct effect of AII on urinary Na excretion, intrarenal
0
saralasin (SAR) was infused to block renal AII receptors. SAR did not significantly affect
Baseline TIVCC Infusion
the natriuresis induced by ANP plus AII. An independent effect of SAR on urinary Na
excretion was excluded by infusing ANP plus SAR and AII plus SAR. These treatments
were without effect. These results were interpreted as indicating that the predominant
cause of resistance to ANP in dogs with low-output congestive heart failure is a reduction
in RPP. (Data from Redfield and coworkers [61].)
FIGURE 2-29
30
Mechanism of extracellular fluid (ECF) vol-
Intersititial volume, L
30
Blood volume, L
+ ume expansion in congestive heart failure.
Fluid intake 20
20 A primary decrease in cardiac output (indi-
Net volume
intake cated by dark blue arrow) leads to a
Nonrenal 10 10 decrease in arterial pressure, which decreas-
fluid loss –
+ es pressure natriuresis and volume excre-
0 0 tion. These decreases expand the ECF vol-
0 10 20 30 ume. The inset graph shows that the ratio
ECF volume, L of interstitial volume (solid line) to plasma
+ – Rate of change + volume (dotted line) increases as the ECF
Arterial Kidney volume Extracellular
of extracellular
pressure output fluid volume volume expands because the interstitial
fluid volume
+
compliance increases [62]. Thus, although
expansion of the ECF volume increases
Total peripheral blood volume and venous return, thereby
+ resistance Blood volume
+ restoring cardiac output toward normal,
+ Autoregulation this occurs at the expense of a dispropor-
+ +
Mean circulatory tionate expansion of interstitial volume,
Cardiac output Venous return
filling pressure often manifested as edema.
2.16 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 2-31
Vasodilators Vasoconstrictors
Alterations in cardiovascular hemodynamics in hepatic cirrhosis. Hepatic dysfunction and
Nitric oxide portal hypertension increase the production and impair the metabolism of several vasoac-
Glucagon
CGRP tive substances. The overall balance of vasoconstriction and vasodilation shifts in favor of
ANP SNS dilation. Vasodilation may also shift blood away from the central circulation toward the
VIP RAAS periphery and away from the kidneys. Some of the vasoactive substances postulated to
Substance P Vasopressin
ET-1 participate in the hemodynamic disturbances of cirrhosis include those shown here.
Prostaglandin E2 ANP—atrial natrivretic peptide; ET-1—endothelin-1; CGRP—calcitonin gene related
Encephalins
TNF peptide; RAAS—renin/angiotensin/aldosterone system; TNF—tumor necrosis factor;
Andrenomedullin VIP— vasoactive intestinal peptide. (Data from Møller and Henriksen [64].)
FIGURE 2-32
C.O.=5.22 L/min C.O.=6.41 L/min
Effects of cirrhosis on central and noncentral blood volumes. The central blood volume is
3.64 L 4.34 L defined as the blood volume in the heart, lungs, and central arterial tree. Compared with
control subjects (A), patients with cirrhosis (B) have decreased central and increased non-
1.31 L central blood volumes. The higher cardiac output (CO) results from peripheral vasodila-
1.81 L
tion. Perfusion of the kidney is reduced significantly in patients with cirrhosis. (Data from
Central blood Hillarp and coworkers [65].)
Central blood volume
volume
Noncentral Noncentral
A blood volume B blood volume
FIGURE 2-33
15 15
Control Contribution of nitric oxide to vasodilation and sodium (Na)
Cirrhosis retention in cirrhosis. Compared with control rats, rats having cir-
Cirrhosis & L-name rhosis induced by carbon tetrachloride and phenobarbital exhibited
PRA, ng/min/h or AVP, pg/mL
UNaV, mmol/d
tion (UNaV) was similar in both groups. After treatment with L-
NAME for 7 days, plasma renin activity decreased to normal lev-
els, AVP concentrations decreased toward normal levels, and
urinary Na excretion increased by threefold. These changes were
5 5 associated with a normalization of mean arterial pressure and car-
diac output. (Data compiled from Niederberger and coworkers
[66,67] and Martin and Schrier [68].)
0 0
PRA AVP UNaV
FIGURE 2-34
30
Mechanisms of sodium (Na) retention in
Intersititial volume, L
(with low albumin)
30
Blood volume, L
4
2
0 2 4 6 8
Plasma protein concentration, g/dL
2.18 Disorders of Water, Electrolytes, and Acid-Base
300 20 35 30
PRA
250 30 ANP
25
UNaV, mmol/24 hrs ( )
15
Albumin, g/L ( )
200 25
ANP, fmol/mL
20
150 10 20
15
15
100
5 10
10
50
5 5
0 0
-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 0 0
Days 20 mEq 300 mEq AGN NS
Controls
FIGURE 2-36
Time course of recovery from minimal change nephrotic syndrome FIGURE 2-37
in five children. Note that urinary Na excretion (squares) increases Plasma renin activity (PRA) and atrial natriuretic peptide (ANP)
before serum albumin concentration increases. The data suggest concentration in the nephrotic syndrome. Shown are PRA and
that the natriuresis reflects a change in intrinsic renal Na retention. ANP concentration (standard error) in normal persons ingesting
The data also emphasize that factors other than hypoalbuminemia diets high (300 mEq/d) and low (20 mEq/d) in sodium (Na) and in
must contribute to the Na retention that occurs in nephrosis. patients with acute glomerulonephritis (AGN), predominantly post-
UNaV—urinary Na excretion volume. (Data from Oliver and streptococcal, or nephrotic syndrome (NS). Note that PRA is sup-
Owings [70].) pressed in patients with AGN to levels below those in normal per-
sons on diets high in Na. PRA suppression suggests that primary
renal NaCl retention plays an important role in the pathogenesis of
volume expansion in AGN. Although plasma renin activity in
patients with nephrotic syndrome is not suppressed to the same
degree, the absence of PRA elevation in these patients suggests that
primary renal Na retention plays a significant role in the pathogen-
esis of Na retention in NS as well. (Data from Rodrígeuez-Iturbe
and coworkers [71].)
FIGURE 2-38
100 100
Control Sites of sodium (Na) reabsorption along the nephron in control
PAN and nephrotic rats (induced by puromycin aminonucleoside
80 80 [PAN]). The glomerular filtration rates (GFR) in normal and
nephrotic rats are shown by the hatched bars. Note the modest
Fractional absorption, %
FIGURE 2-39
30
Mechanisms of extracellular fluid (ECF) vol-
Intersititial volume, L
30
Blood volume, L
ume expansion in nephrotic syndrome.
+ 20
Fluid intake 20 Nephrotic syndrome is characterized by
Net volume hypoalbuminemia, which shifts the relation
intake 10 10 between blood and interstitial volume
Nonrenal
fluid loss – upward (dashed to solid lines in inset). As
+ 0 0 discussed in Figure 2-35, these effects of
0 10 20 30 hypoalbuminemia are evident when serum
ECF volume, L albumin concentrations decrease by more
+ – Rate of change + than half. In addition, however, hypoalbu-
Arterial Kidney volume Extracellular
pressure output
of extracellular
fluid volume
minemia may induce vasodilation and arteri-
fluid volume al hypotension that lead to sodium (Na)
+ retention, independent of transudation of
Total peripheral fluid into the interstitium [73,74]. Unlike
+ resistance Blood volume other states of hypoproteinemia and vasodi-
+ lation, however, nephrotic syndrome usually
+ is associated with normotension or hyperten-
+
Mean circulatory sion. Coupled with the observation made in
Cardiac output Venous return
filling pressure Figure 2-36 that natriuresis may take place
before increases in serum albumin concentra-
tion in patients with nephrotic syndrome,
these data implicate an important role for
primary renal Na retention in this disorder
(dark blue arrow). As suggested by Figure 2-
37, the decrease in urinary Na excretion may
play a larger role in patients with acute
glomerulonephritis than in patients with
minimal change nephropathy [71].
20
15
10
5
0
0 20 40 60 80 100 120
GFR, mL/min
2.20 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 2-41
18 15 Effects of dietary sodium (Na) intake on extracellular fluid (ECF)
Normal
14 volume in chronic renal failure (CRF) [75]. Compared with normal
Mild CRF
17 persons, patients with CRF have expanded ECF volume at normal
Severe CRF 13
12 Na intake. Furthermore, the time necessary to return to neutral
16 balance on shifting from one to another level of Na intake is
11 increased. Thus, whereas urinary Na excretion equals dietary
11 3
2
10 1
0 5 10 15 20 25
Days
References
1. Walser M: Phenomenological analysis of renal regulation of sodium 12. Briggs JP: Whys and the wherefores of juxtaglomerular apparatus
and potassium balance. Kidney Int 1985, 27:837–841. functions.Kidney Int 1996, 49:1724–1726.
2. Simpson FO: Sodium intake, body sodium, and sodium excretion. 13. Barajas L: Architecture of the juxtaglomerular apparatus. In
Lancet 1990, 2:25–29. Hypertension: Pathophysiology, Diagnosis and Treatment. Edited by
3. Luft FC, Weinberger MH, Grim CE: Sodium sensitivity and resistance Laragh JH, Brenner BM. New York: Raven Press; 1990:XX–XX.
in normotensive humans. Am J Med 1982, 72:726–736. 14. Skott O, Briggs JP: Direct demonstration of macula densa mediated
4. Guyton AC: Blood pressure control: special role of the kidneys and renin secretion. Science 1987, 237:1618–1620.
body fluids. Science 1991, 252:1813–1816. 15. Hall JE, Guyton AC: Changes in renal hemodynamics and renin
release caused by increased plasma oncotic pressure. Am J Physiol
5. Lassiter WE: Regulation of sodium chloride distribution within the
1976, 231:1550.
extracellular space. In The Regulation of Sodium and Chloride
Balance. Edited by Seldin DW, Giebisch G. New York: Raven Press; 16. Bachmann S, Bosse HM, Mundel P: Topography of nitric oxide syn-
1990:23–58. thesis by localizing constitutive NO synthetases in mammalian kidney.
Am J Physiol 1995, 268:F885–F898.
6. Hall JE, Jackson TE: The basic kidney-blood volume-pressure regula-
tory system: the pressure diuresis and natriuresis phenomena. In 17. Johnson RA, Freeman RH: Renin release in rats during blockade of
Arterial Pressure and Hypertension. Edited by Guyton AC. nitric oxide synthesis. Am J Physiol 1994, 266:R1723–R1729.
Philadelphia: WB Saunders Co, 1998:87–99. 18. Schricker K, Hegyi I, Hamann M, et al.: Tonic stimulation of renin
7. Gonzalez-Campoy JM, Knox FG: Integrated responses of the kidney gene expression by nitric oxide is counteracted by tonic inhibition
to alterations in extracellular fluid volume. In The Kidney: Physiology through angiotensin II. Proc Natl Acad Sci USA 1995, 92:8006–8010.
and Pathophysiology, edn 2. Edited by Seldin DW, Giebisch G. New 19. Funder JW: Mineralocorticoids, glucocorticoids, receptors and
York: Raven Press; 1992:2041–2097. response elements. Science 1993, 259:1132–1133.
8. Hall JE, Brands MW: The renin-angiotensin-aldosterone systems. In 20. Náray-Fejes-Tóth A, Fejes-Tóth G: Glucocorticoid receptors mediate
The Kidney: Physiology and Pathophysiology, edn 2. Edited by Seldin mineralocorticoid-like effects in cultured collecting duct cells. Am J
DW, Giebisch G. New York: Raven Press; 1992:1455–1504. Physiol Renal Fluid Electrolyte Physiol 1990, 259:F672–F678.
9. Laragh JH, Sealey JE: The intergrated regulation of electrolyte balance 21. Mune T, Rogerson FM, Nikkila H, et al.: Human hypertension caused
and blood pressure by the renin system. In The Regulation of Sodium by mutations in the kidney isozyme of 11*beta*-hydroxysteroid dehy-
and Chloride Balance. Edited by Seldin DW, Giebisch G. New York: drogenase. Nature Genet 1995, 10:394–399.
Raven Press, 1990:133–193. 22. Hollander W, Judson WE: The relationship of cardiovascular and
10. Obermüller N, Kunchaparty S, Ellison DH, Bachmann S: Expression renal hemodynamic function to sodium excretion in patients with
of the Na-K-2Cl cotransporter by macula densa and thick ascending severe heart disease but without edema. J Clin Invest 1956,
limb cells of rat and rabbit nephron. J Clin Invest 1996, 98:635–640. 35:970–979.
11. Lapointe J-Y, Bell PD, Cardinal J: Direct evidence for apical Na+:2Cl- 23. Brenner BM, Ballermann BJ, Gunning ME, Zeidel ML: Diverse bio-
:K+ cotransport in macula densa cells. Am J Physiol 1990, logical actions of atrial natriuretic peptide. Physiol Rev 1990,
258:F1466–F1469. 70:665–700.
Disorders of Sodium Balance 2.21
24. Kishimoto I, Dubois SK, Garbers DL: The heart communicates with 46. Kudo LH, Van Baak AA, Rocha AS: Effects of vasopressin on sodium
the kidney exclusively through the guanylyl cyclase-A receptor: Acute transport across inner medullary collecting duct. Am J Physiol 1990,
handling of sodium and water in response to volume expansion. Proc 258:F1438–F1447.
Natl Acad Sci USA 1996, 93:6215–6219. 47. Nielsen S, Chou C-L, Marples D, et al.: Vasopressin increases water
25. Korner PI: Integrative neural cardiovascular control. Physiol Rev permeability of kidney collecting duct by inducing translocation of
1971, 51:312–367. aquaporin: CD water channels to plasma membrane. Proc Natl Acad
26. Cogan MG: Neurogenic regulation of proximal bicarbonate and chlo- Sci USA 1995, 92:1013–1017.
ride reabsorption. Am J Physiol 1986, 250:F22–F26. 48. Schafer JA: Salt and water homeostasis: Is it just a matter of good
27. Geibel J, Giebisch G, Boron WF: Angiotensin II stimulates both Na+- bookkeeping? J Am Soc Nephrol 1994, 4:1933–1950.
H+ exchange and Na+/HCO-3 cotransport in the rabbit proximal 49. Husted RF, Laplace JR, Stokes JB: Enhancement of electrogenic Na+
tubule. Proc Natl Acad Sci USA 1990, 87:7917–7920. transport across rat inner medullary collecting duct cells in culture.
28. Block RD, Zikos D, Fisher KA, et al.: Peterson DR: Activation of J Clin Invest 1990, 86:498–506.
proximal tubular Na+-H+ exchanger by angiotensin II. Am J Physiol
50. Zeidel ML, Jabs K, Kikeri D, Silva P: Kinins inhibit conductive Na+
1992, 263:F135–F143.
uptake by rabbit inner medullary collecting duct cells. Am J Physiol
29. Bertorello A, Aperia A: Regulation of Na+-K+-ATPase activity in kid- Renal Fluid Electrolyte Physiol 1990, 258:F1584–F1591.
ney proximal tubules: involvement of GTP binding proteins. Am J
Physiol 1989, 256:F57–F62. 51. Zeidel ML: Hormonal regulation of inner medullary collecting duct
sodium transport. Am J Physiol Renal Fluid Electrolyte Physiol 1993,
30. Aperia AC: Regulation of sodium transport. Curr Opinion Nephrol 265:F159–F173.
Hypertens 1995, 4:416–420.
52. Light DB, Ausiello DA, Stanton BA: Guanine nucleotide-binding pro-
31. Bouby N, Bankir L, Trinh-Trang-Tan MM, et al.: Selective ADH- tein, i 3, directly activates a cation channel in rat renal inner
induced hypertrophy of the medullary thick ascending limb in medullary collecting duct cells. J Clin Invest 1989, 84:352–356.
Brattleboro rats. Kidney Int 1985, 28:456–466.
53. Light DB, Schwiebert EM, Karlson KH, Stanton BA: Atrial natriuretic
32. Chabardès D, Gagnan-Brunette M, Imbert-Tébol M: Adenylate
peptide inhibits a cation channel in renal inner medullary collecting
cyclase responsiveness to hormones in various portions of the human
duct cells. Science 1989, 243:383–385.
nephron. J Clin Invest 1980, 65:439–448.
33. Stokes JB: Effects of prostaglandin E2 on chloride transport across the 54. Hostetter TH, Pfeffer JM, Pfeffer MA, et al.: Cardiorenal hemody-
rabbit thick ascending limb of Henle. J Clin Invest 1979, 64:495–502. namics and sodium excretion in rats with myocardial dysfunction. Am
J Physiol 1983, 245:H98–H103.
34. Escalante B, Erlij D, Falck JR, McGiff JC: Effect of cytochrome P450
arachidonate metabolites on ion transport in rabbit kidney loop of 55. Villarreal D, Freeman RH, Brands MW: DOCA administration and
Henle. Science 1991, 251:799–802. atrial natriuretic factor in dogs with chronic heart failure. Am J
Physiol 1989, 257:H739–H745.
35. Amlal H, Legoff C, Vernimmen C, et al.: Na(+)-K+(NH4+)-2Cl-
cotransport in medullary thick ascending limb: control by PKA, PKC, 56. Villarreal D, Freeman RH, Davis JO, et al.: Atrial natriuretic factor
and 20-HETE. Am J Physiol 1996, 271:C455–C463. secretion in dogs with experimental high-output heart failure. Am J
Physiol 1987, 252:H692–H696.
36. Culpepper RM, Adreoli TE: Interactions among prostaglandin E2,
antidiuretic hormone and cyclic adenosine monophosphate in modu- 57. Levy M, Allotey JBK: Temporal relationsips between urinary salt
lating Cl- absorption in single mouse medullary thick ascending limbs retention and altered systemic hemodynamics in dogs with experimen-
of Henle. J Clin Invest 1983, 71:1588–1601. tal cirrhosis. J Lab Clin Med 1978, 92:560–569.
37. Ecelbarger CA, Terris J, Hoyer JR, et al.: Localization and regulation 58. Levy M: Sodium retention and ascites formation in dogs with experi-
of the rat renal Na+-K+-2Cl-, cotransporter, BSC-1. Am J Physiol mental portal cirrhosis. Am J Physiol 1977, 233:F572–F585.
Renal Fluid Electrolyte Physiol 1996, 271:F619–F628.
59. Villarreal D, Freeman RH, Johnson RA: Neurohumoral modulators
38. Chen Z, Vaughn DA, Blakeley P, Fanestil DD: Adrenocortical steroids and sodium balance in experimental heart failure. Am J Physiol Heart
increase renal thiazide diuretic receptor density and response. J Am Circ Physiol 1993, 264:H1187–H1193.
Soc Nephrol 1994, 5:1361–1368.
60. Awazu M, Ichikawa I: Alterations in renal function in experimental
39. Velázquez H, Bartiss A, Bernstein PL, Ellison DH: Adrenal steroids congestive heart failure. Sem Nephrology 1994, 14:401–411.
stimulate thiazide-sensitive NaCl transport by the rat renal distal
tubule. Am J Physiol 1996, 39:F211–F219. 61. Redfield MM, Edwards BS, Heublein DM, Burnett JC Jr: Restoration
of renal response to atrial natriuretic factor in experimental low-out-
40. Wang T, Giebisch G: Effects of angiotensin II on electrolyte transport put heart failure. Am J Physiol 1989, 257:R917–R923.
in the early and late distal tubule in rat kidney. Am J Physiol Renal
Fluid Electrolyte Physiol 1996, 271:F143–F149. 62. Manning RD Jr, Coleman TG, Samar RE: Autoregulation, cardiac
output, total peripheral resistance and the “quantitative cascade” of
41. Wang T, Chan YL: Neural control of distal tubular bicarbonate and
the kidney-blood volume system for pressure control. In Arterial
fluid transport. Am J Physiol 1989, 257:F72–F76.
Pressure and Hypertension. Edited by Guyton AC. Philadelphia: WB
42. Bencsáth P, Szénási G, Takács L: Water and electrolyte transport in Saunders Co; 1980:139–155.
Henle’s loop and distal tubule after renal sympathectomy in the rat.
Am J Physiol 1985, 249:F308–F314. 63. Albillos A, Colombato LA, Groszmann RJ: Vasodilation and sodium
retention in prehepatic portal hypertension. Gastroenterology 1992,
43. Rossier BC, Palmer LG: Mechanisms of aldosterone action on sodium 102:931–935.
and potassium transport. In The Kidney: Physiology and
Pathophysiology, edn 2. Edited by Seldin DW, Giebisch G. New York: 64. Møller S, Henriksen JH: Circulatory abnormalities in cirrhosis with
Raven Press, 1992:1373–1409. focus on neurohumoral aspects. Sem Nephrol 1997, 17:505–519.
44. Breyer MD, Ando Y: Hormonal signalling and regulation of salt and 65. Hillarp A, Zöller B, Dahlbäck M: Activated protein C resistance as a
water transport in the collecting duct. Ann Rev Physiol 1994, basis for venous thrombosis. Am J Med 1996, 101:534–540.
56:711–739. 66. Niederberger M, Martin P-Y, Ginès P, et al.: Normalization of nitric
45. Schafer JA, Hawk CT: Regulation of Na+ channels in the cortical collect- oxide production corrects arterial vasodilation and hyperdynamic cir-
ing duct by AVP and mineralocorticoids. Int Kidney 1992, 41:255–268. culation in cirrhotic rats. Gastroenterology 1995, 109:1624–1630.
2.22 Disorders of Water, Electrolytes, and Acid-Base
67. Niederberger M, Ginès P, Tsai P, et al.: Increased aortic cyclic guano- 71. Rodrígeuez-Iturbe B, Colic D, Parra G, Gutkowska J: Atrial natriuret-
sine monophosphate concentration in experimental cirrhosis in rats: ic factor in the acute nephritic and nephrotic syndromes. Kidney Int
evidence for a role of nitric oxide in the pathogenesis of arterial 1990, 38:512–517.
vasodilation in cirrhosis. Hepatology 1995, 21:1625–1631. 72. Ichikawa I, Rennke HG, Hoyer JR, et al.: Role for intrarenal mecha-
68. Martin P-Y, Schrier RW: Pathogenesis of water and sodium retention nisms in the impaired salt excretion of experimental nephrotic syn-
in cirrhosis. Kidney Int 1997, 51(suppl 59):S-43–S-49. drome. J Clin Invest 1983, 71:91–103.
69. Fadnes HO, Pape JF, Sundsfjord JA: A study on oedema mechanism 73. Manning RD Jr: Effects of hypoproteinemia on renal hemodynamics,
in nephrotic syndrome. Scand J Clin Lab Invest 1986, 46:533–538. arterial pressure, and fluid volume. Am J Physiol 1997, 252:F91–F98.
70. Oliver WJ, Owings CL: Sodium excretion in the nephrotic syn- 74. Manning RD Jr, Guyton AC: Effects of hypoproteinemia on fluid vol-
drome: relation to serum albumin concentration, glomerular filtra- umes and arterial pressure. Am J Physiol 1983, 245:H284–H293.
tion rate, and aldosterone secretion rate. Am J Dis Child 1967, 75. Mitch WE, Wilcox CS: Disorders of body fluids, sodium and potassi-
113:352–362. um in chronic renal failure. Am J Med 1982, 72:536–550.
Disorders of Potassium
Metabolism
Fredrick V. Osorio
Stuart L. Linas
P
otassium, the most abundant cation in the human body, regu-
lates intracellular enzyme function and neuromuscular tissue
excitability. Serum potassium is normally maintained within the
narrow range of 3.5 to 5.5 mEq/L. The intracellular-extracellular
potassium ratio (Ki/Ke) largely determines neuromuscular tissue
excitability [1]. Because only a small portion of potassium is extracel-
lular, neuromuscular tissue excitability is markedly affected by small
changes in extracellular potassium. Thus, the body has developed
elaborate regulatory mechanisms to maintain potassium homeostasis.
Because dietary potassium intake is sporadic and it cannot be rapidly
excreted renally, short-term potassium homeostasis occurs via trans-
cellular potassium shifts [2]. Ultimately, long-term maintenance of
potassium balance depends on renal excretion of ingested potassium.
The illustrations in this chapter review normal transcellular potassium
homeostasis as well as mechanisms of renal potassium excretion.
With an understanding of normal potassium balance, disorders of
potassium metabolism can be grouped into those that are due to
altered intake, altered excretion, and abnormal transcellular distribu-
tion. The diagnostic algorithms that follow allow the reader to limit
the potential causes of hyperkalemia and hypokalemia and to reach a
diagnosis as efficiently as possible. Finally, clinical manifestations of
disorders of potassium metabolism are reviewed, and treatment algo-
rithms for hypokalemia and hyperkalemia are offered.
Recently, the molecular defects responsible for a variety of diseases
associated with disordered potassium metabolism have been discov- CHAPTER
ered [3–8]. Hypokalemia and Liddle’s syndrome [3] and hyper-
kalemia and pseudohypoaldosteronism type I [4] result from muta-
3
tions at different sites on the epithelial sodium channel in the distal
tubules. The hypokalemia of Bartter’s syndrome can be accounted for
by two separate ion transporter defects in the thick ascending limb of
Henle’s loop [5]. Gitelman’s syndrome, a clinical variant of Bartter’s
3.2 Disorders of Water, Electrolytes, and Acid-Base
syndrome, is caused by a mutation in an ion cotransporter in a apparent mineralocorticoid excess [7] and glucocorticoid-
completely different segment of the renal tubule [6]. The genet- remediable aldosteronism [8] have recently been elucidated
ic mutations responsible for hypokalemia in the syndrome of and are illustrated below.
FIGURE 3-2
FACTORS CAUSING TRANSCELLULAR Factors that cause transcellular potassium shifts.
POTASSIUM SHIFTS
Factor Plasma K+
Acid-base status
Metabolic acidosis
Hyperchloremic acidosis ↑↑
Organic acidosis ↔
Respiratory acidosis ↑
Metabolic alkalosis ↓
Respiratory alkalosis ↓
Pancreatic hormones
Insulin ↓↓
Glucagon ↑
Catecholamines
-Adrenergic ↓
-Adrenergic ↑
Hyperosmolarity ↑
Aldosterone ↓, ↔
Exercise ↑
Diseases of Potassium Metabolism 3.3
FIGURE 3-3
Extrarenal potassium homeostasis: insulin and catecholamines.
Schematic representation of the cellular mechanisms by which insulin
and -adrenergic stimulation promote potassium uptake by
extrarenal tissues. Insulin binding to its receptor results in hyperpo-
larization of cell membranes (1), which facilitates potassium uptake.
After binding to its receptor, insulin also activates Na+-K+-ATPase
pumps, resulting in cellular uptake of potassium (2). The second
messenger that mediates this effect has not yet been identified.
Catecholamines stimulate cellular potassium uptake via the 2 adren-
ergic receptor (2R). The generation of cyclic adenosine monophos-
phate (3, 5 cAMP) activates Na+-K+-ATPase pumps (3), causing an
influx of potassium in exchange for sodium [10]. By inhibiting the
degradation of cyclic AMP, theophylline potentiates catecholamine-
stimulated potassium uptake, resulting in hypokalemia (4).
FIGURE 3-4
Renal potassium handling. More than half of filtered potassium is
passively reabsorbed by the end of the proximal convolted tubule
(PCT). Potassium is then added to tubular fluid in the descending
limb of Henle’s loop (see below). The major site of active potassi-
um reabsorption is the thick ascending limb of the loop of Henle
(TAL), so that, by the end of the distal convoluted tubule (DCT),
only 10% to 15% of filtered potassium remains in the tubule
lumen. Potassium is secreted mainly by the principal cells of the
cortical collecting duct (CCD) and outer medullary collecting duct
(OMCD). Potassium reabsorption occurs via the intercalated cells
of the medullary collecting duct (MCD). Urinary potassium repre-
sents the difference between potassium secreted and potassium
reabsorbed [11]. During states of total body potassium depletion,
potassium reabsorption is enhanced. Reabsorbed potassium initial-
ly enters the medullary interstitium, but then it is secreted into the
pars recta (PR) and descending limb of the loop of Henle (TDL).
The physiologic role of medullary potassium recycling may be to
minimize potassium “backleak” out of the collecting tubule lumen
or to enhance renal potassium secretion during states of excess
total body potassium [12]. The percentage of filtered potassium
remaining in the tubule lumen is indicated in the corresponding
nephron segment.
3.4 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 3-10
Hypokalemia and magnesium depletion. Hypokalemia and mag-
nesium depletion can occur concurrently in a variety of clinical
settings, including diuretic therapy, ketoacidosis, aminoglycoside
therapy, and prolonged osmotic diuresis (as with poorly con-
trolled diabetes mellitus). Hypokalemia is also a common finding
in patients with congenital magnesium-losing kidney disease. The
patient depicted was treated with cisplatin 2 months before pre-
sentation. Attempts at oral and intravenous potassium replace-
ment of up to 80 mEq/day were unsuccessful in correcting the
hypokalemia. Once serum magnesium was corrected, however,
serum potassium quickly normalized [14].
Diseases of Potassium Metabolism 3.7
FIGURE 3-11
Diagnostic approach to hypokalemia:
hypokalemia due to renal losses with meta-
bolic alkalosis. The urine chloride value is
helpful in distinguishing the causes of
hypokalemia. Diuretics are a common
cause of hypokalemia; however, after dis-
continuing diuretics, urinary potassium and
chloride may be appropriately low. Urine
diuretic screens are warranted for patients
suspected of surreptious diuretic abuse.
Vomiting results in chloride and sodium
depletion, hyperaldosteronism, and renal
potassium wasting. Posthypercapnic states
are often associated with chloride depletion
(from diuretics) and sodium avidity. If
hypercapnia is corrected without replacing
chloride, patients develop chloride-deple-
tion alkalosis and hypokalemia.
FIGURE 3-13
Diagnostic approach to hypokalemia: hypokalemia due to renal losses with hypertension and metabolic alkalosis.
FIGURE 3-14
CHARACTERISTICS OF HYPOKALEMIA WITH Distinguishing characteristics of
HYPERTENSION AND METABOLIC ALKALOSIS hypokalemia associated with hypertension
and metabolic alkalosis.
Response to
Aldosterone Renin Dexamethasone
Primary aldosteronism ↑ ↓ —
11 -hydroxysteroid ↓ ↓ +
dehydrogenase deficiency
Glucocorticoid remediable ↑ ↓ +
aldosteronism
Liddle’s syndrome ↓→ ↓ —
Diseases of Potassium Metabolism 3.9
FIGURE 3-15
Mechanism of hypokalemia in Liddle’s syndrome. The amiloride-
sensitive sodium channel on the apical membrane of the distal
tubule consists of homologous , , and subunits. Each subunit
is composed of two transmembrane-spanning domains, an extracel-
lular loop, and intracellular amino and carboxyl terminals.
Truncation mutations of either the or subunit carboxyl termi-
nal result in greatly increased sodium conductance, which creates
a favorable electrochemical gradient for potassium secretion.
Although patients with Liddle’s syndrome are not universally
hypokalemic, they may exhibit severe potassium wasting with
thiazide diuretics. The hypokalemia, hypertension, and metabolic
alkalosis that typify Liddle’s syndrome can be corrected with
amiloride or triamterene or restriction of sodium.
FIGURE 3-16
Mechanism of hypokalemia in the syndrome of apparent mineralo-
corticoid excess (AME). Cortisol and aldosterone have equal affini-
ty for the intracellular mineralocorticoid receptor (MR);
however, in aldosterone-sensitive tissues such as the kidney, the
enzyme 11 -hydroxysteroid dehydrogenase (11 -HSD) converts
cortisol to cortisone. Since cortisone has a low affinity for the MR,
the enzyme 11 -HSD serves to protect the kidney from the effects
of glucocorticoids. In hereditary or acquired AME, 11 -HSD is
defective or is inactiveted (by licorice or carbenoxalone). Cortisol,
which is present at concentrations approximately 1000-fold that
of aldosterone, becomes a mineralocorticoid. The hypermineralo-
corticoid state results in increased transcription of subunits of the
sodium channel and the Na+-K+-ATPase pump. The favorable elec-
trochemical gradient then favors potassium secretion [7,15].
3.10 Disorders of Water, Electrolytes, and Acid-Base
Cardiovascular Renal/electrolyte
Abnormal electrocardiogram Functional alterations
Predisposition for digitalis toxicity Decreased glomerular filtration rate
Atrial ventricular arrhythmias Decreased renal blood flow
Hypertension Renal concentrating defect
Neuromuscular Increased renal ammonia production
Smooth muscle Chloride wasting
Constipation/ileus Metabolic alkalosis
Bladder dysfunction Hypercalciuria
Skeletal muscle Phosphaturia
Weakness/cramps Structural alterations
Tetany Dilation and vacuolization of
Paralysis proximal tubules
Myalgias/rhabdomyolysis Medullary cyst formation
Interstitial nephritis
Endocrine/metabolic
Decreased insulin secretion
Carbohydrate intolerance
Increased renin FIGURE 3-19
Decreased aldosterone Electrocardiographic changes associated with hypokalemia. A, The
Altered prostaglandin synthesis U wave may be a normal finding and is not specific for hypokalemia.
Growth retardation B, When the amplitude of the U wave exceeds that of the T wave,
hypokalemia may be present. The QT interval may appear to be
prolonged; however, this is often due to mistaking the QU interval
for the QT interval, as the latter does not change in duration with
FIGURE 3-18 hypokalemia. C, Sagging of the ST segment, flattening of the T wave,
and a prominent U wave are seen with progressive hypokalemia.
Clinical manifestations of hypokalemia.
D, The QRS complex may widen slightly, and the PR interval is
often prolonged with severe hypokalemia. Hypokalemia promotes
the appearance of supraventricular and ventricular ectopic rhythms,
especially in patients taking digitalis [16].
Diseases of Potassium Metabolism 3.11
FIGURE 3-20
Renal lesions associated with hypokalemia. The predominant pathologic finding accompa-
nying potassium depletion in humans is vacuolization of the epithelium of the proximal
convoluted tubules. The vacoules are large and coarse, and staining for lipids is usually
negative. The tubular vacuolation is reversible with sustained correction of the
hypokalemia; however, in patients with long-standing hypokalemia, lymphocytic infiltra-
tion, interstitial scarring, and tubule atrophy have been described. Increased renal ammo-
nia production may promote complement activation via the alternate pathway and can
contribute to the interstitial nephritis [17,18].
Hypokalemia: Treatment
FIGURE 3-21
Treatment of hypokalemia: estimation of potassium deficit. In the
absence of stimuli that alter intracellular-extracellular potassium dis-
tribution, a decrease in the serum potassium concentration from 3.5
to 3.0 mEq/L corresponds to a 5% reduction (~175 mEq) in total
body potassium stores. A decline from 3.0 to 2.0 mEq/L signifies an
additional 200 to 400-mEq deficit. Factors such as the rapidity of
the fall in serum potassium and the presence or absence of symptoms
dictate the aggressiveness of replacement therapy. In general,
hypokalemia due to intracellular shifts can be managed by treating
the underlying condition (hyperinsulinemia, theophylline intoxica-
tion). Hypokalemic periodic paralysis and hypokalemia associated
with myocardial infarction (secondary to endogenous -adrenergic
agonist release) are best managed by potassium supplementation [19].
3.12 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 3-22
Treatment of hypokalemia.
FIGURE 3-24
Approach to hyperkalemia: hyperkalemia
with reduced glomerular filtration rate
(GFR). Normokalemia can be maintained
in patients who consume normal quantities
of potassium until GFR decreases to less
than 10 mL/min; however, diminished GFR
predisposes patients to hyperkalemia from
excessive exogenous or endogenous potassi-
um loads. Hidden sources of endogenous and
exogenous potassium—and drugs that pre-
dispose to hyperkalemia—are listed.
FIGURE 3-25
Approach to hyperkalemia: hyporeninemic
hypoaldosteronism. Hyporeninemic hypoal-
dosteronism accounts for the majority of
cases of unexplained hyperkalemia in patients
with reduced glomerular filtration rate (GFR)
whose level of renal insufficiency is not what
would be expected to cause hyperkalemia.
Interstitial renal disease is a feature of most
of the diseases listed. The transtubular
potassium gradient (see Fig. 3-26) can be
used to distinguish between primary tubule
defects and hyporeninemic hypoaldostero-
nism. Although the transtubular potassium
gradient should be low in both disorders,
exogenous mineralocorticoid would normal-
ize transtubular potassium gradient in
hyporeninemic hypoaldosteronism.
3.14 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 3-26
Physiologic basis of the transtubular potassium concentration
gradient (TTKG). Secretion of potassium in the cortical collecting
duct and outer medullary collecting duct accounts for the vast
majority of potassium excreted in the urine. Potassium secretion in
these segments is influenced mainly by aldosterone, plasma potassi-
um concentrations, and the anion composition of the fluid in the
lumen. Use of the TTKG assumes that negligible amounts of potassi-
um are secreted or reabsorbed distal to these sites. The final urinary
potassium concentration then depends on water reabsorption in the
medullary collecting ducts, which results in a rise in the final urinary
potassium concentration without addition of significant amounts of
potassium to the urine. The TTKG is calculated as follows:
TTKG = ([K+]urine/(U/P)osm)/[K+]plasma
The ratio of (U/P)osm allows for “correction” of the final urinary
potassium concentration for the amount of water reabsorbed in
the medullary collecting duct. In effect, the TTKG is an index of the
gradient of potassium achieved at potassium secretory sites, indepen-
dent of urine flow rate. The urine must at least be iso-osmolal with
respect to serum if the TTKG is to be meaningful [20].
FIGURE 3-27
CAUSES FOR HYPERKALEMIA WITH AN Clinical application of the transtubular potassium gradient (TTKG).
INAPPROPRIATELY LOW TTKG THAT IS UNRESPONSIVE The TTKG in normal persons varies much but is genarally within
TO MINERALOCORTICOID CHALLENGE the the range of 6 to 12. Hypokalemia from extrarenal causes results
in renal potassium conservation and a TTKG less than 2. A higher
value suggests renal potassium losses, as through hyperaldostero-
Potassium-sparing diuretics Increased distal nephron potassium nism. The expected TTKG during hyperkalemia is greater than 10.
Amiloride reabsorption An inappropriately low TTKG in a hyperkalemic patient suggests
Triamterene Pseudohypoaldosteronism type II hypoaldosteronism or a renal tubule defect. Administration of the
Urinary tract obstruction mineralocorticoid 9 -fludrocortisone (0.05 mg) should cause TTKG
Spironolactone
to rise above 7 in cases of hypoaldosteronism. Circumstances are
Tubular resistance to aldosterone
listed in which the TTKG would not increase after mineralocorticoid
Interstitial nephritis
challenge, because of tubular resistance to aldosterone [21].
Sickle cell disease
Urinary tract obstruction
Pseudohypoaldosteronism type I
Drugs
Trimethoprim
Pentamidine
Diseases of Potassium Metabolism 3.15
FIGURE 3-28
Approach to hyperkalemia: low aldosterone
with normal to increased plasma renin.
Heparin impairs aldosterone synthesis by
inhibiting the enzyme 18-hydroxylase.
Despite its frequent use, heparin is rarely
associated with overt hyperkalemia; this
suggests that other mechanisms (eg, reduced
renal potassium secretion) must be present
simultaneously for hyperkalemia to mani-
fest itself. Both angiotensin-converting
enzyme inhibitors and the angiotensin type
1 receptor blockers (AT1) receptor blockers
interfere with adrenal aldosterone synthesis.
Generalized impairment of adrenal cortical
function manifested by combined glucocor-
ticoid and mineralocorticoid deficiencies are
seen in Addison’s disease and in defects of
aldosterone biosynthesis.
FIGURE 3-29
Approach to hyperkalemia: pseudohypoaldosteronism. The mecha-
nism of decreased potassium excretion is caused either by failure
to secrete potassium in the cortical collecting tubule or enhanced
reabsorption of potassium in the medullary or papillary collecting
tubules. Decreased secretion of potassium in the cortical and
medullary collecting duct results from decreases in either apical
sodium or potassium channel function or diminished basolateral
Na+-K+-ATPase activity. Alternatively, potassium may be secreted
normally but hyperkalemia can develop because potassium reab-
sorption is enhanced in the intercalated cells of the medullary col-
lecting duct (see Fig. 3-4). The transtubule potassium gradient
(TTKG) in both situations is inappropriately low and fails to nor-
malize in response to mineralocorticoid replacement.
3.16 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 3-30
Mechanism of hyperkalemia in pseudohypoaldosteronism type I
(PHA I). This rare autosomally transmitted disease is characterized
by neonatal dehydration, failure to thrive, hyponatremia, hyper-
kalemia, and metabolic acidosis. Kidney and adrenal function are
normal, and patients do not respond to exogenous mineralocorti-
coids. Genetic mutations responsible for PHA I occur in the and
subunits of the amiloride-sensitive sodium channel of the collecting
tubule. Frameshift or premature stop codon mutations in the cyto-
plasmic amino terminal or extracellular loop of either subunit dis-
rupt the integrity of the sodium channel and result in loss of chan-
nel activity. Failure to reabsorb sodium results in volume depletion
and activation of the renin-aldosterone axis. Furthermore, since
sodium reabsorption is indirectly coupled to potassium and hydro-
gen ion secretion, hyperkalemia and metabolic acidosis ensue.
Interestingly, when mutations are introduced into the cytoplasmic
carboxyl terminal, sodium channel activity is increased and Liddle’s
syndrome is observed [4].
FIGURE 3-32
Electrocardiographic (ECG) changes associated with hyperkalemia.
A, Normal ECG pattern. B, Peaked, narrow-based T waves are
the earliest sign of hyperkalemia. C, The P wave broadens and the
QRS complex widens when the plamsa potassium level is above
7 mEq/L. D, With higher elevations in potassium, the P wave
becomes difficult to identify. E, Eventually, an undulating sinu-
soidal pattern is evident. Although the ECG changes are depicted
here as correlating to the severity of hyperkalemia, patients with
even mild ECG changes may abruptly progress to terminal rhythm
disturbances. Thus, hyperkalemia with any ECG changes should be
treated as an emergency.
Hyperkalemia: Treatment
FIGURE 3-33
Treatment of hyperkalemia.
References
1. MacNight ADC: Epithelial transport of potassium. Kidney Int 1977, 4. Chang SS, Grunder S, Hanukoglu A, et al.: Mutations in subunits of
11:391–397. the epithelial sodium channel cause salt wasting with hyperkalemic
2. Bia MJ, DeFronzo RA: Extrarenal potassium homeostasis. Am J acidosis, pseudohypoaldosteronism type I. Nature Genetics 1996,
Physiol 1981, 240:F257–262. 12:248–253.
3. Hansson JH, Nelson-Williams C, Suzuki H, et al.: Hypertension caused 5. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogene-
by a truncated epithelial sodium channel gamma subunit: Genetic het- ity of Bartter’s syndrome revealed by mutations in the K+ channel,
erogeneity of Liddle’s syndrome. Nature Genetics 1995, 11:76–82. ROMK. Nature Genetics 1996, 14:152–156.
3.18 Disorders of Water, Electrolytes, and Acid-Base
6. Pollack MR, Delaney VB, Graham RM, Hebert SC. Gitelman’s syn- 14. Whang R, Flink EB, Dyckner T, et al.: Magnesium depletion as a
drome (Bartter’s variant) maps to the thiazide-sensitive co-transporter cause of refractory potassium repletion. Arch Int Med 1985,
gene locus on chromosome 16q13 in a large kindred. J Am Soc 145:1686–1689.
Nephrol 1996, 7:2244–2248.
15. Funder JW: Corticosteroid receptors and renal 11 -hydroxysteroid
7. Sterwart PM, Krozowski ZS, Gupta A, et al.: Hypertension in the syn- dehydrogenase activity. Semin Nephrol 1990, 10:311–319.
drome of apparent mineralocorticoid excess due to a mutation of the 11
16. Marriott HJL: Miscellaneous conditions: Hypokalemia. In Practical
(-hydroxysteroid dehydrogenase type 2 gene. Lancet 1996, 347:88–91.
Electrocardiography, edn 8. Baltimore: Williams and Wilkins; 1988.
8. Pascoe L, Curnow KM, Slutsker L, et al.: Glucocorticoid suppressable
hyperaldosteronism results from hybrid genes created by unequal 17. Riemanschneider TH, Bohle A: Morphologic aspects of low-potassi-
crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci USA um and low-sodium nephropathy. Clin Nephrol 1983, 19:271–279.
1992, 89:8237–8331. 18. Tolins JP, Hostetter MK, Hostetter TH: Hypokalemic nephropathy in
9. Welt LG, Blyth WB. Potassium in clinical medicine. In A Primer on the rat: Role of ammonia in chronic tubular injury. J Clin Invest
Potassium Metabolism. Chicago: Searle & Co.; 1973. 1987, 79:1447–1458.
10. DeFronzo RA: Regulation of extrarenal potassium homeostasis by 19. Sterns RH, Cox M, Fieg PU, et al.: Internal potassium balance and
insulin and catecholamines. In Current Topics in Membranes and the control of the plasma potassium concentration. Medicine 1981,
Transport, vol. 28. Edited by Giebisch G. San Diego: Academic Press; 60:339–344.
1987:299–329. 20. Kamel KS, Quaggin S, Scheich A, Halperin ML: Disorders of potassi-
11. Giebisch G, Wang W: Potassium transport: from clearance to channels um homeostasis: an approach based on pathophysiology. Am J Kidney
and pumps. Kidney Int 1996, 49:1642–1631. Dis 1994, 24:597–613.
12. Jamison RL: Potassium recycling. Kidney Int 1987, 31:695–703. 21. Ethier JH, Kamel SK, Magner PO, et al.: The transtubular potassium
13. Nora NA, Berns AS: Hypokalemic, hypophosphatemic thyrotoxic concentration gradient in patients with hypokalemia and hyper-
periodic paralysis. Am J Kidney Dis 1989, 13:247–251. kalemia. Am J Kidney Dis 1990, 15:309–315.
Divalent Cation
Metabolism: Magnesium
James T. McCarthy
Rajiv Kumar
M
agnesium is an essential intracellular cation. Nearly 99% of the
total body magnesium is located in bone or the intracellular
space. Magnesium is a critical cation and cofactor in numerous
intracellular processes. It is a cofactor for adenosine triphosphate; an
important membrane stabilizing agent; required for the structural integrity
of numerous intracellular proteins and nucleic acids; a substrate or cofac-
tor for important enzymes such as adenosine triphosphatase, guanosine
triphosphatase, phospholipase C, adenylate cyclase, and guanylate
cyclase; a required cofactor for the activity of over 300 other enzymes; a
regulator of ion channels; an important intracellular signaling molecule;
and a modulator of oxidative phosphorylation. Finally, magnesium is
intimately involved in nerve conduction, muscle contraction, potassium
transport, and calcium channels. Because turnover of magnesium in bone
is so low, the short-term body requirements are met by a balance of
gastrointestinal absorption and renal excretion. Therefore, the kidney
occupies a central role in magnesium balance. Factors that modulate and
affect renal magnesium excretion can have profound effects on magne-
sium balance. In turn, magnesium balance affects numerous intracellular
and systemic processes [1–12].
In the presence of normal renal function, magnesium retention and
hypermagnesemia are relatively uncommon. Hypermagnesemia inhibits
magnesium reabsorption in both the proximal tubule and the loop of
Henle. This inhibition of reabsorption leads to an increase in magnesium
excretion and prevents the development of dangerous levels of serum
magnesium, even in the presence of above-normal intake. However, in
familial hypocalciuric hypercalcemia, there appears to be an abnormali- CHAPTER
ty of the thick ascending limb of the loop of Henle that prevents excre-
tion of calcium. This abnormality may also extend to Mg. In familial
4
hypocalciuric hypercalcemia, mild hypermagnesemia does not increase
the renal excretion of magnesium. A similar abnormality may be caused
by lithium [1,2,6,10]. The renal excretion of magnesium also is below
normal in states of hypomagnesemia, decreased dietary magnesium,
dehydration and volume depletion, hypocalcemia, hypothyroidism, and
hyperparathyroidism [1,2,6,10].
4.2 Disorders of Water, Electrolytes, and Acid-Base
Magnesium Distribution
FIGURE 4-1
TOTAL BODY MAGNESIUM (MG) DISTRIBUTION Total distribution of magnesium (Mg) in
the body. Mg (molecular weight, 24.305 D)
is predominantly distributed in bone, mus-
Location Percent of Total Mg Content, mmol* Mg Content, mg* cle, and soft tissue. Total body Mg content
is about 24 g (1 mol) per 70 kg. Mg in
Bone 53 530 12720 bone is adsorbed to the surface of hydroxy-
Muscle 27 270 6480 apatite crystals, and only about one third is
Soft tissue 19.2 192 4608 readily available as an exchangeable pool.
Erythrocyte 0.5 5 120 Only about 1% of the total body Mg is in
Serum 0.3 3 72 the serum and interstitial fluid
Total 1000 24000 [1,2,8,9,11,12].
FIGURE 4-2
Intracellular magnesium (Mg)
Intracellular distribution of magnesium (Mg). Only 1% to 3% of
the total intracellular Mg exists as the free ionized form of Mg,
which has a closely regulated concentration of 0.5 to 1.0 mmol.
Proteins, enzymes, Total cellular Mg concentration can vary from 5 to 20 mmol,
citrate, Endoplasmic depending on the type of tissue studied, with the highest Mg con-
ATP, ADP reticulum centrations being found in skeletal and cardiac muscle cells. Our
– understanding of the concentration and distribution of intracellular
Membrane
– Mg has been facilitated by the development of electron microprobe
proteins
– analysis techniques and fluorescent dyes using microfluorescence
spectrometry. Intracellular Mg is predominantly complexed to
organic molecules (eg, adenosine triphosphatase [ATPase], cell and
Mg2+ nuclear membrane-associated proteins, DNA and RNA, enzymes,
DNA proteins, and citrates) or sequestered within subcellular organelles
(mitochondria and endoplasmic reticulum). A heterogeneous distri-
bution of Mg occurs within cells, with the highest concentrations
Ca • Mg • Mg2+ being found in the perinuclear areas, which is the predominant site
ATPase RNA of endoplasmic reticulum. The concentration of intracellular free
ionized Mg is tightly regulated by intracellular sequestration and
complexation. Very little change occurs in the concentration of
intracellular free Mg, even with large variations in the concentra-
Mitochondria tions of total intracellular or extracellular Mg [1,3,11]. ADP—
adenosine diphosphate; ATP—adenosine triphosphate; Ca+—ion-
ized calcium.
Divalent Cation Metabolism: Magnesium 4.3
Mg Mitochondrion
Ca2+ phate (IP3) may also increase the release of
Nucleus Pi + Mg2+? Mg from endoplasmic reticulum or sar-
ADP ATP•Mg +
coplasmic reticulum (ER or SR, respective-
? Ca2+ ly), which also has a positive effect on this
Mg2+ Mg2+-ATP-Pi exchanger. Other potential
Mg2+?
+? pK C D.G. + IP3 mechanisms affecting cytosolic Mg include
? a hypothetical Ca2+-Mg2+ exchanger locat-
Plasma membrane
Muscarinic receptor or ed in the ER and transport proteins that
Na+ (Ca2+?)
vasopressin receptor can allow the accumulation of Mg within
Extracellular the nucleus or ER. A balance must exist
between passive entry of Mg into the cell
and an active efflux mechanism because
FIGURE 4-3 the concentration gradient favors the
Regulation of intracellular magnesium (Mg2+) in the mammalian cell. Shown is an exam- movement of extracellular Mg (0.7–1.2
ple of Mg2+ movement between intracellular and extracellular spaces and within intracel- mmol) into the cell (free Mg, 0.5 mmol).
lular compartments. The stimulation of adenylate cyclase activity (eg, through stimulation This Mg extrusion process may be energy-
of -adrenergic receptors) increases cyclic adenosine monophosphate (cAMP). The requiring or may be coupled to the move-
increase in cAMP induces extrusion of Mg from mitochondria by way of mitochondrial ment of other cations. The cellular move-
adenine nucleotide translocase, which exchanges 1 Mg2+-adenosine triphosphate (ATP) ment of Mg generally is not involved in the
for adenosine diphosphate (ADP). This slight increase in cytosolic Mg2+ can then be transepithelial transport of Mg, which is
extruded through the plasma membrane by way of a Mg-cation exchange mechanism, primarily passive and occurs between cells
which may be activated by either cAMP or Mg. Activation of other cell receptors (eg, [1–3,7]. (From Romani and coworkers [3];
muscarinic receptor or vasopressin receptor) may alter cAMP levels or produce diacyl- with permission.)
4.4 Disorders of Water, Electrolytes, and Acid-Base
Mg2+
Extracellular
Outer membrane
2+ N
Mg2+ Mg Periplasm
Mg2+
Mg2+ 1 2 3 4 5 6 7 8 9 10 12 3
CorA Periplasm Periplasm
FIGURE 4-4
A, Transport systems of magnesium (Mg). Specific membrane- against their chemical gradient. Low levels of extracellular Mg
associated Mg transport proteins only have been described in bac- are capable of increasing transcription of these transport proteins,
teria such as Salmonella. Although similar transport proteins are which increases transport of Mg into Salmonella. The CorA sys-
believed to be present in mammalian cells based on nucleotide tem has three membrane-spanning segments. This system mediates
sequence analysis, they have not yet been demonstrated. Both Mg influx; however, at extremely high extracellular Mg concen-
MgtA and MgtB (molecular weight, 91 and 101 kDa, respective- trations, this protein can also mediate Mg efflux. Another cell
ly) are members of the adenosine triphosphatase (ATPase) family membrane Mg transport protein exists in erythrocytes (RBCs).
of transport proteins. B, Both of these transport proteins have six This RBC Na+-Mg2+ antiporter (not shown here) facilitates the
C-terminal and four N-terminal membrane-spanning segments, outward movement of Mg from erythrocytes in the presence of
with both the N- and C-terminals within the cytoplasm. Both extracellular Na+ and intracellular adenosine triphosphate (ATP)
proteins transport Mg with its electrochemical gradient, in con- [4,5]. ADP—adenosine diphosphate; C—carbon; N—nitrogen.
trast to other known ATPase proteins that usually transport ions (From Smith and Maguire [4]).
10
7
9 Physiological
Mg-intake,
7 5
6
3 4
5
4 3
3 13
3 2
22
2
3 1
1
12
0 0
0 3 6 9 12 15 18 21 24 0 10 20 30 40
A [Mg] in bicarbonate saline, mEq/L B Oral magnesium dose m, mmol
FIGURE 4-6
Intestinal magnesium (Mg) absorption. In rats, the intestinal Mg
10 absorption is related to the luminal Mg concentration in a curvilin-
ear fashion (A). This same phenomenon has been observed in
Net Mg absorption, mEq/10 hrs
0
0 20 40 60 80
C Mg intake, mEq/meal
FIGURE 4-7
Mechanism of
intestinal magnesium absorption Proposed pathways for movement of magnesium (Mg) across the intestinal epithelium. Two
possible routes exist for the absorption of Mg across intestinal epithelial cells: the transcel-
Nucleus lular route and the intercellular pathway. Although a transcellular route has not yet been
demonstrated, its existence is inferred from several observations. No large chemical gradient
Lumen
Mg2+ exists for Mg movement across the cell membrane; however, a significant uphill electrical
gradient exists for the exit of Mg from cells. This finding suggests the existence and partici-
A pation of an energy-dependent mechanism for extrusion of Mg from intestinal cells. If such
Mg2+ a system exists, it is believed it would consist of two stages. 1) Mg would enter the apical
Mg2+
B membrane of intestinal cells by way of a passive carrier or facilitated diffusion. 2) An active
Mg pump in the basolateral section of the cell would extrude Mg. The intercellular move-
Mg2+
K+ ment of Mg has been demonstrated to occur by both gradient-driven and solvent-drag
Na+ mechanisms. This intercellular path may be the only means by which Mg moves across the
ATPase intestinal epithelium. The change in transport rates at low Mg concentrations would reflect
changes in the “openness” of this pathway. High concentrations of luminal Mg (eg, after a
meal) are capable of altering the morphology of the tight junction complex. High local Mg
concentrations near the intercellular junction also can affect the activities of local mem-
brane-associated proteins (eg, sodium-potassium adenosine triphosphate [Na-K ATPase])
near the tight junction and affect its permeability (see Fig. 4-6) [13–15].
4.6 Disorders of Water, Electrolytes, and Acid-Base
Mg2+ionized Mg2+complexed
Mg2+-ultrafilterable
% of total
Mg2+ serum Mg2+
Ionized Mg 60%
Protein-bound Mg 33% Proximal
Complexed Mg 7% tubule
*Normal total serum Mg =
1.7–2.1 mg/dL (0.70–0.9 mmol/L)
FIGURE 4-10
Mg absorption in cTAL
Magnesium (Mg) reabsorption in the cortical thick ascending limb (cTAL) of the loop of
–78mV Henle. Most Mg reabsorption within the nephron occurs in the cTAL owing primarily to
+8mV 0mV
voltage-dependent Mg flux through the intercellular tight junction. Transcellular Mg
movement occurs only in response to cellular metabolic needs. The sequence of events nec-
essary to generate the lumen-positive electrochemical gradient that drives Mg reabsorption
is as follows: 1) A basolateral sodium-potassium-adenosine triphosphatase (Na+-K+-
6 ATPase) decreases intracellular sodium, generating an inside-negative electrical potential
2Na+ difference; 2) Intracellular K is extruded by an electroneutral K-Cl (chloride) cotrans-
1Cl–
porter; 3) Cl is extruded by way of conductive pathways in the basolateral membrane; 4)
4 1 The apical-luminal Na-2Cl-K (furosemide-sensitive) cotransport mechanism is driven by
3Na+ 3Na+
6Cl– 2K+ the inside-negative potential difference and decrease in intracellular Na; 5) Potassium is
3K+ 2 2K+ recycled back into the lumen by way of an apical K conductive channel; 6) Passage of
2Cl– approximately 2 Na molecules for every Cl molecule is allowed by the paracellular path-
3
3K+ 4Cl– way (intercellular tight junction), which is cation permselective; 7) Mg reabsorption occurs
5
passively, by way of intercellular channels, as it moves down its electrical gradient
[1,2,6,7]. (Adapted from de Rouffignac and Quamme [1].)
Mg
Mg
~1.0mmol
A
Mg Mg 0.5mmol
~1.0mmol
FIGURE 4-11
JMg, pmol.min–1.mm–1
Voltage-dependent net magnesium (Mg) flux in the cortical thick
ascending limb (cTAL). Within the isolated mouse cTAL, Mg flux
0.8
(JMg) occurs in response to voltage-dependent mechanisms. With
a relative lumen-positive transepithelial potential difference (Vt),
0.6
Mg reabsorption increases (positive JMg). Mg reabsorption equals
0.4 zero when no voltage-dependent difference exists, and Mg is
capable of moving into the tubular lumen (negative JMg) when a
(7)
0.2 lumen-negative voltage difference exists [1,16]. (From di Stefano
and coworkers [16]).
Vt, mV
–18 –15 –12 –9 –6 –3 3 6 9 12 15 18
–0.2 (15)
–0.4
(8) –0.6
–0.8
4.8 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 4-12
JMg2+ Effect of hormones on magnesium (Mg)
AVP GLU HCT PTH ISO INS transport in the cortical thick ascending
1.0 limb (cTAL). In the presence of arginine
Net fluxes, pmol • min–1• mm–1
* *
* vasopressin (AVP), glucagon (GLU), human
0.8 calcitonin (HCT), parathyroid hormone
* (PTH), 1,4,5-isoproteronol (ISO), and
0.6
* * insulin (INS), increases occur in Mg reab-
0.4 sorption from isolated segments of mouse
cTALs. These hormones have no effect on
0.2 medullary TAL segments. As already has
C C C C C C C C C C C C been shown in Figure 4-3, these hormones
0
affect intracellular “second messengers”
and cellular Mg movement. These hor-
mone-induced alterations can affect the
paracellular permeability of the intercellular
tight junction. These changes may also
affect the transepithelial voltage across the
cTAL. Both of these forces favor net Mg
reabsorption in the cTAL [1,2,7,8].
Asterisk—significant change from preceding
period; JMg—Mg flux; C—control, absence
of hormone. (Adapted from de Rouffignac
and Quamme [1].)
Magnesium Depletion
FIGURE 4-13
CAUSES OF MAGNESIUM (Mg) DEPLETION The causes of magnesium (Mg) depletion. Depletion of Mg can
develop as a result of low intake or increased losses by way of the
gastrointestinal tract, the kidneys, or other routes [1,2,8–13].
Poor Mg intake Other
Starvation Lactation
Anorexia Extensive burns
Protein calorie malnutrition Exchange transfusions
No Mg in intravenous fluids
Renal losses
see Fig. 4-14
Increased gastrointestinal Mg losses
Nasogastric suction
Vomiting
Intestinal bypass for obesity
Short-bowel syndrome
Inflammatory bowel disease
Pancreatitis
Diarrhea
Laxative abuse
Villous adenoma
Divalent Cation Metabolism: Magnesium 4.9
FIGURE 4-14
Renal magnesium (Mg) wasting
Renal magnesium (Mg) wasting. Mg is normally reabsorbed in the
Thiazides(?)
proximal tubule (PT), cortical thick ascending limb (cTAL), and dis-
Tubular defects tal convoluted tubule (DCT) (see Fig. 4-9). Volume expansion and
Volume Bartter's syndrome osmotic diuretics inhibit PT reabsorption of Mg. Several renal dis-
expansion Gitelman's syndrome eases and electrolyte disturbances (asterisks) inhibit Mg reabsorption
• Osmotic diuresis Renal tubular acidosis in both the PT and cTAL owing to damage to the epithelial cells and
Glucose Medullary calcinosis the intercellular tight junctions, plus disruption of the electrochemi-
Mannitol Drugs/toxins cal forces that normally favor Mg reabsorption. Many drugs and
Urea Cis-platinum
• Diuretic phase toxins directly damage the cTAL. Thiazides have little direct effect
Amphotericin B
acute renal failure* Cyclosporine
on Mg reabsorption; however, the secondary hyperaldosteronism
• Post obstructive diuresis* Pentamidine and hypercalcemia effect Mg reabsorption in CD and/or cTAL.
• Hypercalcemia* ? Aminoglycosides* Aminoglycosides accumulate in the PT, which affects sodium reab-
• Phosphate depletion* Foscarnet (?ATN) sorption, also leading to an increase in aldosterone. Aldosterone leads
• Chronic renal disease* Ticarcillin/carbenicillin
• ? Aminoglycosides* to volume expansion, decreasing Mg reabsorption. Parathyroid
? Digoxin
• Renal transplant* hormone has the direct effect of increasing Mg reabsorption in
• Interstitial nephritis* Electrolyte imbalances cTAL; however, hypercalcemia offsets this tendency. Thyroid hor-
Hypercalcemia*
Phosphate depletion*
mone increases Mg loss. Diabetes mellitus increases Mg loss by way
Metabolic acidosis of both hyperglycemic osmotic diuresis and insulin abnormalities
Starvation (deficiency and resistance), which decrease Mg reabsorption in the
Ketoacidosis proximal convoluted tubule and cTAL, respectively. Cisplatin causes a
Alcoholism Gitelman-like syndrome, which often can be permanent [1,2,8–12].
Hormonal changes
Hyperaldosteronism
Primary
hyperparathyroidism
Hyperthyroidism
Uncontrolled diabetes
mellitus
FIGURE 4-15
SIGNS AND SYMPTOMS OF HYPOMAGNESEMIA Signs and symptoms of hypomagnesemia. Symptoms of hypomag-
nesemia can develop when the serum magnesium (Mg) level falls
below 1.2 mg/dL. Mg is a critical cation in nerves and muscles and
is intimately involved with potassium and calcium. Therefore, neu-
Cardiovascular Muscular
romuscular symptoms predominate and are similar to those seen in
Electrocardiographic results Cramps
hypocalcemia and hypokalemia. Electrocardiographic changes of
Prolonged P-R and Q-T intervals, Weakness
hypomagnesemia include an increased P-R interval, increased Q-T
U waves Carpopedal spasm
duration, and development of U waves. Mg deficiency increases the
Angina pectoris Chvostek’s sign mortality of patients with acute myocardial infarction and conges-
?Congestive heart failure Trousseau’s sign tive heart failure. Mg depletion hastens atherogenesis by increasing
Atrial and ventricular arrhythmias Fasciculations total cholesterol and triglyceride levels and by decreasing high-den-
?Hypertension Tremulous sity lipoprotein cholesterol levels. Hypomagnesemia also increases
Digoxin toxicity Hyperactive reflexes hypertensive tendencies and impairs insulin release, which favor
Atherogenesis Myoclonus atherogenesis. Low levels of Mg impair parathyroid hormone
Neuromuscular Dysphagia (PTH) release, block PTH action on bone, and decrease the activity
Central nervous system Skeletal of renal 1--hydroxylase, which converts 25-hydroxy-vitamin D3
Seizures Osteoporosis into 1,25-dihydroxy-vitamin D3, all of which contribute to
Obtundation Osteomalacia hypocalcemia. Mg is an integral cofactor in cellular sodium-potas-
Depression sium-adenosine triphosphatase activity, and a deficiency of Mg
Psychosis impairs the intracellular transport of K and contributes to renal
Coma wasting of K, causing hypokalemia [6,8–12].
Ataxia
Nystagmus
Choreiform and athetoid movements
4.10 Disorders of Water, Electrolytes, and Acid-Base
↑Platelet
↑Aldosterone Normal Low Low High
aggregation
(> 24 mg/24 hrs) (< 24 mg/24 hrs) (< 24 mg/24 hrs) (> 24 mg/24 hrs)
FIGURE 4-18
MAGNESIUM (Mg) TOLERANCE TEST FOR PATIENTS The magnesium (Mg) tolerance test, in various forms [2,6,8–12,18],
WITH NORMAL SERUM MAGNESIUM has been advocated to diagnose Mg depletion in patients with normal
or near-normal serum Mg levels. All such tests are predicated on the
fact that patients with normal Mg status rapidly excrete over 50% of
an acute Mg load; whereas patients with depleted Mg retain Mg in an
Time Action
effort to replenish Mg stores. (From Ryzen and coworkers [18].)
0 (baseline) Urine (spot or timed) for molar Mg:Cr ratio
0–4 h IV infusion of 2.4 mg (0.1 mmol) of Mg/kg lean body
wt in 50 mL of 50% dextrose
0–24 h Collect urine (staring with Mg infusion) for Mg and Cr
End Calculate % Mg retained (%M)
Mg retained, % Mg deficiency
>50 Definite
20–50 Probable
<20 None
Data from McLean [9], Al-Ghamdi and coworkers [11], Oster and Epstein [19], and Physicians’ Desk Reference [20].
*Magonate®, Fleming & Co, Fenton, MD; MagTab Sr®, Niche Pharmaceuticals, Roanoke, TX; Maalox®, Rhone-Poulenc Rorer Pharmaceutical, Collegeville, PA; Mylanta®,
J & J-Merck Consumer Pharm, Ft Washinton, PA; Riopan®, Whitehall Robbins Laboratories, Madison, NJ; Mag-Ox 400® and Uro-Mag®, Blaine, Erlanger, KY; Beelith®,
Beach Pharmaceuticals, Conestee, SC; Phillips’ Milk of Magnesia, Bayer Corp, Parsippany, NJ.
FIGURE 4-19
Magnesium (Mg) salts that may be used in Mg replacement therapy.
FIGURE 4-20
GUIDELINES FOR MAGNESIUM (Mg) REPLACEMENT Acute Mg replacement for life-threatening events such as seizures or
potentially lethal cardiac arrhythmias has been described [8–12,19].
Acute increases in the level of serum Mg can cause nausea, vomit-
Life-threatening event, eg, seizures and cardiac arrhythmia ing, cutaneous flushing, muscular weakness, and hyporeflexia. As
Mg levels increase above 6 mg/dL (2.5 mmol/L), electrocardio-
I. 2–4 g MgSO4 IV or IM stat II. IV drip over first 24 h graphic changes are followed, in sequence, by hyporeflexia, respira-
(2–4 vials [2 mL each] of 50% MgSO4) to provide no more tory paralysis, and cardiac arrest. Mg should be administered with
Provides 200–400 mg of Mg (8.3–16.7 mmol Mg) than 1200 mg (50
mmol) Mg/24 h
caution in patients with renal failure. In the event of an emergency
Closely monitor: the acute Mg load should be followed by an intravenous (IV) infu-
Deep tendon reflexes sion, providing no more than 1200 mg (50 mmol) of Mg on the
Heart rate first day. This treatment can be followed by another 2 to 5 days of
Blood pressure Mg repletion in the same dosage, which is used in less urgent situa-
Respiratory rate tions. Continuous IV infusion of Mg is preferred to both intramus-
Serum Mg (<2.5 mmol/L [6.0 mg/dL]) cular (which is painful) and oral (which causes diarrhea) adminis-
Serum K tration. A continuous infusion avoids the higher urinary fractional
excretion of Mg seen with intermittent administration of Mg.
Subacute and chronic Mg replacement Patients with mild Mg deficiency may be treated with oral Mg salts
I. 400–600 mg (16.7–25 mmol Mg daily for 2–5 d)
rather than parenteral Mg and may be equally efficacious [8].
Administration of Mg sulfate may cause kaliuresis owing to excre-
IV: continuous infusion
tion of the nonreabsorbable sulfate anion; Mg oxide administration
IM: painful
has been reported to cause significant acidosis and hyperkalemia
Oral: use divided doses to minimize diarrhea
[19]. Parenteral Mg also is administered (often in a manner different
from that shown here) to patients with preeclampsia, asthma, acute
myocardial infarction, and congestive heart failure.
4.12 Disorders of Water, Electrolytes, and Acid-Base
References
1. de Rouffignac C, Quamme G: Renal magnesium handling and its 12. Nadler JL, Rude RK: Disorders of magnesium metabolism.
hormonal control. Physiol Rev 1994, 74:305–322. Endocrinol Metab Clin North Am 1995, 24:623–641.
2. Quamme GA: Magnesium homeostasis and renal magnesium han- 13. Kayne LH, Lee DBN: Intestinal magnesium absorption. Miner
dling. Miner Electrolyte Metab 1993, 19:218–225. Electrolyte Metab 1993, 19:210–217.
3. Romani A, Marfella C, Scarpa A: Cell magnesium transport and 14. Roth P, Werner E: Intestinal absorption of magnesium in man. Int J
homeostasis: role of intracellular compartments. Miner Electrolyte Appl Radiat Isotopes 1979, 30:523–526.
Metab 1993, 19:282–289.
15. Fine KD, Santa Ana CA, Porter JL, Fordtran JS: Intestinal absorption
4. Smith DL, Maguire ME: Molecular aspects of Mg2+ transport systems.
of magnesium from food and supplements. J Clin Invest 1991,
Miner Electrolyte Metab 1993, 19:266–276.
88:396–402.
5. Roof SK, Maguire ME: Magnesium transport systems: genetics and
protein structure (a review). J Am Coll Nutr 1994, 13:424–428. 16. di Stefano A, Roinel N, de Rouffignac C, Wittner M: Transepithelial
Ca+ and Mg+ transport in the cortical thick ascending limb of Henle’s
6. Sutton RAL, Domrongkitchaiporn S: Abnormal renal magnesium han-
loop of the mouse is a voltage-dependent process. Renal Physiol
dling. Miner Electrolyte Metab 1993, 19:232–240.
Biochem 1993, 16:157–166.
7. de Rouffignac C, Mandon B, Wittner M, di Stefano A: Hormonal con-
trol of magnesium handling. Miner Electrolyte Metab 1993, 19:226–231. 17. Nadler JL, Buchanan T, Natarajan R, et al.: Magnesium deficiency
produces insulin resistance and increased thromboxane synthesis.
8. Whang R, Hampton EM, Whang DD: Magnesium homeostasis and
Hypertension 1993, 21:1024–1029.
clinical disorders of magnesium deficiency. Ann Pharmacother 1994,
28:220–226. 18. Ryzen E, Elbaum N, Singer FR, Rude RK: Parenteral magnesium tol-
9. McLean RM: Magnesium and its therapeutic uses: a review. Am J Med erance testing in the evaluation of magnesium deficiency. Magnesium
1994, 96:63–76. 1985, 4:137–147.
10. Abbott LG, Rude RK: Clinical manifestations of magnesium deficien- 19. Oster JR, Epstein M: Management of magnesium depletion. Am J
cy. Miner Electrolyte Metab 1993, 19:314–322. Nephrol 1988, 8:349–354.
11. Al-Ghamdi SMG, Cameron EC, Sutton RAL: Magnesium deficiency: 20. Physicians’ Desk Reference (PDR). Montvale, NJ: Medical Economics
pathophysiologic and clinical overview. Am J Kid Dis 1994, 24:737–752. Company; 1996.
Divalent Cation
Metabolism: Calcium
James T. McCarthy
Rajiv Kumar
C
alcium is an essential element in the human body. Although over
99% of the total body calcium is located in bone, calcium is a
critical cation in both the extracellular and intracellular spaces.
Its concentration is held in a very narrow range in both spaces. In addi-
tion to its important role in the bone mineral matrix, calcium serves a
vital role in nerve impulse transmission, muscular contraction, blood
coagulation, hormone secretion, and intercellular adhesion. Calcium
also is an important intracellular second messenger for processes such
as exocytosis, chemotaxis, hormone secretion, enzymatic activity, and
fertilization. Calcium balance is tightly regulated by the interplay
between gastrointestinal absorption, renal excretion, bone resorption,
and the vitamin D–parathyroid hormone (PTH) system [1–7].
CHAPTER
5
5.2 Disorders of Water, Electrolytes, and Acid-Base
Calcium Distribution
FIGURE 5-1
TOTAL DISTRIBUTION OF CALCIUM IN THE BODY Total distribution of calcium (Ca) in the body. Ca (molecular weight,
40.08 D) is predominantly incorporated into bone. Total body Ca
content is about 1250 g (31 mol) in a person weighing 70 kg. Bone
Ca Content* Ca is incorporated into the hydroxyapatite crystals of bone, and
about 1% of bone Ca is available as an exchangeable pool. Only
Location Concentration mmol mg 1% of the total body calcium exists outside of the skeleton.
Bone 99% ~31.4 103 ~1255 103
Extracellular fluid 2.4 mmol 35 ~1400
Intracellular fluid 0.1 mol <1 <40
Total ~31.5 103 ~1260 103
FIGURE 5-4
Oral calcium intake Soft tissue and Calcium (Ca) flux between body compartments. Ca balance is a
~1000 mg/d intracellular complex process involving bone, intestinal absorption of dietary
calcium
Ca, and renal excretion of Ca. The parathyroid glands, by their
production of parathyroid hormone, and the liver, through its par-
Intestine
ticipation in vitamin D metabolism, also are integral organs in the
400 mg Extracellular 500 mg maintenance of Ca balance. (From Kumar [1]; with permission.)
fluid and
200 mg plasma 500 mg
10,000 mg 9800 mg
Feces Bone
800 mg
Kidney
Urine
200 mg
5.4 Disorders of Water, Electrolytes, and Acid-Base
Osteoblast Osteoclast
Cytokines
Osteocalcin
Osteopontin
Alkaline
Phosphatase
Bone
DNA binding Hinge region Calcitiriol binding 12q12-14 chromosome, near the gene
for the 1--hydroxylase enzyme. The
gly→asp
30 VDR is found in the intestinal epithelium,
his→gln parathyroid cells, kidney cells, osteoblasts,
32 arg→gln and thyroid cells. VDR also can be detect-
70 ed in keratinocytes, monocyte precursor
arg→gln
42 cys→trp tyr→stop cells, muscle cells, and numerous other
arg→gln 187 292 tissues. The allele variations for the vita-
77 min D receptor. Two allele variations
NH2 COOH exist for the vitamin D receptor (VDR):
18 424 the b allele and the B allele. In general,
42 44 149 271
lys→glu phe→ile gln→stop arg→leu normal persons with the b allele seem to
have a higher bone mineral density [9].
ZN Among patients on dialysis, those with
Mutant amino acid the b allele may have higher levels of
circulating parathyroid hormone (PTH)
FIGURE 5-6 [7,9,10,11]. COOH—carboxy terminal;
The vitamin D receptor (VDR). Within its target tissues, calcitriol binds to the VDR. NH2—amino terminal. (From Root [7];
The VDR is a 424 amino acid polypeptide. Its genomic information is encoded on the with permission.)
FIGURE 5-7
VDBP Mechanism of action of 1-25-dihydroxy-vitamin D3 (1,25(OH)2D3).
1,25(OH)2D3 is transported to the target cell bound to the vitamin
VDR-D3 complex D–binding protein (VDBP). The free form of 1,25(OH)2D3 enters the tar-
get cell and interacts with the vitamin D receptor (VDR) at the nucleus.
This complex is phosphorylated and combined with the nuclear accessory
1,25 (OH)2D3 factor (RAF). This forms a heterodimer, which then interacts with the vit-
VDRE amin D responsive element (VDRE). The VDRE then either promotes or
VDR
RAF
inhibits the transcription of messenger RNA (mRNA) for proteins regu-
Pi lated by 1,25(OH)2D3, such as Ca-binding proteins, the 25-hydroxy-vita-
Regulation
min D3 24-hydroxylase enzyme, and parathyroid hormone. Pi—inorganic
mRNA
phosphate. (Adapted from Holick [8].)
transcription
Nucleus
CaBP
24-OHase
PTH
Osteocalcin
Osteopontin
Alkaline phosphatase
Divalent Cation Metabolism: Calcium 5.5
FIGURE 5-8
Parathyroid cell
Metabolism of parathyroid hormone (PTH).
The PTH gene is located on chromosome
Cell membrane 11p15. PTH messenger RNA (mRNA) is
Ca2+ Sensing transcribed from the DNA fragment and
receptor then translated into a 115 amino acid–
DNA containing molecule of prepro-PTH. In the
Ca2+
G-protein VDRE rough endoplasmic reticulum, this under-
VDR
goes hydrolysis to a 90 amino acid–contain-
ing molecule, pro-PTH, which undergoes
Nucleus further hydrolysis to the 84 amino
OH acid–containing PTH molecule. PTH is then
PTH mRNA stored within secretory granules in the cyto-
plasm for release. PTH is metabolized by
hepatic Kupffer cells and renal tubular cells.
Transcription of the PTH gene is inhibited
PTH mRNA by 1,25-dihydroxy-vitamin D3, calcitonin,
HO OH
Degradation and hypercalcemia. PTH gene transcription
1,25 (OH)2D3 is increased by hypocalcemia, glucocorti-
or Calcitriol PTH PTH proPTH preproPTH
coids, and estrogen. Hypercalcemia also can
Secretory
Rough endoplasmic
increase the intracellular degradation of
granules PTH. PTH release is increased by hypocal-
reticulum
Golgi apparatus
cemia, -adrenergic agonists, dopamine,
and prostaglandin E2. Hypomagnesemia
blocks the secretion of PTH [7,12]. VDR—
vitamin D receptor; VDRE—vitamin D
responsive element. (Adapted from Tanaka
and coworkers [12].)
FIGURE 5-9
1 34 84
PTH (mw 9600) N C Parathyroid-hormone–related protein
(PTHrP). PTHrP was initially described as
1 141
PTH-like peptide N C the causative circulating factor in the
(mw 16,000) humoral hypercalcemia of malignancy, par-
ticularly in breast cancer, squamous cell
cancers of the lung, renal cell cancer, and
-2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 other tumors. It is now clear that PTHrP
can be expressed not only in cancer but
PTH LYS ARG SER VAL SER GLU ILE GLN LEU MET HIS ASN LEU GLY LYS
also in many normal tissues. It may play an
PTH-like peptide LYS ARG ALA VAL SER GLU HIS GLN LEU LEU HIS ASP LYS GLY LYS important role in the regulation of smooth
muscle tone, transepithelial Ca transport
(eg, in the mammary gland), and the differ-
entiation of tissue and organ development
[7,13]. Note the high degree of homology
between PTHrP and PTH at the amino end
of the polypeptides. MW—molecular
weight; N—amino terminal; C—carboxy
terminal. (From Root [7]; with permission.)
5.6 Disorders of Water, Electrolytes, and Acid-Base
SP
50
NH2
100
*
X X X
200
HS
X
250
300
X Inactivating
Arg186Gln
400
350
Asp216Glu
Tyr219Glu
450
Glu298Lys
Ser608Stop
Ser658Tyr
550
500
Gly670Arg
Pro749Arg
Arg796Trp
Val818Ile
600
S Stop
* Activating
Glu128Ala
S
X
614 671 684 746 771 829 829
Cell
membrane
636 651 701 726 793 808 863
P
P X
P
P
Cysteline
Conserved
Acidic
P PKC phosphorylation site
N-glycosylation
HOOC
FIGURE 5-10
The calcium-ion sensing receptor (CaSR). The CaSR is a guanosine increases CaSR-Ca binding, which activates the G-protein. The G-
triphosphate (GTP) or G-protein–coupled polypeptide receptor. protein then activates the phospholipase C--1–phosphatidylinosi-
The human CaSR has approximately 1084 amino acid residues. tol-4,5-biphosphate pathway to increase intracellular Ca, which
The CaSR mediates the effects of Ca on parathyroid and renal tis- then decreases translation of parathyroid hormone (PTH), decreas-
sues. CaSR also can be found in thyroidal C cells, brain cells, and es PTH secretion, and increases PTH degradation. The CaSR also
in the gastrointestinal tract. The CaSR allows Ca to act as a first is an integral part of Ca homeostasis within the kidney. The gene
messenger on target tissues and then act by way of other second- for CaSR is located on human chromosome 3q13 [3,4,7,14–16].
messenger systems (eg, phospholipase enzymes and cyclic adeno- PKC—protein kinase C; HS—hydrophobic segment; NH2—amino
sine monophosphate). Within parathyroid cells, hypercalcemia terminal. (From Hebert and Brown [4]; with permission.)
Divalent Cation Metabolism: Calcium 5.7
FIGURE 5-12
Lumen
Proposed pathways for calcium (Ca) absorption across the intestinal
Ca2+ Ca2+ Ca2+ Ca2+ epithelium. Two routes exist for the absorption of Ca across the
1 2 3 4 intestinal epithelium: the paracellular pathway and the transcellular
Microvilli route. The paracellular pathway is passive, and it is the predominant
means of Ca absorption when the luminal concentration of Ca is
high. This is a nonsaturable pathway and can account for one half to
two thirds of total intestinal Ca absorption. The paracellular absorp-
Actin tive route may be indirectly influenced by 1,25-dihydroxy-vitamin D3
Myosin-I (1,25(OH)2D3) because it may be capable of altering the structure of
intercellular tight junctions by way of activation of protein kinase C,
Calmodulin
making the tight junction more permeable to the movement of Ca.
However, 1,25(OH)2D3 primarily controls the active absorption of
Ca. (1) Ca moves down its concentration gradient through a Ca
Ca2+ channel or Ca transporter into the apical section of the microvillae.
Ca2+ Calbindin-Ca2+
complex Because the intestinal concentration of Ca usually is 10-3 mol and the
Free intracellular Ca concentration is 10-6 mol, a large concentration gra-
Ca2+ Calbindin- dient favors the passive movement of Ca. Ca is rapidly and reversibly
Micro- diffusion synthesis
vesicular bound to the calmodulin-actin-myosin I complex. Ca may then move
transport to the basolateral area of the cell by way of microvesicular transport,
Calcitriol or ionized Ca may diffuse to this area of the cell. (2) As the calmod-
ulin complex becomes saturated with Ca, the concentration gradient
Ca2+ Nucleus for the movement of Ca into the microvillae is not as favorable,
which slows Ca absorption. (3) Under the influence of calcitriol,
Exocytosis Ca2+
Na intestinal epithelial cells increase their synthesis of calbindin. (4) Ca
binds to calbindin, thereby unloading the Ca-calmodulin complexes,
~ which then remove Ca from the microvillae region. This decrease in
Na/Ca Ca2+-ATPase Ca concentration again favors the movement of Ca into the microvil-
exchange
Ca2+ Ca2+ lae. As the calbindin-Ca complex dissociates, the free intracellular Ca
Lamina propria is actively extruded from the cell by either the Ca-adenosine triphos-
phatase (ATPase) or Na-Ca exchanger. Calcitriol may also increase
the synthesis of the plasma membrane Ca-ATPase, thereby aiding in
the active extrusion of Ca into the lamina propria [2,7,9,17,18].
5.8 Disorders of Water, Electrolytes, and Acid-Base
Ca2+-ultrafilterable
Proximal
tubule
FIGURE 5-14
Parathyroid hormone Ca2+ ATPase, VDR,
CaBP-D, Na+/Ca2+ exchanger
Renal handling of calcium (Ca). Ca is filtered at the glomerulus,
and 1,25(OH)2D3
colocalized here with the ultrafilterable fraction (UFCa) of plasma Ca entering the
Calcitonin
proximal tubule (PT). Within the proximal convoluted tubule
Thiazides
(PCT) and the proximal straight tubule (PST), isosmotic reabsorp-
CNT tion of Ca occurs such that at the end of the PST the UFCa to TFCa
ratio is about 1.1 and 60% to 70% of the filtered Ca has been
DCT reabsorbed. Passive paracellular pathways account for about 80%
of Ca reabsorption in this segment of the nephron, with the
PCT remaining 20% dependent on active transcellular Ca movement.
Cortex CTAL No reabsorption of Ca occurs within the thin segment of the loop
of Henle. Ca is reabsorbed in small amounts within the medullary
segment of the thick ascending limb (MAL) of the loop of Henle
Medulla MAL and calcitonin (CT) stimulates Ca reabsorption here. However, the
cortical segments (cTAL) reabsorb about 20% of the initially fil-
tered load of Ca. Under normal conditions, most of the Ca reab-
Papilla sorption in the cTAL is passive and paracellular, owing to the
favorable electrochemical gradient. Active transcellular Ca trans-
port can be stimulated by both parathyroid hormone (PTH) and
1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) in the cTAL. In the
early distal convoluted tubule (DCT), thiazide-activated Ca trans-
port occurs. The DCT is the primary site in the nephron at which
Ca reabsorption is regulated by PTH and 1,25(OH)2D3. Active
100 PT DT Urine transcellular Ca transport must account for Ca reabsorption in the
100 DCT, because the transepithelial voltage becomes negative, which
Ca remaining in tubular fluid, %
FIGURE 5-15
Cortical thick ascending limb
Effects of hypercalcemia on calcium (Ca) reabsorption in the
cortical thick ascending limb (cTAL) of the loop of Henle and
+ urinary concentration. (1) Hypercalcemia stimulates the Ca-sensing
5
Ca2+, Mg2+ receptor (CaSR) of cells in the cTAL. (2) Activation of the G-pro-
–
tein increases intracellular free ionized Ca (Ca2+) by way of the
Na +
inositol 1,4,5-trisphosphate (IP3) pathway, which increases the
2Cl– G-protein Ca2+ activity of the P450 enzyme system. The G-protein also increases
+ ↑Ca2+ IP3 activity of phospholipase A2 (PLAA), which increases the concen-
K 2 1
– PK-C tration of arachidonic acid (AA). (3) The P450 enzyme system
PLA2
Urinary 3 CaSR increases production of 20-hydroxy-eicosatetraenoic acid (20-
AA
space P-450 HETE) from AA. (4) 20-HETE inhibits hormone-stimulated pro-
system duction of cyclic adenosine monophosphate (cAMP), blocks sodi-
4
– 20-HETE um reabsorption by the sodium-potassium-chloride (Na-K-2Cl)
– ATP Hormone
recptor cotransporter, and inhibits movement of K out of K-channels. (5)
K+ cAMP These changes alter the electrochemical forces that would normally
5 favor the paracellular movement of Ca (and Mg) such that Ca (and
Ca2+, Mg2+ – Mg) is not passively reabsorbed. Both the lack of movement of Na
+ Hormone into the renal interstitium and inhibition of hormonal (eg, vaso-
pressin) effects impair the ability of the nephron to generate maxi-
mally concentrated urine [3,4,14]. ATP—adenosine triphosphate;
PK-C—protein kinase C.
FIGURE 5-16
DHP sensitive Thiazide sensitive
channel channel Ca2+ Postulated mechanism of the Ca transport pathway shared by PTH
Ca2+ and 1,25(OH)2D3. Cyclic adenosine monophosphate (cAMP) gener-
Tubular lumen
ated by PTH stimulation leads to increased influx of Ca into the
apical dihydropyridine-sensitive Ca channel. There also is increased
+ Distal activity of the basolateral Na-Ca exchanger and, perhaps, of the
Ca2+ Ca2+
convoluted plasma membrane–associated Ca-adenosine triphosphatase
tubule cell (PMCA), which can rapidly extrude the increased intracellular free
Ca (Ca2+). Calcitriol (1,25(OH)2D3), by way of the vitamin D
CaBP28 receptor (VDR), stimulates transcription of calbindin D28k
(CaBP28) and calbindin D9k (CaBP9). CaBP28 increases apical
uptake of Ca by both the dihydropyridine- and thiazide-sensitive Ca
CaBP9 channels by decreasing the concentration of unbound free Ca2+ and
Ca2+ Nucleus facilitates Ca movement to the basolateral membrane. CaBP9 stimu-
cAMP VDR
+ ?+
+ lates PMCA activity, which increases extrusion of Ca by the cell.
ATP Similar hormonally induced mechanisms of Ca transport are
Na+
PTH believed to exist throughout the cortical thick ascending limb, the
~ PMCA DCT, and the connecting tubule (CNT) [6]. ATP—adenosine
Calcitriol
triphosphate; Na+—ionized sodium.
Ca2+ Ca2+
5.10 Disorders of Water, Electrolytes, and Acid-Base
Bone
+
1,25(OH)2D3↑
Normocalcemia
FIGURE 5-18
CAUSES OF HYPOCALCEMIA Causes of hypocalcemia (decrease in ionized plasma calcium).
FIGURE 5-19
Hypercalcemia Thyroid and Physiologic response to hypercalcemia.
parathyroid glands Hypercalcemia directly inhibits both
+ parathyroid hormone (PTH) release
and synthesis. The decrease in PTH and
hypercalcemia decrease the activity of the
C-cells 1--hydroxylase enzyme located in the
– ↑CT
Kidney proximal tubular (PT) cells of the nephron,
which in turn, decreases the synthesis of
– –
+ 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3).
Hypercalcemia stimulates the C cells in the
PTH↑ PTH
Gastrointestinal thyroid gland to increase synthesis of calci-
tract – – tonin (CT). Bone resorption by osteoclasts
Parathyroid cell
PT
DCT Nucleus is blocked by the increased CT and
decreased PTH. Decreased levels of PTH
and 1,25(OH)2D3 inhibit Ca reabsorption
in the distal convoluted tubules (DCT) of
– the nephrons and overwhelm the effects of
– CT, which augment Ca reabsorption in the
medullary thick ascending limb leading to
an increase in renal Ca excretion. The
– Bone decrease in 1,25(OH)2D3 decreases gas-
–
trointestinal (GI) tract absorption of dietary
1,25(OH)2D3↓ Ca. All of these effects tend to return serum
Ca to normal levels [1].
Normocalcemia
FIGURE 5-20
CAUSES OF HYPERCALCEMIA Causes of hypercalcemia (increase in
ionized plasma calcium).
FIGURE 5-21
AVAILABLE THERAPY FOR HYPERCALCEMIA* Therapy available for the treatment of hypercalcemia.
Secondary Hyperparathyroidism
FIGURE 5-22
Renal failure Pathogenesis of secondary hyperparathyroidism (HPT) in chronic
renal failure (CRF). Decreased numbers of proximal tubular (PT)
cells, owing to loss of renal mass, cause a quantitative decrease in
↓Number of nephrons synthesis of 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3). Loss of
renal mass also impairs renal phosphate (P) and acid (H+) excretion.
– These impairments further decrease the activity of the 1--hydroxy-
PT –
lase enzyme in the remaining PT cells, further contributing to the
decrease in levels of 1,25(OH)2D3. 1,25(OH)2D3 deficiency decreas-
es intestinal absorption of calcium (Ca), leading to hypocalcemia,
which is augmented by the direct effect of hyperphosphatemia.
Hypocalcemia and hyperphosphatemia stimulate PTH release and
↓H+ excretion synthesis and can recruit inactive parathyroid cells into activity and
↓P excretion PTH production. Hypocalcemia also may decrease intracellular
degradation of PTH. The lack of 1,25(OH)2D3, which would ordi-
1,25(OH)2D3↓ Hyperphosphatemia narily feed back to inhibit the transcription of prepro-PTH and
exert an antiproliferative effect on parathyroid cells, allows the
↓Ca
absorption Gastrointestinal increased PTH production to continue. In CRF there may be
tract decreased expression of the Ca-sensing receptor (CaSR) in parathy-
roid cells, making them less sensitive to levels of plasma Ca.
Patients with the b allele or the bb genotype vitamin D receptor
(VDR) may be more susceptible to HPT, because the VDR-
1,25(OH)2D3 complex is less effective at suppressing PTH produc-
tion and cell proliferation. The deficiency of 1,25(OH)2D3 may also
decrease VDR synthesis, making parathyroid cells less sensitive to
Hypocalcemia
↓Activity
1,25(OH)2D3. Although the PTH receptor in bone cells is downreg-
↓Activity ulated in CRF (ie, for any level of PTH, bone cell activity is lower in
CRF patients than in normal persons), the increased plasma levels
of PTH may have harmful effects on other systems (eg, cardiovascu-
VDR CaSR lar system, nervous system, and integument) by way of alterations
of intracellular Ca. Current therapeutic methods used to decrease
Increased PTH release in CRF include correction of hyperphosphatemia,
transcription
↓Degradation maintenance of normal to high-normal levels of plasma Ca, admin-
of PTH istration of 1,25(OH)2D3 orally or intravenously, and administra-
Release PTH tion of a Ca-ion sensing receptor (CaSR) agonist [14–16,19–22].
↑PTH
↑Proliferation
ProPTH
Pre-proPTH Nucleus
Hyperparathyroidism
Parathyroid cell
Divalent Cation Metabolism: Calcium 5.13
Data from McCarthy and Kumar [19] and Physicians’ Desk Reference [23].
FIGURE 5-24
Vitamin D preparations.
5.14 Disorders of Water, Electrolytes, and Acid-Base
References
1. Kumar R: Calcium metabolism. In The Principles and Practice of 13. Philbrick WM, Wysolmerski JJ, Galbraith S, et al.: Defining the roles
Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: of parathyroid hormone-related protein in normal physiology. Physiol
Mosby-Year Book; 1995, 964–971. Rev 1996, 76:127–173.
2. Johnson JA, Kumar R: Renal and intestinal calcium transport: roles of 14. Goodman WG, Belin TR, Salusky IB: In vivo> assessments of
vitamin D and vitamin D-dependent calcium binding proteins. Semin calcium-regulated parathyroid hormone release in secondary
Nephrol 1994, 14:119–128. hyperparathyroidism [editorial review]. Kidney Int 1996,
3. Hebert SC, Brown EM, Harris HW: Role of the Ca2+-sensing receptor 50:1834–1844.
in divalent mineral ion homeostasis. J Exp Biol 1997, 200:295–302.
15. Chattopadhyay N, Mithal A, Brown EM: The calcium-sensing
4. Hebert SC, Brown EM: The scent of an ion: calcium-sensing and its roles receptor: a window into the physiology and pathophysiology of
in health and disease. Curr Opinion Nephrol Hypertens 1996, 5:45–53.
mineral ion metabolism. Endocrine Rev 1996, 17:289–307.
5. Berridge MJ: Elementary and global aspects of calcium signalling.
16. Nemeth EF, Steffey ME, Fox J: The parathyroid calcium receptor:
J Exp Biol 1997, 200:315–319.
a novel therapeutic target for treating hyperparathyroidism. Pediatr
6. Friedman PA, Gesek FA: Cellular calcium transport in renal epithelia: Nephrol 1996, 10:275–279.
measurement, mechanisms, and regulation. Physiol Rev 1995,
75:429–471. 17. Wasserman RH, Fullmer CS: Vitamin D and intestinal calcium transport:
7. Root AW: Recent advances in the genetics of disorders of calcium facts, speculations and hypotheses. J Nutr 1995, 125:1971S–1979S.
homeostasis. Adv Pediatr 1996, 43:77–125. 18. Johnson JA, Kumar R: Vitamin D and renal calcium transport. Curr
8. Holick MF: Defects in the synthesis and metabolism of vitamin D. Opinion Nephrol Hypertens 1994, 3:424–429.
Exp Clin Endocrinol 1995, 103:219–227. 19. McCarthy JT, Kumar R: Renal osteodystrophy. In The Principles and
9. Kumar R: Calcium transport in epithelial cells of the intestine and Practice of Nephrology. Edited by Jacobson HR, Striker GE, Klahr S.
kidney. J Cell Biochem 1995, 57:392–398. St. Louis: Mosby-Year Book; 1995, 1032–1045.
10. White CP, Morrison NA, Gardiner EM, Eisman JA: Vitamin D recep- 20. Felsenfeld AJ: Considerations for the treatment of secondary hyper-
tor alleles and bone physiology. J Cell Biochem 1994, 56:307–314. parathyroidism in renal failure. J Am Soc Nephrol 1997, 8:993–1004.
11. Fernandez E, Fibla J, Betriu A, et al.: Association between vitamin D 21. Parfitt AM. The hyperparathyroidism of chronic renal failure: a
receptor gene polymorphism and relative hypoparathyroidism in disorder of growth. Kidney Int 1997, 52:3–9.
patients with chronic renal failure. J Am Soc Nephrol 1997,
8:1546–1552. 22. Salusky IB, Goodman WG: Parathyroid gland function in secondary
hyperparathyroidism. Pediatr Nephrol 1996, 10:359–363.
12. Tanaka Y, Funahashi J, Imai T, et al.: Parathyroid function and bone
metabolic markers in primary and secondary hyperparathyroidism. 23. Physicians’ Desk Reference (PDR). Montvale NJ: Medical Economics
Sem Surg Oncol 1997, 13:125–133. Company; 1996.
Disorders of
Acid-Base Balance
Horacio J. Adrogué
Nicolaos E. Madias
M
aintenance of acid-base homeostasis is a vital function of the
living organism. Deviations of systemic acidity in either
direction can impose adverse consequences and when severe
can threaten life itself. Acid-base disorders frequently are encountered
in the outpatient and especially in the inpatient setting. Effective man-
agement of acid-base disturbances, commonly a challenging task, rests
with accurate diagnosis, sound understanding of the underlying
pathophysiology and impact on organ function, and familiarity with
treatment and attendant complications [1].
Clinical acid-base disorders are conventionally defined from the
vantage point of their impact on the carbonic acid-bicarbonate buffer
system. This approach is justified by the abundance of this buffer pair
in body fluids; its physiologic preeminence; and the validity of the iso-
hydric principle in the living organism, which specifies that all the
other buffer systems are in equilibrium with the carbonic acid-bicar-
bonate buffer pair. Thus, as indicated by the Henderson equation,
-
[H+] = 24 PaCO2/[HCO3] (the equilibrium relationship of the car-
bonic acid-bicarbonate system), the hydrogen ion concentration of
blood ([H+], expressed in nEq/L) at any moment is a function of the
prevailing ratio of the arterial carbon dioxide tension (PaCO2,
expressed in mm Hg) and the plasma bicarbonate concentration
-
([HCO3], expressed in mEq/L). As a corollary, changes in systemic
acidity can occur only through changes in the values of its two deter-
minants, PaCO2 and the plasma bicarbonate concentration. Those
acid-base disorders initiated by a change in PaCO2 are referred to as CHAPTER
respiratory disorders; those initiated by a change in plasma bicarbon-
ate concentration are known as metabolic disorders. There are four
6
cardinal acid-base disturbances: respiratory acidosis, respiratory alka-
losis, metabolic acidosis, and metabolic alkalosis. Each can be
encountered alone, as a simple disorder, or can be a part of a mixed-
disorder, defined as the simultaneous presence of two or more simple
6.2 Disorders of Water, Electrolytes, and Acid-Base
acid-base disturbances. Mixed acid-base disorders are frequent- illustrated: the underlying pathophysiology, secondary
ly observed in hospitalized patients, especially in the critically ill. adjustments in acid-base equilibrium in response to the initi-
The clinical aspects of the four cardinal acid-base ating disturbance, clinical manifestations, causes, and thera-
disorders are depicted. For each disorder the following are peutic principles.
Respiratory Acidosis
FIGURE 6-1
Arterial blood [H+], nEq/L Quantitative aspects of adaptation to respiratory acidosis.
150 125 100 80 70 60 50 40 30 20 Respiratory acidosis, or primary hypercapnia, is the acid-base dis-
turbance initiated by an increase in arterial carbon dioxide tension
PaCO2 120 100 90 80 70 60 50
mm Hg (PaCO2) and entails acidification of body fluids. Hypercapnia elic-
40 its adaptive increments in plasma bicarbonate concentration that
50 should be viewed as an integral part of respiratory acidosis. An
immediate increment in plasma bicarbonate occurs in response to
Chron acidosis
Arterial plasma [HCO–3], mEq/L
Pump Load
Spinal cord
Airway resistance
Phrenic and
intercostal nerves
Effectors Lung elastic recoil
Muscles
of respiration ∆V
∆V
Ppl Chest wall elastic recoil
Pabd Diaphragm
Abdominal
cavity
FIGURE 6-4
Main components of the ventilatory system. The ventilatory system is responsible for maintaining
the arterial carbon dioxide tension (PaCO2) within normal limits by adjusting minute ventilation
•
(V) to match the rate of carbon dioxide production. The main elements of ventilation are the res-
piratory pump, which generates a pressure gradient responsible for air flow, and the loads that
oppose such action. The machinery of the respiratory pump includes the cerebrum, brain stem,
spinal cord, phrenic and intercostal nerves, and the muscles of respiration. Inspiratory muscle con-
traction lowers pleural pressure (Ppl) thereby inflating the lungs (V). The diaphragm, the most
important inspiratory muscle, moves downward as a piston at the floor of the thorax, raising
abdominal pressure (Pabd). The inspiratory decrease in Ppl by the respiratory pump must be suffi-
cient to counterbalance the opposing effect of the combined loads, including the airway flow resis-
tance, and the elastic recoil of the lungs and chest wall. The ventilatory requirement influences the
load by altering the frequency and depth of the ventilatory cycle. The strength of the respiratory
pump is evaluated by the pressure generated (P = Ppl - Pabd).
Disorders of Acid-Base Balance 6.5
FIGURE 6-5
Determinants and causes of carbon dioxide retention. When the res- muscle dysfunction. A higher load can be caused by increased venti-
piratory pump is unable to balance the opposing load, respiratory latory demand, augmented airway flow resistance, and stiffness of
acidosis develops. Decreases in respiratory pump strength, increases the lungs or chest wall. In most cases, causes of the various determi-
in load, or a combination of the two, can result in carbon dioxide nants of carbon dioxide retention, and thus respiratory acidosis, are
retention. Respiratory pump failure can occur because of depressed categorized into acute and chronic subgroups, taking into consider-
central drive, abnormal neuromuscular transmission, or respiratory ation their usual mode of onset and duration [2].
6.6 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 6-6
Spontaneous Mechanical ventilation
breathing Posthypercapnic metabolic alkalosis. Development of posthypercap-
nic metabolic alkalosis is shown after abrupt normalization of the
arterial carbon dioxide tension (PaCO2) by way of mechanical ven-
80
tilation in a 70-year-old man with respiratory decompensation who
PaCO2, mm Hg
Low-Cl– diet
–
Rather, gradual return toward the patient’s baseline PaCO2 level
30 Cl - rich diet should be pursued [1,2]. [H+]—hydrogen ion concentration.
7.60
[H+], nEq/L
7.50 30
pH
7.40 40
7.30 50
7.20 60
0 2 4 6 8
Days
FIGURE 6-7
No Remove dentures, foreign bodies, or food particles; Heimlich maneuver Acute respiratory acidosis management.
Airway patency
secured? (subdiaphragmatic abdominal thrust); tracheal intubation; tracheotomy Securing airway patency and delivering an
oxygen-rich mixture are critical initial steps
ent
Yes
ay pat in management. Subsequent measures must
w • Administer O2 via nasal mask or prongs to maintain
Air PaO2 > 60 mm Hg. be directed at identifying and correcting the
Oxygen-rich mixture • Correct reversible causes of pulmonary dysfunction underlying cause, whenever possible [1,9].
delivered with antibiotics, bronchodilators, and PaCO2—arterial carbon dioxide tension.
corticosteroids as needed.
• Monitor patient with arterial blood gases initially at
Alert, blood pH > 7.10, intervals of 20 to 30 minutes and less frequently
or PaCO2 <60 mm Hg thereafter.
Mental status and
blood gases evaluated • If PaO2 does not increase to > 60 mm Hg or PaCO2
rises to > 60 mm Hg proceed to steps described in
the box below.
FIGURE 6-8
Severe Chronic respiratory acidosis management.
hypercapnic Therapeutic measures are guided by the
encephalopathy No Yes presence or absence of severe hypercapnic
PaO2 > 60 mm Hg Observation, routine care.
or hemodynamic on room air encephalopathy or hemodynamic instability.
instability An aggressive approach that favors the
• Administer O2 via nasal cannula or Venti mask early use of ventilator assistance is most
No • Correct reversible causes of pulmonary appropriate for patients with acute respira-
dysfuntion with antibiotics, bronchodilators,
and corticosteroids as needed.
tory acidosis. In contrast, a more conserva-
tive approach is advisable in patients with
Respiratory Alkalosis
FIGURE 6-9
Arterial blood [H+], nEq/L Adaptation to respiratory alkalosis. Respiratory alkalosis, or
150 125 100 80 70 60 50 40 30 20 primary hypocapnia, is the acid-base disturbance initiated by a
decrease in arterial carbon dioxide tension (PaCO2) and entails
PaCO2 120 100 90 80 70 60 50
mm Hg
alkalinization of body fluids. Hypocapnia elicits adaptive decre-
40 ments in plasma bicarbonate concentration that should be viewed
50 as an integral part of respiratory alkalosis. An immediate decre-
ment in plasma bicarbonate occurs in response to hypocapnia. This
Arterial plasma [HCO–3], mEq/L
alkalo iratory
ro alk
10
ato
FIGURE 6-10
Eucapnia Stable Hypocapnia Renal acidification response to chronic hypocapnia. A, Sustained
Net acid excretion
FIGURE 6-11
SIGNS AND SYMPTOMS OF RESPIRATORY ALKALOSIS Signs and symptoms of respiratory alkalo-
sis. The manifestations of primary hypocap-
nia frequently occur in the acute phase, but
Central Nervous System Cardiovascular System Neuromuscular System seldom are evident in chronic respiratory
alkalosis. Several mechanisms mediate these
Cerebral vasoconstriction Chest oppression Numbness and paresthesias clinical manifestations, including cerebral
Reduction in intracranial pressure Angina pectoris of the extremities hypoperfusion, alkalemia, hypocalcemia,
Light-headedness Ischemic electrocardiographic changes Circumoral numbness hypokalemia, and decreased release of oxy-
Confusion Normal or decreased blood pressure Laryngeal spasm gen to the tissues by hemoglobin. The car-
Increased deep tendon reflexes Cardiac arrhythmias Manifestations of tetany diovascular effects of respiratory alkalosis
Generalized seizures Peripheral vasoconstriction Muscle cramps are more prominent in patients undergoing
Carpopedal spasm mechanical ventilation and those with
Trousseau’s sign ischemic heart disease [2].
Chvostek’s sign
Disorders of Acid-Base Balance 6.9
Central Nervous
Hypoxemia or Tissue Hypoxia System Stimulation Drugs or Hormones Stimulation of Chest Receptors Miscellaneous
Decreased inspired oxygen tension Voluntary Nikethamide, ethamivan Pneumonia Pregnancy
High altitude Pain Doxapram Asthma Gram-positive septicemia
Bacterial or viral pneumonia Anxiety syndrome- Xanthines Pneumothorax Gram-negative septicemia
Aspiration of food, foreign object, hyperventilation syndrome Salicylates Hemothorax Hepatic failure
or vomitus Psychosis Catecholamines Flail chest Mechanical hyperventilation
Laryngospasm Fever Angiotensin II Acute respiratory distress syndrome Heat exposure
Drowning Subarachnoid hemorrhage Vasopressor agents Cardiogenic and noncardiogenic Recovery from metabolic acidosis
Cyanotic heart disease Cerebrovascular accident Progesterone pulmonary edema
Severe anemia Meningoencephalitis Medroxyprogesterone Pulmonary embolism
Left shift deviation of Tumor Dinitrophenol Pulmonary fibrosis
oxyhemoglobin curve Trauma Nicotine
Hypotension
Severe circulatory failure
Pulmonary edema
FIGURE 6-12
Respiratory alkalosis is the most frequent acid-base disorder to permit full chronic adaptation to occur. Consequently, no
encountered because it occurs in normal pregnancy and high- attempt has been made to separate these conditions into acute
altitude residence. Pathologic causes of respiratory alkalosis and chronic categories. Some of the major causes of respiratory
include various hypoxemic conditions, pulmonary disorders, cen- alkalosis are benign, whereas others are life-threatening. Primary
tral nervous system diseases, pharmacologic or hormonal stimu- hypocapnia is particularly common among the critically ill,
lation of ventilation, hepatic failure, sepsis, the anxiety-hyper- occurring either as the simple disorder or as a component of
ventilation syndrome, and other entities. Most of these causes mixed disturbances. Its presence constitutes an ominous prog-
are associated with the abrupt occurrence of hypocapnia; howev- nostic sign, with mortality increasing in direct proportion to the
er, in many instances, the process might be sufficiently prolonged severity of the hypocapnia [2].
FIGURE 6-13
Respiratory alkalosis Respiratory alkalosis management. Because chronic respiratory alka-
losis poses a low risk to health and produces few or no symptoms,
measures for treating the acid-base disorder itself are not required. In
Acute Chronic contrast, severe alkalemia caused by acute primary hypocapnia
requires corrective measures that depend on whether serious clinical
No manifestations are present. Such measures can be directed at reducing
Manage underlying disorder. -
Blood pH ≥ 7.55 plasma bicarbonate concentration ([HCO3]), increasing the arterial
No specific measures indicated.
carbon dioxide tension (PaCO2), or both. Even if the baseline plasma
Yes bicarbonate is moderately decreased, reducing it further can be partic-
ularly rewarding in this setting. In addition, this maneuver combines
Hemodynamic instability, No • Consider having patient rebreathe effectiveness with relatively little risk [1,2].
altered mental status, into a closed system.
or cardiac arrhythmias • Manage underlying disorder.
Yes
FIGURE 6-14
Lungs Pseudorespiratory alkalosis. This entity
develops in patients with profound depres-
sion of cardiac function and pulmonary
perfusion but relative preservation of alveo-
Normal lar ventilation. Patients include those with
advanced circulatory failure and those
undergoing cardiopulmonary resuscitation.
The severely reduced pulmonary blood flow
limits the amount of carbon dioxide deliv-
pH 7.40
LV RV
pH 7.38 ered to the lungs for excretion, thereby
PCO2 40 PCO2 46 increasing the venous carbon dioxide ten-
– –
[HCO3 ] 24 [HCO3 ] 26 sion (PCO2). In contrast, the increased ven-
PO2 95 PO2 40
FiO2 0.21 tilation-to-perfusion ratio causes a larger
Peripheral tissues than normal removal of carbon dioxide per
unit of blood traversing the pulmonary cir-
culation, thereby giving rise to arterial
hypocapnia [12,13]. Note a progressive
Arterial Venous widening of the arteriovenous difference in
compartment compartment
pH and PCO2 in the two settings of cardiac
dysfunction. The hypobicarbonatemia in
the setting of cardiac arrest represents a
Circulatory Failure
complicating element of lactic acidosis.
Despite the presence of arterial hypocapnia,
pseudorespiratory alkalosis represents a
special case of respiratory acidosis, as
pH 7.42 pH 7.29 absolute carbon dioxide excretion is
PCO2 35 LV RV PCO2 60 decreased and body carbon dioxide balance
– –
[HCO3 ] 22 [HCO3 ] 28
is positive. Furthermore, the extreme oxy-
PO2 80 PO2 30
FiO2 0.35 gen deprivation prevailing in the tissues
might be completely disguised by the rea-
sonably preserved arterial oxygen values.
Appropriate monitoring of acid-base com-
position and oxygenation in patients with
advanced cardiac dysfunction requires
mixed (or central) venous blood sampling
in addition to arterial blood sampling.
Management of pseudorespiratory alkalosis
Cardiac Arrest must be directed at optimizing systemic
hemodynamics [1,13].
pH 7.37 pH 7.00
PCO2 27 LV RV PCO2 75
[HCO3– ] 15 [HCO–3 ] 18
PO2 116 PO2 17
FiO2 1.00
Disorders of Acid-Base Balance 6.11
Metabolic Acidosis
FIGURE 6-15
Arterial blood [H+], nEq/L
Ninety-five percent confidence intervals for metabolic acidosis.
150 125 100 80 70 60 50 40 30 20 Metabolic acidosis is the acid-base disturbance initiated by a
-
PaCO2 120 100 90 80 70 60 50 decrease in plasma bicarbonate concentration ([HCO3]). The resul-
mm Hg tant acidemia stimulates alveolar ventilation and leads to the sec-
40 ondary hypocapnia characteristic of the disorder. Extensive obser-
50
vations in humans encompassing a wide range of stable metabolic
acidosis indicate a roughly linear relationship between the steady-
Arterial plasma [HCO–3], mEq/L
color in the acid-base template. The black ellipse near the center of
ac tab
e
M
10 the figure indicates the normal range for the acid-base parameters
10 [3]. Assuming a steady state is present, values falling within the
area in color are consistent with but not diagnostic of simple meta-
bolic acidosis. Acid-base values falling outside the area in color
denote the presence of a mixed acid-base disturbance [4]. [H+]—
6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 hydrogen ion concentration.
Arterial blood pH
FIGURE 6-16
SIGNS AND SYMPTOMS OF METABOLIC ACIDOSIS Signs and symptoms of metabolic acidosis.
Among the various clinical manifestations,
particularly pernicious are the effects of
Respiratory Central severe acidemia (blood pH < 7.20) on the car-
System Cardiovascular System Metabolism Nervous System Skeleton diovascular system. Reductions in cardiac
output, arterial blood pressure, and hepatic
Hyperventilation Impairment of cardiac Increased Impaired metabolism Osteomalacia and renal blood flow can occur and life-
Respiratory distress contractility, arteriolar metabolic demands Inhibition of cell Fractures threatening arrhythmias can develop. Chronic
and dyspnea dilation, venoconstriction, Insulin resistance volume regulation
and centralization of
acidemia, as it occurs in untreated renal tubu-
Decreased strength Inhibition of Progressive obtundation lar acidosis and uremic acidosis, can cause
of respiratory blood volume anaerobic glycolysis Coma calcium dissolution from the bone mineral
muscles and Reductions in cardiac Reduction in adenosine
promotion of output, arterial blood and consequent skeletal abnormalities.
triphosphate synthesis
muscle fatigue pressure, and hepatic
Hyperkalemia
and renal blood flow
Increased
Sensitization to reentrant
protein degradation
arrhythmias and reduction
in threshold for ventricular
fibrillation
Increased sympathetic
discharge but attenuation of
cardiovascular responsiveness
to catecholamines
6.12 Disorders of Water, Electrolytes, and Acid-Base
Lactic acidosis
duce lactate during the course of glycolysis, those listed contribute
Glucose substantial quantities of lactate to the extracellular fluid under nor-
mal aerobic conditions. In turn, lactate is extracted by the liver and
Gluconeogenesis to a lesser degree by the renal cortex and primarily is reconverted to
glucose by way of gluconeogenesis (a smaller portion of lactate is
oxidized to carbon dioxide and water). This cyclical relationship
Cori between glucose and lactate is known as the Cori cycle. The basal
cycle turnover rate of lactate in humans is enormous, on the order of 15
to 25 mEq/kg/d. Precise equivalence between lactate production and
its use ensures the stability of plasma lactate concentration, normally
Muscle Brain Skin RBC Liver Kidney cortex ranging from 1 to 2 mEq/L. Hydrogen ions (H+) released during lac-
tate generation are quantitatively consumed during the use of lactate
Anaerobic glycolysis
H+ + Lactate such that acid-base balance remains undisturbed. Accumulation of
lactate in the circulation, and consequent lactic acidosis, is generated
Overproduction Lactic acidosis Underutilization whenever the rate of production of lactate is higher than the rate of
utilization. The pathogenesis of this imbalance reflects overproduc-
tion of lactate, underutilization, or both. Most cases of persistent lac-
tic acidosis actually involve both overproduction and underutiliza-
FIGURE 6-18 tion of lactate. During hypoxia, almost all tissues can release lactate
Lactate-producing and lactate-consuming tissues under basal condi- into the circulation; indeed, even the liver can be converted from the
tions and pathogenesis of lactic acidosis. Although all tissues pro- premier consumer of lactate to a net producer [1,14].
Disorders of Acid-Base Balance 6.13
Glycolysis
tion. Increased production of pyruvate occurs because the reduced
NAD+
cytosolic supply of ATP stimulates the activity of 6-phosphofruc-
tokinase (PFK), thereby accelerating glycolysis. Decreased utiliza-
tion of pyruvate reflects the fact that both pathways of its con-
NADH
sumption depend on mitochondrial oxidative reactions: oxidative
Pyruvate LDH decarboxylation to acetyl coenzyme A (acetyl-CoA), a reaction cat-
Lactate
Gluconeogenesis + alyzed by pyruvate dehydrogenase (PDH), requires a continuous
high NADH
NAD+ Cytosol supply of NAD+; and carboxylation of pyruvate to oxaloacetate, a
Mitochondrial membrane reaction catalyzed by pyruvate carboxylase (PC), requires ATP. The
increased [NADH]/[NAD+] ratio (NADH refers to the reduced
Mitochondria
form of the dinucleotide) shifts the equilibrium of the lactate dehy-
PD – high NADH+ drogenase (LDH) reaction (that catalyzes the interconversion of
low ATP – H NAD
PC
ADP NAD+ pyruvate and lactate) to the right. In turn, this change coupled with
Acetyl-CoA
NADH the accumulation of pyruvate in the cytosol results in increased
Oxaloacetate TCA – accumulation of lactate. Despite the prevailing mitochondrial dys-
cycle function, continuation of glycolysis is assured by the cytosolic
regeneration of NAD+ during the conversion of pyruvate to lactate.
Provision of NAD+ is required for the oxidation of glyceraldehyde
FIGURE 6-19 3-phosphate, a key step in glycolysis. Thus, lactate accumulation
Hypoxia-induced lactic acidosis. Accumulation of lactate during can be viewed as the toll paid by the organism to maintain energy
hypoxia, by far the most common clinical setting of the disorder, production during anaerobiosis (hypoxia) [14]. ADP—adenosine
originates from impaired mitochondrial oxidative function that diphosphate; TCA cycle—tricarboxylic acid cycle.
FIGURE 6-20
CAUSES OF LACTIC ACIDOSIS Conventionally, two broad types of lactic
acidosis are recognized. In type A, clinical
evidence exists of impaired tissue oxygena-
Type A: tion. In type B, no such evidence is apparent.
Impaired Tissue Oxygenation Type B: Preserved Tissue Oxygenation Occasionally, the distinction between the
two types may be less than obvious. Thus,
Shock Diseases and conditions Drugs and toxins inadequate tissue oxygenation can at times
Severe hypoxemia Diabetes mellitus Epinephrine, defy clinical detection, and tissue hypoxia
Generalized convulsions Hypoglycemia norepinephrine, can be a part of the pathogenesis of certain
Vigorous exercise Renal failure vasoconstrictor agents
causes of type B lactic acidosis. Most cases
Salicylates
Exertional heat stroke Hepatic failure of lactic acidosis are caused by tissue hypox-
Hypothermic shivering Severe infections Ethanol ia arising from circulatory failure [14,15].
Massive pulmonary emboli Alkaloses Methanol
Severe heart failure Malignancies (lymphoma, Ethylene glycol
Profound anemia leukemia, sarcoma) Biguanides
Mesenteric ischemia Thiamine deficiency Acetaminophen
Carbon monoxide poisoning Acquired Zidovudine
Cyanide poisoning immunodeficiency syndrome Fructose, sorbitol,
Pheochromocytoma and xylitol
Iron deficiency Streptozotocin
D-Lactic acidosis Isoniazid
Nitroprusside
Congenital enzymatic defects
Papaverine
Nalidixic acid
6.14 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 6-21
• Antibiotics (sepsis) Lactic acidosis management. Management
• Dialysis (toxins) of lactic acidosis should focus primarily on
• Discontinuation of incriminated securing adequate tissue oxygenation and on
drugs
No • Insulin (diabetes) aggressively identifying and treating the
Inadequate tissue Cause-specific measures underlying cause or predisposing condition.
oxygenation? • Glucose (hypoglycemia, alcoholism)
• Operative intervention (trauma, Monitoring of the patient’s hemodynamics,
tissue ischemia) oxygenation, and acid-base status should be
Yes
No • Thiamine (thiamine deficiency) used to guide therapy. In the presence of
• Low carbohydrate diet and
Oxygen-rich mixture antibiotics (D-lactic acidosis) severe or worsening metabolic acidemia,
and ventilator support, Circulatory failure? these measures should be supplemented by
if needed judicious administration of sodium bicar-
Yes
bonate, given as an infusion rather than a
bolus. Alkali administration should be
regarded as a temporizing maneuver adjunc-
• Volume repletion tive to cause-specific measures. Given the
• Preload and afterload
No • Continue therapy ominous prognosis of lactic acidosis, clini-
reducing agents Severe/Worsening
• Myocardial stimulants • Manage predisposing cians should strive to prevent its develop-
metabolic acidemia?
(dobutamine, dopamine) conditions ment by maintaining adequate fluid balance,
• Avoid vasoconstrictors optimizing cardiorespiratory function, man-
Yes aging infection, and using drugs that predis-
pose to the disorder cautiously. Preventing
Alkali administration to the development of lactic acidosis is all the
maintain blood pH ≥ 7.20
more important in patients at special risk
for developing it, such as those with dia-
betes mellitus or advanced cardiac, respira-
tory, renal, or hepatic disease [1,14–16].
FIGURE 6-23
Insulin deficiency/resistance
Clinical features of diabetic ketoacidosis (DKA) and nonketotic
Severe Mild
hyperglycemia (NKH). DKA and NKH are the most important
acute metabolic complications of patients with uncontrolled dia-
betes mellitus. These disorders share the same overall pathogene-
Pure DKA Pure NKH sis that includes insulin deficiency and resistance and excessive
Mixed forms
profound DKA + NKH profound counterregulation; however, the importance of each of these
ketosis hyperglycemia endocrine abnormalities differs significantly in DKA and NKH.
As depicted here, pure NKH is characterized by profound hyper-
glycemia, the result of mild insulin deficiency and severe coun-
Mild Severe terregulation (eg, high glucagon levels). In contrast, pure DKA is
Excessive counterregulation characterized by profound ketosis that largely is due to severe
insulin deficiency, with counterregulation being generally of less-
Feature Pure DKA Mixed forms Pure NKH er importance. These pure forms define a continuum that
includes mixed forms incorporating clinical and biochemical fea-
Incidence 5–10 times higher 5–10 times lower
Mortality 5–10% 10–60%
tures of both DKA and NKH. Dyspnea and Kussmaul’s respira-
Onset Rapid (<2 days) Slow (> 5 days) tion result from the metabolic acidosis of DKA, which is general-
Age of patient Usually < 40 years Usually > 40 years ly absent in NKH. Sodium and water deficits and secondary
Type I diabetes Common Rare renal dysfunction are more severe in NKH than in DKA. These
Type II diabetes Rare Common deficits also play a pathogenetic role in the profound hypertonic-
First indication of diabetes Often Often ity characteristic of NKH. The severe hyperglycemia of NKH,
Volume depletion Mild/moderate Severe
often coupled with hypernatremia, increases serum osmolality,
Renal failure (most com- Mild, inconstant Always present
monly of prerenal nature)
thereby causing the characteristic functional abnormalities of the
Severe neurologic Rare Frequent central nervous system. Depression of the sensorium, somno-
abnormalities (coma in 25–50%) lence, obtundation, and coma, are prominent manifestations of
Subsequent therapy with Always Not always NKH. The degree of obtundation correlates with the severity of
insulin serum hypertonicity [17].
Glucose < 800 mg/dL > 800 mg/dL
Ketone bodies ≥ 2 + in 1:1 dilution < 2+ in 1:1 dilution
Effective osmolality < 340 mOsm/kg > 340 mOsm/kg
pH Decreased Normal
[HCO–3] Decreased Normal
[Na+] Normal or low Normal or high
[K+] Variable Variable
CO2—carbon dioxide; IV—intravenous; K+—potassium ion; NaCl—sodium chloride; NaHCO3—sodium bicarbonate; SQ—subcutaneous.
FIGURE 6-24
Diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH) NKH, in which ketoacidosis is generally absent. Because the fluid
management. Administration of insulin is the cornerstone of manage- deficit is generally severe in patients with NKH, many of whom have
ment for both DKA and NKH. Replacement of the prevailing water, preexisting heart disease and are relatively old, safe fluid replacement
sodium, and potassium deficits is also required. Alkali are adminis- may require monitoring of central venous pressure, pulmonary capil-
tered only under certain circumstances in DKA and virtually never in lary wedge pressure, or both [1,17,18].
6.16 Disorders of Water, Electrolytes, and Acid-Base
-
Tm HCO3—maximum reabsorption of bicarbonate; U-B PCO2—difference between partial pressure of carbon
dioxide values in urine and arterial blood.
*This syndrome signifies generalized proximal tubule dysfunction and is characterized by impaired reabsorption of
glucose, amino acids, phosphate, and urate.
Disorders of Acid-Base Balance 6.17
B. CAUSES OF HYPERKALEMIC
Lumen Principal cell Blood DISTAL RENAL TUBULAR ACIDOSIS
Na+
FIGURE 6-28
A and B, Potential defects and causes of hyperkalemic distal renal hyporeninemia, impaired conversion of angiotensin I to angiotensin
tubular acidosis (RTA) (type 4). This syndrome represents the most II, or abnormal aldosterone synthesis. Aldosterone resistance can
common type of RTA encountered in adults. The characteristic reflect the following: blockade of the mineralocorticoid receptor;
hyperchloremic metabolic acidosis in the company of hyperkalemia destruction of the target cells in the collecting tubule (tubulointer-
emerges as a consequence of generalized dysfunction of the collect- stitial nephropathies); interference with the sodium channel of the
ing tubule, including diminished sodium reabsorption and impaired principal cell, thereby decreasing the lumen-negative potential dif-
hydrogen ion and potassium secretion. The resultant hyperkalemia ference and thus the secretion of potassium and hydrogen ions
causes impaired ammonium excretion that is an important contri- (voltage-mediated defect); inhibition of the basolateral sodium ion,
bution to the generation of the metabolic acidosis. The causes of potassium ion–adenosine triphosphatase; and enhanced chloride
this syndrome are broadly classified into disorders resulting in ion permeability in the collecting tubule, with consequent shunting
aldosterone deficiency and those that impose resistance to the of the transepithelial potential difference. Some disorders cause
action of aldosterone. Aldosterone deficiency can arise from combined aldosterone deficiency and resistance [20].
6.20 Disorders of Water, Electrolytes, and Acid-Base
FIGURE 6-29
Management of acute metabolic acidosis Treatment of acute metabolic acidosis. Whenever possible, cause-
specific measures should be at the center of treatment of metabolic
acidosis. In the presence of severe acidemia, such measures should
be supplemented by judicious administration of sodium bicarbon-
Alkali therapy for severe ate. The goal of alkali therapy is to return the blood pH to a safer
Cause-specific measures level of about 7.20. Anticipated benefits and potential risks of
acidemia (blood pH<7.20)
alkali therapy are depicted here [1].
Benefits Risks
• Prevents or reverses acidemia- • Hypernatremia/
related hemodynamic compromise. hyperosmolality
• Reinstates cardiovascular • Volume overload
responsiveness to catecholamines. • "Overshoot" alkalosis
• "Buys time," thus allowing cause- • Hypokalemia
specific measures and endogenous • Decreased plasma ionized
reparatory processes to take effect. calcium concentration
• Provides a measure of safety against • Stimulation of organic
additional acidifying stresses. acid production
• Hypercapnia
Metabolic Alkalosis
Arterial blood [H+], nEq/L
FIGURE 6-30
Ninety-five percent confidence intervals for metabolic alkalosis.
150 125 100 80 70 60 50 40 30 20
Metabolic alkalosis is the acid-base disturbance initiated by an
-
PaCO2 120 100 90 80 70 60 50 increase in plasma bicarbonate concentration ([HCO3]). The
mm Hg resultant alkalemia dampens alveolar ventilation and leads to the
40
50 secondary hypercapnia characteristic of the disorder. Available
observations in humans suggest a roughly linear relationship
between the steady-state increase in bicarbonate concentration
Arterial plasma [HCO–3], mEq/L
FIGURE 6-31
Milk alkali syndrome
Excess alkali Pathogenesis of metabolic alkalosis. Two
Alkali gain Calcium supplements
Enteral crucial questions must be answered when
Absorbable alkali
evaluating the pathogenesis of a case of
Nonabsorbable alkali plus K+
exchange resins metabolic alkalosis. 1) What is the source
of the excess alkali? Answering this ques-
Ringer's solution
Source? Bicarbonate
tion addresses the primary event responsible
Parenteral Blood products for generating the hyperbicarbonatemia. 2)
Nutrition What factors perpetuate the hyperbicarbon-
Dialysis atemia? Answering this question addresses
the pathophysiologic events that maintain
Vomiting the metabolic alkalosis.
Gastric
H+ loss Suction
Villous adenoma
Intestinal
Congenital chloridorrhea
Chloruretic diuretics
Renal Inherited transport defects
Mineralocorticoid excess
Posthypercapnia
H+ shift
K+ depletion
Reduced GFR
Mode of perpetuation?
Increased
renal acidification Cl– responsive defect
Cl– resistant defect
FIGURE 6-32
Baseline Vomiting Maintenance Correction Changes in plasma anionic pattern and body electrolyte balance
Low NaCl and KCl intake High NaCl and KCl intake
45 during development, maintenance, and correction of metabolic
alkalosis induced by vomiting. Loss of hydrochloric acid from the
40
stomach as a result of vomiting (or gastric drainage) generates the
[HCO3– ],
mEq/L
100
and potassium chloride (KCl) in the correction phase repairs the
95 electrolyte deficits incurred and normalizes the plasma bicarbonate
and chloride concentration ([Cl-]) levels [22,23].
0
–200
Cl–
–400
Cumulative balance, mEq
0
Na+
–100
–200
K+
–400
–2 0 2 4 6 8 10 12 14 16 18
Days
6.22 Disorders of Water, Electrolytes, and Acid-Base
7.0 40
[HCO3– ],
mEq/L
6.0 35
5.0 30
25
Urine HCO–3 excretion,
75
105
50
mEq/d
mEq/L
[Cl– ],
100
25
95
0
125
excretion, mEq/d
Urine net acid
100 100
75 75
Urine net acid excretion,
50 50
mEq/d
25
0 0
–200
Cl–
–25
–50 –400
Cumulative balance, mEq
–2 0 2 4 6 8 10 12 14 16 18 0
Na+
Days –100
FIGURE 6-33 0
K+
Cl–
P-cell +
+ K
Na+ K
Na
K
+
↑Na+ reabsorption and consequent ↑H+ and K+ secretion
Na+
Cl–
H+, NH+4
Na+
–
↓GFR K+ Cl
α-cell
HCO3
NH4
+ H+ Cl ↑H+ secretion ↑H+ secretion coupled to K+ reabsorption
↑HCO3 reabsorption
–
K+ + H+
H K+
+ +
NH4 , K Na+ Cl–
Na+ HCO–3 ß-cell
2Cl– + H+
K Cl– Cl
NH4+ Cl HCO3– secretion
↑NH4+ synthesis and HCO3
luminal entry
NH3 NH3
H 2O NH3
NH3
↑NH4+ entry in medulla and secretion
in medullary collecting duct
NH4+
FIGURE 6-35
Maintenance of chloride-responsive metabolic alkalosis. each of these factors is a vexing task. Notwithstanding, here
Increased renal bicarbonate reabsorption frequently coupled depicted is our current understanding of the participation of
with a reduced glomerular filtration rate are the basic mecha- each of these factors in the nephronal processes that maintain
nisms that maintain chloride-responsive metabolic alkalosis. chloride-responsive metabolic alkalosis [22–24]. In addition to
These mechanisms have been ascribed to three mediating fac- these factors, the secondary hypercapnia of metabolic alkalosis
tors: chloride depletion itself, extracellular fluid (ECF) volume contributes importantly to the maintenance of the prevailing
depletion, and potassium depletion. Assigning particular roles to hyperbicarbonatemia [25].
6.24 Disorders of Water, Electrolytes, and Acid-Base
Cl–
P-cell +
K
Na+ Na
K ↑Na+ reabsorption and consequent ↑H+ and K+ secretion
Na+
Cl–
H+, NH+4
Na+
K+ Cl
α-cell
HCO–3
NH+4 H +
Cl– ↑H+ secretion coupled to K+ reabsorption ↑H+ secretion
↑HCO3 reabsorption
–
K+ + H+
H K+
+
NH+4, K Na+ Cl–
Na+ HCO–3 ß-cell
2Cl– H+
+
K Cl– Cl–
NH+4 –Cl
–
↑NH4+ synthesis and HCO 3
luminal entry
NH3 NH3
H 2O NH3
NH3
↑NH4+entry in medulla and secretion
in medullary collecting duct
NH+4
FIGURE 6-36
Maintenance of chloride-resistant metabolic alkalosis. Increased ened bicarbonate reabsorption and include mineralocorticoid
renal bicarbonate reabsorption is the sole basic mechanism that excess and potassium depletion. The participation of these factors
maintains chloride-resistant metabolic alkalosis. As its name in the nephronal processes that maintain chloride-resistant meta-
implies, factors independent of chloride intake mediate the height- bolic alkalosis is depicted [22–24, 26].
FIGURE 6-37
Virtually absent
(< 10 mEq/L)
Urinary composition in the diagnostic evaluation of metabolic alka-
Urinary [Cl–] • Vomiting, gastric suction losis. Assessing the urinary composition can be an important aid in
• Postdiuretic phase of loop the diagnostic evaluation of metabolic alkalosis. Measurement of uri-
and distal agents
• Posthypercapnic state nary chloride ion concentration ([Cl-]) can help distinguish between
Abundant chloride-responsive and chloride-resistant metabolic alkalosis. The
• Villous adenoma of the colon
(> 20 mEq/L)
• Congenital chloridorrhea virtual absence of chloride (urine [Cl-] < 10 mEq/L) indicates signifi-
• Post alkali loading cant chloride depletion. Note, however, that this test loses its diag-
nostic significance if performed within several hours of administra-
Urinary [K+]
tion of chloruretic diuretics, because these agents promote urinary
chloride excretion. Measurement of urinary potassium ion concen-
Low (< 20 mEq/L) • Laxative abuse tration ([K+]) provides further diagnostic differentiation. With the
• Other causes of profound K+ depletion
exception of the diuretic phase of chloruretic agents, abundance of
Abundant both urinary chloride and potassium signifies a state of mineralocor-
(> 30 mEq/L) • Diuretic phase of loop and distal agents ticoid excess [22].
• Bartter's and Gitelman's syndromes
• Primary aldosteronism
• Cushing's syndrome
• Exogenous mineralocorticoid agents
• Secondary aldosteronism
malignant hypertension
renovascular hypertension
primary reninism
• Liddle's syndrome
Disorders of Acid-Base Balance 6.25
FIGURE 6-38
Signs and symptoms of metabolic alkalosis. Mild to moderate these clinical manifestations. The arrhythmogenic potential of alka-
metabolic alkalosis usually is accompanied by few if any symp- lemia is more pronounced in patients with underlying heart disease
toms, unless potassium depletion is substantial. In contrast, severe and is heightened by the almost constant presence of hypokalemia,
-
metabolic alkalosis ([HCO3] > 40 mEq/L) is usually a symptomatic especially in those patients taking digitalis. Even mild alkalemia
disorder. Alkalemia, hypokalemia, hypoxemia, hypercapnia, and can frustrate efforts to wean patients from mechanical ventilation
decreased plasma ionized calcium concentration all contribute to [23,24].
FIGURE 6-41
Management of Metabolic alkalosis management. Effective
For alkali gain
metabolic alkalosis Discontinue administrationof management of metabolic alkalosis requires
bicarbonate or its precursors. sound understanding of the underlying
via gastric route pathophysiology. Therapeutic efforts should
Administer antiemetics;
discontinue gastric suction; focus on eliminating or moderating the
For H+ loss administer H2 blockers or processes that generate the alkali excess and
Eliminate source H+-K+ ATPase inhibitors. on interrupting the mechanisms that perpet-
of excess alkali via renal route
Discontinue or decrease loop uate the hyperbicarbonatemia. Rarely, when
and distal diuretics; substitute the pace of correction of metabolic alkalo-
with amiloride, triamterene, or
spironolactone; discontinue
sis must be accelerated, acetazolamide or an
or limit drugs with mineralo- infusion of hydrochloric acid can be used.
For H+ shift corticoid activity. Treatment of severe metabolic alkalosis can
Potassium repletion be particularly challenging in patients with
For decreased GFR advanced cardiac or renal dysfunction. In
ECF volume repletion; such patients, hemodialysis or continuous
renal replacement therapy hemofiltration might be required [1].
For Cl– responsive
Interrupt perpetuating acidification defect
Administer NaCl and KCl
mechanisms
References
1. Adrogué HJ, Madias NE: Management of life-threatening acid-base 12. Adrogué HJ, Rashad MN, Gorin AB, et al.: Arteriovenous acid-base
disorders. N Engl J Med, 1998, 338:26–34, 107–111. disparity in circulatory failure: studies on mechanism. Am J Physiol
2. Madias NE, Adrogué HJ: Acid-base disturbances in pulmonary medi- 1989, 257:F1087–F1093.
cine. In Fluid, Electrolyte, and Acid-Base Disorders. Edited by Arieff 13. Adrogué HJ, Rashad MN, Gorin AB, et al.: Assessing acid-base status
Al, DeFronzo RA. New York: Churchill Livingstone; 1995:223–253. in circulatory failure: differences between arterial and central venous
3. Madias NE, Adrogué HJ, Horowitz GL, et al.: A redefinition of nor- blood. N Engl J Med 1989, 320:1312–1316.
mal acid-base equilibrium in man: carbon dioxide tension as a key 14. Madias NE: Lactic acidosis. Kidney Int 1986, 29:752–774.
determinant of plasma bicarbonate concentration. Kidney Int 1979, 15. Kraut JA, Madias NE: Lactic acidosis. In Textbook of Nephrology.
16:612–618. Edited by Massry SG, Glassock RJ. Baltimore: Williams and Wilkins;
4. Adrogué HJ, Madias NE: Mixed acid-base disorders. In The 1995:449–457.
Principles and Practice of Nephrology. Edited by Jacobson HR, 16. Hindman BJ: Sodium bicarbonate in the treatment of subtypes of
Striker GE, Klahr S. St. Louis: Mosby-Year Book; 1995:953–962. acute lactic acidosis: physiologic considerations. Anesthesiology 1990,
5. Krapf R: Mechanisms of adaptation to chronic respiratory acidosis in 72:1064–1076.
the rabbit proximal tubule. J Clin Invest 1989, 83:890–896. 17. AdroguÈ HJ: Diabetic ketoacidosis and hyperosmolar nonketotic syn-
6. Al-Awqati Q: The cellular renal response to respiratory acid-base dis- drome. In Therapy of Renal Diseases and Related Disorders. Edited
orders. Kidney Int 1985, 28:845–855. by Suki WN, Massry SG. Boston: Kluwer Academic Publishers;
7. Bastani B: Immunocytochemical localization of the vacuolar H+- 1997:233–251.
ATPase pump in the kidney. Histol Histopathol 1997, 12:769–779. 18. Adrogué HJ, Barrero J, Eknoyan G: Salutary effects of modest fluid
8. Teixeira da Silva JC Jr, Perrone RD, Johns CA, Madias NE: Rat kid- replacement in the treatment of adults with diabetic ketoacidosis.
ney band 3 mRNA modulation in chronic respiratory acidosis. Am J JAMA 1989, 262:2108–2113.
Physiol 1991, 260:F204–F209. 19. Bastani B, Gluck SL: New insights into the pathogenesis of distal
9. Respiratory pump failure: primary hypercapnia (respiratory acidosis). renal tubular acidosis. Miner Electrolyte Metab 1996, 22:396–409.
In Respiratory Failure. Edited by Adrogué HJ, Tobin MJ. Cambridge, 20. DuBose TD Jr: Hyperkalemic hyperchloremic metabolic acidosis:
MA: Blackwell Science; 1997:125–134. pathophysiologic insights. Kidney Int 1997, 51:591–602.
10. Krapf R, Beeler I, Hertner D, Hulter HN: Chronic respiratory alkalo- 21. Madias NE, Bossert WH, Adrogué HJ: Ventilatory response to chron-
sis: the effect of sustained hyperventilation on renal regulation of acid- ic metabolic acidosis and alkalosis in the dog. J Appl Physiol 1984,
base equilibrium. N Engl J Med 1991, 324:1394–1401. 56:1640–1646.
11. Hilden SA, Johns CA, Madias NE: Adaptation of rabbit renal cortical 22. Gennari FJ: Metabolic alkalosis. In The Principles and Practice of
Na+-H+-exchange activity in chronic hypocapnia. Am J Physiol 1989, Nephrology. Edited by Jacobson HR, Striker GE, Klahr S. St Louis:
257:F615–F622. Mosby-Year Book; 1995:932–942.
6.28 Disorders of Water, Electrolytes, and Acid-Base
23. Sabatini S, Kurtzman NA: Metabolic alkalosis: biochemical mecha- 28. Simon DB, Karet FE, Hamdan JM, et al.: Bartter’s syndrome,
nisms, pathophysiology, and treatment. In Therapy of Renal Diseases hypokalaemic alkalosis with hypercalciuria, is caused by mutations in
and Related Disorders Edited by Suki WN, Massry SG. Boston: the Na-K-2Cl cotransporter NKCC2. Nat Genet 1996, 13:183–188.
Kluwer Academic Publishers; 1997:189–210. 29. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogene-
24. Galla JH, Luke RG: Metabolic alkalosis. In Textbook of Nephrology. ity of Bartter’s syndrome revealed by mutations in the K+ channel,
Edited by Massry SG, Glassock RJ. Baltimore: Williams & Wilkins; ROMK. Nat Genet 1996, 14:152–156.
1995:469–477. 30. International Collaborative Study Group for Bartter-like Syndromes.
25. Madias NE, Adrogué HJ, Cohen JJ: Maladaptive renal response to Mutations in the gene encoding the inwardly-rectifying renal potassi-
secondary hypercapnia in chronic metabolic alkalosis. Am J Physiol um channel, ROMK, cause the antenatal variant of Bartter syndrome:
1980, 238:F283–289. evidence for genetic heterogeneity. Hum Mol Genet 1997, 6:17–26.
26. Harrington JT, Hulter HN, Cohen JJ, Madias NE: Mineralocorticoid- 31. Simon DB, Nelson-Williams C, et al.: Gitelman’s variant of Bartter’s
stimulated renal acidification in the dog: the critical role of dietary syndrome, inherited hypokalaemic alkalosis, is caused by mutations
sodium. Kidney Int 1986, 30:43–48. in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 1996,
27. Beall DP, Scofield RH: Milk-alkali syndrome associated with calcium 12:24–30.
carbonate consumption. Medicine 1995, 74:89–96.
Disorders of
Phosphate Balance
Moshe Levi
Mordecai Popovtzer
T
he physiologic concentration of serum phosphorus (phosphate) in
normal adults ranges from 2.5 to 4.5 mg/dL (0.80–1.44 mmol/L).
A diurnal variation occurs in serum phosphorus of 0.6 to 1.0
mg/dL, the lowest concentration occurring between 8 AM and 11 AM.
A seasonal variation also occurs; the highest serum phosphorus concen-
tration is in the summer and the lowest in the winter. Serum phosphorus
concentration is markedly higher in growing children and adolescents
than in adults, and it is also increased during pregnancy [1,2].
Of the phosphorus in the body, 80% to 85% is found in the skele-
ton. The rest is widely distributed throughout the body in the form of
organic phosphate compounds. In the extracellular fluid, including in
serum, phosphorous is present mostly in the inorganic form. In serum,
more than 85% of phosphorus is present as the free ion and less than
15% is protein-bound.
Phosphorus plays an important role in several aspects of cellular
metabolism, including adenosine triphosphate synthesis, which is the
source of energy for many cellular reactions, and 2,3-diphosphoglycerate
concentration, which regulates the dissociation of oxygen from hemo-
globin. Phosphorus also is an important component of phospholipids in
cell membranes. Changes in phosphorus content, concentration, or
both, modulate the activity of a number of metabolic pathways.
Major determinants of serum phosphorus concentration are dietary
intake and gastrointestinal absorption of phosphorus, urinary excretion
of phosphorus, and shifts between the intracellular and extracellular
spaces. Abnormalities in any of these steps can result either in CHAPTER
hypophosphatemia or hyperphosphatemia [3–7].
The kidney plays a major role in the regulation of phosphorus
7
homeostasis. Most of the inorganic phosphorus in serum is ultrafil-
terable at the level of the glomerulus. At physiologic levels of serum
phosphorus and during a normal dietary phosphorus intake, approx-
imately 6 to 7 g/d of phosphorous is filtered by the kidney. Of that
7.2 Disorders of Water, Electrolytes, and Acid-Base
amount, 80% to 90% is reabsorbed by the renal tubules and (type I and type II Na-Pi cotransport proteins). Most of the
the rest is excreted in the urine. Most of the filtered phospho- hormonal and metabolic factors that regulate renal tubular
rus is reabsorbed in the proximal tubule by way of a sodium phosphate reabsorption, including alterations in dietary phos-
gradient-dependent process (Na-Pi cotransport) located on the phate content and parathyroid hormone, have been shown to
apical brush border membrane [8–10]. Recently two distinct modulate the proximal tubular apical membrane expression of
Na-Pi cotransport proteins have been cloned from the kidney the type II Na-Pi cotransport protein [11–16].
FIGURE 7-1
Summary of phosphate metabolism for
a normal adult in neutral phosphate bal-
ance. Approximately 1400 mg of phosphate
is ingested daily, of which 490 mg is excret-
ed in the stool and 910 mg in the urine.
Bone
The kidney, gastrointestinal (GI) tract, and
bone are the major organs involved in
phosphorus homeostasis.
GI intake
1400 mg/d Digestive juice
phosphorus
Formation Resorption
210 mg/d 210 mg/d
210 mg/d
Extracellular fluid
Total absorbed
intestinal phosphorus
1120 mg/d
Urine
910 mg/d
Stool
490 mg/d
FIGURE 7-2
Major determinants of ECF or serum Major determinants of extracellular fluid or serum inorganic phos-
inorganic phosphate (Pi) concentration phate (Pi) concentration include dietary Pi intake, intestinal Pi
absorption, urinary Pi excretion and shift into the cells.
Dietary intake
Intestinal
absorption Serum Pi Cells
Urinary excretion
Disorders of Phosphate Balance 7.3
PST
10-20% CCT
2-5%
IMCD
<1%
0.2%-20% Urine
FIGURE 7-4
Lumen Blood
Cellular model for renal tubular reabsorption of phosphorus in the
Na+ Pi proximal tubule. Phosphate reabsorption from the tubular fluid is
sodium gradient–dependent and is mediated by the sodium gradient–
Na + 3 Na+ ?An dependent phosphate transport (Na-Pi cotransport) protein located
Na+ on the apical brush border membrane. The sodium gradient for phos-
Pi
phate reabsorption is generated by then sodium-potassium adenosine
Pi
Pi triphosphatase (Na-K ATPase) pump located on the basolateral mem-
Gluconeogenesis Glycolysis
brane. Recent studies indicate that the Na-Pi cotransport system is
[HPO4= H2PO4– ] electrogenic [8,11]. ADP—adenosine diphosphate; An—anion.
Pi+ADP ATP
Na-K
ATPase
P +ADP ATP
i
Respiratory chain
Oxidative phosphorylation
–65mV –65mV
7.4 Disorders of Water, Electrolytes, and Acid-Base
Cellular model of proximal tubule Pi-reabsorption FACTORS REGULATING RENAL PROXIMAL TUBULAR
PHOSPHATE REABSORPTION
Lumen Blood
FIGURE 7-6
Factors regulating renal proximal tubular phosphate reabsorption.
A B
490 600
Cholesterol,
nmol/mg
ng/mg
GlcCer,
440
A 390
1600
0
A PDMP Control DEX
pmol/5s/mg
Na-Pi,
1100 1600
pmol/5s/mg
Na-Pi,
600
Low Pi diet Control High Pi diet
B and/or young and/or aged
FIGURE 7-9
0
Renal cholesterol content modulates renal tubular phosphate reab- B PDMP Control DEX
sorption. In aged rats versus young rats and rats fed a diet high in
phosphate versus a diet low in phosphate, an inverse correlation
exists between the brush border membrane (BBM) cholesterol con- FIGURE 7-10
tent (A) and Na-Pi cotransport activity (B). Studies in isolated BBM Renal glycosphingolipid content modulates renal tubular phosphate
vesicles and recent studies in opossum kidney cells grown in culture reabsorption. In rats treated with dexamethasone (DEX) and in rats
indicate that direct alterations in cholesterol content per se modu- fed a potassium-deficient diet, an inverse correlation exists between
late Na-Pi cotransport activity [15]. CON—controls. brush border membrane (BBM) glucosylceramide (GluCer)—and
ganglioside GM3, content and Na-Pi cotransport activity. Treatment
of rats with a glucosylceramide synthase inhibitor PDMP lowers
BBM glucosylceramide content (A) and increases Na-Pi cotransport
activity (B) [16].
7.6 Disorders of Water, Electrolytes, and Acid-Base
Hypophosphatemia/Hyperphosphatemia
FIGURE 7-11
MAJOR CAUSES OF HYPOPHOSPHATEMIA Major causes of hypophosphatemia. (From
Angus [1]; with permission.)
Pseudohypophosphatemia Hormonal effects Cellular uptake syndromes Increased excretion into urine
Mannitol Insulin Recovery from hypothermia Hyperparathyroidism
Bilirubin Glucagon Burkitt’s lymphoma Renal tubule defects
Acute leukemia Epinephrine Histiocytic lymphoma Fanconi’s syndrome
Decreased dietary intake Androgens Acute myelomonocytic leukemia X-linked hypophosphatemic rickets
Decreased intestinal absorption Cortisol Acute myelogenous leukemia Hereditary hypophosphatemic rickets
Vitamin D deficiency Anovulatory hormones Chronic myelogenous leukemia with hypercalciuria
Malabsorption Nutrient effects in blast crisis Polyostotic fibrous dysphasia
Steatorrhea Glucose Treatment of pernicious anemia Panostotic fibrous dysphasia
Secretory diarrhea Fructose Erythropoietin therapy Neurofibromatosis
Vomiting Glycerol Erythrodermic psoriasis Kidney transplantation
PO34-binding antacids Lactate Hungry bone syndrome Oncogenic osteomalacia
Amino acids After parathyroidectomy Recovery from hemolytic-uremic
Shift from serum into cells
Xylitol Acute leukemia syndrome
Respiratory alkalosis
Aldosteronism
Sepsis
Licorice ingestion
Heat stroke
Volume expansion
Neuroleptic malignant syndrome
Inappropriate secretion of antidiuretic
Hepatic coma
hormone
Salicylate poisoning
Mineralocorticoid administration
Gout
Corticosteroid therapy
Panic attacks
Diuretics
Psychiatric depression
Aminophylline therapy
FIGURE 7-12
Causes of moderate hypophosphatemia. (From Popovtzer, et al. [6];
with permission.)
Disorders of Phosphate Balance 7.7
FIGURE 7-13
Causes of severe hypophosphatemia. (From Popovtzer, et al. [6];
with permission.)
FIGURE 7-15
Causes of hypophosphatemia in patients with alcoholism.
FIGURE 7-17
MAJOR CONSEQUENCES OF HYPOPHOSPHATEMIA Major consequences of hypophosphatemia.
FIGURE 7-18
Signs and symptoms of hypophosphatemia. (Adapted from Hruska
and Slatopolsky [2] and Hruska and Gupta [7].)
FIGURE 7-19
Pseudofractures (Looser’s transformation zones) at the margins of
the scapula in a patient with oncogenic osteomalacia. Similar to the
genetic X-linked hypophosphatemic rickets, a circulating phospha-
turic factor is believed to be released by the tumor, causing phos-
phate wasting and reduced calcitriol formation by the kidney. Note
the radiolucent ribbonlike decalcification extending into bone at a
right angle to its axillary margin. Pseudofractures are pathogno-
monic of osteomalacia with a low remodeling rate.
FIGURE 7-22
USUAL DOSAGES FOR PHOSPHORUS REPLETION Usual dosages for phosphorus repletion.
FIGURE 7-23
PHOSPHATE PREPARATIONS FOR ORAL USE Phosphate preparations for oral use.
FIGURE 7-24
PHOSPHATE PREPARATIONS FOR INTRAVENOUS USE Phosphate preparations for intravenous use.
(From Popovtzer, et al. [6]; with permission.)
CAUSES OF HYPERPHOSPHATEMIA
FIGURE 7-25
Causes of hyperphosphatemia. (From Knochel and Agarwal [5];
with permission.)
FIGURE 7-26
Clinical manifestations of hyperphosphatemia.
Disorders of Phosphate Balance 7.11
A B
FIGURE 7-28
Periarticular calcium phosphate deposits in a patient with end- resolution of calcific masses after dietary phosphate restriction and
stage renal disease who has severe hyperphosphatemia and a high oral phosphate binders. Left shoulder joint before (A) and after (B)
level of the product of calcium and phosphorus. Note the partial treatment. (From Pinggera and Popovtzer [17]; with permission.)
A B
FIGURE 7-29
Resolution of soft tissue calcifications. The palms of the hands of patient has a high level of the product of calcium and phosphorus.
the patient in Figure 7-28 with end-stage renal disease are shown (From Pinggera and Popovtzer [17]; with permission.)
before (A) and after (B) treatment of hyperphosphatemia. The
7.12 Disorders of Water, Electrolytes, and Acid-Base
A B
FIGURE 7-30
A, B, Bone sections from the same patient as in Figures 7-28 and 7-29, illustrating osteitis
fibrosa cystica caused by renal secondary hyperparathyroidism with hyperphosphatemia.
FIGURE 7-33
Massive periarticular calcium phosphate deposit (around the hip joint) in a patient with
genetic tumoral calcinosis. The patient exhibits hyperphosphatemia and increased renal
tubular phosphate reabsorption. Normal parathyroid hormone levels and elevated calcitriol
levels are present. The same disease affects two of the patient’s brothers.
Disorders of Phosphate Balance 7.13
FIGURE 7-36 (see Color Plate) FIGURE 7-37 (see Color Plate)
The same bone section as in Figure 7-35 but under polarizing lens- The same bone section as in Figure 7-35 with positive aluminum
es, illustrating the partially woven appearance of osteoid typical of stain of the trabecular surface. These findings are consistent with
chronic renal failure. aluminum-related osteomalacia.
Acknowledgments
The authors thank Sandra Nickerson and Teresa Autrey for secretarial assistance and the Medical Media Department at the Dallas
VA Medical Center for the illustrations.
7.14 Disorders of Water, Electrolytes, and Acid-Base
References
1. Agus ZS: Phosphate metabolism. In UpToDate, Inc.. Edited by Burton 10. Suki WN, Rouse D: Renal Transport of calcium, magnesium, and
D. Rose, 1998. phosphate. In The Kidney, edn 5. Edited by Brenner BM.
2. Hruska KA, Slatopolsky E: Disorders of phosphorus, calcium, and Philadelphia: WB Saunders; 1996.
magnesium metabolism. In Diseases of the Kidney, edn 6. Edited by 11. Levi M, Kempson, SA, Lõtscher M, et al.: Molecular regulation of
Schrier RW, Gottschalk CW. Boston: Little and Brown; 1997. renal phosphate transport. J Membrane Biol 1996, 154:1–9.
3. Levi M, Knochel JP: The management of disorders of phosphate 12. Levi M, Lõtscher M, Sorribas V, et al.: Cellular mechanisms of acute
metabolism. In Therapy of Renal Diseases and Related Disorders. and chronic adaptation of rat renal phosphate transporter to alter-
Edited by Massry SG, Suki WN. Boston, Martinus Nijhoff; 1990. ations in dietary phosphate. Am J Physiol 1994, 267:F900–F908.
4. Levi M, Cronin RE, Knochel JP: Disorders of phosphate and magne- 13. Kempson SA, Lõtscher M, Kaissling B, et al.: Effect of parathyroid
sium metabolism. In Disorders of Bone and Mineral Metabolism. hormone on phosphate transporter mRNA and protein in rat renal
Edited by Coe FL, Favus MJ. New York: Raven Press; 1992. proximal tubules. Am J Physiol 1995, 268:F784–F791.
5. Knochel JP, Agarwal R: Hypophosphatemia and hyperphosphatemia. 14. Lõtscher M, Biber J, Murer H, et al.: Role of microtubules in the
In The Kidney, edn 5. Edited by Brenner BM. Philadelphia: WB rapid upregulation of rat renal proximal tubular Na-Pi cotransport
Saunders; 1996. following dietary P restriction. J Clin Invest 1997, 99:1302–1312.
6. Popovtzer M, Knochel JP, Kumar R: Disorders of calcium, phosphorus, 15. Levi M, Baird B, Wilson P: Cholesterol modulates rat renal brush border
vitamin D, and parathyroid hormone activity. In Renal Electrolyte membrane phosphate transport. J Clin Invest 1990, 85:231–237.
Disorders, edn 5. Edited by Schrier RW. Philadelphia: Lippincott- 16. Levi M, Shayman J, Abe A, et al.: Dexamethasone modulates rat renal
Raven; 1997. brush border membrane phosphate transporter mRNA and protein
7. Hruska K, Gupta A: Disorders of phosphate homeostasis. In abundance and glycosphingolipid composition. J Clin Invest 1995,
Metabolic Bone Disease, edn 3. Edited by Avioli LV, SM Krane. 96:207–216.
New York: Academic Press; 1998. 17. Pinggera WF, Popovtzer MM: Uremic osteodystrophy: the therapeutic
8. Murer H, Biber J: Renal tubular phosphate transport: cellular mecha- consequences of effective control of serum phosphorus. JAMA 1972,
nisms. In The Kidney: Physiology and Pathophysiology, edn 2. Edited 222:1640–1642.
by Seldin DW, Giebisch G. New York: Raven Press; 1997.
9. Berndt TJ, Knox FG: Renal regulation of phosphate excretion. In
The Kidney: Physiology and Pathophysiology, edn 2. Edited by Seldin
DW, Giebisch G. New York: Raven Press; 1992.
Acute Renal Failure:
Causes and Prognosis
Fernando Liaño
Julio Pascual
T
here are many causes—more than fifty are given within this
present chapter—that can trigger pathophysiological mecha-
nisms leading to acute renal failure (ARF). This syndrome is
characterized by a sudden decrease in kidney function, with a conse-
quence of loss of the hemostatic equilibrium of the internal medium.
The primary marker is an increase in the concentration of the nitroge-
nous components of blood. A second marker, oliguria, is seen in 50%
to 70% of cases.
In general, the causes of ARF have a dynamic behavior as they
change as a function of the economical and medical development of
the community. Economic differences justify the different spectrum in
the causes of ARF in developed and developing countries. The setting
where ARF appears (community versus hospital), or the place where
ARF is treated (intensive care units [ICU] versus other hospital areas)
also show differences in the causes of ARF.
While functional outcome after ARF is usually good among the sur-
viving patients, mortality rate is high: around 45% in general series
and close to 70% in ICU series. Although it is unfortunate that these
mortality rates have remained fairly constant over the past decades, it
should be noted that today’s patients are generally much older and
display a generally much more severe condition than was true in the
past. These age and severity factors, together with the more aggressive
therapeutical possibilities presently available, could account for this
apparent paradox.
As is true for any severe clinical condition, a prognostic estimation CHAPTER
of ARF is of great utility for both the patients and their families, the
medical specialists (for analysis of therapeutical maneuvers and
8
options), and for society in general (demonstrating the monetary costs
of treatment). This chapter also contains a brief review of the prog-
nostic tools available for application to ARF.
8.2 Acute Renal Failure
FIGURE 8-4
Most common causes of tubulointerstitial nephritis. During the last
years, acute tubulointerstitial nephritis is increasing in importance as FIGURE 8-5
a cause of acute renal failure. For decades infections were the most Causes of obstructive acute renal failure. Obstruction at any level of
important cause. At present, antimicrobials and other drugs are the the urinary tract frequently leads to acute renal failure. These are the
most common causes. most frequent causes.
FIGURE 8-6
Arterial disease Other parenchymal This figure shows a comparison of the percent-
2.5% 4.5% ages of the different types of acute renal failure
ATN ATN ATIN (ARF) in a western European country in
43.1% Other parenchymal 45% 1.6% 1977–1980 and 1991: A, distribution in a typi-
6.4% Arterial disease cal Madrid hospital; B, the Madrid ARF Study
Obstructive Obstructive 1%
[1]. There are two main differences: 1) the
3.4% 10%
Prerenal Prerenal
appearance of a new group in 1991, “acute
40.6% 21% on chronic ARF,” in which only mild forms
Acute-on-chronic (serum creatinine concentrations between 1.5
13% and 3.0 mg/dL) were considered, for method-
n = 202 n = 748 ological reasons; 2) the decrease in prerenal
A 1977–1980 B 1991 ARF suggests improved medical care. This low
rate of prerenal ARF has been observed by
other workers in an intensive care setting [2].
The other types of ARF remain unchanged.
FIGURE 8-7
FINDINGS OF THE MADRID STUDY Incidences of different forms of acute renal
failure (ARF) in the Madrid ARF Study [1].
Figures express cases per million persons per
year with 95% confidence intervals (CI).
Condition Incidence (per million persons per year) 95% CI
Acute tubular necrosis 88 79–97
Prerenal acute renal failure 46 40–52
Acute on chronic renal failure 29 24–34
Obstructive acute renal failure 23 19–27
Glomerulonephritis (primary or secondary) 6.3 4.8–8.3
Acute tubulointerstitial nephritis 3.5 1.7–5.3
Vasculitis 3.5 1.7–5.3
Other vascular acute renal failure 2.1 0.8–3.4
Total 209 195–223
8.4 Acute Renal Failure
FIGURE 8-8
The most frequent causes of acute renal
Sclerodermal crisis 1
failure (ARF) in patients with preexisting
Tumoral obstruction 1
ATN Secondary glomerulonephritis 1 chronic renal failure are acute tubular
43% Vasculitis 1 necrosis (ATN) and prerenal failure. The
Other Malignant hypertension 2.1 distribution of causes of ARF in these
15% patients is similar to that observed in
Myeloma 2.1
patients without previous kidney diseases.
Prerenal Acute tubulointerstitial nephritis 2.1 (Data from Liaño et al. [1])
Not recorded
27% 15%
Atheroembolic disease 4.2
FIGURE 8-9
Discovering the cause of acute renal
Bun/SCr
increase
failure (ARF). This is a great challenge
for clinicians. This algorithm could help
Normal or big kidneys to determine the cause of the increase in
Small kidneys (excluding amiloidosis and blood urea nitrogen (BUN) or serum
polycystic kidney disease
creatinine (SCr) in a given patient.
and/or and/or
↑ SCr < 0.5 mg/dL/d ↑ SCr > 0.5 mg/dL/d
CRF ARF
+
Echography Urinary tract
dilatation
↑ SCr < 0.5 mg/dL/d
Normal Repeat
echograph
after 24 h
Flare of previous Acute-on-chronic
disease renal failure
Normal
FIGURE 8-10
BIOPSY RESULTS IN THE MADRID STUDY Biopsy results in the Madrid acute renal failure (ARF) study. Kidney
biopsy has had fluctuating roles in the diagnostic work-up of ARF.
After extrarenal causes of ARF are excluded, the most common
Disease Patients, n cause is acute tubular necrosis (ATN). Patients with well-established
clinical and laboratory features of ATN receive no benefit from renal
Primary GN 12
Extracapillary 6 biopsy. This histologic tool should be reserved for parenchymatous
Acute proliferative 3 ARF cases when there is no improvement of renal function after 3
Endocapillary and extracapillary 2 weeks’ evolution of ARF. By that time, most cases of ATN have
Focal sclerosing 1 resolved, so other causes could be influencing the poor evolution.
Secondary GN 6 Biopsy is mandatory when a potentially treatable cause is suspected,
Antiglomerular basement membrane 3 such as vasculitis, systemic disease, or glomerulonephritis (GN) in
Acute postinfectious 2 adults. Some types of parenchymatous non-ATN ARF might have
Diffuse proliferative (systemic lupus erythematosus) 1*
histologic confirmation; however kidney biopsy is not strictly neces-
Vasculitis 10
Necrotizing 5* sary in cases with an adequate clinical diagnosis such as myeloma,
Wegener’s granulomatosis 3 uric acid nephropathy, or some types of acute tubulointerstitial
Not specified 2 nephritis . Other parenchymatous forms of ARF can be accurately
Acute tubular necrosis 4* diagnosed without a kidney biopsy. This is true of acute post-strepto-
Acute tubulointerstitial nephritis 4 coccal GN and of hemolytic-uremic syndrome in children. Kidney
Atheroembolic disease 2 biopsy was performed in only one of every 16 ARF cases in the
Kidney myeloma 2* Madrid ARF Study [1]. All patients with primary GN, 90% with
Cortical necrosis 1 vasculitis and 50% with secondary GN were diagnosed by biopsy at
Malignant hypertension 1 the time of ARF. As many as 15 patients were diagnosed as having
ImmunoglobulinA GN + ATN 1 acute tubulointerstitial nephritis, but only four (27%) were biopsied.
Hemolytic-uremic syndrome 1 Only four of 337 patients with ATN (1.2%) underwent biopsy.
Not recorded 2 (Data from Liaño et al. [1].)
FIGURE 8-14
EPIDEMIOLOGY OF ACUTE RENAL FAILURE: Number of patients needing dialysis for acute renal failure (ARF),
NEED OF DIALYSIS expressed as cases per million population per year (pmp/y). This has
been another way of assessing the incidence of the most severe cases
of ARF. Local situations, mainly economics, have an effect on dialy-
Investigator, Year Country Cases (pmp/y) sis facilities for ARF management. In 1973 Israeli figures showed a
lower rate of dialysis than other countries at the same time. The
Lunding et al., 1964 [9] Scandinavia 28
very limited access to dialysis in developing countries supports this
Eliahou et al., 1973 [4] Israel 17*
hypothesis. At present, the need for dialysis in a given area depends
Lachhein et al., 1978 [10] West Germany 30
on the level of health care offered there. In two different countries
Wing et al., 1983 [11] European Dialysis and 29
Transplant Association (eg, the United Kingdom and Spain) the need for dialysis for ARF
Wing et al., 1983 [11] Spain 59 was very much lower when only secondary care facilities were avail-
Abraham et al., 1989 [5] Kuwait 31 able. At this level of health care, both countries had the same rate
Sanchez et al., 1992 [7] Spain 21† of dialysis. The Spanish data of the EDTA-ERA Registry in 1982
McGregor et al., 1992 [6] United Kingdom 31 gave a rate of dialysis for ARF of 59 pmp/y. This rate was similar to
Gerrard et al., 1992 [12] United Kingdom 71 that found in the Madrid ARF Study 10 years later. These data sug-
Feest et al., 1993 [8] United Kingdom 22† gest that, when a certain economical level is achieved, the need of
Madrid ARF Study Group [1] Spain 57 ARF patients for dialysis tends to stabilize.
FIGURE 8-15
HISTORICAL PATTERNS OF ACUTE RENAL FAILURE Historical perspective of acute renal failure
(ARF) patterns in France, India, and South
Africa. In the 1960s and 1970s, obstetrical
Proportion of Cases, % causes were a great problem in both France
and India and overall incidences of ARF were
India France India South Africa similar. Surgical cases were almost negligible in
France 1973 1965–1974 1981–1986 1981–1986 1986–1988 India at that time, probably because of the rel-
Surgical 46 11 30 30 8 ative unavailability of hospital facilities. During
Medical 30 67 70 61 77 the 1980s surgical and medical causes were
Obstetric 24 22 2 9 15 similar in both countries. In India, the increase
in surgical cases may be explained by advances
in health care, so that more surgical procedures
could be done. The decrease in surgical cases
in France, despite the fact that surgery had
become very sophisticated, could be explained
by better management of surgical patients.
(Legend continued on next page)
Acute Renal Failure: Causes and Prognosis 8.7
25
Percentage of total ARF cases
HD HD UF
20 68% 60% 1%
15 PD
Diarrhea Hemolysis
Obstetric 5%
CRRT PD CRRT
10 1% 31% 33%
80
70
Medical dept.
60
Mortality, %
34%
50
Trauma
2% 40
ICUs
27% Nephrology 30
13% 20
*
10
Surgical dept. 0
23% Gynecology All cases ICUs Medical Surgical Nephrol
1%
A B *P<0.001 respect to all cases
FIGURE 8-19
Acute renal failure: initial hospital location and mortality. A, two reasons: 1) polytrauma patients are now treated in the ICU
Initial departmental location of ARF patients in a hospital in a and 2) early and effective treatments applied today to trauma
Western country. The majority of the cases initially were seen in patients at the accident scene, and quick transfer to hospital, have
medical, surgical, and intensive care units (ICUs). The cases decreased this cause of ARF. B, Mortality was greater for patients
initially treated in nephrology departments were community initially treated in the ICU and lower in the nephrology setting
acquired, whereas the ARF patients in the other settings generally than rates observed in other departments. These figures were
acquired ARF in those settings. Obstetric-gynecologic ARF cases obtained from 748 ARF patients admitted to 13 different adult
have almost disappeared. ARF of traumatic origin is also rare, for hospitals. (Data from Liaño et al. [1].)
FIGURE 8-20
EPIDEMIOLOGIC VARIABLES Epidemiologic variable. The incidence of hospital-acquired acute
renal failure (ARF) depends on what epidemiologic method is used.
In case-control studies the incidence varied between 49 and 19 per
Acute Renal Failure in Hospitalized Patients thousand. When the real occurrence was measured in large popula-
Investigator, Year (per 1000 admissions) tions over longer intervals, the incidence of hospital-acquired ARF
decreased to 1.5 per thousand admissions. (Data from
Hou et al., 1983* 49.0 [1,5,16,17,18].)
Shusterman et al., 1987* 19.0
Lauzurica et al., 1989*
First period 16.0
Second period 6.5
Abraham et al., 1989 1.3
Madrid Study, 1992 1.5
* Case-control studies.
Acute Renal Failure: Causes and Prognosis 8.9
Prognosis
FIGURE 8-21
Estimating prognosis. The criteria for estimating prognosis in development of multivariable analysis. Theoretically, few of these
acute renal failure can be classified into four periods. The methods can give an individual prognosis [19]. They have not
Classical or heuristic way is similar to that used since the been used for triage. The next step will need a great deal of
Hippocratic aphorisms. The Traditional one based on simple work to design and implement adequate tools to stratify risks
statistical procedures, is not useful for individual prognosis. The and individual prognosis. In addition, the estimate of residual
Present form is more or less complex, depending on what method renal function and survivors’ quality of life, mainly for older
is used, and it is possible, thanks to computing facilities and the people, are future challenges.
60
ARF Outcome
40
20 16 20
11 11 11 131110 9
13
10 8 Number
7 8 9 6 55 478 6
6 5 57 5 5 5 64 of
10 2 3 3 1 34 2 3 2
publi-
0 cations
Prognosis 1951 55 60 65 70 75 80 85 1990
Year
FIGURE 8-23
Mortality trends in acute renal failure (ARF). This figure shows the
evolution of mortality during a 40-year period, starting in 1951. The
graphic was elaborated after reviewing the outcome of 32,996 ARF
FIGURE 8-22 patients reported in 258 published papers. As can be appreciated,
Ideally, prognosis should be established as the problem, the episode mortality rate increases slowly but constantly during this follow-up,
of acute renal failure (ARF), starts. Correct prognostic estimation despite theoretically better availability of therapeutic armamentarium
gives the real outcome for a patient or group of patients as precisely (mainly antibiotics and vasoactive drugs), deeper knowledge of dialy-
as possible. In this ideal scenario, this fact is illustrated by giving sis techniques, and wider access to intensive care facilities. This
the same surface area for the concepts of outcome and prognosis. improvement in supporting measures allows the physician to keep
alive, for longer periods of time patients who otherwise would have
died. A complementary explanation could be that the patients treat-
ed now are usually older, sicker, and more likely to be treated more
aggressively. (From Kierdorf et al. [20]; with permission.)
8.10 Acute Renal Failure
Prognostic
systems used
in ARF
ICU Specific
methods ARF
methods
Apache
system SAPS MPM OSF Liano
APACHE II APACHE III SAPS I SAPS II MPM I MPM II OSF MODS SOFA Rasmussen
Lohr
Schaefer
Brivet
FIGURE 8-24
Ways of estimating prognosis in acute renal failure (ARF). This can be Sepsis-Related Organ Failure Assessment Score (SOFA) [29] are those
done using either general intensive care unit (ICU) score systems or that seem most suitable for this purpose. APACHE II used to be most
methods developed specifically for ARF patients. ICU systems include used. Other systems (white boxes) have been used in ARF.
Acute Physiological and Chronic Health Evaluation (APACHE) On the other hand, at least 17 specific ARF prognostic methods
[21,22], Simplified Physiologic Score (SAPS)[23,24], Mortality have been developed [20,30]. The figure shows only those that
Prediction Model (MPM) [25,26], and Organ System Failure scores have been used after their publication [31], plus one recently pub-
(OSF) [27]. Multiple Organ Dysfunction Score (MODS) [28] and lished system which is not yet in general use [2].
100
ACUTE RENAL FAILURE: VARIABLES
Age Hypotension
60 Survivors
Jaundice Catabolism
Sepsis Hemolysis
Burns Hepatic disease 40
Trauma Kind of surgery
NSAIDs Hyperkalemia 20
BUN increments Need for dialysis
Coma Assisted respiration
Oliguria Site of war injuries 0
1 5 10 15 20 25 30 35 40 45 50 55 60
Obstetric origin Disseminated intravascular coagulopathy
Days of ARF evolution
Malignancies Pancreatitis
Cardiovascular disease Antibiotics
X-ray contrast agents Timing of treatment FIGURE 8-27
Acidosis Duration and resolution of acute renal failure (ARF). Most of the
episodes of ARF resolved in the first month of evolution. Mean
duration of ARF was 14 days. Seventy-eight percent of the patients
with ARF who died did so within 2 weeks after the renal insult.
FIGURE 8-26 Similarly, 60% of survivors had recovered renal function at that time.
Individual factors that have been associated with acute renal failure After 30 days, 90% of the patients had had a final resolution of the
(ARF) outcome. Most of these innumerable variables have been ARF episode, one way or the other. Patients who finally lost renal
related to an adverse outcome, whereas few (nephrotoxicity as a function and needed to be included in a chronic periodic dialysis
cause of ARF and early treatment) have been associated with more program usually had severe forms of glomerulonephritis, vasculitis,
favorable prognosis. For a deep review of variables studied with or systemic disease. (From Liaño et al. [1]; with permission.)
univariate statistical analysis [34, 35]. NSAID—nonsteroidal anti-
inflammatory drugs; BUN—blood urea nitrogen.
Mortality, %
60
ARF patients, %
60 60
P<0.001 P<0.001
40 40 40
33 32
20 20
20
0 0
0 Yes No Yes No
ss
pir ted
ma
on
n
on
ice
Jaundice Oliguria
ria
iou al
sne
sio
nsc rm
ati
ati
Co
100 100
igu
nd
res ssis
ten
Sed
co No
Jau
Ol
A
po
80 80
Hy
Mortality, %
Mortality, %
67
60 P<0.001 60 52
40 P<0.02
FIGURE 8-28 40 40 36
FIGURE 8-30
100 92 Consciousness level and mortality. Coma patients had a Glasgow
coma score of 5 or lower. Sedation refers to the use of this kind of
80 77 treatment, primarily in patients with assisted respiration. Both situ-
ations are associated with significantly higher mortality (P<0.001)
Mortality rate, %
20
0
Normal Sedation Coma All cases
FIGURE 8-31
Outcome of acute renal failure (ARF). Two groups of factors play
a role on ARF outcome. The first includes factors that affect the
2
Original patient: 1) previous health condition; 2) initial disease—usually,
disease the direct or indirect (eg, treatments) cause of kidney failure; 3)
the kind and severity of kidney injury. While 1 is a conditioning
element, 2 and 3 trigger the second group of factors: the response
of the patient to the insult. If this response includes a systemic
inflammatory response syndrome (SIRS) like that usually seen in
intensive care patients (eg, sepsis, pancreatitis, burns), a multiple
1 3 organ dysfunction syndrome (MODS) frequently appears and
Previous health Kind and severity consequently outcome is associated with a higher fatality rate
condition of kidney insult (thick line). On the contrary, if SIRS does not develop and isolated
ARF predominates, death (thin line, right) is less frequent than
survival (thick line).
Depending on 2 and 3
S No
SIR SIR
S
Death
Depending on:
*2,3, & 1
Recovery Recovery
*No. of failing organs
*Recovery process
Acute Renal Failure: Causes and Prognosis 8.13
FIGURE 8-32
INDIVIDUAL SEVERITY INDEX Individual severity index (ISI). The ISI was published in its second
version in 1993 [36]. The ISI estimates the probability of death.
Nephrotoxic indicates an ARF of that origin; the other variables
ISI=0.032 (age-decade) 0.086 (male) 0.109 (nephrotoxic) 0.109 (oliguria) have been defined in preceding figures. The numbers preceding
0.116 (hypotension) 0.122 (jaundice) 0.150 (coma) 0.154 (consciousness) these keys denote the contribution of each one to the prognosis
0.182 (assisted respiration) 0.210 and are the factor for multiplying the clinical variables; 0.210 is
Case example the equation constant. Each clinical variable takes a value of 1 or
A 55-year-old man was seen because of oliguria following pancreatic surgery. At 0, depending, respectively, on its presence or absence (with the
that moment he was hypotensive and connected to a respirator, and jaundice exception of the age, which takes the value of the patient’s decade).
was evident. He was diagnosed with acute tubular necrosis. His ISI was calculated The parameters are recorded when the nephrologist sees the patient
as follows: the first time. Calculation is easy: only a card with the equation
ISI=0.032(6) 0.086 0.109 0.116 0.122 0.182 0.210 = 0.845 values, a pen, and paper are necessary. A real example is given.
FIGURE 8-33
ATN Acute GN Outcome of acute renal failure (ARF). Long-term outcome of ARF
66 No recovery 11
11 has been studied only in some series of intrinsic or parenchymatous
24 No recovery
31
31
ARF. The figure shows the different long-term prognoses for intrin-
Partial recovery 32
32 47
sic ARF of various causes. Left, The percentages of recovery rate of
35 renal function 1 year after the acute episode of renal failure. Right,
Partial recovery The situation of renal function 5 years after the ARF episode.
24
63
63 57 Acute tubulointerstitial nephritis (TIN) carries the better prognosis:
Total recovery 57
the vast majority of patients had recovered renal function after 1
41 Total recovery 29 and 5 years. Two thirds of the patients with acute tubule necrosis
(ATN) recovered normal renal function, 31% showed partial
1 yr 5 yr 1 yr 5 yr recovery, and 6% experienced no functional recovery. Some
Acute TIN patients with ATN lost renal function over the years. Patients with
HUS/ACN ARF due to glomerular lesions have a poorer prognosis; 24% at 1
No recovery 8 year and 47% at 5 years show terminal renal failure. The poorest
25 Partial recovery evolution is observed with severe forms of acute cortical necrosis
25
or hemolytic-uremic syndrome. GN—glomerulonephritis; HUS—
63 No recovery hemolytic-uremic syndrome; ACN—acute cortical necrosis.
91 (Data from Bonomini et al. [37].)
75 Total recovery
67
27
Partial recovery 9
1 yr 5 yr 1 yr 5 yr
FIGURE 8-34
Age as a prognostic factor in acute renal failure (ARF). There is a
Dead Dead Dead tendency to treat elders with ARF less aggressively because of the
174 113 50 presumed worse outcomes; however, prognosis may be similar to
that found in the younger population. In the multicenter prospec-
Alive Alive Alive tive longitudinal study in Madrid, relative risk for mortality in
225 143 53 patients older than 80 years was not significantly different (1.09 as
compared with 1 for the group younger than 65 years). Age proba-
< 65 yr 65–79 yr > 80 yr bly is not a poor prognostic sign, and outcome seems to be within
(n = 399) (n = 256) (n = 103) acceptable limits for elderly patients with ARF. Dialysis should not
be withheld from patients purely because of their age.
8.14 Acute Renal Failure
1960–1969 P 1980–1989
Assisted respiration 11
No. 119 124
Hypotension or inotropic support 10
Mortality (%) 51 NS 63
Age 8
Mean age (y) 50.9 < 0.0001 63
Cardiac failure/complications 6
Median APACHE II score 32 < 0.0001 35
Jaundice 6
Range (22–45) (25–49)
Diuresis volume 5
Coma 5
Male sex 4
Sepsis 3 FIGURE 8-36
Chronic disease 3
Prognosis in acute renal failure (ARF). This figure shows the utility
Neoplastic disease 2 of a prognostic system for evaluating the severity of ARF over
Other organ failures 2 time, using the experience of Turney [38]. He compared the age,
Serum creatinine 2 mortality, and APACHE II score of ARF patients treated at one
Other conditions 12 hospital between 1960 and 1969 and 1980 and 1989. In the latter
Summary period there were significant increases in both the severity of the
Clinical variables 20 illness as measured by APACHE II and age. Although there was a
Laboratory variables 6
tendency to a higher mortality rate in the second period, this
tendency was not great enough to be statistically significant.
FIGURE 8-35
Outcome of acute renal failure (ARF). A great number of variables
have been associated with outcome in ARF by multivariate analy-
sis. This figure gives the frequency with which these variables
appear in 16 ARF studies performed with multivariable analysis
(all cited in [30]).
70 68
Time Nonsurvivors Survivors
60
50 Admission in ICU 24 22
42
Mortality, %
40 Before dialysis 22 22
30 24 h after dialysis 25 22
48 h after dialysis 24 22
20
10
22 ± 6 Apache II score 22 ± 6
0
A Dialysis patients Nondialysis patients B
FIGURE 8-37
APACHE score. The APACHE II score is not a good method for median APACHE II score was similar in both the surviving or
estimating prognosis in acute renal failure (ARF) patients. A, nonsurviving ARF patients treated in an intensive care unit.
Data from Verde and coworkers show how mortality was higher Recently Brivet and associates have found that APACHE II score
in their ICU patients with ARF needing dialysis than in those influences ARF prognosis when included as a factor in a more
without need of dialysis, despite the fact that the APACHE II complex logistic equation [2]. Although not useful for prognostic
score before dialysis was equal in both groups [39]. B, Similar estimations, APACHE II score has been used in ARF for risk
data were observed by Schaefer’s group [40], who found that the stratification.
Acute Renal Failure: Causes and Prognosis 8.15
FIGURE 8-38
Analysis of the severity and mortality in acute renal failure (ARF)
Mortality, %
P<0.001 Severity index patients needing dialysis. This figure is an example of the uses of a
80 0.8 severity index for analyzing the effect of treatment on the outcome
P<0.001
66 of ARF. Looking at the mortality rate, it is clear that it is higher in
patients who need dialysis than in those who do not. It could lead
Severity index
60 0.57 0.6
to the sophism that dialysis is not a good treatment; however, it is
%
0.35 also clear that the severity index score for ARF was higher in
40 33 0.4
patients who needed dialysis. Severity index is the mean of the
individual severity index of each of the patients in each group [36].
20 0.2 (Data from Liaño et al. [1].)
0 0
Dialysis No dialysis
FIGURE 8-39
200 Causes of death. The causes of death from acute renal failure
(ARF) were analyzed in 337 patients in the Madrid ARF Study [1].
In this work all the potential causes of death were recorded; thus,
Number of cases
150
more than one cause could be present in a given patient. In fact,
100
each dead patient averaged two causes, suggesting multifactorial
origin. This could be the expression of a high presence of multiple
organ dysfunction syndrome (MODS) among the nonsurviving
50
patients. The main cause of death was the original disease, which
was present in 55% of nonsurviving patients. Infection and shock
0 were the next most common causes of death, usually concurrent in
septic patients. It is worth noting that, if we exclude from the
a se
eas ry
ion
l
e
k
r
C
US
ing na
he
eas
oc
dis ato
DI
ise
ec t
ed sti
ICT
Ot
dis
r
ble inte
al d
spi
Inf
ac
o
rdi
str
Ga
References
1. Liaño F, Pascual J the Madrid ARF Study Group: Epidemiology of 9. Lunding M, Steiness I, Thaysen JH: Acute renal failure due to tubular
acute renal failure: A prospective, multicenter, community-based necrosis. Immediate prognosis and complications. Acta Med Scand
study. Kidney Int 1996, 50:811–818. 1964, 176:103–119.
2. Brivet FG, Kleinknecht DJ, Loirat P, et al.: Acute renal failure in inten- 10. Lachhein L, Kielstein R, Sauer K, et al.: Evaluation of 433 cases of
sive care units—causes, outcome and prognostic factors of hospital acute renal failure. Proc EDTA 1978, 14:628–629.
mortality: A prospective, multicenter study. Crit Care Med 1995, 11. Wing AJ, Broyer M, Brunner FP, et al.: Combined report on regular
24:192–197. dialysis and transplantation in Europe XIII-1982. Proc EDTA 1983,
3. Pascual J, Liaño F, the Madrid ARF Study Group: Causes and prog- 20:5–78.
nosis of acute renal failure in the very old. J Am Geriatr Soc 1998, 12. Gerrard JM, Catto GRD, Jones MC: Acute renal failure: An iceberg
46:1–5. revisited (Abstract). Nephrol Dial Transplant 1992, 7:458.
4. Eliahou HE, Modan B, Leslau V, et al.: Acute renal failure in the com- 13. Kleinknecht D: Epidemiology of acute renal failure in France today.
munity: An epidemiological study. Acute Renal Failure Conference, In Acute Renal Failure in the Intensive Therapy Unit. Edited by Bihari
Proceedings. New York 1973. D, Neild G. London:Springer-Verlag; 1990:13–21.
5. Abraham G, Gupta RK, Senthilselvan A, et al.: Cause and prognosis 14. Chugh S, Sakhuja V, Malhotra HS, Pereira BJG: Changing trends in
of acute renal failure in Kuwait: A 2-year prospective study. J Trop acute renal failure in Third-World countries—Chandigarh study.
Med Hyg 1989, 92:325–329. Q J Med 1989, 272:1117–1123.
6. McGregor E, Brown I, Campbell H, et al.: Acute renal failure. A 15. Seedat YK, Nathoo BC: Acute renal failure in blacks and Indians in
prospective study on incidence and outcome (Abstract). XXIX South Africa—Comparison after 10 years. Nephron 1993,
Congress of EDTA-ERA, Paris, 1992, p 54.
64:198–201.
7. Sanchez Rodrìguez L, MartÌn Escobar E, Lozano L, et al.: Aspectos
16. Hou SH, Bushinsky DA, Wish JB, et al.: Hospital-acquired renal
epidemiolûgicos del fracaso renal agudo en el ·rea sanitaria de
insufficiency: A prospective study. Am J Med 1983, 74:243–248.
Cuenca. Nefrologìa 1992, 12(Suppl 4):87–91.
8. Feest TG, Round A, Hamad S: Incidence of severe acute renal failure 17. Shusterman N, Strom BL, Murray TG, et al.: Risk factors and out-
in adults: Results of a community based study. Br Med J 1993, come of hospital-acquired acute renal failure. Am J Med 1987,
306:481–483. 83:65–71.
8.16 Acute Renal Failure
18. Lauzurica R, Caralps A: Insuficiencia renal aguda producida en el 29. Vincent JL, Moreno R, Takala J, et al.: The SOFA (sepsis-related
hospital: Estudio prospectivo y prevenciûn de la misma. Med ClÌn organ failure assessment) score to describe organ dysfunction/failure.
(Barc) 1989, 92:331–334. Intensive Care Med 1996, 22:707–710.
19. Liaño F, Solez K, Kleinknecht D: Scoring the patient with ARF. In 30. Liaño F, Pascual J: Acute renal failure, critical illness and the artificial
Critical Care Nephrology. Edited by Ronco C, Bellomo R. kidney: Can we predict outcome? Blood Purif 1997, 15:346–353.
Dordrecht:Kluwer Academic; 1998; Section 23.1: 1535–1545. 31. Douma CE, Redekop WK, Van der Meulen JHP, et al.: Predicting
20. Kierdorf H, Sieberth HG: Continuous treatment modalities in acute mortality in intensive care patients with acute renal failure treated
renal failure. Nephrol Dial Transplant 1995; 10:2001–2008. with dialysis. J Am Soc Nephrol 1997, 8:111–117.
21. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: A 32. Viviand X, Gouvernet J, Granthil C, Francois G: Simplification of the
severity of disease classification system. Crit Care Med 1985, SAPS by selecting independent variables. Intensive Care Med 1991,
13:818–829. 17:164–168.
22. Knaus WA, Wagner DP, Draper EA, et al.: The APACHE III prognostic 33. Bion JF, Aitchison TC, Edlin SA, Ledingham IM: Sickness scoring and
system: Risk prediction of hospital mortality for critically ill hospitalized response to treatment as predictors of outcome from critical illness.
adults. Chest 1991, 100:1619–1636. Intensive Care Med 1988, 14:167–172.
23. Le Gall JR, Loirat P, Alperovitch A, et al.: A simplified acute physiology 34. Chew SL, Lins RL, Daelemans R, De Broe ME: Outcome in acute
renal failure. Nephrol Dial Transplant 1993, 8:101–107.
score for ICU patients. Crit Care Med 1984, 12:975–977.
35. Liaño F: Severity of acute renal failure: The need of measurement.
24. Le Gall, Lemeshow S, Saulnier F: A new Simplified Acute Phisiology
Nephrol Dial Transplant 1994, 9(Suppl. 4):229–238.
Score (SAPS II) based on a European/North American multicenter
study. JAMA 1993, 270:2957–2963. 36. Liaño F, Gallego A, Pascual J, et al.: Prognosis of acute tubular necro-
sis: An extended prospectively contrasted study. Nephron 1993,
25. Lemeshow S, Teres D, Pastides H, et al.: A method for predicting 63:21–23.
survival and mortality of ICU patients using objectively derived
weights. Crit Care Med 1985, 13:519–525. 37. Bonomini V, Stefoni S, Vangelista A: Long-term patient and renal
prognosis in acute renal failure. Nephron 1984, 36:169–172.
26. Lemeshow S, Teres D, Klar J, et al.: Mortality probability models
38. Turney JH: Why is mortality persistently high in acute renal failure?
(MPM II) based on an international cohort of intensive care unit
Lancet 1990, 335:971.
patients. JAMA 1993, 270:2478–2486.
39. Verde E, Ruiz F, Vozmediano MC, et al.: Valor predictivo del
27. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: Prognosis in
APACHE II en el fracaso renal agudo de las unidades de cuidados
acute organ-system failure. Ann Surg 1985, 202:685–693.
intensivos (Abstract). Nefrologìa 1996, 16(Suppl. 19):32.
28. Marshall JC, Cook DJ, Christou NV, et al.: Multiple organ dysfunction 40. Schaefer JH, Jochimsen F, Keller F, et al.: Outcome prediction of acute
score: A reliable descriptor of a complex clinical outcome. Crit Care renal failure in medical intensive care. Intensive Care Med 1991,
Med 1995, 23:1638–1652. 17:19–24.
Renal Histopathology, Urine
Cytology, and Cytopathology
of Acute Renal Failure
Lorraine C. Racusen
Cynthia C. Nast
C
auses of acute renal failure can be divided into three categories:
1) prerenal, due to inadequate perfusion; 2) postrenal, due to
obstruction of outflow; and 3) intrinsic, due to injury to renal
parenchyma. Among the latter, diseases of, or injury to, glomeruli,
vessels, interstitium, or tubules may lead to a decrease in glomerular
filtration rate (GFR).
Glomerular diseases that lead to acute renal failure are the proliferative
glomerulonephritides, including postinfectious and membranoprolif-
erative glomerulonephritis secondary to glomerular deposition of
immune complexes. If glomerular injury is severe enough to damage
the glomerular basement membrane, leakage of fibrin and other
plasma proteins stimulates formation of cellular extracapillary
“crescents” composed of epithelial cells and monocytes and
macrophages. Crescents may form as a result of an inflammatory
reaction to immune complexes formed to nonglomerular antigens;
antibody reaction to intrinsic glomerular antigens, as in anti–glomerular
basement membrane disease; and, in the absence of immune
complexes, the pauci-immune processes, which include the small
vessel vasculitides, including Wegener’s granulomatosis and microscopic
polyarteritis. Immunohistologic examination and electron microscopy
play important roles in the diagnosis of these processes. Extensive
crescent formation is accompanied by rapidly progressive acute renal CHAPTER
failure. The urine sediment in these diseases often contains red blood
cells and red cell casts.
9
Vascular diseases (involving veins, arteries, or arterioles and capillar-
ies) can lead to hypoperfusion and acute renal failure. Venous thrombo-
sis, most often due to trauma or a nephrotic state, and arterial throm-
bosis due to trauma or vasculitis, cause parenchymal ischemia and
9.2 Acute Renal Failure
infarction. Small vessel vasculitides involve small arteries, arteri- process or associated with immune glomerular injury. Tubulitis
oles, and glomerular capillaries, causing injury and necrosis in the is seen when the inflammatory reaction extends into the tubu-
glomerular tuft, which may result in crescent formation. lar epithelium. Epithelial cell injury is often produced by such
Thrombotic microangiopathies result from endothelial injury inflammatory processes. The urine sediment reveals white
damage in small arteries and arterioles, producing thrombosis, blood cells and white cell casts, which may include numerous
obstruction to blood flow, and glomerular hypoperfusion. Urine polymorphonuclear leukocytes or eosinophils.
sediment in these diseases often shows hematuria or cellular casts, The most common cause of acute renal failure is injury to
reflecting ischemia. tubule epithelium. Primary tubule cell injury typically results
Interstitial inflammatory processes lead to acute renal failure from ischemia, toxic injury, or both. Cell injury results in dis-
via compression of peritubular capillaries or injury to tubules. ruption of the epithelium and its normal reabsorptive func-
Causes of acute interstitial nephritis include infection, and tions, and may lead to obstruction of tubule lumens. Cell exfo-
immune-mediated reactions. With infection, polymorphonu- liation often occurs, and intact cells and cell fragments and
clear leukocytes may be seen in tubules as well as in intersti- debris can be seen in the urine sediment; these may be in the
tium. Inflammatory infiltrates in hypersensitivity reactions, form of casts. Necrotic cells may be seen in situ along the
often due to drug exposure, feature eosinophils. Immuno- tubule epithelium or in the tubule lumen, but often overt cell
histologic studies may reveal the presence of immune complexes; necrosis is not prominent. Apoptosis of tubule cells is seen
immune complex deposition around tubules occurs as a primary after injury as well.
Glomerular Diseases
FIGURE 9-1 (see Color Plate) FIGURE 9-2 (see Color Plate)
Early postinfectious glomerulonephritis. Numerous polymorphonu- A large epithelial crescent fills Bowman’s space and compresses the
clear leukocytes in glomerular capillary loops contribute to the capillary loops in the glomerular tuft. This silver stain highlights
hypercellular appearance of the glomerulus. There is also a segmental the glomerular mesangium and the basement membrane of the
increase in mesangial cells (hematoxylin and eosin, original magnifica- glomerular capillaries (silver stain, original magnification 400).
tion 400). This reactive inflammatory process occurs in response The patient presented with hematuria and acute renal failure.
to glomerular deposition of immune complexes, including the large Immunostains were negative in this case, a finding consistent with
subepithelial “hump-like” deposits which are typical of post-infec- a pauci-immune process. The differential diagnosis includes small
tious glomerulonephritis. The glomerulonephritis is usually self- vessel vasculitis, and anti-neutrophil cytoplasmic antibody may
limited and reversible, and especially with appropriate treatment of be positive. Crescentic glomerulonephritis may also occur with
the underlying infection, long-term prognosis is excellent [1]. anti-glomerular basement membrane antibody disease, or as a
complication of immune complex glomerulonephritis [2].
Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure 9.3
Vascular Diseases
FIGURE 9-4 (see Color Plate)
An early thrombus is seen in a small renal artery in a patient with
patchy cortical infarction (original magnification 250). The
patient presented with acute renal failure. The thrombosis may be
due to a hypercoaggulable state (eg, disseminated intravascular
coaggulation) or endothelial injury (eg, hemolytic uremic syn-
drome). If the cortical necrosis is patchy, recovery of adequate
renal function may occur [3].
A B
FIGURE 9-6 (see Color Plate)
A fine-needle aspirate in renal infarction. A, Low magnification shows edge of an infarct is aspirated (May-Grunwald Giemsa, original mag-
many degenerating cells with a “dirty background” containing cellular nification 40). B, Diffusely degenerated and necrotic cells with con-
debris and scattered neutrophils. Compare to acute tubular necrosis, densed and disrupted cytoplasm and pyknotic nuclei, and an adjacent
which has only scattered degenerated or necrotic cells without the neutrophil. No significant numbers of viable tubule epithelial cells
extensive necrosis and cell debris. Neutrophils may be numerous if the remain (May-Grunwald Giemsa, original magnification 160).
Interstitial Disease
FIGURE 9-10 (see Color Plate) FIGURE 9-11 (see Color Plate)
Interstitial nephritis with edema and a mononuclear inflammatory Tubulitis, with infiltration of mononuclear cells into the tubular
infiltrate. Eosinophils in the infiltrate suggest a possible hypersensi- epithelium (hematoxylin and eosin, original magnification 400).
tivity reaction (hematoxylin and eosin, original magnification There is a mononuclear infiltrate and edema in the surrounding
400). Drugs are the most common cause of such a reaction, which interstitium. Tubule cells may show evidence of lethal or sublethal
often presents with acute renal failure [6]. Inflammatory cells and injury as the inflammatory cells release damaging enzymes. Tubulitis
cell casts may be seen in the urine sediment in these cases, as is often seen in interstitial nephritis especially if the targets of the
inflammatory cells infiltrate the tubular epithelium. inflammatory reaction are tubular cell antigens or antigens deposited
around the tubules. Immunofluorescence may reveal granular or lin-
ear deposits of immunoglobulin and complement around the tubules.
9.6 Acute Renal Failure
A B
FIGURE 9-13 (see Color Plate)
Fine-needle aspirate of acute infectious interstitial nephritis (acute breakdown. In bacterial infection there are many infiltrating neu-
pyelonephritis). A 25-gauge needle attached to a 10-cc syringe was trophils and there may be associated necrosis of tubule epithelial
utilized to withdraw the aspirate into 4 cc of RPMI-based medi- cells (original magnification 80). B, A neutrophil contains
um. The specimen was then cytocentrifuged and stained with phagocytosed bacteria within the cytoplasm; bacteria stain with
May-Grunwald Giemsa. A, The renal aspirate contains large Giemsa, so are readily detectable in this setting. Adjacent tubule
numbers of intrarenal neutrophils, which are focally undergoing epithelial cells have cytoplasmic granules but do not phagocytize
degenerative changes with cytoplasmic vacuolization and nuclear bacteria (original magnification 160).
A B
FIGURE 9-15 (see Color Plate)
Fine-needle aspirate from patient with intrarenal cytomegalovirus viral infections have a similar appearance, and immunostaining or in
(CMV) infection. A, There are activated and transformed lympho- situ hybridization is required to identify specific viruses (May-
cytes with immature nuclear chromatin and abundant blue cyto- Grunwald Giemsa, original magnification 80). B, Tubular epithe-
plasm that infiltrate the kidney in response to the infection; large lial cells stained with antibody to CMV immediate and early nuclear
granular lymphocytes (NK cells) may be seen as well, but few neu- proteins in active intrarenal CMV infection. With an immunoalka-
trophils. Similar activated lymphocytes, NK cells, and atypical line phosphatase method, cytoplasmic and prominent nuclear stain-
monocytes can be observed within the peripheral blood. The tubule ing for these early proteins are observed in the tubular epithelium. In
epithelial cells are virtually never seen to contain CMV inclusions in very early infection, neutrophils also may have cytoplasmic staining
aspirate material, in contrast to core biopsy specimens. All intrarenal for these proteins (original magnification 240).
A B
FIGURE 9-17 (see Color Plate)
Fine-needle aspirate of acute allergic interstitial nephritis. A, The present (May-Grunwald Giemsa, original magnification 80).
aspirate contains numerous lymphocytes, occasional activated B, Higher magnification showing the typical infiltrating cells,
lymphocytes, and eosinophils without fully transformed lymphocytes, including a monocyte, activated lymphocyte, and an eosinophil.
corresponding to the inflammatory component within the tubuloint- A neutrophil is present, likely owing to blood contamination
erstitium observed on routine renal biopsy. Monocytes often are (May-Grunwald Giemsa, original magnification 160).
Tubular Diseases
FIGURE 9-18 (see Color Plate) FIGURE 9-19 (see Color Plate)
Severe vacuolization of tubular cells in injured tubular epithelium Necrotic tubular cells and cell debris in tubular lumina. One tubule
(hematoxylin and eosin, original magnification 400). The vacuoles shows extensive cell loss, with tubular epithelium lined only by a very
reflect cell injury and derangement of homeostatic mechanisms that flattened layer of cytoplasm. The dilated lumen contains numerous
maintain the normal intracellular milieu. In this case, the vacuoles necrotic tubular cells with pyknotic nuclei. Several tubules contain cell
developed on exposure to intravenous immunoglobulin in a sucrose debris and one contains red blood cells (hematoxylin and eosin, origi-
vehicle; the morphology is reminiscent of the severe changes pro- nal magnification 250). Such changes are more often seen with
duced by osmotic agents. While generally a nonspecific marker of toxic than with ischemic injury [6], unless the latter is very severe.
cell injury, a distinctive pattern of “isometric” vacuolization, in
which there are numerous intracellular vacuoles of uniform size
(not shown here) is very typical of cyclosporine/FK506 effect [6].
Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure 9.9
FIGURE 9-20 (see Color Plate) FIGURE 9-21 (see Color Plate)
This micrograph shows sites of cell exfoliation, attenuation of Outer medulla shows in situ cell necrosis and loss in medullary thick
remaining cells, and reactive and regenerative changes (hema- ascending limb (hematoxylin and eosin, original magnification
toxylin and eosin, original magnification 400). Exfoliation 250). Tubules contain cells and cell debris. Changes reflect
occurs with disruption of cell-cell and cell-substrate adhesion, and ischemic injury. Impaction of cells and cast material may lead to
may involve viable as well as non-viable cells [7]. Reactive and tubular obstruction, especially in narrow regions of the nephron.
regenerative changes may include basophilia of cell cytoplasm, Adhesion molecules on the surface of exfoliated cells may contribute
increased nuclear:cytoplasmic ratio, heterogeneity of nuclear size to aggregation of cells within the tubule and adhesion of detached
and appearance, hyperchromatic nuclei and mitotic figures. cells to in situ tubular cells [8].
A B
FIGURE 9-22 (see Color Plate)
Fine-needle aspirate showing acute tubular cell injury and necrosis. cytoplasm, and a pyknotic nucleus. Another cell has more advanced
A, The aspirate shows scattered tubular epithelial cells with swelling necrosis with additional cytoplasmic disruption and a very small
and focal degenerative changes, and a minimal associated inflamma- pyknotic nucleus. Compare the adjacent swollen damaged tubular
tory infiltrate. There is no significant background cell debris (May- cell which has not yet undergone necrosis (May-Grunwald Giemsa,
Grunwald Giemsa, original magnification 40). B, One tubular original magnification 160).
cell is degenerated with reduction in cell size, condensed gray-blue
9.10 Acute Renal Failure
A B
FIGURE 9-24 (see Color Plate)
Myoglobin casts in the tubules of a patient who abused cocaine. A, (original magnification 250). These casts may obstruct the
Hematoxylin and eosin stained casts have a dark red, coarsely gran- nephron, especially with dehydration and low tubular fluid flow
ular appearance (original magnification 250). B, Immunoperoxi- rates. Rhabdomyolysis with formation of intrarenal myoglobin casts
dase stain for myoglobin confirms positive staining in the casts may also occur with severe trauma, crush injury, or extreme exercise.
Renal Histopathology, Urine Cytology, and Cytopathology of Acute Renal Failure 9.11
FIGURE 9-26
Disintegrating Apoptosis-schematic of histologic changes in tubular epithelium.
fragments The process begins with condensation of the cytoplasm and of the
nucleus, a process which involves endonucleases, which digest the
Shrunken cell with DNA into ladder-like fragments characteristic of this process. The
peripheral condensed nuclear cell disintegrates into discrete membrane-bound fragments, so-called
chromatin and intact
“apoptotic bodies.” These fragments may be rapidly extruded into
organelles
the tubular lumen or phagocytosed by neighboring epithelial cells
or inflammatory cells. (Modified from Arends, et al. [10];
with permission.)
Phagocytosed
apoptic cell
fragments
9.12 Acute Renal Failure
Ischemia Toxins
Compression of
peritubular capillaries Loss of tubular
integrity Exfoliation
FIGURE 9-27
A schematic showing the relationship between morphologic and Histology reflects the altered hemodynamics, epithelial derange-
functional changes with injury to the renal tubule due to ischemia ments, and obstruction which contribute to loss of renal function.
or nephrotoxins. Morphologic changes are shown in italics. (Modified from Racusen [11]; with permission.)
References
1. Popovic-Rolovic M, Kostic M, Antic-Peco A, et al.: Medium and 7. Racusen LC, Fivush BA, Li Y-L, et al.: Dissociation of tubular
long-term prognosis of patients with acute post-streptococcal detachment and tubular cell death in clinical and experimental
glomerulonephritis. Nephron 1991, 58:393–399. “acute tubular necrosis.” Lab Invest 1991, 64:546–556.
2. Jennette JC: Crescentic glomerulonephritis. In Heptinstall’s Pathology 8. Goligorsky MS, Lieberthal W, Racusen L, Simon EE: Integrin recep-
of the Kidney, edn. 5. Edited by Jennette JC, JL Olson, M Schwarz, tors in renal tubular epithelium: New insights into pathophysiology
FG Silva. New York:Lippincott-Raven, 1998. of acute renal failure. Am J Physiol 1993, 264:F1–F8.
3. Racusen LC, Solez K: Renal cortical necrosis, infarction and 9. Schumer KM, Olsson CA, Wise GJ, Buttyan R: Morphologic,
atheroembolic disease. In Renal Pathology. Edited by Tisher C, biochemical and molecular evidence of apoptosis during the
B Brenner. Philadelphia:Lippincott-Raven, 1993:811. reperfusion phase after brief periods of renal ischemia.
4. Evert BH, Jennette JC, Falk RJ: The pathogenic role of antineutrophil Am J Pathol 1992, 140:831–838.
cytoplasmic autoantibodies. Am J Kidney Dis 1991, 8:188–195. 10. Arends MJ, Wyllie AH: Apoptosis: Mechanisms and role in
5. Remuzzi G, Ruggenenti P: The hemolytic uremic syndrome. Kidney pathology. Int Rev Exp Pathol 1991, 32:225–254.
Int 1995, 47:2–19. 11. Racusen LC: Pathology of acute renal failure: Structure/function
6. Nadasdy T, Racusen LC: Renal injury caused by therapeutic and correlations. Advances in Renal Replacement Therapy, 1997
diagnostic agents, and abuse of analgesics and narcotics. In Heptinstalls 4(Suppl. 2): 3–16.
Pathology of the Kidney, edn. 5. Edited by Jennette JC, JL Olson,
MM Schwartz, FG Silva. New York:Lippincott-Raven, 1998.
Acute Renal Failure in
the Transplanted Kidney
Kim Solez
Lorraine C. Racusen
A
cute renal failure (ARF) in the transplanted kidney represents a
high-stakes area of nephrology and of transplantation practice.
A correct diagnosis can lead to rapid return of renal function;
an incorrect diagnosis can lead to loss of the graft and severe sequelae
for the patient. The diagnostic possibilities are many (Fig. 10-1) and
treatments quite different, although the clinical presentations of new-
onset functional renal impairment and of persistent nonfunctioning
after transplant may be identical.
In transplant-related ARF percutaneous kidney allograft biopsy
is crucial in differentiating such diverse entities as acute rejection
(Figs. 10-2 to 10-9), acute tubular necrosis (Figs. 10-10 to 10-14),
cyclosporine toxicity (Figs. 10-15 and 10-16), posttransplant lympho-
proliferative disorder (Fig. 10-17), and other, rarer, conditions.
In the case of acute rejection, standardization of transplant biopsy
interpretation and reporting is necessary to guide therapy and to estab-
lish an objective endpoint for clinical trials of new immunosuppressive
agents. The Banff Classification of Renal Allograft Pathology [1] is an
internationally accepted standard for the assessment of renal allograft
biopsies sponsored by the International Society of Nephrology
Commission of Acute Renal Failure. The classification had its origins in
a meeting held in Banff, Alberta, in the Canadian Rockies, in August,
1991, where subsequent meetings have been held every 2 years. Hot
topics likely to influence the Banff Classification of Renal Allograft
Pathology in 1999 and beyond are shown in Figs. 10-17 to 10-19.
CHAPTER
10
10.2 Acute Renal Failure
Acute Rejection
FIGURE 10-1
DIAGNOSTIC POSSIBILITIES IN TRANSPLANT- Diagnostic possibilities in transplant-related acute renal failure.
RELATED ACUTE RENAL FAILURE
FIGURE 10-2
Diagnosis of rejection in the Banff classification makes use of two
basic lesions, tubulitis and intimal arteritis. The 1993–1995 Banff
classification depicted in this figure is the standard in use in virtually
lit gr is re
bu de it ve
is) ee
Lesions-tubulitis, intimal arteritis
and severe forms. The 1997 Banff classification is similar, having the
ild
features of the various types (eg, the finding of tubulitis should not
ve itis
tu ode
re
M
No tubulitis
FIGURE 10-3
Tubulitis is not absolutely specific for acute rejection. It can be
found in mild forms in acute tubular necrosis, normally functioning
kidneys, and in cyclosporine toxicity and in conditions not related
to rejection. Therefore, quantitation is necessary. The number of
lymphocytes situated between and beneath tubular epithelial cells is
compared with the number of tubular cells to determine the severity
of tubulitis. Four lymphocytes per most inflamed tubule cross sec-
tion or per ten tubular cells is required to reach the threshold for
diagnosing rejection. In this figure, the two tubule cross sections in
the center have eight mononuclear cells each. Rejection with intimal
arteritis or transmural arteritis can occur without any tubulitis
whatsoever, although usually in well-established rejection both
tubulitis and intimal arteritis are observed.
Acute Renal Failure in the Transplanted Kidney 10.3
FIGURE 10-8
Arterial lesions in acute rejection Diagram of arterial lesions of acute rejection.
1 8 7 The initial changes (1–5) before intimal
Adventitia arteritis (6) occurs are completely nonspecific.
These early changes are probably mechanisti-
3 10 cally related to the diagnostic lesions but can
occur as a completely self-limiting phenome-
non unrelated to clinical rejection. Lesions 7
Media to 10 are those characteristic of “transmural”
2 rejection. Lesion 1 is perivascular inflamma-
tion; lesion 2, myocyte vacuolization; lesion
Endothelium 11
3, apoptosis; lesion 4, endothelial activation
and prominence; lesion 5, leukocyte adher-
Lumen 6
ence to the endothelium; lesion 6 (specific),
penetration of inflammatory cells under the
endothelium (intimal arteritis); lesion 7,
4 5 9
inflammatory cell penetration of the media;
lesion 8, necrosis of medial smooth muscle
cells; lesion 9, platelet aggregation; lesion 10,
fibrinoid change; and lesion 11 is thrombosis.
FIGURE 10-11 (see Color Plate) FIGURE 10-12 (see Color Plate)
A completely necrotic tubule in the center of the picture in a case of Calcium oxalate crystals seen under polarized light. These are very
acute tubular necrosis (ATN) in an allograft. The tubule is difficult to characteristic of transplant acute tubular necrosis (ATN), probably
identify because, in contrast to the appearance in native kidney ATN, because they relate to some degree to the duration of uremia, which
no residual tubular cells survive; the epithelium is 100% necrotic. is often much longer in transplant ATN (counting the period of
uremia before transplantation) than in native ATN. With prolonged
uremia elevation of plasma oxalate is greater and more persistent
and consequently tissue deposition is greater [4].
Cyclosporine Toxicity
Subclinical Rejection
FIGURE 10-18 (see Color Plate)
Subclinical rejection. Subclinical rejection characterized by moderate
to severe tubulitis may be found in as many as 35% of normally
functioning grafts. Far from representing false-positive readings, such
findings now appear to represent bona fide smoldering rejection that,
if left untreated, is associated with increased incidence of chronic
renal functional impairment and graft loss [10,11]. The important
debate for the future is when to perform protocol biopsies to identify
subclinical rejection and how best to treat it. This picture shows
severe tubulitis in a normally functioning graft 15 months after
transplantation. In the tubule in the center are 30 lymphocytes
(versus 14 tubule cells). A year and a half later the patient developed
renal functional impairment.
Thrombotic Microangiopathy
FIGURE 10-19
Thrombotic microangiopathy in renal allografts. A host of different
conditions and influences can lead to arteriolar and capillary throm-
bosis in renal allografts and these are as various as the first dose reac-
tion to OKT3, HIV infection, episodes of cyclosporine toxicity, and
antibody-mediated rejection [2, 12, 13]. It is hoped that further study
will allow for more accurate diagnosis in patients manifesting this
lesion. The figure shows arteriolar thrombosis and ischemic capillary
collapse in a case of transplant thrombotic microangiopathy.
10.8 Acute Renal Failure
A B
FIGURE 10-20 (see Color Plate)
Peritubular capillary basement membrane ultrastructural changes, of diagnostic utility [16]. Ongoing studies of large numbers of
A, and staining for VCAM-1 as specific markers for chronic rejec- patients using these parameters will test the value of these parame-
tion, B [14–16]. Splitting and multilayering of peritubular capillary ters which may eventually be added to the Banff classification.
basement membranes by electron microscopy holds promise as a A, Multilayering of peritubular capillary basement membrane in a
relatively specific marker for chronic rejection [14,15]. VCAM-1 case of chronic rejection; B, shows staining of peritubular capillaries
staining by immunohistology in these same structures may also be for VCAM-1 by immunoperoxidase in chronic rejection.
References
1. Solez K, Axelsen RA, Benediktsson H, et al.: International standardiza- 9. Wood A, Angus B, Kestevan P, et al.: Alpha interferon gene deletions
tion of criteria for the histologic diagnosis of renal allograft rejection: in post-transplant lymphoma. Br J Haematol 1997, 98(4):1002–1003.
The Banff working classification of kidney transplant pathology. 10. Nickerson P, Jeffrey J, McKenna R, et al.: Do renal allograft function
Kidney Int 1993, 44:411–422. and histology at 6 months posttransplant predict graft function at 2
2. Trpkov K, Campbell P, Pazderka F, et al.: Pathologic features of acute years? Transplant Proc 1997, 29(6):2589–2590.
renal allograft rejection associated with donor-specific antibody, 11. Rush D: Subclinical rejection. Presentation at Fourth Banff
analysis using the Banff grading schema. Transplantation 1996, Conference on Allograft Pathology, March 7–12, 1997.
61(11):1586–1592.
12. Wiener Y, Nakhleh RE, Lee MW, et al.: Prognostic factors and early
3. Solez K, Racusen LC, Marcussen N, et al.: Morphology of ischemic resumption of cyclosporin A in renal allograft recipients with throm-
acute renal failure, normal function, and cyclosporine toxicity in botic microangiopathy and hemolytic uremic syndrome. Clin
cyclosporine-treated renal allograft recipients. Kidney Int 1993, Transplant 1997, 11(3):157–162.
43(5):1058–1067.
13. Frem GJ, Rennke HG, Sayegh MH: Late renal allograft failure
4. Salyer WR, Keren D:Oxalosis as a complication of chronic renal secondary to thrombotic microangiopathy—human immunodeficiency
failure. Kidney Int 1973, 4(1):61–66. virus nephropathy. J Am Soc Nephrol 1994, 4(9):1643–1648.
5. Strom EH, Epper R, Mihatsch MJ: Cyclosporin-associated arteri- 14. Monga G, Mazzucco G, Messina M, et al.: Intertubular capillary
olopathy: The renin producing vascular smooth muscle cells are more changes in kidney allografts: A morphologic investigation on 61 renal
sensitive to cyclosporin toxicity. Clin Nephrol 1995, 43(4):226–231. specimens. Mod Pathol 1992, 5(2):125–130.
6. Trpkov K, Marcussen N, Rayner D, et al.: Kidney allograft with a 15. Mazzucco G, Motta M, Segoloni G, Monga G: Intertubular capillary
lymphocytic infiltrate: Acute rejection, post-transplantation lympho- changes in the cortex and medulla of transplanted kidneys and their
proliferative disorder, neither, or both entities? Am J Kidney Dis 1997, relationship with transplant glomerulopathy: An ultrastructural study
30(3):449–454. of 12 transplantectomies. Ultrastruct Pathol 1994, 18(6):533–537.
7. Sasaki TM, Pirsch JD, D’Alessandro AM, et al.: Increased 2-micro- 16. Solez K, Racusen LC, Abdulkareem F, et al.: Adhesion molecules and
globulin (B2M) is useful in the detection of post-transplant lympho- rejection of renal allografts. Kidney Int 1997, 51(5):1476–1480.
proliferative disease (PTLD). Clin Transplant 1997, 11(1):29–33.
8. Chetty R, Biddolph S, Kaklamanis L, et al.: bcl-2 protein is strongly
expressed in post-transplant lymphoproliferative disorders. J Pathol
1996, 180(3):254–258.
Renal Injury Due To
Environmental Toxins,
Drugs, and Contrast Agents
Marc E. De Broe
T
he kidneys are susceptible to toxic or ischemic injury for sever-
al reasons. Thus, it is not surprising that an impressive list of
exogenous drugs and chemicals can cause clinical acute renal
failure (ARF) [1]. On the contrary, the contribution of environmental
toxins to ARF is rather limited. In this chapter, some of the most com-
mon drugs and exogenous toxins encountered by the nephrologist in
clinical practice are discussed in detail.
The clinical expression of the nephrotoxicity of drugs and chemi-
cals is highly variable and is influenced by several factors. Among
these is the direct toxic effect of drugs and chemicals on a particular
type of nephron cell, the pharmacologic activity of some substances
and their effects on renal function, the high metabolic activity (ie, vul-
nerability) of particular segments of the nephron, the multiple trans-
port systems, which can result in intracellular accumulation of drugs
and chemicals, and the high intratubule concentrations with possible
precipitation and crystallization of particular drugs.
CHAPTER
11
11.2 Acute Renal Failure
ACE inhibitors
NSAIDs
Aminoglycosides
S1 Acyclovir
Cisplatinum
S3 HgCl2
S2 Lithium
S3 Ischemia
Outer
stripe
Outer medulla
Mechanisms
M1 Reduction in renal perfusion through alteration of intrarenal hemodynamics M4 Intratubular obstruction by precipitation of the agents or its metabolites or byproducts
M2 Direct tubular toxicity M5 Allergic interstitial nephritis
M3 Heme pigment–induced toxicity (rhabdomyolysis) M6 Hemolytic-uremic syndrome
M1 M2 M3 M4 M5* M6 Drugs
✓ ✓ ✓ Cyclosporine, tacrolimus
✓ ✓ Amphotericin B, radiocontrast agents
✓ ✓ Nonsteroidal anti-inflammatory drugs
✓ Angiotensin-converting enzyme inhibitors, interleukin-2†
✓ ✓ ✓ Methotrexate§
✓ Aminoglycosides, cisplatin, foscarnet, heavy metals, intravenous immunoglobulin¶, organic solvents, pentamidine
✓ ✓ Cocaine
✓ Ethanol, lovastatin**
✓ ✓ Sulfonamides
✓ Acyclovir, Indinavir, chemotherapeutic agents, ethylene glycol***
✓ Allopurinol, cephalosporins, cimetidine, ciprofloxacin, furosemide, penicillins, phenytoin, rifampin, thiazide diuretics
✓ Conjugated estrogens, mitomycin, quinine
* Many other drugs in addition to the ones listed can cause renal failure by this mechanism.
† Interleukin-2 produces a capillary leak syndrome with volume contractions.
§ Uric acid crystals form as a result of tumor lysis.
¶ The mechanism of this agent is unclear but may be due to additives.
** Acute renal failure is most likely to occur when lovastatin is given in combination with cyclosporine.
*** Ethylene glycol–induced toxicity can cause calcium oxalate crystals.
FIGURE 11-2
Drugs and chemicals associated with acute renal failure. (Apapted from Thadhani, et al. [2].)
11.4 Acute Renal Failure
Aminoglycosides
1. Filtration 2. Binding
+
- + -
Glomerulus
Lysosomal phospholipidosis
- -
ABOVE
threshold: *
lysosomal
swelling, BELOW
3. Adsorptive
pinocytosis disruption * threshold:
or leakage exocytosis
shuttle
4. Lysosomal trapping *
Proximal tubule
and storage
*
Regression of
* drug-induced
changes
Cell necrosis * Aminoglycoside
regeneration * Hydrolase
Toxins
FIGURE 11-3
Renal handling of aminoglycosides: 1) glomerular filtration; After charge-mediated binding, the drug is taken up into the cell
2) binding to the brush border membranes of the proximal in small invaginations of the cell membrane, a process in which
tubule; 3) pinocytosis; and 4) storage in the lysosomes [3]. megalin seems to play a role [6]. Within 1 hour of injection, the
Nephrotoxicity and otovestibular toxicity remain frequent side drug is located at the apical cytoplasmic vacuoles, called endocy-
effects that seriously limit the use of aminoglycosides, a still impor- totic vesicles. These vesicles fuse with lysosomes, sequestering the
tant class of antibiotics. Aminoglycosides are highly charged, poly- unchanged aminoglycosides inside those organelles.
cationic, hydrophilic drugs that cross biologic membranes little, if Once trapped in the lysosomes of proximal tubule cells, amino-
at all [4,5]. They are not metabolized but are eliminated unchanged glycosides electrostatically attached to anionic membrane phospho-
almost entirely by the kidneys. Aminoglycosides are filtered by the lipids interfere with the normal action of some enzymes (ie, phos-
glomerulus at a rate almost equal to that of water. After entering pholipases and sphingomyelinase). In parallel with enzyme inhibi-
the luminal fluid of proximal renal tubule, a small but toxicologi- tion, undigested phospholipids originating from the turnover of cell
cally important portion of the filtered drug is reabsorbed and membranes accumulate in lysosomes, where they are normally
stored in the proximal tubule cells. The major transport of amino- digested. The overall result is lysosomal phospholipidosis due to
glycosides into proximal tubule cells involves interaction with nonspecific accumulation of polar phospholipids as “myeloid bod-
acidic, negatively charged phospholipid-binding sites at the level ies,” so called for their typical electron microscopic appearance.
of the brush border membrane. (Adapted from De Broe [3].)
B
FIGURE 11-4
Ultrastructural appearance of proximal tubule cells in aminoglycoside-treated patients (4 days
of therapeutic doses). Lysosomes (large arrow) contain dense lamellar and concentric struc-
tures. Brush border, mitochondria (small arrows) and peroxisomes are unaltered. At higher
magnification the structures in lysosomes show a periodic pattern. The bar in A represents 1
µm, in part B, 0.1 µm [7].
A
Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents 11.5
A B
FIGURE 11-5 (see Color Plate)
Administration of aminoglycosides for days induces progression
of lysosomal phospholipidosis. The overloaded lysosomes continue
to swell, even if the drug is then withdrawn. In vivo this overload
may result in loss of integrity of the membranes of lysosomes and
release of large amounts of lysosomal enzymes, phospholipids, and
aminoglycosides into the cytosol, but this has not been proven.
Thus, these aminoglycosides can gain access to and injure other
organelles, such as mitochondria, and disturb their functional
integrity, which leads rapidly to cell death. As a consequence
of cell necrosis, A, intratubular obstruction by cell debris increased
intratubule pressure, a decrease in the glomerular filtration rate
and cellular infiltration, B, may ensue. In parallel with these lethal
processes in the kidney, a striking regeneration process is observed
that is characterized by a dramatic increase in tubule cell turnover
C and proliferation, C, in the cortical interstitial compartment.
FIGURE 11-6
200 A, Relationship between constant serum levels and concomitant
renal cortical accumulation of gentamicin after a 6 hour intra-
Vmax= 149.83 + 9.08 µg/g/h
venous infusion in rats. The rate of accumulation is expressed in
micrograms of aminoglycoside per gram of wet kidney cortex per
Renal cortical gentamicin accumulation rate, µg/g/h
100
accumulation rate, µ g/g/h
Renal cortical gentamicin
60
40
50
20 V= 6.44 + 4.88 C
r= 0.96
0
0 5 10 15
Serum gentamicin concentration, µg/ml
0
0 10 20 30 40 50 60 70 80 90 100
A Serum gentamicin concentration, µg/ml
11.6 Acute Renal Failure
Three injections a day ** or by continuous infusion over 8 days. Each block represents the
800 Continuous infusion ** mean of seven rats ±SD. Significance is shown only between cortical
Total daily dose: levels achieved after continuous infusion and single injections (aster-
10 mg/kg i.p. isk—P < 0.05; double asterisk—P < 0.01) [9].
600 **
In rats, nephrotoxicity of gentamicin is more pronounced when the
total daily dose is administered by continuous infusion rather than as a
400 ** single injection. Thus, a given daily drug does not produce the same
degree of toxicity when it is given by different routes. Indeed, renal
cortical uptake is “less efficient” at high serum concentration than at
200 low ones. A single injection results in high peak serum levels that over-
come the saturation limits of the renal uptake mechanism. The high
plasma concentrations are followed by fast elimination and, finally,
0
absence of the drug for a while. This contrasts with the continuous
1 2 4 6 8
low serum levels obtained with more frequent dosing when the uptake
B Days of administration
at the level of the renal cortex is not only more efficient but remains
available throughout the treatment period. Vmax—maximum velocity.
40 40
Renal cortical concentration after one day, µ g/g
One injection a day Continuous infusion (n–6)
25 25
150
20 20
Single injection Single injection
100
15 15
50
10 Continuous infusion 10 Continuous infusion
0
5 5 Gentamicin Netilmicin Tobramycin Amikacin
B 4.5 mg/kg 5 mg/kg 4.5 mg/kg/d 15 mg/kg/d
0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24 FIGURE 11-7
40 90 Course of serum concentrations, A, and of renal cortical concentra-
tions, B, of gentamicin, netilmicin, tobramycin, and amikacin after
Tobramycin Amikacin
dosing by a 30-minute intravenous injection or continuous infusion
35 80
4.5 mg/kg/d 15 mg/kg/d
over 24 hours [10,11].
70 Two trials in humans found that the dosage schedule had a criti-
30
cal effect on renal uptake of gentamicin, netilmicin [10], amikacin,
60 and tobramycin [11]. Subjects were patients with normal renal
Serum levels, µg/ml
FIGURE 11-8
RISK FACTORS FOR AMINOGLYCOSIDE NEPHROTOXICITY Risk factors for aminoglycoside nephro-
toxicity. Several risk factors have been
identified and classified as patient related,
Patient-Related Factors Aminoglycoside-Related Factors Other Drugs aminoglycoside related, or related to con-
current administration of certain drugs.
Older age* Recent aminoglycoside therapy Amphotericin B The usual recommended aminoglycoside
Preexisting renal disease Cephalosporins dose may be excessive for older patients
Female gender Larger doses* Cisplatin because of decreased renal function and
Magnesium, potassium, or Treatment for 3 days or more* Clindamycin decreased regenerative capacity of a dam-
calcium deficiency* aged kidney. Preexisting renal disease
Intravascular volume depletion* Cyclosporine clearly can expose patients to inadvertent
Hypotension* Dose regimen* Foscarnet overdosing if careful dose adjustment is
Hepatorenal syndrome Furosemide not performed. Hypomagnesemia,
Sepsis syndrome Piperacillin hypokalemia, and calcium deficiency may
Radiocontrast agents be predisposing risk factors for conse-
Thyroid hormone quences of aminoglycoside-induced dam-
age [13]. Liver disease is an important
clinical risk factor for aminoglycoside
* Similar to experimental data.
nephrotoxicity, particularly in patients
with cholestasis [13]. Acute or chronic
endotoxemia amplifies the nephrotoxic
potential of the aminoglycosides [14].
FIGURE 11-9
PREVENTION OF AMINOGLYCOSIDE Prevention of aminoglycoside nephrotoxicity. Coadministration
NEPHROTOXICITY of other potentially nephrotoxic drugs enhances or accelerates the
nephrotoxicity of aminoglycosides. Comprehension of the phar-
macokinetics and renal cell biologic effects of aminoglycosides,
Identify risk factor allows identification of aminoglycoside-related nephrotoxicity risk
Patient related factors and makes possible secondary prevention of this important
Drug related
clinical nephrotoxicity.
Other drugs
Give single daily dose of gentamicin, netilmicin, or amikacin
Reduce the treatment course as much as possible
Avoid giving nephrotoxic drugs concurrently
Make interval between aminoglycoside courses as long as possible
Calculate glomerular filtration rate out of serum creatinine concentration
11.8 Acute Renal Failure
Amphotericin B
FIGURE 11-10
Proposed partial model for the amphotericin B (AmB)–induced
Water Lipid
pore in the cell membrane. AmB is an amphipathic molecule: its
Phospho- structure enhances the drug’s binding to sterols in the cell mem-
lipid branes and induces formation of aqueous pores that result in weak-
ening of barrier function and loss of protons and cations from the
cell. The drug acts as a counterfeit phospholipid, with the C15
hydroxyl, C16 carboxyl, and C19 mycosamine groups situated at
the membrane-water interface, and the C1 to C14 and C20 to C33
chains aligned in parallel within the membrane. The heptaene
chain seeks a hydrophobic environment, and the hydroxyl groups
seek a hydrophilic environment. Thus, a cylindrical pore is formed,
Cholesterol the inner wall of which consists of the hydroxyl-substituted carbon
chains of the AmB molecules and the outer wall of which is formed
by the heptaene chains of the molecules and by sterol nuclei [15].
C20-C33 heptaene segment
Amphotericin B
Pore
C
O
N
H
Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents 11.9
FIGURE 11-11
RISK FACTORS IN THE DEVELOPMENT OF Risk factors for development of amphotericin B (AmB) nephrotoxic-
AMPHOTERICIN NEPHROTOXICITY ity. Nephrotoxicity of AmB is a major problem associated with clin-
ical use of this important drug. Disturbances in both glomerular
and tubule function are well described. The nephrotoxic effect of
Age AmB is initially a distal tubule phenomenon, characterized by a loss
Concurrent use of diuretics of urine concentration, distal renal tubule acidosis, and wasting of
Abnormal baseline renal function
potassium and magnesium, but it also causes renal vasoconstriction
leading to renal ischemia. Initially, the drug binds to membrane
Larger daily doses
sterols in the renal vasculature and epithelial cells, altering its mem-
Hypokalemia
brane permeability. AmB-induced vasoconstriction and ischemia to
Hypomagnesemia
very vulnerable sections of the nephron, such as medullary thick
Other nephrotoxic drugs (aminoglycosides, cyclosporine)
ascending limb, enhance the cell death produced by direct toxic
action of AmB on those cells. This explains the salutary effect on
AmB nephrotoxicity of salt loading, furosemide, theophylline, or
calcium channel blockers, all of which improve renal blood flow or
inhibit transport in the medullary thick ascending limb.
FIGURE 11-12
Indication for amphotericin B therapy Proposed approach for management of
Clinical evaluation: Correction: amphotericin B (AmB) therapy. Several new
Is patient salt depleted? Correct salt depletion formulations of amphotericin have been
yes Avoid diuretics developed either by incorporating ampho-
Liberalize dietary sodium
tericin into liposomes or by forming com-
Will salt loading exacerbate underlying disease? yes Weigh risk-benefit ratio plexes to phospholipid. In early studies,
Seek alternatives nephrotoxicity was reduced, allowing an
Does patient require concommitant antibiotics? yes Select drug with high salt content increase of the cumulative dose. Few studies
have established a therapeutic index
Is potassium (K) or magnesium (Mg) depleted? yes Correct abnormalities
between antifungal and nephrotoxic effects
No of amphotericin. To date, the only clinically
Begin amphotericin B with sodium supplement, 150 mEq/d Begin amphotericin B therapy proven intervention that reduces the inci-
dence and severity of nephrotoxicity is salt
supplementation, which should probably be
Routine Monitoring:
given prophylactically to all patients who
Clinical evaluation (cardiovascular/respiratory status; body weight; fluid intake and excretion) can tolerate it. (From Bernardo JF, et al.
Laboratory tests (renal function; serum electrolyte levels; 24 -hours urinary electrolyte excretion)
[16]; with permission.)
Cyclosporine
release of vasoconstrictor prostaglandins such as thromboxane A2,
and activation of the sympathetic nervous system, are among the
candidates for cyclosporine-induced vasoconstriction [18].
The diagnosis of cyclosporine-induced acute renal dysfunction
is not difficult when the patient has no other reason for reduced
renal function (eg, psoriasis, rheumatoid arthritis). In renal trans-
plant recipients, however, the situation is completely different. In
this clinical setting, the clinician must differentiate between cyclo-
sporine injury and acute rejection. The incidence of this acute
cyclosporine renal injury can be enhanced by extended graft preser-
vation, preexisting histologic lesions, donor hypotension, or preop-
erative complications. The gold standard for this important dis-
tinction remains renal biopsy.
In addition, cyclosporine has been associated with hemolytic-ure-
mic syndrome with thrombocytopenia, red blood cell fragmenta-
tion, and intravascular (intraglomerular) coagulation. Again, this
drug-related intravascular coagulation has to be differentiated from
that of acute rejection. The absence of clinical signs and of rejec-
FIGURE 11-13 (see Color Plate) tion-related interstitial edema and cellular infiltrates can be helpful.
Intravascular coagulation in a cyclosporine-treated renal transplant Vanrenterghem and coworkers [19] found a high incidence of
recipient. Cyclosporine produces a dose-related decrease in renal venous thromboembolism shortly after (several of them within
function in experimental animals and humans [17] that is attrib- days) cadaveric kidney transplantation in patients treated with
uted to the drug’s hemodynamic action to produce vasoconstriction cyclosporine, in contrast to those treated with azathioprine. Recent
of the afferent arteriole entering the glomerulus. When severe studies [20] have shown that impaired fibrinolysis, due mainly to
enough, this can decrease glomerular filtration rate. Although the excess plasminogen activator inhibitor (PAI-1), may also contribute
precise pathogenesis of the renal hemodynamic effects of to this imbalance in coagulation and anticoagulation during
cyclosporine are unclear, endothelin, inhibition of nitric oxide, cyclosporine treatment.
FIGURE 11-15
DRUG INTERACTIONS WITH LITHIUM Drug interactions with lithium [24]. Acute renal failure, with or
without oliguria, can be associated with lithium treatment, and with
severe dehydration. In this case, acute renal failure can be consid-
Salt depletion strongly impairs renal elimination of lithium. ered a prerenal type; consequently, it resolves rapidly with appropri-
Salt loading increases absolute and fractional lithium clearance.
ate fluid therapy. Indeed, the histologic appearance in such cases is
remarkable for its lack of significant abnormalities. Conditions that
Diuretics stimulate sodium retention and consequently lithium reabsorption,
Acetazolamide Increased lithium clearance such as low salt intake and loss of body fluid by way of vomiting,
Thiazides Increased plasma lithium level due to decreased diarrhea, or diuretics, decreasing lithium clearance should be avoid-
lithium clearance ed. With any acute illness, particularly one associated with gastroin-
Loop diuretics Acute increased lithium clearance testinal symptoms such as diarrhea, lithium blood levels should be
Amiloride Usually no change in plasma lithium level; may be closely monitored and the dose adjusted when necessary. Indeed,
used to treat lithium-induced polyuria most episodes of acute lithium intoxication are largely predictable,
and thus avoidable, provided that precautions are taken [25].
Nonsteroidal Increased plasma lithium level due to decreased Removing lithium from the body as soon as possible the is the
anti-inflammatory drugs renal lithium clearance (exceptions are aspirin mainstay of treating lithium intoxication. With preserved renal func-
and sulindac)
tion, excretion can be increased by use of furosemide, up to 40 mg/h,
Bronchodilators (amino- Decreased plasma lithium level due to increased
phylline, theophylline) obviously under close monitoring for excessive losses of sodium and
renal lithium clearance
Angiotensin-converting
water induced by this loop diuretic. When renal function is impaired
May increase plasma lithium level
enzyme inhibitors in association with severe toxicity, extracorporeal extraction is the
Cyclosporine most efficient way to decrease serum lithium levels. One should,
Decreased lithium clearance
however, remember that lithium leaves the cells slowly and that plas-
ma levels rebound after hemodialysis is stopped, so that longer dialy-
sis treatment or treatment at more frequent intervals is required.
FIGURE 11-18
PREDISPOSING FACTORS FOR NSAID- Conditions associated with risk for nonsteroidal anti-inflammatory
INDUCED ACUTE RENAL FAILURE drugs (NSAID)-induced acute renal failure. NSAIDs can induce
acute renal decompensation in patients with various renal and
extrarenal clinical conditions that cause a decrease in blood perfu-
Severe heart disease (congestive heart failure) sion to the kidney [32]. Renal prostaglandins play an important
Severe liver disease (cirrhosis) role in the maintenance of homeostasis in these patients, so disrup-
Nephrotic syndrome (low oncotic pressure)
tion of counter-regulatory mechanisms can produce clinically
important, and even severe, deterioration in renal function.
Chronic renal disease
Age 80 years or older
Protracted dehydration (several days)
FIGURE11-19
Physiologic stimulus Inflammatory stimuli Inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) on
pathways of cyclo-oxygenase (COX) and prostaglandin synthesis
Inhibition
- by NSAID - [33]. The recent demonstration of the existence of functionally dis-
tinct isoforms of the cox enzyme has major clinical significance, as
COX-1 COX-2
it now appears that one form of cox is operative in the gastric
constitutive inducible mucosa and kidney for prostaglandin generation (COX-1) whereas
Stomach Kidney Inflammatory sites an inducible and functionally distinct form of cox is operative in
Intestine Platelets (macrophages, the production of prostaglandins in the sites of inflammation and
Endothelium synoviocytes) pain (COX-2) [33]. The clinical therapeutic consequence is that an
NSAID with inhibitory effects dominantly or exclusively upon the
O2 -
cox isoenzyme induced at a site of inflammation may produce the
PGE2 TxA2 PGI2 Inflamma- Proteases
tory PGs desired therapeutic effects without the hazards of deleterious effects
on the kidneys or gastrointestinal tract. PG—prostaglandin;
TxA2—thromboxane A2.
Physiologic functions Inflammation
11.14 Acute Renal Failure
References
1. Bennett WM, Porter GA: Overview of clinical nephrotoxicity. In 20. Verpooten GA, Cools FJ, Van der Planken MG, et al.: Elevated plas-
Toxicology of the Kidney, edn 2. Edited by Hook JB, Goldstein RS. minogen activator inhibitor levels in cyclosporin-treated renal allo-
Raven Press, 1993:61–97. graft recipients. Nephrol Dial Transplant 1996, 11:347–351.
2. Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl J 21. Vestergaard P, Amdisen A, Hansen AE, Schou M: Lithium treatment
Med 1996, 334:1448–1460. and kidney function. Acta Psychiatry Scand 1979; 60:504–520.
3. De Broe ME: Prevention of aminoglycoside nephrotoxicity. In Proc 22. Johnson GF, Hunt G, Duggin GG, et al.: Renal function and lithium
EDTA-ERA. Edited by Davison AM, Guillou PJ. London:BailliËre treatment: initial and follow-up tests in manic-depressive patients.
Tindal, 1985:959–973. J Affective Disord 1984; 6:249–263.
4. Lietman PS: Aminoglycosides and spectinoycin: aminocylitols. In 23. Coppen A, Bishop ME, Bailey JE, et al.: Renal function in lithium
Principles and Practice of Infectious Diseases, edn 2, Part I. Edited by and non–lithium-treated patients with affective disorders. Acta
Mandel GL, Doublas RG Jr, Bennett JE. New York: John Wiley & Psychiatry Scand 1980; 62:343–355.
Sons, 1985:192–206. 24. Battle DC, Dorhout-Mees EJ: Lithium and the kidney. In Clinical
5. Kaloyanides GJ, Pastoriza-Munoz E: Aminoglycoside nephrotoxicity. nephrotoxins—renal injury from drugs and chemicals. Edited by De
Kidney Int 1980, 18:571–582. Broe ME, Porter GA, Bennett WM, Verpooten GA. Dordrecht:
6. Molitoris BA. Cell biology of aminoglycoside nephrotoxicity: newer Kluwer Academic, 1998:383–395.
aspects. Curr Opin Nephrol Hypertens 1997, 6:384–388. 25. Jorgensen F, Larsen S, Spanager E, et al.: Kidney function and quanti-
7. De Broe ME, Paulus GJ, Verpooten GA, et al.: Early effects of gen- tative histological changes in patients on long-term lithium therapy.
tamicin, tobramycin, and amikacin on the human kidney. Kidney Int Acta Psychiatry Scand 1984, 70:455–462.
1984, 25:643–652. 26. Hricik DE, Browning PJ, Kopelman R, et al.: Captopril-induced func-
8. Giuliano RA, Verpooten GA, Verbist L, et al.: In vivo uptake kinetics tional renal insufficiency in patients with bilateral renal artery stenosis
of aminoglycosides in the kidney cortex of rats. J Pharmacol Exp or renal artery stenosis in a solitary kidney. N Engl J Med 1983,
Ther 1986, 236:470–475. 308:373–376.
9. Giuliano RA, Verpooten GA, De Broe ME: The effect of dosing strat- 27. Textor SC: ACE inhibitors in renovascular hypertension. Cardiovasc
egy on kidney cortical accumulation of aminoglycosides in rats. Am J Drugs Ther 1990; 4:229–235.
Kidney Dis 1986, 8:297–303. 28. de Jong PE, Woods LL: Renal injury from angiotensin I converting
10. Verpooten GA, Giuliano RA, Verbist L, et al.: A once-daily dosage enzyme inhibitors. In Clinical nephrotoxins—renal injury from drugs
schedule decreases the accumulation of gentamicin and netilmicin in and chemicals. Edited by De Broe ME, Porter GA, Bennett WM,
the renal cortex of humans. Clin Pharmacol Ther 1989, 44:1–5. Verpooten GA. Dordrecht: Kluwer Academic, 1998:239–250.
11. De Broe ME, Verbist L, Verpooten GA: Influence of dosage schedule 29. Smith WR, Neil J, Cusham WC, Butkus DE: Captopril associated
on renal cortical accumulation of amikacin and tobramycin in man. J acute interstitial nephritis. Am J Nephrol 1989, 9:230–235.
Antimicrob Chemother 1991, 27 (suppl C):41–47. 30. Opie LH: Angiotensin-converting enzyme inhibitors. New York:
12. Bennett WM, Plamp CE, Gilbert DN, et al.: The influence of dosage Willy-Liss, 1992; 3.
regimen on experimental gentamicin nephrotoxicity: dissociation of 31. Whelton A, Watson J: Nonsteroidal anti-inflammatory drugs: effects
peak serum levels from renal failure. J Infect Dis 1979, 140:576–580. on kidney function. In Clinical Nephrotoxins—Renal Injury From
13. Moore RD, Smith CR, Lipsky JJ, et al.: Risk factors for nephrotoxici- drugs and Chemicals. Edited by De Broe ME, Porter GA, Bennett
ty in patients treated with aminoglycosides. Ann Intern Med 1984, WM, Verpooten GA. Dordrecht: Kluwer Academic, 1998:203–216.
100:352–357.
32. De Broe ME, Elseviers MM: Analgesic nephropathy. N Engl J Med
14. Zager RA: A focus of tissue necrosis increases renal susceptibility to 1998, 338:446–452.
gentamicin administration. Kidney Int 1988; 33:84–90.
33. Mitchell JA, Akarasereenont P, Thiemermann C, et al.: Selectivity of
15. Andreoli TE: On the anatomy of amphotericin B-cholesterol pores in nonsteroidal antiinflammatory drugs as inhibitors of constitutive and
lipid bilayer membranes. Kidney Int 1973, 4:337–45. inducible cyclooxygenase. Proc Natl Acad Sci USA 1993,
16. Bernardo J, Sabra R, Branch RA: Amphotericin B. In Clinical 90(24):11693–11697.
Nephrotoxins—Renal Injury From Drugs and Chemicals. Edited by 34. Bennett WM, Henrich WL, Stoff JS: The renal effects of nonsteroidal
De Broe ME, Porter GA, Bennett WM, Verpooten GA. Dordrecht: anti-inflammatory drugs: summary and recommendations. Am J
Kluwer Academic, 1998:135–151. Kidney Dis 1996, 28(1 Suppl 1):S56–S62.
17. Bennett WM: Mechanisms of acute and chronic nephrotoxicity from 35. Heyman SN, Rosen S, Brezis M: Radiocontrast nephropathy: a para-
immunosuppressive drugs. Renal Failure 1996, 18:453–460. digm for the synergism between toxic and hypoxic insults in the kid-
18. de Mattos AM, Olyaei AJ, Bennett WM: Pharmacology of immuno- ney. Exp Nephrol 1994, 2:153.
suppressive medications used in renal diseases and transplantation. 36. Porter GA, Kremer D: Contrast associated nephropathy: presentation,
Am J Kidney Dis 1996, 28:631–667. pathophysiology and management. In Clinical nephrotoxins—Renal
19. Vanrenterghem Y, Lerut T, Roels L, et al.: Thromboembolic complica- Injury From Drugs and Chemicals. Edited by De Broe ME, Porter
tions and haemostatic changes in cyclosporin-treated cadaveric kidney GA, Bennett WM, Verpooten GA. Dordrecht: Kluwer Academic,
allograft recipients. Lancet 1985, 1:999–1002. 1998:317–331.
Diagnostic Evaluation of
the Patient with Acute
Renal Failure
Brian G. Dwinnell
Robert J. Anderson
A
cute renal failure (ARF) is abrupt deterioration of renal func-
tion sufficient to result in failure of urinary elimination of
nitrogenous waste products (urea nitrogen and creatinine).
This deterioration of renal function results in elevations of blood urea
nitrogen and serum creatinine concentrations. While there is no dis-
agreement about the general definition of ARF, there are substantial
differences in diagnostic criteria various clinicians use to define ARF
(eg, magnitude of rise of serum creatinine concentration). From a clin-
ical perspective, for persons with normal renal function and serum
creatinine concentration, glomerular filtration rate must be dramati-
cally reduced to result in even modest increments (eg, 0.1 to 0.3
mg/dL) in serum creatinine concentration. Moreover, several studies
demonstrate a direct relationship between the magnitude of serum
creatinine increase and mortality from ARF. Thus, the clinician must
carefully evaluate all cases of rising serum creatinine.
The process of urine formation begins with delivery of blood to the
glomerulus, filtration of the blood at the glomerulus, further process-
ing of the filtrate by the renal tubules, and elimination of the formed
urine by the renal collecting system. A derangement of any of these
processes can result in the clinical picture of rapidly deteriorating
renal function and ARF. As the causes of ARF are multiple and since
subsequent treatment of ARF depends on a clear delineation of the CHAPTER
cause, prompt diagnostic evaluation of each case of ARF is necessary.
12
12.2 Acute Renal Failure
Common
Common Rising BUN or creatinine
Present in 1%–2% of hospital admissions Oligoanuria
Develops after admission in 1%–5% of noncritically ill patients Less common
Develops in 5%–20% after admission to an intensive care unit Symptoms of uremia
Multiple causes Characteristic laboratory abnormalities
Prerenal
Postrenal
Renal
Therapy dependent upon diagnosing cause FIGURE 12-2
Prerenal: improve renal perfusion Presenting features of acute renal failure (ARF). ARF usually comes
Postrenal: relieve obstruction to clinical attention by the finding of either elevated (or rising)
Renal: identify and treat specific cause blood urea nitrogen (BUN) or serum creatinine concentration. Less
Poor outcomes commonly, decreased urine output ( less than 20 mL per hour) her-
Twofold increased length of stay alds the presence of ARF. It is important to acknowledge, however,
Two- to eightfold increased mortality that at least half of all cases of ARF are nonoliguric [2–6]. Thus,
Substantial morbidity healthy urine output does not ensure normal renal function. Rarely,
ARF comes to the attention of the clinician because of symptoms
of uremia (eg, anorexia, nausea, vomiting, confusion, pruritus) or
laboratory findings compatible with renal failure (metabolic acido-
sis, hyperkalemia, hyperphosphatemia, hypocalcemia, hyper-
FIGURE 12-1
uricemia, hypermagnesemia, anemia).
Rationale for an organized approach to acute renal failure (ARF).
An organized approach to the patient with ARF is necessary, as this
disorder is common and is caused by several insults that operate via
numerous mechanisms. Successful amelioration of the renal failure
state depends on early identification and treatment of the cause of
the disorder [1–7]. If not diagnosed and treated and reversed quick-
ly, it can lead to substantial morbidity and mortality.
FIGURE 12-4
BLOOD UREA NITROGEN (BUN)-CREATININE RATIO The blood urea nitrogen (BUN)-creatinine ratio. Based on the infor-
mation in Figure 12-3, the BUN-creatinine ratio often deviates from
the usual value of about 10:1. These deviations may have modest
diagnostic implications. As an example, for reasons as yet unclear,
> 10 < 10
tubular reabsorption of urea nitrogen is enhanced in low-urine flow
Increased protein intake Starvation states. Thus, a high BUN-creatinine ratio often occurs in prerenal
Catabolic state Advanced liver disease and postrenal (see Fig. 12-6) forms of renal failure. Similarly,
Fever Postdialysis state enhanced delivery of amino acids to the liver (as with catabolism,
Sepsis Drugs that impair tubular secretion corticosteroids, etc.) can enhance urea nitrogen formation and
Trauma Cimetidine increase the BUN-creatinine ratio. A BUN-creatinine ratio lower
Corticosteroids Trimethoprim than 10:1 can occur because of decreased urea nitrogen formation
Tissue necrosis Rhabdomyolysis (eg, in protein malnutrition, advanced liver disease), enhanced creati-
Tetracyclines nine formation (eg, with rhabdomyolysis), impaired tubular secretion
of creatinine (eg, secondary to trimethoprim, cimetidine), or relative-
Diminished urine flow
ly enhanced removal of the small substance urea nitrogen by dialysis.
Prerenal state
Postrenal state
FIGURE 12-5
CORRELATION OF STEADY-STATE SERUM Correlation of steady-state serum creatinine concentration and
CREATININE CONCENTRATION AND glomerular filtration rate (GFR).
GLOMERULAR FILTRATION RATE (GFR)
FIGURE 12-6
Renal Failure Categories of renal failure. Once the presence of renal failure is
ascertained by elevated blood urea nitrogen (BUN) or serum creati-
nine value, the clinician must decide whether it is acute or chronic.
Favors Favors When previous values are available for review, this judgment is
acute chronic made relatively easily. In the absence of such values, the factors
depicted here may be helpful. Hemoglobin potentially undergoes
Normal Kidney size Small nonenzymatic carbamylation of its terminal valine [8]. Thus, simi-
lar to the hemoglobin A1C value as an index of blood sugar con-
Normal Carbamylated hemoglobin High trol, the level of carbamylated hemoglobin is an indicator of the
degree and duration of elevated BUN, but, this test is not yet wide-
Absent Broad casts on urinalysis Present ly available. The presence of small kidneys strongly suggests that
renal failure is at least in part chronic. From a practical standpoint,
History of kidney disease, because even chronic renal failure often is partially reversible, the
Absent hypertension, Present clinician should assume and evaluate for the presence of acute
abnormal urinalysis
reversible factors in all cases of acute renal failure.
Usually Sometimes,
complete Reversibility with time partial
12.4 Acute Renal Failure
FIGURE 12-8
VASOMOTOR MECHANISMS CONTRIBUTING TO ACUTE RENAL FAILURE Vasomotor mechanisms contributing to acute
renal failure (ARF). Most prerenal forms of
ARF have operational one or more of the
Decreased Renal vasomotor mechanisms depicted here [6].
Perfusion Pressure Afferent Arteriolar Constriction Efferent Arteriolar Dilation Collectively, these factors lead to diminished
glomerular filtration and ARF. NSAIDs—
Extracellular fluid volume loss Sepsis Converting enzyme inhibitors nonsteroidal anti-inflammatory drugs.
or sequestration Medications (NSAIDs, cyclosporine, Angiotensin II receptor antagonists
Impaired cardiac output contrast medium, amphotericin,
Antihypertensive medications alpha-adrenergic agonists)
Sepsis Hypercalcemia
Postoperative state
Hepatorenal syndrome
Diagnostic Evaluation of the Patient with Acute Renal Failure 12.5
FIGURE 12-9
DIAGNOSIS OF POSSIBLE PRERENAL CAUSES OF ACUTE RENAL FAILURE Diagnosis of possible prerenal causes of
acute renal failure (ARF). Prerenal events
are the most common factors that lead to
History Examination Laboratory/Other contemporary ARF. The historical, physical
examination, and laboratory and other
Extracellular fluid loss or sequestra- Orthostatic hypotension Normal urinalysis investigations involved in identifying a pre-
tion from skin, gastrointestinal and tachycardia Urinary indices compatible with normal renal form of ARF are outlined here [1].
and/or renal source (see Fig. 12-15) Dry mucous membranes tubular function (see Fig. 12-14) BUN—blood urea nitrogen.
Orthostatic lightheadedness No axillary moisture Elevated BUN-creatinine ratio
Thirst Decreased skin turgor Improved renal function with correction
Oliguria Evidence of congestive of the underlying cause
Symptoms of heart failure heart failure Rarely, chest radiography, cardiac ultra-
Edema Presence of edema sound, gated blood pool scan, central
venous and/or Swan-Ganz wedge
pressure recordings
FIGURE 12-10
DIAGNOSIS OF POSSIBLE POSTRENAL CAUSES OF ACUTE RENAL FAILURE Diagnosis of possible postrenal causes of
acute renal failure (ARF). Postrenal causes
of ARF are less common (5% to 15% of
History Examination Laboratory/Other ARF population) but are nearly always
amenable to therapy. This figure depicts the
Very young or very old age Distended bladder Abnormal urinalysis historical, physical examination and tests
Nocturia Enlarged prostate Elevated BUN-creatinine ratio that can lead to an intrarenal (crystal depo-
Decreased size or force of urine stream Abnormal pelvic examination Elevated postvoiding sition) or extrarenal (blockade of the col-
Anticholinergic or alpha-adrenergic residual volume lecting system) form of obstructive uropa-
agonist medications Abnormal renal ultrasound, thy [1, 6, 9, 10]. BUN—blood urea nitro-
Bladder, prostate, pelvic, or CT or MRI findings gen; CT—computed tomography;
intra-abdominal cancer Improvement after drainage MRI—magnetic resonance imaging.
Fluctuating urine volume
Oligoanuria
Suprapubic pain
Urolithiasis
Medication known to produce
crystalluria (sulfonamides, acyclovir,
methotrexate, protease inhibitors)
FIGURE 12-11
POSTOPERATIVE ACUTE RENAL FAILURE Postoperative acute renal failure (ARF).
The postoperative setting of ARF is very
common. This figure depicts data on the
Frequency Predisposing Factors Preventive Strategies frequency, predisposing factors, and poten-
tial strategies for preventing postoperative
Elective surgery 1%–5% Comorbidity results in decreased Avoid nephrotoxins ARF [11, 12].
Emergent or vascular renal reserve Minimize hospital-acquired infections
surgery 5%–10% The surgical experience decreases (invasive equipment)
renal function (volume shifts, Selective use of volume expansion,
vasoconstriction) vasodilators, inotropes
A second insult usually occurs Preoperative hemodynamic optimization
(sepsis, reoperation, nephrotoxin, in selected cases
volume/cardiac issue) Increase tissue oxygenation delivery to
supranormal levels in selected cases
12.6 Acute Renal Failure
FIGURE 12-13
First step in evaluation of acute renal failure.
FIGURE 12-14
SECOND STEP IN EVALUATION Second step in evaluation of acute renal failure.
OF ACUTE RENAL FAILURE
Normal Abnormal
FIGURE 12-15
Urinalysis in acute renal failure (ARF). A normal urinalysis suggests White blood cells (WBCs) can also be present in small numbers in
a prerenal or postrenal form of ARF; however, many patients with the urine of patients with ARF. Large numbers of WBCs and WBC
ARF of postrenal causes have some cellular elements on urinalysis. casts strongly suggest the presence of either pyelonephritis or acute
Relatively uncommon causes of ARF that usually present with interstitial nephritis. Eosinolphiluria (Hansel’s stain) is often present
oligoanuria and a normal urinalysis are mannitol toxicity and large in either allergic interstitial nephritis or atheroembolic disease [13,
doses of dextran infusion. In these disorders, a “hyperoncotic state” 14]. Renal tubular epithelial (RTE) cells and casts and pigmented
occurs in which glomerular capillary oncotic pressure, combined granular casts typically are present in pigmenturia-associated ARF
with the intratubular hydrostatic pressure, exceeds the glomerular (see Fig. 12-21) and in established acute tubular necrosis (ATN).
capillary hydrostatic pressure and stop glomerular filtration. Red The presence of large numbers of crystals on urinalysis, in conjunc-
blood cells (RBCs) can be seen with all renal forms of ARF. When tion with the clinical history, may suggest uric acid, sulfonamides, or
RBC casts are present, glomerulonephritis or vasculitis is most likely. protease inhibitors as a cause of the renal failure.
FIGURE 12-16
Urinary diagnostic indices Urinary diagnostic indices in acute renal failure (ARF). These
in acute renal failure indices have traditionally been used in the setting of oliguria, to
help differentiate between prerenal (intact tubular function) and
acute tubular necrosis (ATN, impaired tubular function). Several
caveats to interpretation of these indices are in order [1]. First, none
Prerenal Renal of these is completely sensitive or specific in differentiating the prer-
enal from the ATN form of ARF. Second, often a continuum exists
Hyaline casts Urinalysis Abnormal between early prerenal conditions and late prerenal conditions that
>1.020 Specific gravity ~1.010 lead to ischemic ATN. Most of the data depicted here are derived
>500 Uosm (mOsm/kg H2O) >300 from patients relatively late in the progress of ARF when the serum
<20 Una (mEq/L) >40 creatinine concentrations were 3 to 5 mg/dL. Third, there is often a
<1 FE Na (%) >2
relatively large “gray area,” in which the various indices do not give
<7 FE uric acid (%) >15
<7 FE lithium (%) >20
definitive results. Finally, some of the indices (eg, fractional excre-
tion of endogenous lithium [FE lithium]) are not readily available in
the clinical setting. The fractional excretion (FE) of a substance is
determined by the formula: U/P substance U/P creatinine 100.
U/P—urine-plasma ratio.
Diagnostic Evaluation of the Patient with Acute Renal Failure 12.9
FIGURE 12-18
DIAGNOSIS OF POSSIBLE VASCULAR CAUSE OF ACUTE RENAL FAILURE Diagnosis of a possible vascular cause of
acute renal failure (ARF). This figure depicts
the historical, physical examination, and
History Examination Laboratory/Other testing procedures that often lead to diagno-
sis of a “vascular cause” of ARF [1, 15, 16].
Factors that predispose to vascular disease Marked hypertension Thrombocytopenia
(smoking, hypertension, diabetes mellitus, Atrial fibrillation Microangiopathic hemolysis
hyperlipidemia) Scleroderma Coagulopathy
Claudication, stroke, myocardial infarction Palpable purpura Urinalysis with hematuria and
Surgical procedure on aorta Abdominal low-grade proteinuria
Catheterization procedure involving aorta aortic aneurysm Abnormal renal isotope scan
Selected clinical states (scleroderma, pregnancy) Diminished pulses and/or Doppler ultrasonography
Selected medications, toxins (cyclosporine, Infarcted toes Renal angiography
mitomycin C, cocaine, tacrolimus) Hollendhorst plaques Renal or extrarenal tissue analysis
Constitutional symptoms Vascular bruits
Stigmata of
bacterial endocarditis
Illeus
12.10 Acute Renal Failure
Acute Glomerulonephritis
FIGURE 12-19
DIAGNOSIS OF A POSSIBLE ACUTE GLOMERULAR Diagnosis of a possible acute glomerular
PROCESS AS THE CAUSE OF ACUTE RENAL FAILURE process as the cause of acute renal failure
(ARF). Acute glomerulonephritis is a rela-
tively rare cause of ARF in adults. In the
History Examination Laboratory/Other pediatric age group, acute glomerulonephri-
tis and a disorder of small renal arteries
Recent infection Hypertension Urinalysis with hematuria, red cell (hemolytic-uremic syndrome) are relatively
Sudden onset of edema, dyspnea Edema casts, and proteinuria common causes. This figure depicts the his-
Systemic disorder Rash Serologic or culture evidence of torical, examination, and laboratory find-
(eg, lupus erythematosus, Wegener’s recent infection
Arthropathy ings that collectively may support a diagno-
granulomatosis, Goodpasture’s syndrome) Laboratory evidence of immune-
Prominent sis of acute glomerulonephritis as the cause
No evidence of other causes of renal failure pulmonary findings mediated process (low complement,
cryoglobulinemia, antinuclear anti- of ARF [16, 17].
Stigmata of bacterial
body, anti-DNA, rheumatoid factor,
endocarditis or
anti–glomerular basement mem-
visceral abscess
brane antibody, antineutrophilic
cytoplasmic antibody)
Renal tissue examination
Interstitial Nephritis
FIGURE 12-20
DIAGNOSIS OF POSSIBLE ACUTE INTERSTITIAL Diagnosis of possible acute interstitial
NEPHRITIS AS THE CAUSE OF ACUTE RENAL FAILURE nephritis as the cause of acute renal failure
(ARF). This figure outlines the historical,
physical examination and other investiga-
History Examination Laboratory/Other tive methods that can lead to identification
of acute interstitial nephritis as the cause
Medication exposure Fever Abnormal urinalysis (white blood cells or cell casts, of ARF [18].
Severe pyelonephritis Rash eosinophils, eosinophilic casts, low-grade proteinuria,
Systemic infection Back or flank pain sometimes hematuria)
Eosinophilia
Urinary diagnositc indices compatible with a renal cause
of renal failure (see Fig. 12-16)
Uptake on gallium or indium scan
Renal biopsy
Diagnostic Evaluation of the Patient with Acute Renal Failure 12.11
Myoglobinuria Hemoglobinuria
History Examination Laboratory History Examination Laboratory
Trauma to muscles Can be normal Serum creatinine disproportionately Condition associated with Can be normal Normocytic anemia
Condition known Muscle edema, elevated related to BUN intravascular hemolysis Pallor High red cell LDH fraction
to predispose to weakness, pain Elevated (10-fold) enzymes (red cell trauma, antibody- Flank pain Reticulocytosis
nontraumatic Neurovascular (CK, SGOT, LDH, adolase) mediated hemolysis, direct red
Low haptoglobin
rhabdomyolysis entrapment or com- Elevations of plasma potassium, cell toxicity, sickle cell disease)
Urinalysis with pigmented
Muscle pain partment syndromes uric acid, phosphorus, and granular casts, () stick
or stiffness in severe cases hypocalcemia reaction for blood in absence
Dark urine Flank pain Urinalysis with pigmented granular of hemataria and reddish
casts, () stick reaction for blood brown or pink plasma
in the absence of hematuria, and
myoglobin test if available
Clear plasma
FIGURE 12-21
Diagnosis of possible pigment-associated forms of acute renal failure of ATN is supported by the absence of other causes of ARF, the pres-
(ARF). Once prerenal and postrenal forms of ARF have been ruled ence of one or more predisposing factors, and the presence of urinary
out and renal vascular, glomerular, and interstitial processes seem diagnostic indices and urinalysis suggested of ATN (see Figs. 12-15
unlikely, a diagnosis of acute tubular necrosis (ATN) is probable. A and 12-16). A pigmenturic disorder (myloglobinuria or hemoglobin-
diagnosis of ATN is thus one of exclusion (of other causes of ARF). uria) can predispose to ARF. This figure depicts the historical, physi-
In the majority of cases when ATN is present, one or more of the cal examination, and supporting diagnostic tests that often lead to a
three predisposing conditions have been identified to be operational. diagnosis of pigment-associated ARF [19]. BUN—blood urea nitro-
These conditions include renal ischemia due to a prolonged prerenal gen; CK—creatinine kinase; SGOT—serum glutamic-oxaloacetic
state, nephrotoxin exposure, and sometimes pigmenturia. A diagnosis transaminase; LDH—lactic dehydrogenase.
References
1. Anderson RJ, Schrier RW: Acute renal failure. In Diseases of the 12. Kellerman PS: Perioperative care of the renal patient. Arch Intern Med
Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown; 1994, 154:1674–1681.
1997:1069–1113. 13. Nolan CR, Anger MS, Kelleher SP: Eosinophiluria —a new method of
2. Hou SH, Bushinsky D, Wish JB, Harrington JT: Hospital-acquired detection and definition of the clinical spectrum. N Engl J Med 1986,
renal insufficiency: A prospective study. Am J Med 1983, 315:1516–1519.
74:243–248. 14. Wilson DM, Salager TL, Farkouh ME: Eosinophiluria in atheroem-
3. Shusterman N, Strom BL, Murray TG, et al.: Risk factors and out- bolic renal disease. Am J Med 1991, 91:186–191.
come of hospital-acquired acute renal failure. Am J Med 1987, 15. Abuelo JG: Diagnosing vascular causes of acute renal failure. Ann
83:65–71. Intern Med 1995, 123:601–614.
4. Levy EM, Viscoli CM, Horwitz RI: The effect of acute renal failure 16. Falk RJ, Jennette JC: ANCA small-vessel vasculitis. J Am Soc Nephrol
on mortality. JAMA 1996, 275:1489–1494. 1997, 8:314–322.
~ F, Pascual J: Epidemiology of acute renal failure: A prospective,
5. Liano 17. Kobrin S, Madacio MP: Acute poststreptococcal glomerulonephritis
multicenter, community-based study. Kid Int 1996, 50:811–818. and other bacterial infection-related glomerulonephritis. In Diseases
6. Thadhani R, Pascual M, Bonventre JV: Acute renal failure. New Engl of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little,
J Med 1996, 334:1448–1460. Brown; 1997:1579–1594.
7. Feest TG, Round A, Hamad S: Incidence of severe acute renal failure 18. Eknoyan G: Acute tubulointerstitial nephritis. In Diseases of the
in adults: Results of a community-based study. Br Med J 1993, Kidney. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown;
306:481–483. 1997:1249–1272.
8. Davenport A: Differentiation of acute from chronic renal impairment 19. Don BR, Rodriguez RA, Humphreys MH: Acute renal failure associ-
by detection of carbamylated hemoglobin. Lancet 1993, ated with pigmenturia as crystal deposits. In Diseases of the Kidney.
341:1614–1616. Edited by Schrier RW, Gottschalk CW. Boston: Little, Brown;
9. Mendell JA, Chertow GM: A practical approach to acute renal fail- 1997:1273–1302.
ure. Med Clin North Am 1997, 81:731–748. 20. Chaudbury O, Ahmed Z: Drug-induced nephrotoxicity. Med Clin
10. Kopp JB, Miller KD, Mican JM, et al.: Crystalluria and urinary tract North Am 1997, 81:705–717.
abnormalities associated with indinovir. Ann Intern Med 1997, 21. Palmer B, Henrich WL: Nephrotoxicity of nonsteroidal anti-inflamma-
127:119–125. tory agents, analgesics, and angiotensin converting enzyme inhibitors. In
11. Charlson ME, MacKenzie CR, Gold JP, Shires T: Postoperative Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW. Boston:
changes in serum creatinine. Ann Surg 1989, 209:328–335. Little, Brown; 1997:1167–1188.
Pathophysiology of Ischemic
Acute Renal Failure:
Cytoskeletal Aspects
Bruce A. Molitoris
Robert Bacallao
I
schemia remains the major cause of acute renal failure (ARF) in the
adult population [1]. Clinically a reduction in glomerular filtration
rate (GFR) secondary to reduced renal blood flow can reflect
prerenal azotemia or acute tubular necrosis (ATN). More appropriate
terms for ATN are acute tubular dysfunction or acute tubular injury,
as necrosis only rarely is seen in renal biopsies, and renal tubular cell
injury is the hallmark of this process. Furthermore, the reduction in GFR
during acute tubular dysfunction can now, in large part, be related to
tubular cell injury. Ischemic ARF resulting in acute tubular dysfunc-
tion secondary to cell injury is divided into initiation, maintenance,
and recovery phases. Recent studies now allow a direct connection to
be drawn between these clinical phases and the cellular phases of
ischemic ARF (Fig. 13-1). Thus, renal function can be directly related
to the cycle of cell injury and recovery.
Renal proximal tubule cells are the cells most injured during renal
ischemia (Fig. 13-2) [2,3]. Proximal tubule cells normally reabsorb 70%
to 80% of filtered sodium ions and water and also serve to selectively
reabsorb other ions and macromolecules. This vectorial transport across
the cell from lumen to blood is accomplished by having a surface mem-
brane polarized into apical (brush border membrane) and basolateral
membrane domains separated by junctional complexes (Fig. 13-3) [4].
Apical and basolateral membrane domains are biochemically and CHAPTER
functionally different with respect to many parameters, including
enzymes, ion channels, hormone receptors, electrical resistance,
13
membrane transporters, membrane lipids, membrane fluidity, and
cytoskeletal associations. This epithelial cell polarity is essential for
normal cell function, as demonstrated by the vectorial transport of
sodium from the lumen to the blood (see Fig. 13-3). The establishment
13.2 Acute Renal Failure
and maintenance of this specialized organization is a dynamic induced by ischemia can be mimicked by F-actin disassembly
and ATP dependent multistage process involving the formation mediated by cytochalasin D [11]. Although these correlations
and maintenance of cell-cell and cell-substratum attachments are highly suggestive of a central role for actin alterations in the
and the targeted delivery of plasma membrane components to pathophysiology of ischemia-induced surface membrane dam-
the appropriate domains [5]. These processes are very dependent age they fall short in providing mechanistic data that directly
on the cytoskeleton, in general, and the cytoskeletal membrane relate actin cytoskeletal changes to cell injury.
interactions mediated through F-actin (see Fig. 13-2, 13-3), in Proximal tubule cell injury during ischemia is also known to
particular. be principally responsible for the reduction in GFR. Figure 13-5
Ischemia in vivo and cellular ATP depletion in cell culture illustrates the three known pathophysiologic mechanisms that
models (“chemical ischemia”) are known to produce character- relate proximal tubule cell injury to a reduction in GFR.
istic surface membrane structural, biochemical, and functional Particularly important is the role of the cytoskeleton in mediating
abnormalities in proximal tubule cells. These alterations occur these three mechanisms of reduced GFR. First, loss of apical
in a duration-dependent fashion and are illustrated in Figures membrane into the lumen and detachment of PTC result in sub-
13-2 and 13-3 and listed in Figure 13-4. Ischemia-induced strate for cast formation. Both events have been related to actin
alterations in the actin cytoskeleton have been postulated to cytoskeletal and integrin polarity alterations [12–15]. Cell
mediate many of the aforementioned surface membrane detachment and the loss of integrin polarity are felt to play a
changes [2,6,7]. This possible link between ischemia-induced central role in tubular obstruction (Fig. 13-6). Actin cytoskeletal-
actin cytoskeletal alterations and surface membrane structural mediated tight junction opening during ischemia occurs and
and functional abnormalities is suggested by several lines. First, results in back-leak of glomerular filtrate into the blood. This
the actin cytoskeleton is known to play fundamental roles in results in ineffective glomerular filtration (Fig. 13-7). Finally,
surface membrane formation and stability, junctional complex abnormal proximal sodium ion reabsorption results in large
formation and regulation, Golgi structure and function, and distal tubule sodium delivery and a reduction in GFR via tubu-
cell–extracellular membrane attachment [2,4,5,8]. Second, loglomerular feedback mechanisms [2,16,17].
proximal tubule cell actin cytoskeleton is extremely sensitive to In summary, ischemia-induced alterations in proximal tubule
ischemia and ATP depletion [9,10]. Third, there is a strong cell surface membrane structure and function are in large part
correlation between the time course of actin and surface mem- responsible for cell and organ dysfunction. Actin cytoskeletal
brane alterations during ischemia or ATP depletion [2,9,10]. dysregulation during ischemia has been shown to be responsi-
Finally, many of the characteristic surface membrane changes ble for much of the surface membrane structural damage.
FIGURE 13-1
RELATIONSHIP BETWEEN THE CLINICAL AND CELLULAR Relationship between the clinical and cellular phases of ischemic
PHASES OF ISCHEMIC ACUTE RENAL FAILURE acute renal failure. Prerenal azotemia results from reduced renal
blood flow and is associated with reduced organ function (decreased
glomerular filtration rate), but cellular integrity is maintained
Clinical Phases Cellular Phases through vascular and cellular adaptive responses. The initiation
phase occurs when renal blood flow decreases to a level that results
Prerenal azotemia Vascular and cellular adaptation in severe cellular ATP depletion that, in turn, leads to acute cell
↓ ↓ injury. Severe cellular ATP depletion causes a constellation of cellular
Initiation ATP depletion, cell injury alterations culminating in proximal tubule cell injury, cell death, and
↓ ↓ organ dysfunction [2]. During the clinical phase known as mainte-
Maintenance Repair, migration, apoptosis, proliferation nance, cells undergo repair, migration, apoptosis, and proliferation in
↓ ↓ an attempt to re-establish and maintain cell and tubule integrity [3].
Recovery Cellular differentiation This cellular repair and reorganization phase results in slowly
improving cell and organ function. During the recovery phase,
cell differentiation continues, cells mature, and normal cell and
organ function return [18].
Pathophysiology of Ischemic Acute Renal Failure: Cytoskeletal Aspects 13.3
A B C
D E F
FIGURE 13-2
Ischemic acute renal failure in the rat kidney. Light A, B, trans-
mission electron, C, D, and immunofluorescence E, F, micro-
MV scopy of control renal cortical sections, A, C, E, and after mod-
erate ischemia induced by 25 minutes of renal artery occlusion,
B, D, F. Note the extensive loss of apical membrane structure,
B, D, in proximal (PT) but not distal tubule cells. This has been
shown to correlate with extensive alterations in F-actin as shown
ZO by FITC-phalloidin labeling, E, F. G, Drawing of a proximal
tubule cell under physiologic conditions. Note the orderly
arrangement of the actin cytoskeleton and its extensive interac-
tion with the surface membrane at the zonula occludens (ZO,
ZA tight junction) zonula adherens (ZA, occludens junction), inter-
actions with ankyrin to mediate Na+, K+-ATPase [2] stabilization
MT
x and cell adhesion molecule attachment [5,8]. The actin cyto-
N skeleton also mediates attachment to the extracellular matrix
(ECM) via integrins [12,15]. Microtubules (MT) are involved in
the polarized delivery of endocytic and exocytic vesicles to the
surface membrane. Finally, F-actin filaments bundle together via
x actin-bundling proteins [19] to mediate amplification of the api-
HD cal surface membrane via microvilli (MV). The actin bundle
attaches to the surface membrane by the actin-binding proteins
ECM myosin I and ezrin [19,20].
G
13.4 Acute Renal Failure
FIGURE 13-3
Proximal tubule cell Fate of an injured proximal tubule cell.
The fate of a proximal tubule cell after an
ischemic episode depends on the extent and
ADP ATP duration of the ischemia. Cell death can
+
+P
1 K occur immediately via necrosis or in a more
programmed fashion (apoptosis) hours to
Ischemia Necrosis days after the injury. Fortunately, most cells
Death recover either in a direct fashion or via
+ Na+
d Na d an intermediate undifferentiated cellular
ate ure
nti Inj
+ Recovery +
re K ADP K ADP Apoptosis pathway. Again, the severity of the injury
D iffe ATP +P ATP +P
1 1 determines the route taken by a particular
ECM cell. Adjacent cells are often injured to
Na+ varying degrees, especially during mild to
moderate ischemia. It is believed that the
rate of organ functional recovery relates
directly to the severity of cell injury during
d the initiation phase. ECM—extracellular
ate
enti
iffe
r membrane; Na+—sodium ion; K+—potassi-
d
Un um ion; P1—phosphate.
FIGURE 13-4
ISCHEMIA INDUCED PROXIMAL TUBULE CELL ALTERATIONS Ischemia induced proximal tubule cell
alterations.
Alterations References
Surface Membrane Alterations
1. Microvilli fusion, internalization, fragmentation and luminal shedding resulting in loss of [21]
surface membrane area and tubular obstruction
2. Loss of surface membrane polarity for lipids and proteins [2,22,23]
3. Junctional complex dissociation with unregulated paracellular permeability (backleak) [6,24–27]
4. Reduced PTC vectorial transport [28]
Actin Cytoskeletal Alterations
1. Polymerization of actin throughout the cell cytosol [6,16,29]
2. Disruption and delocalization of F-actin structures including stress fibers, cortical actin [2,7,16]
and the junctional ring
3. Accumulation of intracellular F-actin aggregates containing surface membrane pro- [20,30]
teins—myosin I, the tight junction proteins ZO-1, ZO-2, cingulin
4. Disruption and dissociation of the spectrin cytoskeleton [31,32]
5. Disruption of microtubules during early reflow in vivo [33]
6. The cytoskeleton of proximal tubule cells, as compared to distal tubule cells, is more [6,16,34]
sensitive to ischemia in vivo and ATP depletion in vitro
Pathophysiology of Ischemic Acute Renal Failure: Cytoskeletal Aspects 13.5
FIGURE 13-5
A Normal
Mechanisms of proximal tubule cell—medi-
Afferent arteriole Efferent arteriole ated reductions in glomerular filtration rate
(GFR) following ischemic injury. A, GFR
Glomerular depends on four factors: 1) adequate blood
plasma flow flow to the glomerulus; 2) an adequate
glomerular capillary pressure as determined
by afferent and efferent arteriolar resis-
Glomerular tance; 3) glomerular permeability; and
hydrostatic 4) low intratubular pressure. B, Afferent
pressure
Glomerular arteriolar constriction diminishes GFR by
filtration reducing blood flow—and, therefore,
Intratubular glomerular capillary pressure. This occurs
pressure in response to a high distal sodium delivery
and is mediated by tubular glomerular
feedback. C, Obstruction of the tubular
B Afferent C D
arteriolar Obstruction Backleak lumen by cast formation increases tubular
constriction pressure and, when it exceeds glomerular
capillary pressure, a marked decrease or no
filtration occurs. D, Back-leak occurs when
the paracellular space between cells is open
for the flux of glomerular filtrate to leak
back into the extracellular space and into
Glomerular Obstructing Leakage of the blood stream. This is believed to occur
pressure cast filtrate through open tight junctions.
RG
RG
RGD
RG
D
RGD RG RG
D
D
FIGURE 13-6
Overview of potential therapeutic effects of cyclic integrin-binding
peptides. A, During ischemic injury, tubular obstruction occurs as a
result of loss of apical membrane, cell contents, and detached cells
released into the lumen. B, Also, basolateral integrins diffuse to the
apical region of the cell. Biotinylated cyclic peptides containing the
sequence cRGDDFV bind to desquamated cells in the ascending
limb of the loop of Henle and in proximal tubule cells in ischemic
A rat kidneys. The desquamated cells can adhere to injured cells or
aggregate, causing tubule obstruction.
(Continued on next page)
13.6 Acute Renal Failure
200
0
C 0 Pre-Op Day 1 Day 2 Day 3
50
TER, Ω -cm2
40
30
20
10
A 0
0 10 20 30 40 60 90 120 150
C Time,min
FIGURE 13-7
Functional and morphologic changes in tight junction integrity asso-
ciated with ischemic injury or intracellular ATP depletion. A and B,
Ruthenium red paracellular permeability in rat proximal tubules.
A, In control kidneys, note the electron-dense staining of the brush
border, which cuts off at the tight junctions (tj, arrows). B, Sections
from a perfusion-fixed kidney after 20 minutes of renal artery cross-
clamp [35]. The electron-dense staining can be seen at cell contact
sites beyond the tight junction (arrows). The paracellular pathway
is no longer sealed by the tight junction, permitting backleak of
the electron-dense ruthenium red. C, Changes in the transepithelial
resistance (TER) versus time during ATP depletion and ATP reple-
tion [36]. Paracellular resistance to electron movement
(Continued on next page)
B
Pathophysiology of Ischemic Acute Renal Failure: Cytoskeletal Aspects 13.7
Acknowledgment
These studies were in part supported by the National Institute Association Established Investigator Award (BAM), a VA
of Diabetes and Digestive and Kidney Diseases Grants DK Merrit Review Grant (BAM), and a NKF Clinical Scientist
41126 (BAM) and DK4683 (RB) and by an American Heart Award (RB).
13.8 Acute Renal Failure
References
1. ~o F, Pascual J, Madrid Acute Renal Failure Study Group:
Lian 20. Wagner MC, Molitoris BA: ATP depletion alters myosin Ib cellular
Epidemiology of acute renal failure: A prospective, multicenter, location in LLC-PK1 cells. Am J Physiol 1997, 272:C1680–C1690.
community-based study. Kidney Int 1996, 50:811–818. 21. Venkatachalam MA, Jones DB, Rennke HG, et al.: Mechanism of
2. Molitoris BA, Wagner MC: Surface membrane polarity of proximal proximal tubule brush border loss and regeneration following mild
tubular cells: Alterations as a basis for malfunction. Kidney Int 1996, ischemia. Lab Invest 1981, 45:355–365.
49:1592–1597. 22. Ritter D, Dean AD, Guan ZH, et al.: Polarized distribution of renal
3. Thadhani R, Pascual M, Bonventre JV: Acute renal failure. N Engl natriuretic peptide receptors in normal physiology and ischemia.
J Med 1996, 334:1448–1457. Am J Physiol 1995, 269:F918–F925.
4. Drubin DG, Nelson WJ: Origins of cell polarity. Cell 1996, 23. Alejandro VSJ, Nelson WJ, Huie P, et al.: Postischemic injury, delayed
84:335–344. function and Na+/K+-ATPase distribution in the transplanted kidney.
5. Mays RW, Nelson WJ, Marrs JA: Generation of epithelial cell polarity: Kidney Int 1995, 48:1308–1315.
Roles for protein trafficking, membrane-cytoskeleton, and E-cad- 24. Donohoe JF, Venkatachalam MA, Benard DB, et al.: Tubular leakage
herin–mediated cell adhesion. Cold Spring Harbor Symposia on and obstruction after renal ischemia: Structural-functional correla-
Quantitative Biol 1995, 60:763–773. tions. Kidney Int 1978, 13:208–222.
6. Bacallao R, Garfinkel A, Monke S, et al.: ATP depletion: A novel 25. Molitoris BA, Falk SA, Dahl RH: Ischemic-induced loss of epithelial
method to study junctional properties in epithelial tissues. I. polarity. Role of the tight junction. J Clin Invest 1989, 84:1334–1339.
Rearrangement of the actin cytoskeleton. J Cell Sci 1994, 26. Mandel LJ, Bacallao R, Zampighi G: Uncoupling of the molecular
107:3301–3313. fence and paracellular gate functions in epithelial tight junctions.
7. Kroshian VM, Sheridan AM, Lieberthal W: Functional and cytoskeletal Nature 1993, 361:552–555.
changes induced by sublethal injury in proximal tubular epithelial 27. Kwon O, Nelson J, Sibley RK, et al.: Backleak, tight junctions and
cells. Am J Physiol 1994, F21–F30. cell-cell adhesion in postischemic injury to the renal allograft
8. Fish EM, Molitoris BA: Alterations in epithelial polarity and the (Abstract). J Am Soc Nephrol 1996, 7:A2907.
pathogenesis of disease states. N Engl J Med 1994, 330:1580–1588. 28. Molitoris BA. Na+-K+-ATPase that redistributes to apical membrane
9. Glaumann B, Glauman H, Berezesky IK, et al.: Studies on the cellular during ATP depletion remains functional. Am J Physiol 1993,
recovery from injury II. Ultrastructural studies on the recovery of the 265:F693–F597.
pars convoluta of the proximal tubule of the rat kidney from tempo- 29. Kellerman PS: Exogenous adenosine triphosphate (ATP) proximal
rary ischemia. Virchows Arch B 1977, 24:1–18. tubule microfilament structure and function in vivo in a maleic acid
10. Kellerman PS, Norenberg SL, Jones GM: Early recovery of the actin model of ATP depletion. J Clin Invest 1993, 92:1940–1949.
cytoskeleton during renal ischemic injury in vivo. Am J Kidney Dis 30. Tsukamoto T, Nigam SK: ATP depletion causes tight junction proteins
1996, 16:33–42. to form large, insoluble complexes with cytoskeletal proteins in renal
11. Kellerman PS, Clark RAF, Hoilien CA, et al.: Role of microfilaments epithelial cells. J Biol Chem 1997, 273:F463–F472.
in the maintenance of proximal tubule structural and functional 31. Molitoris BA, Dahl R, Hosford M: Cellular ATP depletion induces
integrity. Am J Physiol 1990, 259:F279–F285. disruption of the spectrin cytoskeletal network. Am J Physiol 1996,
12. Noiri E, Gailit J, Gurrath M, et al.: Cyclic RGD peptides ameliorate 271:F790–F798.
ischemic acute renal failure in rats. Kidney Int 1994, 46:1050–1058. 32. Edelstein CL, Ling H, Schrier RW: The nature of renal cell injury.
13. Noiri E, Goligorsky MS, Som P: Radiolabeled RGD peptides as diag- Kidney Int 1997, 51:1341–1351.
nostic tools in acute renal failure and tubular obstruction. J Am Soc 33. Abbate M, Bonventre JV, Brown D: The microtubule network of renal
Nephrol 1996, 7:2682–2688. epithelial cells is disrupted by ischemia and reperfusion. Am J Physiol
14. Romanov V, Noiri E, Czerwinski G, et al.: Two novel probes reveal 1994, 267:F971–F978.
tubular and vascular RGD binding sites in the ischemic rat kidney. 34. Sheridan AM, Schwartz JH, Kroshian VM, et al.: Renal mouse proxi-
Kidney Int 1997, 52:92–102. mal tubular cells are more susceptible than MDCK cells to chemical
15. Goligorsky MS, Noiri E, Romanov V, et al.: Therapeutic potential of anoxia. Am J Physiol 1993, 265:F342–F350.
RGD peptides in acute renal failure. Kidney Int 1997, 51:1487–1493. 35. Molitoris BA, Falk SA, Dahl RH: Ischemia-induced loss of epithelial
16. Molitoris BA, Dahl R, Geerdes AE: Cytoskeleton disruption and polarity. Role of the tight junction. J Clin Invest 1989, 84:1334–1339.
apical redistribution of proximal tubule Na+,K+-ATPase during 36. Doctor RB, Bacallao R, Mandel LJ: Method for recovering ATP
ischemia. Am J Physiol 1992, 263:F488–F495. content and mitochondrial function after chemical anoxia in renal
17. Alejandro V, Scandling JD, Sibley RK, et al.: Mechanisms of filtration cell cultures. Am J Physiol 1994, 266:C1803–C1811.
failure during postischemic injury of the human kidney: A study of 37. Stevenson BR, Siliciano JD, Mooseker MS, et al.: Identification of
the reperfused renal allograft. J Clin Invest 1995, 95:820–831. ZO-1: A high molecular weight polypeptide associated with the tight
18. Bacallao R, Fine LG: Molecular events in the organization of renal junction (zonula occludens) in a variety of epithelia. J Cell Biol 1986,
tubular epithelium: From nephrogenesis to regeneration. Am J Physiol 103:755–766.
1989, 257:F913–F924. 38. Mandel LJ, Bacallao R, Zampighi G: Uncoupling of the molecular
19. Molitoris BA: Putting the actin cytoskeleton into perspective: patho- ‘fence’ and paracellular ‘gate’ functions in epithelial tight junctions.
physiology of ischemic alterations. Am J Physiol 1997, Nature 1993, 361:552–555.
272:F430–F433.
Pathophysiology
of Ischemic Acute
Renal Failure
Michael S. Goligorsky
Wilfred Lieberthal
A
cute renal failure (ARF) is a syndrome characterized by an
abrupt and reversible kidney dysfunction. The spectrum of
inciting factors is broad: from ischemic and nephrotoxic agents
to a variety of endotoxemic states and syndrome of multiple organ
failure. The pathophysiology of ARF includes vascular, glomerular
and tubular dysfunction which, depending on the actual offending
stimulus, vary in the severity and time of appearance. Hemodynamic
compromise prevails in cases when noxious stimuli are related to
hypotension and septicemia, leading to renal hypoperfusion with sec-
ondary tubular changes (described in Chapter 13). Nephrotoxic
offenders usually result in primary tubular epithelial cell injury,
though endothelial cell dysfunction can also occur, leading to the
eventual cessation of glomerular filtration. This latter effect is a con-
sequence of the combined action of tubular obstruction and activation
of tubuloglomerular feedback mechanism. In the following pages we
shall review the existing concepts on the phenomenology of ARF
including the mechanisms of decreased renal perfusion and failure of
glomerular filtration, vasoconstriction of renal arterioles, how formed
elements gain access to the renal parenchyma, and what the sequelae
are of such an invasion by primed leukocytes.
CHAPTER
14
14.2 Acute Renal Failure
Vasoactive Hormones
Reduced GPF and P Reduced glomerular Increased delivery of Backleak of urea, Compromises patency
filtration surface area NaCl to distal nephron creatinine, of renal tubules and
available for filtration (macula densa) and and reduction in prevents the recovery
and a fall in Kf activation of TG feedback "effective GFR" of renal function
FIGURE 14-1
Pathophysiology of ischemic and toxic acute renal which directly reduce GFR. Tubular injury reduces
failure (ARF). The severe reduction in glomerular GFR by causing tubular obstruction and by allow-
filtration rate (GFR) associated with established ing backleak of glomerular filtrate. Abnormalities in
ischemic or toxic renal injury is due to the com- tubular reabsorption of solute may contribute to
bined effects of alterations in intrarenal hemody- intrarenal vasoconstriction by activating the tubu-
namics and tubular injury. The hemodynamic alter- loglomerular (TG) feedback system. GPF—glomeru-
ations associated with ARF include afferent arterio- lar plasmaflow; P—glomerular pressure; Kf—
lar constriction and mesangial contraction, both of glomerular ultrafiltration coefficient.
FIGURE 14-2
Ischemic or toxic injury Vasoactive hormones that may be responsible for the hemodynamic abnormalities in acute
to the kidney tubule necrosis (ATN). A persistent reduction in renal blood flow has been demonstrated
in both animal models of acute renal failure (ARF) and in humans with ATN. The mecha-
Increase in Deficiency of nisms responsible for the hemodynamic alterations in ARF involve an increase in the
vasoconstrictors vasodilators intrarenal activity of vasoconstrictors and a deficiency of important vasodilators. A num-
ber of vasoconstrictors have been implicated in the reduction in renal blood flow in ARF.
Angiotensin II The importance of individual vasoconstrictor hormones in ARF probably varies to some
Endothelin extent with the cause of the renal injury. A deficiency of vasodilators such as endothelium-
Thromboxane derived nitric oxide (EDNO) and/or prostaglandin I2 (PGI2) also contributes to the renal
Adenosine PGI2
EDNO hypoperfusion associated with ARF. This imbalance in intrarenal vasoactive hormones
Leukotrienes
Platelet-activating favoring vasoconstriction causes persistent intrarenal hypoxia, thereby exacerbating tubu-
factor lar injury and protracting the course of ARF.
FIGURE 14-3
Glomerular basement The mesangium regulates single-nephron glomerular filtration rate
membrane (SNGFR) by altering the glomerular ultrafiltration coefficient (Kf).
This schematic diagram demonstrates the anatomic relationship
Glomerular capillary
between glomerular capillary loops and the mesangium. The
endothelial cells mesangium is surrounded by capillary loops. Mesangial cells (M)
M are specialized pericytes with contractile elements that can respond
to vasoactive hormones. Contraction of mesangium can close and
Glomerular epithelial prevent perfusion of anatomically associated glomerular capillary
M cells loops. This decreases the surface area available for glomerular fil-
tration and reduces the glomerular ultrafiltration coefficient.
Mesangial cell contraction
Angiotensin II
Endothelin–1
Thromboxane Mesangial cell relaxation
Sympathetic nerves Prostacyclin
EDNO
FIGURE 14-4
A, The topography of juxtaglomerular apparatus (JGA), including
macula densa cells (MD), extraglomerular mesangial cells (EMC),
Afferent arteriole
and afferent arteriolar smooth muscle cells (SMC). Insets schemati-
Periportal cally illustrate, B, the structure of JGA; C, the flow of information
cell within the JGA; and D, the putative messengers of tubuloglomeru-
lar feedback responses. AA—afferent arteriole; PPC—peripolar cell;
Extraglomerular EA—efferent arteriole; GMC—glomerular mesangial cells.
mesangial cells (Modified from Goligorsky et al. [1]; with permission.)
Macula densa
cells Glomerus
AA
MD
AA AA
MD MD SMC+GC PPC
PPC G
PPC EMC GMC
G G
EMC GMC EMC GMC
Chloride
Adenosine EA
PGE2
EA EA Angiotensin
Nitric oxide
Osmolarity
B C D Unknown?
14.4 Acute Renal Failure
FIGURE 14-5
The normal tubuloglomerular (TG) feedback mechanism The tubuloglomerular (TG) feedback mech-
anism. A, Normal TG feedback. In the nor-
4. Afferent arteriolar and mesangial 3. Renin is released from specialized
contraction reduce SNGFR back toward cells of JGA and the intrarenal renin mal kidney, the TG feedback mechanism is
control levels. angiotensin system generates release a sensitive device for the regulation of the
of angiotensin II locally. single nephron glomerular filtration rate
(SNGFR). Step 1: An increase in SNGFR
increases the amount of sodium chloride
(NaCl) delivered to the juxtaglomerular
apparatus (JGA) of the nephron. Step 2:
The resultant change in the composition of
the filtrate is sensed by the macula densa
cells and initiates activation of the JGA.
Step 3: The JGA releases renin, which
results in the local and systemic generation
of angiotensin II. Step 4: Angiotensin II
2. The composition of filtrate induces vasocontriction of the glomerular
1. SNGFR increases passing the macula densa is arterioles and contraction of the mesangial
causing increase altered and stimulates the JGA. cells. These events return SNGFR back
in delivery of solute
to the distal nephron. toward basal levels. B, TG feedback in
ARF. Step 1: Ischemic or toxic injury to
renal tubules leads to impaired reabsorption
of NaCl by injured tubular segments proxi-
mal to the JGA. Step 2: The composition of
the filtrate passing the macula densa is
altered and activates the JGA. Step 3:
Angiotensin II is released locally. Step 4:
A
SNGFR is reduced below normal levels. It
is likely that vasoconstrictors other than
angiotensin II, as well as vasodilator hor-
Role of TG feedback in ARF mones (such as PGI2 and nitric oxide) are
also involved in modulating TG feedback.
4. Afferent arteriolar and mesangial 3. Local release of Abnormalities in these vasoactive hormones
contraction reduce SNGFR below angiotensin II in ARF may contribute to alterations in TG
normal levels. is stimulated.
feedback in ARF.
B
Pathophysiology of Ischemic Acute Renal Failure 14.5
FIGURE 14-6
Osswald's Hypothesis
Metabolic basis for the adenosine hypothesis. A, Osswald’s
Increased ATP hydrolysis (increased distal Na+ load) hypothesis on the role of adenosine in tubuloglomerular feedback.
B, Adenosine metabolism: production and disposal via the salvage
and degradation pathways. (A, Modified from Osswald et al. [2];
Increased generation of adenosine
with permission.)
Activation of JGA
Nerve endings
ANG II
Vascular
–
[Cl ] smooth ↓ GFR
muscle
ANG I
A1 A2
Receptors
e
se
se
as
Transporter
P-
P-
id
AT
AD
ot
cle
nu
5'-
Phosphorylation
or
degradation
FIGURE 14-7
20 Elevated concentration of adenosine, inosine,
15 and hypoxanthine in the dog kidney and
Adenosine,
nmoles/mL
15
10
5
0
30
25
Hypoxanthine,
20
nmoles/mL
15
10
5
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Volume collected, mL
Post Ischemia
Glomerul I
SNGFR: 17.4±1.7 nL/min
PFR: 66.6±5.6 nL/min
Glomeruli II
SNGFR: 27.0±3.1 nL/min
B Anti-endothelin PFR: 128.7±14.4 nL/min
FIGURE 14-8
Endothelin (ET) is a potent renal vasoconstrictor. Endothelin (ET)
is a 21 amino acid peptide of which three isoforms—ET-1, ET-2
and ET-3—have been described, all of which have been shown to
be present in renal tissue. However, only the effects of ET-1 on the
kidney have been clearly elucidated. ET-1 is the most potent vaso-
constrictor known. Infusion of ET-1 into the kidney induces pro-
found and long lasting vasoconstriction of the renal circulation. A,
The appearance of the rat kidney during the infusion of ET-1 into
the inferior branch of the main renal artery. The lower pole of the
A kidney perfused by this vessel is profoundly vasoconstricted and
hypoperfused. B, Schematic illustration of function in separate
populations of glomeruli within the same kidney. The entire kidney
underwent 25 minutes of ischemia 48 hours before micropuncture.
Glomeruli I are nephrons not exposed to endothelin antibody;
Glomeruli II are nephrons that received infusion with antibody
through the inferior branch of the main renal artery. SNGFR—sin-
gle nephron glomerular filtration rate; PFR—glomerular renal plas-
ma flow rate. (From Kon et al. [4]; with permission.)
Pathophysiology of Ischemic Acute Renal Failure 14.7
FIGURE 14-9
Pre–proendothelin–1
Biosynthesis of mature endothelin-1 (ET-1). The mature ET-1
NH2 COOH peptide is produced by a series of biochemical steps. The precur-
sor of active ET is pre-pro ET, which is cleaved by dibasic pair-
53 74 92 203
specific endopeptidases and carboxypeptidases to yield a
39–amino acid intermediate termed big ET-1. Big ET-1, which
Lys–Arg Arg–Arg has little vasoconstrictor activity, is then converted to the mature
21–amino acid ET by a specific endopeptidase, the endothelin-
Dibasic pair–specific converting enzyme (ECE). ECE is localized to the plasma mem-
endopeptidase(s) brane of endothelial cells. The arrows indicate sites of cleavage
of pre-pro ET and big ET.
FIGURE 14-10
Plasma ET Regulation of endothelin (ET) action; the
Mature ET role of the ET receptors. Pre-pro ET is pro-
duced and converted to big ET. Big ET is
converted to mature, active ET by endothe-
lin-converting enzyme (ECE) present on the
E ETB receptor endothelial cell membrane. Mature ET
EC
secreted onto the basolateral aspect of the
Endothelium NO PGI2 endothelial cell binds to two ET receptors
(ETA and ETB); both are present on vascu-
lar smooth muscle (VSM) cells. Interaction
of ET with predominantly expressed ETA
receptors on VSM cells induces vasocon-
striction. ETB receptors are predominantly
ECE located on the plasma membrane of
endothelial cells. Interaction of ET-1 with
these endothelial ETB receptors stimulates
Mature ET production of nitric oxide (NO) and prosta-
cyclin by endothelial cells. The production
Cyclic Cyclic of these two vasodilators serves to counter-
ETA receptor ETB receptor
GMP AMP balance the intense vasoconstrictor activity
Vascular
smooth of ET-1. PGI2—prostaglandin I2.
muscle
Vasoconstriction Vasodilation
14.8 Acute Renal Failure
FIGURE 14-11
Ischemia Vehicle
Endothelin-1 (ET-1) receptor blockade ameliorates severe ischemic
10 BQ123(0.1mg/kg • min, for 3h)
BQ123 acute renal failure (ARF) in rats. The effect of an ETA receptor
Number of rats
Ischemia
8
6
4
2
0
Basal 24h 1 2 3 4 5 6 14
control
C Posttreatment days
FIGURE 14-12
Production of prostaglandins. Arachidonic acid is released from the
Lipid Membrane plasma membrane by phospholipase A2. The enzyme cycloxygenase
catalyses the conversion of arachidonate to two prostanoid interme-
diates (PGH2 and PGG2). These are converted by specific enzymes
into a number of different prostanoids as well as thromboxane
(TXA2). The predominant prostaglandin produced varies with the
Phospholipase A2
cell type. In endothelial cells prostacyclin (PGI2) (in the circle) is the
Arachidonic acid major metabolite of cycloxygenase activity. Prostacyclin, a potent
vasodilator, is involved in the regulation of vascular tone. TXA2 is
NSAID Cycloxygenase not produced in endothelial cells of normal kidneys but may be pro-
duced in increased amounts and contribute to the pathophysiology
PGG2 of some forms of acute renal failure (eg, cyclosporine A–induced
Prostaglandin nephrotoxicity). The production of all prostanoids and TXA2 is
intermediates blocked by nonsteroidal anti-inflammatory agents (NSAIDs), which
inhibit cycloxygenase activity.
Thromboxane
PGH2
TxA2
FIGURE 14-13
Aorta
Endothelin (ET) receptor blockade ameliorates acute cyclosporine-
induced nephrotoxicity. Cyclosporine A (CSA) was administered
Cyclosporine A intravenously to rats. Then, an ET receptor anatgonist was infused
in circulation directly into the right renal artery. Glomerular filtration rate (GFR)
Intra–arterial
infusion of ETA and renal plasma flow (RPF) were reduced by the CSA in the left
receptor antagonist
CSA
kidney. The ET receptor antagonist protected GFR and RPF from
the effects of CSA on the right side. Thus, ET contributes to the
intrarenal vasoconstriction and reduction in GFR associated with
acute CSA nephrotoxicity. (From Fogo et al. [6]; with permission.)
FIGURE 14-14
Normal basal state
Prostacyclin is important in maintaining
Circulating levels of vasoconstrictors: Low renal blood flow (RBF) and glomerular fil-
tration rate (GFR) in “prerenal” states.
Afferent arteriolar tone
normal A, When intravascular volume is normal,
prostacyclin production in the endothelial
Intrarenal levels of prostacyclin: Low cells of the kidney is low and prostacyclin
Intraglomerular P plays little or no role in control of vascular
normal
tone. B, The reduction in absolute or
“effective” arterial blood volume associated
with all prerenal states leads to an increase
A GFR normal in the circulating levels of a number of of
vasoconstrictors, including angiotensin II,
Intravascular volume depletion
catecholamines, and vasopressin. The
Circulating levels of vasoconstrictors: High increase in vasoconstrictors stimulates
phospholipase A2 and prostacyclin produc-
Afferent arteriolar tone
tion in renal endothelial cells. This increase
normal or mildly reduced
in prostacyclin production partially coun-
Intrarenal levels of prostacyclin: High teracts the effects of the circulating vaso-
constrictors and plays a critical role in
Intraglomerular P
normal or mildly reduced
maintaining normal or nearly normal RBF
and GFR in prerenal states. C, The effect of
cycloxygenase inhibition with nonsteroidal
B GFR anti-inflammatory drugs (NSAIDs) in pre-
normal or mildly reduced renal states. Inhibition of prostacyclin
production in the presence of intravascular
Intravascular volume depletion volume depletion results in unopposed
and NSAID administration action of prevailing vasoconstrictors and
Circulating levels of vasoconstrictors: High results in severe intrarenal vascasoconstric-
tion. NSAIDs can precipitate severe acute
Afferent arteriolar tone
renal failure in these situations.
severely increased
GFR
C severely reduced
14.10 Acute Renal Failure
Time Given in
Vasodilator ARF Disorder Relation to Induction Observed Effect
Propranolol Ischemic Before, during, after ↓Scr, BUN if given before,
during; no effect if given after
Phenoxybenzamine Toxic Before, during, after Prevented fall in RBF
Clonidine Ischemic After ↓Scr, BUN
Bradykinin Ischemic Before, during ↑RBF, GFR
Acetylcholine Ischemic Before, after ↑RBF; no change in GFR
Prostaglandin E1 Ischemic After ↑RBF; no change in GFR
Prostaglandin E2 Ischemic, toxic Before, during ↑GFR
Prostaglandin I2 Ischemic Before, during, after ↑GFR
Saralasin Toxic, ischemic Before ↑RBF; no change in Scr, BUN
Captopril Toxic, ischemic Before ↑RBF; no change in Scr, BUN
Verapamil Ischemic, toxic Before, during, after ↑RBF, GFR in most studies
Nifedipine Ischemic Before ↑GFR
Nitrendipine Toxic Before, during ↑GFR
Diliazem Toxic Before, during, after ↑GFR; ↓recovery time
Chlorpromazine Toxic Before ↑GFR; ↓recovery time
Atrial natriuretic Ischemic, toxic After ↑RBF, GFR
peptide
BUN—blood urea nitrogen; GFR—glomerular filtration rate; RBF—renal blood flow; Scr–serum creatinine.
Ccr—creatinine clearance; NE—norepinephrine; RBF—renal blood flow; Scr—serum creatinine; V—urine flow rate.
FIGURE 14-15
Vasodilators used in acute renal failure (ARF). A, Vasodilators used in experimental
acute ARF. B, Vasodilators used to alter the course of clinical ARF. (From Conger [7];
with permission.)
Pathophysiology of Ischemic Acute Renal Failure 14.11
NH2 + NH2 NH2 + NOH NH2 + O Modular structure of nitric oxide synthases
H BH4 ARG CaM FMN FAD NADPH
NADPH NADP+ 1/
2 NADPH /2 NADP
1 +
Target domain Oxygenase domain Reductase domain
O2 H 2O O2 H 2O
NH NH NH Dimerization site(s) 13–14 18–20
+ • NO nNOS
2–3 4–5 6 7–9 10–12 1516–17 21–23 24–29
BH4 BH4 nitric oxide 11–12 16–18
eNOS
+
NH3 COO– +
NH3 COO– +
NH3 COO– 1 2–3 4 5–7 8–10 1314–15 19–21 22–26
M 12–13
G
A L-arginine N -hydroxy-L-arginine L-citrulline iNOS
2–3 4–5 6 7–9 10–11 13 14–18 19–21 22–26
2–3 4–8 9–12 13–16
FIGURE 14-16 Mammalian P450 Reductases
Chemical reactions leading to the generation of nitric oxide (NO), Bacterial Flavodoxins
Plant Ferredoxin NADPH Reductases
A, and enzymes that catalize them, B. (Modified from Gross [8]; B. mega P450
with permission.) DHF Reductases
B Mammalian Syntrophins (GLGF Motif)
L-arginine
M
DNA damage Cell death
NOS L-citrulline NO concentration Activation of Apoptosis
mM apoptotic signal
Nitric oxide Thiols Induction of stress proteins
GTP
Heme- & iron- Inactivation of enzymes
Smooth muscle GC Vasodilatation µM containing proteins
ROIs Antioxidant
cGMP Guanylate cyclase cGMP (cellular signal)
nM
Inhibition of B Time Consequences
Target cell
Immune cells iron-containing
death
enzymes
FIGURE 14-17
CNS and PNS Neurotransmission
Hemoglobin Major organ, A, and cellular, B, targets of nitric oxide (NO).
A, Synthesis and function of NO. B, Intracellular targets for NO
and pathophysiological consequences of its action. C, Endothelium-
NO3– + NO2– dependent vasodilators, such as acetylcholine and the calcium
ionophore A23187, act by stimulating eNOS activity thereby
cGMP increasing endothelium-derived nitric oxide (EDNO) production.
In contrast, other vasodilators act independently of the endotheli-
A Urine excretion um. Some endothelium-independent vasodilators such as nitroprus-
side and nitroglycerin induce vasodilation by directly releasing nitric
oxide in vascular smooth muscle cells. NO released by these agents,
Leukocyte like EDNO, induces vasodilation by stimulating the production of
– migration cyclic guanosine monophosphate (cGMP) in vascular smooth mus-
Endothelium-dependent
vasodilators cle (VSM) cells. Atrial natriuretic peptide (ANP) is also an endothe-
Platelet
– lium-independent vasodilator but acts differently from NO. ANP
+ aggregation
NO• directly stimulates an isoform of guanylyl cyclase (GC) distinct from
+
Shear stress soluble GC (called particulate GC) in VSM. CNS—central nervous
L-Arginine + NOS system; GTP—guanosine triphosphate; NOS—nitric oxide synthase;
PGC—particulate guanylyl cyclase; PNS—peripheral nervous sys-
NO• tem; ROI—reduced oxygen intermediates; SGC—soluble guanylyl
cyclase. (A, From Reyes et al. [9], with permission; B, from Kim
Nitroglycerin ANP et al. [10], with permission.)
+ +
sGC + pGC
GTP cGMP
Relaxation
C
14.12 Acute Renal Failure
FIGURE 14-18
Ischemia (I) Impaired production of endothelium-dependent nitric oxide (EDNO) contributes to the
alone vasoconstriction associated with established acute renal failure (ARF). Ischemia-reperfu-
sion injury in the isolated erythrocyte-perfused kidney induced persistant intarenal vaso-
I + ANP constriction. The endothelium-independent vasodilators (atrial natriuretic peptide [ANP]
and nitroprusside) administered during the reflow period caused vasodilation and restored
I+ the elevated intrarenal vascular resistance (RVR) to normal. In marked contrast, two
nitroprusside endothelium-dependent vasodilators (acetylcholine and A23187) had no effect on renal
I+ vascular resistance after ischemia-reflow. These data suggest that EDNO production is
Acetylcholine impaired following ischemic injury and that this loss of EDNO activity contributes to the
vasoconstriction associated with ARF. (Adapted from Lieberthal [11]; with permission.)
I + A23187
0 20 40 60 80
Increase in RVR above control, %
60 150
O2 BUN
50 *
Hypoxia 100
mg/dL
*
40 *
30 P<.001
50
Hypoxia + L-NAME
20 P<.001
0
Percent LDH release
Control 3.0
10
0 Cr
2.5
1.5
60 O2 Hypoxia + L-Arg
mg/dL
P<.05
50 *
1.0 *
P<.01 Hypoxia *
40
P<.001
30 0.5
P<.001
20
Control 0
10 Ischemia
Control
0
S
SCR
AS
Vehicle
0 10 20 30 40 50
A Time, min B
FIGURE 14-19
P<.001 Deleterious effects of nitric oxide (NO) on the viability of renal
50 tubular epithelia. A, Hypoxia and reoxygenation lead to injury of
tubular cells (filled circles); inhibition of NO production improves
40 the viability of tubular cells subjected to hypoxia and reoxygena-
tion (triangles in upper graph), whereas addition of L-arginine
LDH release, %
Iothalamate Radiocontrast
100 100
Chronic renal
Normal kidneys
Cortex
50 50 insufficiency
Percent of baseline
0 0
Iothalamate Compensatory increase in Increased Reduced or absent
200
PGI2 and EDNO release endothelin increase in PGI2 or EDNO
150
Medulla
100 100
50 50
Iothalamate Mild vasoconstriction Severe vasoconstriction
0 0
0 20 40 60 0 20 40 60
Minutes Minutes
No pretreatment Pretreatment with
No loss of GFR Acute renal failure
A (n = 6) L-NAME (n = 6) B
FIGURE 14-20
Proposed role of nitric oxide (NO) in radiocontrast-induced acute the normal kidney. The vasodilators counteract the effects of the
renal failure (ARF). A, Administration of iothalamate, a radiocon- vasoconstrictors so that intrarenal vasoconstriction in response to
trast dye, to rats increases medullary blood flow. Inhibitors of radiocontrast is usually modest and is associated with little or no
either prostaglandin production (such as the NSAID, loss of renal function. However, in situations when there is pre-
indomethacin) or inhibitors of NO synthesis (such as L-NAME) existing chronic renal insufficiency (CRF) the vasodilator response
abolish the compensatory increase in medullary blood flow that to radiocontrast is impaired, whereas production of endothelin and
occurs in response to radiocontrast administration. Thus, the stim- other vasoconstrictors is not affected or even increased. As a result,
ulation of prostaglandin and NO production after radiocontrast radiocontrast administration causes profound intrarenal vasocon-
administration is important in maintaining medullary perfusion striction and can cause ARF in patients with CRF. This hypothesis
and oxygenation after administration of contrast agents. B, would explain the predisposition of patients with chronic renal
Radiocontrast stimulates the production of vasodilators (such as dysfunction, and especially diabetic nephropathy, to contrast-
prostaglandin [PGI2] and endothelium-dependent nitric oxide induced ARF. (A, Adapted from Agmon and Brezis [15], with per-
[EDNO]) as well as endothelin and other vasoconstrictors within mission; B, from Agmon et al. [16], with permission.)
FIGURE 14-21
Cellular calcium metabolism and potential targets of the elevated
cytosolic calcium. A, Pathways of calcium mobilization. B, Patho-
physiologic mechanisms ignited by the elevation of cytosolic calci-
um concentration. (A, Adapted from Goligorsky [17], with permis-
sion; B, from Edelstein and Schrier [18], with permission.)
14.14 Acute Renal Failure
Pre NE Post NE
* 60 NS Verapamil before NE
400 100 P<.001
40
* * P<.05
Estimated [Ca2+]i , nM
80
Pl stained nuclei, %
*
20
* * *
CIn, mL/min
* 60
300 * 0
40 60 Verapamil after NE
NS
200 * Significant 20
vs. time 0 40
P<.02
150 0 P<.001
Hypoxia 20
0 10 20 30 0
A Time, min B Control 1h 24 h
FIGURE 14-22
Pathophysiologic sequelae of the elevated cytosolic calcium (C2+). verapamil before injection of norepinephrine (cross-hatched bars) sig-
A, The increase in cytosolic calcium concentration in hypoxic rat nificantly attenuated the drop in inulin clearance induced by norepi-
proximal tubules precedes the tubular damage as assessed by propidi- nephrine alone (open bars). (A, Adapted from Kribben et al. [19], with
um iodide (PI) staining. B, Administration of calcium channel inhibitor permission; B, adapted from Burke et al. [20], with permission.)
FIGURE 14-23
Dynamics of heat shock
proteins (HSP) in stressed
cells. Mechanisms of acti-
vation and feedback con-
trol of the inducible heat
shock gene. In the nor-
mal unstressed cell, heat
shock factor (HSF) is
rendered inactive by
association with the con-
stitutively expressed
HSP70. After hypoxia or
ATP depletion, partially
denatured proteins (DP)
become preferentially
associated with HSC73,
releasing HSF and allow-
ing trimerization and
binding to the heat shock
element (HSE) to initiate
the transcription of the
heat shock gene. After
translation, excess
inducible HSP (HSP72)
interacts with the trimer-
ized HSF to convert it
back to its monomeric
state and release it from
the HSE, thus turning off
the response. (Adapted
from Kashgarian [21];
with permission.)
Pathophysiology of Ischemic Acute Renal Failure 14.15
+ Catalase peroxidase
OH
O2 (tetramer) (PHGPx) R
Lipid
peroxide
LH
LO
Inside O RH
H
L LOO Outside
LOOH H cell
LH
e– Lipid
Vitamin E (a-Tocopherol–)
inhibits lipid peroxidation chain collpases
chain reaction (now hydrophilic)
FIGURE 14-24
Cellular sources of reactive oxygen species (ROS) defense systems from free radicals. Superoxide and hydro-
gen peroxide are produced during normal cellular metabolism. ROS are constantly being produced by the
normal cell during a number of physiologic reactions. Mitochondrial respiration is an important source of
superoxide production under normal conditions and can be increased during ischemia-reflow or gentamycin-
induced renal injury. A number of enzymes generate superoxide and hydrogen peroxide during their catalytic
cycling. These include cycloxygenases and lipoxygenes that catalyze prostanoid and leukotriene synthesis.
Some cells (such as leukocytes, endothelial cells, and vascular smooth muscle cells) have NADH/ or NADPH
oxidase enzymes in the plasma membrane that are capable of generating superoxide. Xanthine oxidase, which
converts hypoxathine to xanthine, has been implicated as an important source of ROS after ischemia-reperfu-
sion injury. Cytochrome p450, which is bound to the membrane of the endoplasmic reticulum, can be
increased by the presence of high concentrations of metabolites that are oxidized by this cytochrome or by
injurious events that uncouple the activity of the p450. Finally, the oxidation of small molecules including free
heme, thiols, hydroquinines, catecholamines, flavins, and tetrahydropterins, also contribute to intracellular
superoxide production. (Adapted from [22]; with permission.)
14.16 Acute Renal Failure
FIGURE 14-25
EVIDENCE SUGGESTING A ROLE FOR Evidence suggesting a role for reactive oxygen metabolites in acute
REACTIVE OXYGEN METABOLITES IN renal failure. The increased ROS production results from two
ISCHEMIC ACUTE RENAL FAILURE major sources: the conversion of hypoxanthine to xanthine by xan-
thine dehydrogenase and the oxidation of NADH by NADH oxi-
dase(s). During the period of ischemia, oxygen deprivation results
Enhanced generation of reactive oxygen metabolites and xanthine oxidase and in the massive dephosphorylation of adenine nucleotides to hypox-
increased conversion of xanthine dehydrogenase to oxidase occur in in vitro and in anthine. Normally, hypoxanthine is metabolized by xanthine dehy-
vivo models of injury. drogenase which uses NAD+ rather than oxygen as the acceptor of
Lipid peroxidation occurs in in vitro and in vivo models of injury, and this can be pre- electrons and does not generate free radicals. However, during
vented by scavengers of reactive oxygen metabolites, xanthine oxidase inhibitors, or ischemia, xanthine dehydrogenase is converted to xanthine oxi-
iron chelators. dase. When oxygen becomes available during reperfusion, the
Glutathione redox ratio, a parameter of “oxidant stress” decreases during ischemia and metabolism of hypoxanthine by xanthine oxidase generates super-
markedly increases on reperfusion. oxide. Conversion of NAD+ to its reduced form, NADH, and the
Scavengers of reative oxygen metabolites, antioxidants, xanthine oxidase inhibitors, accumulation of NADH occurs during ischemia. During the reper-
and iron chelators protect against injury. fusion period, the conversion of NADH back to NAD+ by NADH
A diet deficient in selenium and vitamin E increases susceptibility to injury. oxidase also results in a burst of superoxide production. (From
Inhibition of catalase exacerbates injury, and transgenic mice with increased superoxide Ueda et al. [23]; with permission.)
dismutase activity are less susceptible to injury.
250 3.0
FIGURE 14-26
24 Effect of different scavengers of reactive
16
2.5 oxygen metabolites and iron chelators on,
200
Plasma urea nitrogen, mg/dL
HB
HB
FO
FO
nz
nz
U
U
t
t
t
t
Con
Con
Gen
Gen
MT
MT
MS
MS
+Be
+Be
+D
+D
+D
+D
+D
+D
+D
+D
A B
FIGURE 14-27
Superoxide Production of the hydroxyl radical: the Haber-Weiss reaction. Superoxide is converted to
O2– +Fe3+ hydrogen peroxide by superoxide dismutase. Superoxide and hydrogen peroxide per se
are not highly reactive and cytotoxic. However, hydrogen peroxide can be converted to
Iron stores the highly reactive and injurious hydroxyl radical by an iron-catalyzed reaction that
(Ferritin) requires the presence of free reduced iron. The availability of free “catalytic iron” is a
Release of Hydrogen critical determinant of hydroxyl radical production. In addition to providing a source of
free iron Peroxide hydroxyl radical, superoxide potentiates hydroxyl radical production in two ways: by
(H2O2) releasing free iron from iron stores such as ferritin and by reducing ferric iron and recy-
Fe2+ cling the available free iron back to the ferrous form. The heme moiety of hemoglobin,
myoglobin, or cytochrome present in normal cells can be oxidized to metheme (Fe3+).
Fe3+ The further oxidation of metheme results in the production of an oxyferryl moiety
OH Hydroxyl (Fe4+=O), which is a long-lived, strong oxidant which likely plays a role in the cellular
Radical injury associated with hemoglobinuria and myoglobinuria.
(OH–) Activated leukocytes produce superoxide and hydrogen peroxide via the activity of a
membrane-bound enzyme NADPH oxidase. This superoxide and hydrogen peroxide can
be converted to hydroxyl radical via the Haber-Weiss reaction. Also, the enzyme myeloper-
oxidase, which is specific to leukocytes, converts hydrogen peroxide to another highly
reactive and injurious oxidant, hypochlorous acid.
Pathophysiology of Ischemic Acute Renal Failure 14.17
FIGURE 14-28
:O–O• + •N–O :O–O–N–O 22 kcal/mol Initiation LH + OH• H2O + L• Cell injury: point of convergence between
...Large Gibbs energy
the reduced oxygen intermediates–generat-
ONOO– Propagation L• + O2 LOO• ing and reduced nitrogen intermediates–
:O2•– 6.7 x 109 M–1•s–1 [NO] ...Faster than SOD generating pathways, A, and mechanisms
O 2 + H 2O 2 of lipid peroxidation, B.
1 x 109 M–1•s–1 [SOD] LOO• + LH LOOH + L•
H
O O O O Termination L• + L• L–L
N O N O N O•
OH
...Peroxynitrous LOO• + NO• LOONO
A OH• acid in trans B
ONOO–
Cortex Medulla
X X: SOD, Cu2+, Fe3+
XO
NO2•
Tyr
116 KD 116 KD
NO2
OH R Nitrotyrosine
A
66 KD 66 KD
C CI LN C CI LN
Free
R R' radical
Unsaturated fatty acid R R'
• O2
O O
Free OO•
Control Control Ischemia L-Nil + Ischemia R • R' radical
R R'
B O2 Lipid based
peroxyradical (LOO•)
OO• O O
FIGURE 14-29 OH
O
Detection of peroxynitrite production and lipid peroxidation in R R'
ischemic acute renal failure. A, Formation of nitrotyrosine as an HNE
indicator of ONOO- production. Interactions between reactive
oxygen species such as the hydroxyl radical results in injury to Ab
the ribose-phosphate backbone of DNA. This results in single- HNE OH
O OH
O
and double-strand breaks. ROS can also cause modification and
deletion of individual bases within the DNA molecule. Interaction
between reactive oxygen and nitrogen species results in injury to X X
the ribose-phosphate backbone of DNA, nuclear DNA fragmenta- Protein
tion (single- and double-strand breaks) and activation of poly- (X: Cys, His, Lys) Formation of stable
D hemiacetal adducts
(ADP)-ribose synthase. B, Immunohistochemical staining of kid-
neys with antibodies to nitrotyrosine. C, Western blot analysis of
nitrotyrosine. D, Reactions describing lipid peroxidation and for- process is called lipid peroxidation. In addition to impairing the
mation of hemiacetal products. The interaction of oxygen radi- structural and functional integrity of cell membranes, lipid perox-
cals with lipid bilayers leads to the removal of hydrogen atoms idation can lead to a self-perpetuating chain reaction in which
from the unsaturated fatty acids bound to phospholipid. This additional ROS are generated.
(Continued on next page)
14.18 Acute Renal Failure
Cortex Medulla
Firm adhesion of
Selection–mediated
leukocytes
rolling of leukocytes
(integrin–mediated)
Diapedesis
Release of
oxidants
Tissue injury proteases
A elastases
Pathophysiology of Ischemic Acute Renal Failure 14.19
FIGURE 14-31
125
Anti-ICAM Anti-ICAM Neutralizing anti–ICAM antibody amelio-
antibody 2 antibody rates the course of ischemic renal failure
100 Vehicle Vehicle
with blood urea nitrogen, A, and plasma
Blood urea nitrogen
1.5
75 of bilateral renal ischemia or a sham-opera-
tion were divided into three groups that
1
50 received either anti-ICAM antibody or its
vehicle. Plasma creatinine levels are shown
25 0.5 at 24, 48, and 72 hours. ICAM antibody
ameliorates the severity of renal failure at
0 0 all three time points. (Adapted from Kelly
0 24 48 72 0 24 48 72 96 et al. [24]; with permission.)
A Time following ischemia-reperfusion, d B Time following ischemia-reperfusion, d
250
0
0 4 24 48 72
Time after reperfusion, hrs
14.20 Acute Renal Failure
A B
FIGURE 14-34
Hypothetical schema of cellular events trig-
Induction phase
Mitochondrion Regulation by
Hcl-2 and
Mitochondrial permeability transition its relatives
? Activation of
Positive feedback loop ICE/ced-3-like
Effector phase
proteases ?
Consequences of permeability transition:
Disruption of ∆ψm and mitochondrial biogenesis
Breakdown of energy metabolism
Uncoupling of respiratory chain
Calcium release frommitochondrial matrix
Hyperproduction of superoxide anion
Depletion of glutathione
?
FIGURE 14-35
Phagocytosis of an apoptotic body by a renal tubular epithelial cell.
Epithelial cells dying by apoptosis are not only phagocytosed by
macrophages and leukocytes but by neighbouring epithelial cells as
well. This electron micrograph shows a normal-looking epithelial cell
containing an apoptotic body within a lyzosome. The nucleus of an
epithelial cell that has ingested the apoptotic body is normal (white
arrow). The wall of the lyzosome containing the apoptotic body (black
arrow) is clearly visible. The apoptotic body consists of condensed
chromatin surrounded by plasma membrane (black arrowheads).
FIGURE 14-36
DNA fragmentation in apoptosis vs necrosis. DNA is made up of nucleosomal units. Each
Nucleosome nucleosome of DNA is about 200 base pairs in size and is surrounded by histones. Between
~200 bp nucleosomes are small stretches of DNA that are not surrounded by histones and are called
linker regions. During apoptosis, early activation of endonuclease(s) causes double-strand
Internucleosome breaks in DNA between nucleosomes. No fragmentation occurs in nucleosomes because the
"Linker" regions
DNA is “protected” by the histones. Because of the size of nucleosomes, the DNA is frag-
mented during apoptosis into multiples of 200 base pair pieces (eg, 200, 400, 600, 800).
When the DNA of apoptotic cells is electrophoresed, a characteristic ladder pattern is found.
DNA fragmentation In contrast, necrosis is associated with the early release of lyzosomal proteases, which
cause proteolysis of nuclear histones, leaving “naked” stretches of DNA not protected by
histones. Activation of endonucleases during necrosis therefore cause DNA cleavage at
multiple sites into double- and single-stranded DNA fragments of varying size.
Apoptosis Necrosis Electrophoresis of DNA from necrotic cells results in a smear pattern.
Loss
of
histones
DNA electrophoresis
Apoptic Necrotic
"ladder" "smear"
pattern pattern
14.22 Acute Renal Failure
FIGURE 14-37
POTENTIAL CAUSES OF APOPTOSIS Potential causes of apoptosis in acute renal failure (ARF). The
IN ACUTE RENAL FAILURE same cytotoxic stimuli that induce necrosis cause apoptosis. The
mechanism of cell death induced by a specific injury depends in
large part on the severity of the injury. Because most cells require
Loss of survival factors constant external signals, called survival signals, to remain viable,
Deficiency of renal growth factors (eg, IGF-1, EGF, HGF) the loss of these survival signals can trigger apoptosis. In ARF, a
Loss of cell-cell and cell-matrix interactions
deficiency of growth factors and loss of cell-substrate adhesion are
potential causes of apoptosis. The death pathways induced by
Receptor-mediated activators of apoptosis
engagement of tumour necrosis factor (TNF) with the TNF recep-
Tumor necrosis factor
tor or Fas with its receptor (Fas ligand) are well known causes of
Fas/Fas ligand
apoptosis in immune cells. TNF and Fas can also induce apoptosis
Cytotoxic events
in epithelial cells and may contribute to cell death in ARF.
Ischemia; hypoxia; anoxia
Oxidant injury
Nitric oxide
Cisplati
FIGURE 14-38
Apoptotic Trigger Apoptosis is mediated by a highly coordinated and genetically pro-
grammed pathway. The response to an apoptotic stimulus can be
divided into a commitment and execution phases. During the com-
mitment phase the balance between a number of proapoptotic and
Commitment phase antiapoptotic mechanisms determine whether the cell survives or
dies by apoptosis. The BCL-2 family of proteins consists of at least
Anti-apoptic factors Pro-apoptic factors 12 isoforms, which play important roles in this commitment phase.
Some of the BCL-2 family of proteins (eg, BCL-2 and BCL-XL) pro-
BclXL BAD tect cells from apoptosis whereas other members of the same family
Bcl–2 Bax (eg, BAD and Bax) serve proapoptotic functions. Apoptosis is exe-
cuted by a final common pathway mediated by a class of cysteine
proteases-caspases. Caspases are proteolytic enzymes present in cells
Execution phase
in an inactive form. Once cells are commited to undergo apoptosis,
Crma
these caspases are activated. Some caspases activate other caspases
Caspase activation in a hierarchical fashion resulting in a cascade of caspase activation.
p35
Eventually, caspases that target specific substrates within the cell are
? Point of no return?
activated. Some substrates for caspases that have been identified
Proteolysis of multiple include nuclear membrane components (such as lamin), cytoskeletal
intracellular substrates elements (such as actin and fodrin) and DNA repair enzymes and
transcription elements. The proteolysis of this diverse array of sub-
strates in the cell occurs in a predestined fashion and is responsible
for the characteristic morphologic features of apoptosis.
Apoptosis
Pathophysiology of Ischemic Acute Renal Failure 14.23
FIGURE 14-39
Stress Therapeutic approaches, both experimental
and in clinical use, to prevent and manage
acute renal failure based on its pathogenetic
Loss of tubular mechanisms. ETR—ET receptor; GFR—
• Restoration of Hemodynamic integrity and • Avoidance and
fluid and compromise glomerular filtration rate; HGF—hepatocyte
function discontinuation
electrolyte of nephrotoxins growth factor 1; IGF-1—insulin-like growth
balance • Survival factors factor 1; Kf—glomerular ultrafiltration coef-
• ETR antagonists PMN Back (HGF, IGF-1) ficient; NOS—nitric oxide synthase; PMN—
Kf RBF Obstruction
• Ca channel infiltration leak • ATP-Mg polymorphonuclear leukocytes; RBF—renal
inhibitors • T4
• ATP-Mg
blood flow; T4—thyroxine.
• ETR • Dopamine • ICAM-1 • Mannitol • IGF-1l • NOS inhibitors
antagonists • ANP antibody • Lasix • T4
• Ca channel • IGF-1 • RGD • ANP • HGF
inhibitors • RGD
GFR and
maintenance
phase
Restoration Reparation of
of renal tubular integrity
hemodynamics and function
Recovery
References
1. Goligorsky M, Iijima K, Krivenko Y, et al.: Role of mesangial cells in 14. Ling H, Gengaro P, Edelstein C, et al.: Injurious isoform of NOS in
macula densa-to-afferent arteriole information transfer. Clin Exp mouse proximal tubular injury. Kidney Int, 1998, 53:1642
Pharm Physiol 1997, 24:527–531. 15. Agmon Y, et al.: Nitric oxide and prostanoids protect the renal outer
2. Osswald H, Hermes H, Nabakowski G: Role of adenosine in signal medulla from radiocontrast toxicity in the rat. J Clin Invest 1994,
transmission of TGF. Kidney Int 1982, 22(Suppl. 12):S136–S142. 94:1069–1075.
3. Miller W, Thomas R, Berne R, Rubio R: Adenosine production in the 16. Agmon Y, Brezis M: NO and the medullary circulation. In: Nitric
ischemic kidney. Circ Res 1978, 43(3):390–397. Oxide and the Kidney. Edited by Goligorsky M, Gross S. New
4. Kon V, et al.: Glomerular actions of endothelin in vivo. J Clin Invest York:Chapman and Hall, 1997.
1989, 83:1762–1767. 17. Goligorsky MS: Cell biology of signal transduction. In: Hormones,
5. Gellai M, Jugus M, Fletcher T, et al.: Reversal of postischemic acute autacoids, and the kidney. Edited by Goldfarb S, Ziyadeh F. New
renal failure with a selective endothelin A receptor antagonist in the York:Churchill Livingstone, 1991.
rat. J Clin Invest 1994, 93:900–906. 18. Edelstein C, Schrier RW: The role of calcium in cell injury. In: Acute
6. Fogo, et al.: Endothelin receptor antagonism is protective in vivo in Renal Failure: New Concepts and Therapeutic Strategies. Edited by
acute cyclosporine toxicity. Kidney Int 1992, 42:770–774. Goligorsky MS, Stein JH. New York:Churchill Livingstone, 1995.
7. Conger J: NO in acute renal failure. In: Nitric Oxide and the Kidney. 19. Kribben A, Wetzels J, Wieder E, et al.:Evidence for a role of cytosolic
Edited by Goligorsky M, Gross S. New York:Chapman and Hall, free calcium in hypoxia-induced proximal tubule injury. J Clin Invest
1997. 1994, 93:1922.
8. Gross S: Nitric oxide synthases and their cofactors. In: Nitric Oxide 20. Burke T, Arnold P, Gordon J, Schrier RW: Protective effect of
and the Kidney. Edited by Goligorsky M, Gross S. New intrarenal calcium channel blockers before or after renal ischemia.
York:Chapman and Hall, 1997. J Clin Invest 1984, 74:1830.
9. Reyes A, Karl I, Klahr S: Role of arginine in health and in renal dis- 21. Kashgarian M: Stress proteins induced by injury to epithelial cells. In:
ease. Am J Physiol 1994, 267:F331–F346. Acute Renal Failure: New Concepts and therapeutic strategies. Edited
10. Kim Y-M, Tseng E, Billiar TR: Role of NO and nitrogen intermediates by Goligorsky MS, Stein JH. New York:Churchill Livingstone, 1995.
in regulation of cell functions. In: Nitric Oxide and the Kidney. Edited 22. J NIH Research
by Goligorsky M, Gross S. New York:Chapman and Hall, 1997. 23. Ueda N, Walker P, Shah SV: Oxidant stress in acute renal failure.
11. Lieberthal W:Renal ischemia and reperfusion impair endothelium- In: Acute Renal Failure: New Concepts and Therapeutic Strategies.
dependent vascular relaxation. Am J Physiol 1989, 256:F894–F900. Edited by Goligorsky MS, Stein JH. New York:Churchill
12. Yu L, Gengaro P, Niederberger M, et al.: Nitric oxide: a mediator in Livingstone, 1995.
rat tubular hypoxia/reoxygenation injury. Proc Natl Acad Sci USA 24. Kelly KJ, et al.: Antibody to anyi-cellular adhesion molecule-1 pro-
1994, 91:1691–1695. tects the kidney against ischemic injury. Proc Natl Acad Sci USA
13. Noiri E, Peresleni T, Miller F, Goligorsky MS: In vivo targeting of 1994, 91:812–816.
iNOS with oligodeoxynucleotides protects rat kidney against 25. Kroemer G, Petit P, Zamzami N, et al.: The biochemistry of pro-
ischemia. J Clin Invest 1996, 97:2377–2383. grammed cell death. FASEB J 1995, 9:1277–1287.
Pathophysiology of
Nephrotoxic Acute
Renal Failure
Rick G. Schnellmann
Katrina J. Kelly
H
umans are exposed intentionally and unintentionally to a
variety of diverse chemicals that harm the kidney. As the list
of drugs, natural products, industrial chemicals and environ-
mental pollutants that cause nephrotoxicity has increased, it has
become clear that chemicals with very diverse chemical structures pro-
duce nephrotoxicity. For example, the heavy metal HgCl2, the myco-
toxin fumonisin B1, the immunosuppresant cyclosporin A, and the
aminoglycoside antibiotics all produce acute renal failure but are not
structurally related. Thus, it is not surprising that the cellular targets
within the kidney and the mechanisms of cellular injury vary with dif-
ferent toxicants. Nevertheless, there are similarities between chemical-
induced acute tubular injury and ischemia/reperfusion injury.
The tubular cells of the kidney are particularly vulnerable to toxi-
cant-mediated injury due to their disproportionate exposure to circu-
lating chemicals and transport processes that result in high intracellu-
lar concentrations. It is generally thought that the parent chemical or
a metabolite initiates toxicity through its covalent or noncovalent
binding to cellular macromolecules or through their ability to produce
reactive oxygen species. In either case the activity of the macromole-
cule(s) is altered resulting in cell injury. For example, proteins and
lipids in the plasma membrane, nucleus, lysosome, mitochondrion and
cytosol are all targets of toxicants. If the toxicant causes oxidative
CHAPTER
stress both lipid peroxidation and protein oxidation have been shown
15
to contribute to cell injury.
In many cases mitochondria are a critical target and the lack of
adenosine triphosphate (ATP) leads to cell injury due to the depen-
dence of renal function on aerobic metabolism. The loss of ATP leads
15.2 Acute Renal Failure
to disruption of cellular ion homeostasis with decreased cellular Following exposure to a chemical insult those cells sufficiently
K+ content, increased Na+ content and membrane depolariza- injured die by one of two mechanisms, apoptosis or oncosis.
tion. Increased cytosolic free Ca2+ concentrations can occur in Clinically, a vast number of nephrotoxicants can produce a
the early or late phase of cell injury and plays a critical role lead- variety of clinical syndromes-acute renal failure, chronic renal
ing to cell death. The increase in Ca2+ can activate calcium acti- failure, nephrotic syndrome, hypertension and renal tubular
vated neutral proteases (calpains) that appear to contribute to defects. The evolving understanding of the pathophysiology of
the cell injury that occurs by a variety of toxicants. During the toxicant-mediated renal injury has implications for potential
late phase of cell injury, there is an increase in Cl- influx, fol- therapies and preventive measures. This chapter outlines some
lowed by the influx of increasing larger molecules that leads to of the mechanisms thought to be important in toxicant-mediat-
cell lysis. Two additional enzymes appear to play an important ed renal cell injury and death that leads to the loss of tubular
role in cell injury, particularly oxidative injury. Phospholipase A2 epithelial cells, tubular obstruction, “backleak” of the glomeru-
consists of a family of enzymes in which the activity of the lar filtrate and a decreased glomerular filtration rate. The recov-
cytosolic form increases during oxidative injury and contributes ery from the structural and functional damage following chemi-
to cell death. Caspases are a family of cysteine proteases that are cal exposures is dependent on the repair of sublethally-injured
activated following oxidative injury and contribute to cell death. and regeneration of noninjured cells.
Nephrotoxins may account for approximately 50% of all cases of acute and chronic Receives 25% of the cardiac output
renal failure. Sensitive to vasoactive compounds
Nephrotoxic renal injury often occurs in conjunction with ischemic acute renal failure. Concentrates toxicants through reabsorptive and secretive processes
Acute renal failure may occur in 2% to 5% of hospitalized patients and 10% to 15% of Many transporters result in high intracellular concentrations
patients in intensive care units. Large luminal membrane surface area
The mortality of acute renal failure is approximatley 50% which has not changed Large biotransformation capacity
significantly in the last 40 years.
Baseline medullary hypoxia
Radiocontrast media and aminoglycosides are the most common agents associated
with nephrotoxic injury in hospitalized patients.
Aminoglycoside nephrotoxicity occurs in 5% to 15% of patients treated with
these drugs.
FIGURE 15-2
Reasons for the kidney’s susceptibility to toxicant injury.
FIGURE 15-1
Clinical significance of toxicant-mediated renal failure.
FIGURE 15-3
FACTORS THAT PREDISPOSE THE Factors that predispose the kidney to toxicant injury.
KIDNEY TO TOXICANT INJURY
FIGURE 15-4
Exogenous and endogenous chemicals that cause acute renal failure.
FIGURE 15-5
Proximal convoluted tubule Nephrotoxicants may act at different sites in the kidney, resulting
(S1/S2 segments) in altered renal function. The sites of injury by selected nephrotoxi-
Aminoglycosides cants are shown. Nonsteroidal anti-inflammatory drugs (NSAIDs),
Cephaloridine Glomeruli angiotensin-converting enzyme (ACE) inhibitors, cyclosporin A,
Cadmium chloride Interferon–α and radiographic contrast media cause vasoconstriction. Gold,
Potassium dichromate Gold interferon-alpha, and penicillamine can alter glomerular function
Penicillamine and result in proteinuria and decreased renal function. Many
Proximal straight tubule nephrotoxicants damage tubular epithelial cells directly.
Renal vessels (S3 segment) Aminoglycosides, cephaloridine, cadmium chloride, and potassium
NSAIDs Cisplatin dichromate affect the S1 and S2 segments of the proximal tubule,
ACE inhibitors Mercuric chloride whereas cisplatin, mercuric chloride, and dichlorovinyl-L-cysteine
Cyclosporin A Dichlorovinyl–L–cysteine affect the S3 segment of the proximal tubule. Cephalosporins, cad-
mium chloride, and NSAIDs cause interstitial nephritis whereas
phenacetin causes renal papillary necrosis.
Interstitium
Papillae Cephalosporins
Phenacetin Cadmium
NSAIDs
15.4 Acute Renal Failure
Glomerular ultrafiltration
Obstruction Postrenal failure FIGURE 15-7
Renal injury from exposure to cyclosporin A. Cyclosporin A is one
FIGURE 15-6 example of a toxicant that acts at several sites within the kidney.
Mechanisms that contribute to decreased glomerular filtration rate It can injure both endothelial and tubular cells. Endothelial injury
(GFR) in acute renal failure. After exposure to a nephrotoxicant, results in increased vascular permeability and hypovolemia, which
one or more mechanisms may contribute to a reduction in the activates the sympathetic nervous system. Injury to the endotheli-
GFR. These include renal vasoconstriction resulting in prerenal um also results in increases in endothelin and thromboxane A2
azotemia (eg, cyclosporin A) and obstruction due to precipitation and decreases in nitric oxide and vasodilatory prostaglandins.
of a drug or endogenous substances within the kidney or collecting Finally, cyclosporin A may increase the sensitivity of the vascula-
ducts (eg, methotrexate). Intrarenal factors include direct tubular ture to vasoconstrictors, activate the renin-angiotensin system, and
obstruction and dysfunction resulting in tubular backleak and increase angiotensin II levels. All of these changes lead to vasocon-
increased tubular pressure. Alterations in the levels of a variety of striction and hypertension. Vasoconstriction in the kidney con-
vasoactive mediators (eg, prostaglandins following treatment with tributes to the decrease in glomerular filtration rate (GFR), and
nonsteroidal anti-inflammatory drugs) may result in decreased the histologic changes in the kidney are the result of local ischemia
renal perfusion pressure or efferent arteriolar tone and increased and hypertension.
afferent arteriolar tone, resulting in decreased in glomerular hydro-
static pressure. Some nephrotoxicants may decrease glomerular
function, leading to proteinuria and decreased renal function.
Necrosis Apoptosis
α
β Sloughing of viable
and nonviable cells
with intraluminal
cell-cell adhesion
Cytoskeleton
Extracellular matrix
Cast formation
Na+/K+=ATPase
and tubuler
β1 Integrin obstruction
RGD peptide
FIGURE 15-9
After injury, alterations can occur in the cytoskeleton and in may be sloughed into the tubular lumen. Adhesion of sloughed
the normal distribution of membrane proteins such as Na+, K+- cells to other sloughed cells and to cells remaining adherent to
ATPase and 1 integrins in sublethally injured renal tubular the basement membrane may result in cast formation, tubular
cells. These changes result in loss of cell polarity, tight junction obstruction, and further compromise the glomerular filtration
integrity, and cell-substrate adhesion. Lethally injured cells rate. (Adapted from Fish and Molitoris [1], and Gailit et al. [2];
undergo oncosis or apoptosis, and both dead and viable cells with permission.)
FIGURE 15-10
Sublethally Migrating Cell
Potential sites where nephrotoxicants can interfere with the struc-
injured cells spreading cells proliferation
tural and functional recovery of nephrons.
Basement
membrane
Toxicant inhibition Toxicant inhibition Toxicant inhibition
of cell repair of cell migration/spreading of cell proliferation
15.6 Acute Renal Failure
140
120
100
Percent of control
Oncosis Apoptosis
80
60
Cell number/confluence
40 Mitochondrial function
Active Na+ transport
20 +
Na -coupled glucose transport
GGT activity Blebbing Budding
0
0 1 2 3 4 5 6
Time after exposure, d
Cell death
Apoptosis
Apoptosis
FIGURE 15-14
GSH-Hg-GSH The importance of cellular transport in mediating toxicity.
GSH-Hg-GSH Proximal tubular uptake of inorganic mercury is thought to be the
GSH-Hg-GSH result of the transport of mercuric conjugates (eg, diglutathione
CYS-Hg-CYS γ-GT Urine
GLY-CYS-Hg-CYS-GLY ? mercury conjugate [GSH-Hg-GSH], dicysteine mercuric conjugate
CYS-Hg-CYS Acivicin [CYS-Hg-CYS]). At the luminal membrane, GSH-Hg-GSH appears
Dipeptidase to be metabolized by (-glutamyl transferase ((-GT) and a dipepti-
Lumen +
CYS-Hg-CYS Na
dase to form CYS-Hg-CYS. The CYS-Hg-CYS may be taken up by
Neutral amino an amino acid transporter. At the basolateral membrane, mercuric
–
R-Hg-R–
acid transporter conjugates appear to be transported by the organic anion trans-
Proximal +
tubular cell CYS-Hg-CYS Na CYS-Hg-CYS porter. (-Ketoglutarate and the dicarboxylate transporter seem to
GSH-Hg-GSH
play important roles in basolateral membrane uptake of mercuric
Na+ α-Ketoglutarate α-Ketoglutarate conjugates. Uptake of mercuric-protein conjugates by endocytosis
Dicarboxylate Organic anion
transporter transporter may play a minor role in the uptake of inorganic mercury trans-
port. PAH—para-aminohippurate. (Courtesy of Dr. R. K. Zalups.)
α-Ketoglutarate Organic anions
Na+
Blood (PAH or
Dicarboxylic α-Ketoglutarate probenecid)
acids –
R-Hg-R–
CYS-Hg-CYS
GSH-Hg-GSH
FIGURE 15-15
Toxicant Covalent and noncovalent binding versus oxidative stress mecha-
nisms of cell injury. Nephrotoxicants are generally thought to pro-
duce cell injury and death through one of two mechanisms, either
Biotransformation
alone or in combination. In some cases the toxicant may have a
high affinity for a specific macromolecule or class of macromole-
High-affinity binding Reactive intermediate Redox cycling cules that results in altered activity (increase or decrease) of these
to macromolecules molecules, resulting in cell injury. Alternatively, the parent nephro-
toxicant may not be toxic until it is biotransformed into a reactive
Covalent binding Increased reactive intermediate that binds covalently to macromolecules and in turn
Altered activity of to macromolecules oxygen species alters their activity, resulting in cell injury. Finally, the toxicant may
critical macromolecules increase reactive oxygen species in the cells directly, after being bio-
transformed into a reactive intermediate or through redox cycling.
Damage to critical Oxidative damage to
critical macromolecules
The resulting increase in reactive oxygen species results in oxida-
macromolecules
tive damage and cell injury.
Cell injury
FIGURE 15-16
Plasma RSG Plasma RSG
This figure illustrates the renal proximal tubular uptake, biotransfor-
R + SG Glomerular filtration mation, and toxicity of glutathione and cysteine conjugates and mer-
1. 2. capturic acids of haloalkanes and haloalkenes (R). 1) Formation of a
6.
R-SG R-SG R-SG 3. glutathione conjugate within the renal cell (R-SG). 2) Secretion of the
Na+ R-SG into the lumen. 3) Removal of the -glutamyl residue (-Glu)
4. γ-Glu by -glutamyl transferase. 4) Removal of the glycinyl residue (Gly) by
Plasma 7. 5. Gly a dipeptidase. 5) Luminal uptake of the cysteine conjugate (R-Cys).
R-Cys R-Cys R-Cys
R-Cys 12. NH3+H3CCOCO2H Basolateral membrane uptake of R-SG (6), R-Cys (7), and a mercap-
Na+ turic acid (N-acetyl cysteine conjugate; R-NAC)(8). 9) Secretion of
10. 11. R-SH 13.
R-NAC into the lumen. 10) Acetylation of R-Cys to form R-NAC.
Covalent binding
11) Deacetylation of R-NAC to form R-Cys. 12) Biotransformation
8. Cell injury
Plasma of the penultimate nephrotoxic species (R-Cys) by cysteine conjugate
R-NAC R-NAC R-NAC
R-NAC 9. -lyase to a reactive intermediate (R-SH), ammonia, and pyruvate.
Na+
Basolateral Brush border 13) Binding of the reactive thiol to cellular macromolecules (eg, lipids,
membrane membrane proteins) and initiation of cell injury. (Adapted from Monks and Lau
[5]; with permission.)
15.8 Acute Renal Failure
FIGURE 15-17
Covalent binding of a nephrotoxicant
metabolite in vivo to rat kidney tissue, local-
ization of binding to the mitochondria, and
identification of three proteins that bind to
the nephrotoxicant. A, Binding of tetrafluo-
roethyl-L-cysteine (TFEC) metabolites in vivo
to rat kidney tissue detected immunohisto-
chemically. Staining was localized to the S3
segments of the proximal tubule, the segment
that undergoes necrosis. B, Immunoreactivity
in untreated rat kidneys. C, Isolation and
A B fractionation of renal cortical mitochondria
from untreated and TFEC treated rats and
Representative immunoblot analysis revealed numerous pro-
starting Submitochondrial fractions teins that bind to the nephrotoxicant (inner-
material A. Untreated B. TFEC (30 mg/kg) inner membrane, matrix-soluble matrix,
Mr (kDa) outer-outer membrane, inter-intermembrane
space). The identity of three of the proteins
228
that bound to the nephrotoxicant: P84,
P99 109 mortalin (HSP70-like); P66, HSP 60; and
P84 P42, aspartate aminotransferase. Mr—rela-
P66 70
tive molecular weight. (From Hayden et al.
P52
P42 44 [6], and Bruschi et al. [7]; with permission.)
Matrix
Inner
Outer
Matrix
Inter
Inner
Outer
Inter
50 100
Control Control
TBHP (0.5 mmol) DCVC
40 TBHP + DEF (1 mM) 80 DCVC + DEF (1 mM)
TBHP + DPPD (2 µM) DCVC + DPPD (50µM)
LDH release, %
LDH release, %
30 60
20 40
10 20
0 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
A Time, h B Time, h
1.2 2.0
+1 mM DEF
1.0 +50 µM DPPD
1.6
nmol MDA•mg protein–1
Lipid peroxidation,
0.8
1.2
0.6
0.8
0.4
0.4
0.2
0.0 0.0
C Control TBHP +1 mM DEF +2 µM DPPD D Control DCVC
FIGURE 15-19
A–D, Similarities and differences between oxidant-induced and peroxidation and cell death caused by TBHP. In contrast,
halocarbon-cysteine conjugate–induced renal proximal tubular while DEF and DPPD completely blocked the lipid peroxidation
lipid peroxidation and cell death. The model oxidant t-butylhy- caused by DCVC, cell death was only delayed. These results
droperoxide (TBHP) and the halocarbon-cysteine conjugate suggest that the iron-mediated oxidative stress caused by TBHP
dichlorovinyl-L-cysteine (DCVC) caused extensive lipid peroxi- is responsible for the observed toxicity, whereas the iron-mediat-
dation after 1 hour of exposure and cell death (lactate dehydro- ed oxidative stress caused by DCVC accelerates cell death. One
genase (LDH) release) over 6-hours’ exposure. The iron chelator reason that cells die in the absence of iron-mediated oxidative
deferoxamine (DEF) and the antioxidant N,N’-diphenyl-1, stress is that DCVC causes marked mitochondrial dysfunction.
4-phenylenediamine (DPPD) completely blocked both the lipid (Data from Groves et al. [8], and Schellmann [9].)
FIGURE 15-20
ALTERATION OF RENAL TUBULAR CELL Mechanisms by which nephrotoxicants can alter renal tubular
ENERGETICS AFTER EXPOSURE TO TOXICANTS cell energetics.
FIGURE 15-21
Substrates Some of the mitochondrial targets of nephro-
11 toxicants: 1) nicotinamide adenine dinu-
Cephaloridine Atractyloside cleotide (NADH) dehydrogenase; 2) succi-
TCA Ochratoxin A nate dehydrogenase; 3) coenzyme
cycle Q–cytochrome C reductase; 4) cytochrome
ADP C; 5) cytochrome C oxidase; 6) cytochrome
Bromohydroquinone 9
ATP Aa3; 7) H+-Pi contransporter; 8) F0F1-
Dichlorovinyl–L–cysteine ATPase; 9) adenine triphosphate/diphosphate
1
Tetrafluoroethyl–L–cysteine H+ ATP (ATP/ADP) translocase; 10) protonophore
Pentachlorobutadienyl–L–cysteine 8
2 H+ (uncoupler); 11) substrate transporters.
Citrinin 3
Ochratoxin A H+
Hg2+ CN– 4 Oligomycin
5
H+
Pi Pi
6 7
H+
Matrix
O2 H 2O Ochratoxin A
10
Pentachlorobutadienyl–L–cysteine
H+ Inner membrane
Citrinin
FCCP Outer membrane
Na+ H 2O
100
Na+ 90
Relative cellular changes
80 Na+
Na+ Na+ ATPase
Na+ ATPase 70
ATP 60
– – Cl–
ATP – Cl– 50 QO2 Membrane
– potential
40
Cl– Cl –
– K+ – 30 K+
– H 2O
K + – 20
10
ATP
A K+ B Antimycin A K+ 0
0 5 10 15 20 25 30
Antimycin A Time, min
FIGURE 15-22
Early ion movements after mitochondrial dysfunction. A, A control
renal proximal tubular cell. Within minutes of mitochondrial inhibi- FIGURE 15-23
tion (eg, by antimycin A), ATP levels drop, resulting in inhibition of A graphic of the phenomena diagrammed in Figure 15-22.
the Na+, K+-ATPase. B, Consequently, Na+ influx, K+ efflux, mem-
brane depolarization, and a limited degree of cell swelling occur.
FIGURE 15-24
Na+
The late ion movements after mitochondrial dysfunction that leads
Na+
to cell death/lysis. A, Cl- influx occurs as a distinct step subsequent
ATPase
Na+
to Na+ influx and K+ efflux. B, Following Cl- influx, additional
Na+ ATPase Na+ and water influx occur resulting in terminal cell swelling.
ATP Ultimately cell lysis occurs.
ATP Cl– Cl–
Cl– Cl–
K+
K+
H 2O
A Antimycin A K+ B Antimycin A K+
Pathophysiology of Nephrotoxic Acute Renal Failure 15.11
FIGURE 15-25
100
A graph of the phenomena depicted in Figures 15-22 through 15-
90 24, illustrating the complete temporal sequence of events following
Relative cellular changes
80 +
Na mitochondrial dysfunction. QO2—oxygen consumption.
70
60 Cl–
H 2O
50 QO2 Membrane
potential
40
30 K+ Ca++
20
10
ATP
0
0 5 10 15 20 25 30
Antimycin A Time, min
FIGURE 15-26
A simplified schematic drawing of the regulation of cytosolic
free Ca2+. FIGURE 15-27
Biochemical characteristics of calpain.
FIGURE 15-28
Calpain translocation. Proposed pathways of calpain activation
and translocation. Both calpain subunits may undergo calcium
(Ca2+)-mediated autolysis within the cytosol and hydrolyze cytoso-
lic substrates. Calpains may also undergo Ca2+-mediated transloca-
tion to the membrane, Ca2+-mediated, phospholipid-facilitated
autolysis and hydrolyze membrane-associated substrates. The
autolyzed calpains may be released from the membrane and
hydrolyze cytosolic substrates. (From Suzuki and Ohno [10], and
Suzuki et al. [11]; with permission.)
15.12 Acute Renal Failure
35 40
30 35
30
LDH release, %
LDH release, %
25
25
20
20
15
15
10 10
5 5
0 0
A CON TFEC +C12 BHQ +C12 TBHP +C12 B CON TFEC +PD BHQ +PD TBHP +PD
FIGURE 15-29
A, B, Dissimilar types of calpain inhibitors block renal proximal domain on the enzyme. The toxicants used were the haloalkane
tubular toxicity of many agents. Renal proximal tubular suspen- cysteine conjugate tetrafluoroethyl-L-cysteine (TFEC), the alkylat-
sions were pretreated with the calpain inhibitor 2 (CI2) or ing quinone bromohydroquinone (BHQ), and the model oxidant t-
PD150606 (PD). CI2 is an irreversible inhibitor of calpains that butylhydroperoxide (TBHP). The release of lactate dehydrogenase
binds to the active site of the enzyme. PD150606 is a reversible (LDH) was used as a marker of cell death. CON—control. (From
inhibitor of calpains that binds to the calcium (Ca2+)-binding Waters et al. [12]; with permission.)
FIGURE 15-30
One potential pathway in which calcium (Ca2+) and calpains play a role in renal proximal
tubule cell death. These events are subsequent to mitochondrial inhibition and ATP deple-
tion. 1) -Calpain releases endoplasmic reticulum (er) Ca2+ stores. 2) Release of er Ca2+
stores increases cytosolic free Ca2+ concentrations. 3) The increase in cytosolic free Ca2+
concentration mediates extracellular Ca2+ entry. (This may also occur as a direct result of er
Ca2+ depletion.) 4) The influx of extracellular Ca2+ further increases cytosolic free Ca2+
concentrations. 5) This initiates the translocation of nonactivated m-calpain to the plasma
membrane (6). 7) At the plasma membrane nonactivated m-calpain is autolyzed and
hydrolyzes a membrane-associated substrate. 8) Either directly or indirectly, hydrolysis of
the membrane-associated substrate results in influx of extracellular chloride ions (Cl-). The
influx of extracellular Cl- triggers terminal cell swelling. Steps a–d represent an alternate
pathway that results in extracellular Ca2+ entry. (Data from Waters et al. [12,13,14].)
FIGURE 15-31
PROPERTIES OF PHOSPHOLIPASE A2 GROUP Biochemical characteristics of several identi-
fied phospholipase A2s.
50 80
LLC-cPLA2 LLC-cPLA2
70
LLC-vector LLC-PK1
40
60
30 50
40
20 30
20
10
10
0 0
30 60 90 120 0.0 0.1 0.2 0.3 0.4 0.5
A Time, min B [H2O2], mmol
FIGURE 15-32
80
LLC-cPLA2 The importance of the cytosolic phospholipase A2 in oxidant
70 injury. A, Time-dependent release of arachidonic acid (AA)
LLC-sPLA2
60 from LLC-PK1 cells exposed to hydrogen peroxide (0.5 mM).
LDH release, % total
LLC-vector
50
B and C, The concentration-dependent effects of hydrogen perox-
ide on LLC-PK1 cell death (using lactate dehydrogenase [LDH]
40 release as marker) after 3 hours’ exposure. Cells were transfected
30 with 1) the cytosolic PLA2 (LLC-cPLA2), 2) the secretory PLA2
20 (LLC-sPLA2), 3) vector (LLC-vector), or 4) were not transfected
(LLC-PK1). Cells transfected with cytosolic PLA2 exhibited
10
greater AA release and cell death in response to oxidant exposure
0 than cells transfected with the vector or secretory PLA2 or not
0.0 0.1 0.2 0.3 0.4 0.5 transfected. These results suggest that activation of cytosolic
C [H2O2], mmol PLA2 during oxidant injury contributes to cell injury and death.
(From Sapirstein et al. [15]; with permission.)
50
200
100
Residual double-stranded DNA, %
∆ Increase in caspase activity,
40
150 75
Cell death, %
units/mg protein
30
100 50
20
50 25 10
0 0
0
cin A
cin A
r II
r II
rI
rI
trol
trol
0 10 20 30
bito
bito
bito
bito
Con
Con
imy
imy
Inhi
Inhi
Inhi
Ant
Ant
A min B C
FIGURE 15-33
Potential role of caspases in cell death in LLC-PK1 cells exposed to Inhibitor 1 is IL-1 converting enzyme inhibitor 1 (YVAD-CHO) and
antimycin A. A, Time-dependent effects of antimycin A treatment on inhibitor II is CPP32/apopain inhibitor (DEVD-CHO). These results
caspase activity in LLC-PK1 cells. B, C, The effect of two capase suggest that caspases are activated after mitochondrial inhibition and
inhibitors on antimycin A–induced DNA damage and cell death, respec- that caspases may contribute to antimycin A–induced DNA damage
tively. Antimycin A is an inhibitor of mitochondrial electron transport. and cell death. (From Kaushal et al. [16]; with permission.)
15.14 Acute Renal Failure
References
1. Fish EM, Molitoris BA: Alterations in epithelial polarity and the 10. Suzuki K, Ohno S: Calcium activated neutral protease: Structure-func-
pathogenesis of disease states. N Engl J Med 1994, 330:1580. tion relationship and functional implications. Cell Structure Function
2. Gailit J, Colfesh D, Rabiner I, et al.: Redistribution and dysfunction 1990, 15:1.
of integrins in cultured renal epithelial cells exposed to oxidative 11. Suzuki K, Sorimachi H, Yoshizawa T, et al.: Calpain: Novel family
stress. Am J Physiol 1993, 264:F149. members, activation, and physiologic function. Biol Chem Hoppe-
3. Nowak G, Aleo MD, Morgan JA, Schnellmann RG: Recovery of cellu- Seyler 1995, 376:523.
lar functions following oxidant injury. Am J Physiol 1998, 274:F509. 12. Waters SL, Sarang SS, Wang KKW, Schnellmann RG: Calpains medi-
4. Majno G, Joris I: Apoptosis, oncosis and necrosis. Am J Pathol 1995, ate calcium and chloride influx during the late phase of cell injury. J
146:3. Pharmacol Exp Ther 1997, 283:1177.
5. Monks TJ, Lau SS: Renal transport processes and glutathione conju- 13. Waters SL, Wong JK, Schnellmann RG: Depletion of endoplasmic
gate–mediated nephrotoxicity. Drug Metab Dispos 1987, 15:437. reticulum calcium stores protects against hypoxia- and mitochondrial
inhibitor–induced cellular injury and death. Biochem Biophys Res
6. Hayden PJ, Ichimura T, McCann DJ, et al.: Detection of cysteine con-
Commun 1997, 240:57.
jugate metabolite adduct formation with specific mitochondrial pro-
teins using antibodies raised against halothane metabolite adducts. 14. Waters SL, Miller GW, Aleo MD, Schnellmann RG: Neurosteroid
J Biol Chem 1991, 266:18415. inhibition of cell death. Am J Physiol 1997, 273:F869.
7. Bruschi SA, West KA, Crabb JW, et al.: Mitochondrial HSP60 (P1 15. Sapirstein A, Spech RA, Witzgall R, Bonventre JV: Cytosolic phospho-
protein) and a HSP70-like protein (mortalin) are major targets for lipase A2 (PLA2), but not secretory PLA2, potentiates hydrogen perox-
modification during S-(1,1,2,2-tetrafluoroethyl)-L-cysteine–induced ide cytotoxicity in kidney epithelial cells. J Biol Chem 1996,
nephrotoxicity. J Biol Chem 1993, 268:23157. 271:21505.
8. Groves CE, Lock EA, Schnellmann RG: Role of lipid peroxidation in 16. Kaushal GP, Ueda N, Shah SV: Role of caspases (ICE/CED3 proteases)
renal proximal tubule cell death induced by haloalkene cysteine conju- in DNA damage and cell death in response to a mitochondrial
gates. Toxicol Appl Pharmacol 1991, 107:54. inhibitor, antimycin A. Kidney Int 1997, 52:438.
9. Schnellmann RG: Pathophysiology of nephrotoxic cell injury. In
Diseases of the Kidney. Edited by Schrier RW, Gottschalk CW.
Boston:Little Brown; 1997:1049.
Acute Renal Failure:
Cellular Features of
Injury and Repair
Kevin T. Bush
Hiroyuki Sakurai
Tatsuo Tsukamoto
Sanjay K. Nigam
A
lthough ischemic acute renal failure (ARF) is likely the result of
many different factors, much tubule injury can be traced back
to a number of specific lesions that occur at the cellular level in
ischemic polarized epithelial cells. At the onset of an ischemic insult,
rapid and dramatic biochemical changes in the cellular environment
occur, most notably perturbation of the intracellular levels of ATP and
free calcium and increases in the levels of free radicals, which lead to
alterations in structural and functional cellular components charac-
teristic of renal epithelial cells [1–7]. These alterations include a loss
of tight junction integrity, disruption of actin-based microfilaments,
and loss of the apical basolateral polarity of epithelial cells. The result
is loss of normal renal cell function [7–12].
After acute renal ischemia, the recovery of renal tubule function is
critically dependent on reestablishment of the permeability barrier,
which is crucial to proper functioning of epithelial tissues such as renal
tubules. After ischemic injury the formation of a functional perme-
ability barrier, and thus of functional renal tubules, is critically depen-
dent on the establishment of functional tight junctions. The tight junc-
CHAPTER
tion is an apically oriented structure that functions as both the “fence”
that separates apical and basolateral plasma membrane domains and
16
the major paracellular permeability barrier (gate). It is not yet clear
how the kidney restores tight junction structure and function after
ischemic injury. In fact, tight junction assembly under normal physio-
logical conditions remains ill-understood; however, utilization of the
16.2 Acute Renal Failure
“calcium switch” model with cultured renal epithelial cells has protein, E-cadherin) are membrane proteins. Matrix proteins and
helped to elucidate some of the critical features of tight junction their integrin receptors may need to be resynthesized, along with
bioassembly. In this model for tight junction reassembly, signal- growth factors and cytokines, all of which pass through the endo-
ing events involving G proteins, protein kinase C, and calcium plasmic reticulum (ER). The rate-limiting events in the biosynthe-
appear necessary for the reestablishment of tight junctions sis and assembly of these proteins occur in the ER and are cat-
[13–19]. Tight junction injury and recovery, like that which alyzed by a set of ER-specific molecular chaperones, some of
occurs after ischemia and reperfusion, has similarly been mod- which are homologs of the cytosolic heat-shock proteins [20]. The
eled by subjecting cultured renal epithelial cells to ATP deple- levels of mRNAs for these proteins may increase 10-fold or more
tion (“chemical anoxia”) followed by repletion. While there are in the ischemic kidney, to keep up with the cellular need to syn-
many similarities to the calcium switch, biochemical studies thesize and transport these new membrane proteins, as well as
have recently revealed major differences, for example, in the secreted ones.
way tight junction proteins interact with the cytoskeleton [12]. If the ischemic insult is sufficiently severe, cell death and/or
Thus, important insights into the basic and applied biology of detachment leads to loss of cells from the epithelium lining the
tight junctions are likely to be forthcoming from further analy- kidney tubules. To recover from such a severe insult, cell regen-
sis of the ATP depletion-repletion model. Nevertheless, it is like- eration, differentiation, and possibly morphogenesis, are neces-
ly that, as in the calcium switch model, tight junction reassem- sary. To a limited extent, the recovery of kidney tubule function
bly is regulated by classical signaling pathways that might after such a severe ischemic insult can be viewed as a recapitu-
potentially be pharmacologically modulated to enhance recov- lation of various steps in renal development. Cells must prolif-
ery after ischemic insults. erate and differentiate, and, in fact, activation of growth fac-
More prolonged insults can lead to greater, but still sublethal, tor–mediated signaling pathways (some of the same ones
injury. Key cellular proteins begin to break down. Many of these involved in kidney development) appears necessary to amelio-
(eg, the tight junction protein, occludin, and the adherens junction rate renal recovery after acute ischemic injury [21–30].
Cell loss
Cellular
(detachment
repair
or death)
Cell regenertation,
differentiation, and
morphogenesis
Remove insult
Acute Renal Failure: Cellular Features of Injury and Repair 16.3
FIGURE 16-2
Typical renal epithelial cell. Diagram of a typical renal epithelial
cell. Sublethal injury to polarized epithelial cells leads to multiple
Brush lesions, including loss of the permeability barrier and apical-basolat-
border eral polarity [7–12]. To recover, cells must reestablish intercellular
junctions and repolarize to form distinct apical and basolateral
domains characteristic of functional renal epithelial cells. These
Tight
junction
junctions include those necessary for maintaining the permeability
barrier (ie, tight junctions), maintaining cell-cell contact (ie,
Adherens Terminal web adherens junctions and desmosomes), and those involved in cell-cell
junction Actin cortical ring communication (ie, gap junctions). In addition, the cell must estab-
lish and maintain contact with the basement membrane through its
integrin receptors. Thus, to understand how kidney cells recover
from sublethal ischemic injury it is necessary to understand how
renal epithelial cells form these junctions. Furthermore, after lethal
Desmosome Intermediate
injury to tubule cells new cells may have to replace those lost during
filaments the ischemic insult, and these new cells must differentiate into
epithelial cells to restore proper function to the tubules.
Gap
junction
Extracellular matrix
FIGURE 16-3
Symplekin Occludin The tight junction. The tight junction, the most apical component of the junctional complex
of epithelial cells, serves two main functions in epithelial cells: 1) It separates the apical and
7H6 p130 basolateral plasma membrane domains of the cells, allowing for vectorial transport of ions
Cingulin ZO–1 and molecules; 2) it provides the major framework for the paracellular permeability barrier,
allowing for generation of chemical and electrical gradients [31]. These functions are criti-
cally important to the proper functioning of renal tubules. The tight junction is comprised
ZO–2
of a number of proteins (cytoplasmic and transmembrane) that interact with a similar
group of proteins between adjacent cells to form the permeability barrier [16, 32–37].
Actin These proteins include the transmembrane protein occludin [35, 38] and the cytosolic pro-
filaments
teins zonula occludens 1 (ZO-1), ZO-2 [36], p130, [39], cingulin [33, 40], 7H6 antigen
[34] and symplekin [41], although other as yet unidentified components likely exist. The
Fodrin Paracellular tight junction also appears to interact with the actin-based cytoskeleton, probably in part
space through ZO-1–fodrin interactions.
16.4 Acute Renal Failure
occludin ZO-1 fodrin occludens 1 (ZO-1), and the transmembrane protein occludin are
integral components of the tight junction that are intimately asso-
ciated at the apical border of epithelial cells. This is demonstrated
control here by indirect immunofluorescent localization of these two pro-
teins in normal kidney epithelial cells. After 1 hour of ATP deple-
tion this association appears to change, occludin can be found in
the cell interior, whereas ZO-1 remains at the apical border of the
ATP depletion (1 hr) plasma membrane. Interestingly, the intracellular distribution of
the actin-cytoskeletal–associated protein fodrin also changes after
ATP depletion. Fodrin moves from a random, intracellular distrib-
ution and appears to become co-localized with ZO-1 at the apical
ATP repletion (3hrs) border of the plasma membrane. These changes are completely
reversible after ATP repletion. These findings suggest that disrup-
tion of the permeability barrier could be due, at least in part, to
altered association of ZO-1 with occludin. In addition, the appar-
FIGURE 16-5 ent co-localization of ZO-1 and fodrin at the level of the tight
Immunofluorescent localization of proteins of the tight junction junction suggests that ZO-1 is becoming intimately associated
after ATP depletion and repletion. The cytosolic protein zonula with the cytoskeleton.
FIGURE 16-6
Occludin Occludin
ATP depletion causes disruption of tight junctions. Diagram of the
ZO–1 Fodrin ZO–1 changes induced in tight junction structure by ATP depletion. ATP
depletion causes the cytoplasmic tight junction proteins zonula
Fodrin Ischemia
ZO–2 ZO–2 occludens 1 (ZO-1) and ZO-2 to form large insoluble complexes,
ATP depletion probably in association with the cytoskeletal protein fodrin [12],
Actin
Actin though aggregation may also be significant. Furthermore, occludin,
filament
filament the transmembrane protein of the tight junction, becomes localized
to the cell interior, probably in membrane vesicles. These kinds of
studies have begun to provide insight into the biochemical basis of
tight junction disruption after ATP depletion, although how the
tight junction reassembles during recovery of epithelial cells from
ischemic injury remains unclear.
Membrane vesicle?
Acute Renal Failure: Cellular Features of Injury and Repair 16.5
FIGURE 16-7
Madin-Darby canine kidney (MDCK) cell calcium switch. Insight into the molecular mecha-
nisms involved in the assembly of tight junctions (that may be at least partly applicable to the
ischemia-reperfusion setting) has been gained from the MDCK cell calcium switch model [43].
MDCK cells plated on a permeable support form a monolayer with all the characteristics of a
tight, polarized transporting epithelium. Exposing such cell monolayers to conditions of low
extracellular calcium (less than 5M) causes the cells to lose cell-cell contact and to “round
up.” Upon switching back to normal calcium media (1.8 mM), the cells reestablish cell-cell
Low calcium (LC) contact, intercellular junctions, and apical-basolateral polarity. These events are accompanied
by profound changes in cell shape and reorganization of the actin cytoskeleton. (From Denker
and Nigam [19]; with permission)
FIGURE 16-8
Protein kinase C (PKC) is important for
tight junction assembly. Immunofluorescent
localization of the tight junction protein
zonula occludens 1 (ZO-1) during the
Madin-Darby canine kidney (MDCK) cell
calcium switch. In low-calcium media
MDCK cells are round and have little cell-
cell contact. Under these conditions, ZO-1
is found in the cell interior and has little, if
any, membrane staining, A. After 2 hours
incubation in normal calcium media,
A B MDCK cells undergo significant changes in
cell shape and make extensive cell-cell con-
tact along the lateral portions of the plasma
membrane. B, Here, ZO-1 has redistributed
to areas of cell-cell contact with little
apparent intracellular staining. This process
is blocked by treatment with either 500
nM calphostin C, C, or 25M H7, D,
inhibitors of PKC. These results suggest
that PKC plays a role in regulating tight
junction assembly. Similar studies have
demonstrated roles for a number of other
signaling molecules, including calcium and
G proteins, in the assembly of tight junc-
tions [12, 13, 16–19, 37, 44–46]. An
C D analogous set of signaling events is likely
responsible for tight junction reassembly
after ischemia. (From Stuart and Nigam
[16]; with permission.)
16.6 Acute Renal Failure
FIGURE 16-9
Signalling molecules that may be involved in tight junction assembly. Model of the poten-
tial signaling events involved in tight junction assembly. Tight junction assembly probably
depends on a complex interplay of several signaling molecules, including protein kinase C
(PKC), calcium (Ca2+), heterotrimeric G proteins, small guanodine triphosphatases
PKC
(Rab/Rho), and tyrosine kinases [13–16, 18, 37, 44–53]. Although it is not clear how this
P-Tyr process is initiated, it depends on cell-cell contact and involves wide-scale changes in levels
of intracellular free calcium. Receptor/CAM—cell adhesion molecule; DAG—diacylglyc-
P-Ser erol; ER—endoplasmic reticulum; G—alpha subunit of GTP-binding protein; IP3—inosi-
tol trisphosphate. (From Denker and Nigam [19]; with permission.)
P
Gα
Effector
DAG 2+
Tyr-kinases Ca
+
?TP IP3
Rab/Rho
?Receptor/CAM
ER
FIGURE 16-11
45' Ischemia 15' Ischemia Ischemia upregulates endoplasmic reticulum
(ER) molecular chaperones. Molecular
chaperones of the ER are believed to func-
GAPDH GAPDH tion normally to prevent inappropriate
intra- or intermolecular interactions during
the folding and assembly of proteins [20,
54]. However, ER molecular chaperones are
BiP BiP also part of the “quality control” apparatus
involved in the recognition, retention, and
degradation of proteins that fail to fold or
assemble properly as they transit the ER
grp94 grp94
[20, 54]. In fact, the messages encoding the
ER molecular chaperones are known to
increase in response to intraorganelle accu-
ERp72 ERp72 mulation of such malfolded proteins [11,
20, 54, 55]. Here, Northern blot analysis of
1 2 3 1 2 3 total RNA from either whole kidney or cul-
A A
B tured epithelial cells demonstrates that
ischemia or ATP depletion induces the
mRNAs that encode the ER molecular
Kidney Cell Line Thyroid Cell Line chaperones, including immunoglobulin
binding protein (BiP), 94 kDa glucose regu-
28 S lated protein (grp94), and 72 kDa endo-
GAPDH rRNA plasmic reticulum protein (Erp72) [11].
BiP This suggests not only that ischemia or ATP
depletion causes the accumulation of mal-
BiP folded proteins in the ER but that a major
grp94 effect of ischemia and ATP depletion could
be perturbation of the “folding environ-
grp94 ment” of the ER and disruption of protein
processing. GAPDH—glyceraldehyde-3-
ERp72
phosphate dehydrogenase; Hsp70—70 kDa
ERp72 heat-shock protein. (From Kuznetsov et al.
[11]; with permission.)
Hsp70
Hsp70
1 2 3 4 5 6 1 2 3 4
C D
C
FIGURE 16-12
Antimycin A ATP depletion perturbs normal endoplas-
mic reticulum (ER) function. Because ATP
10M
5M
MED
PBS
C D
FIGURE 16-13
Antimycin A ATP depletion increases the stability of chaperone-folding
MED PBS 1 5 10 polypeptide interactions in the endoplasmic reticulum (ER).
Immunoglobulin binding protein (BiP), and perhaps other ER
molecular chaperones, associate with nascent polypeptides as they
are folded and assembled in ER [20, 54, 56, 57, 65–73]. The dis-
Tg sociation of these proteins requires hydrolysis of ATP [69]. Thus,
when levels of ATP drop, BiP should not dissociate from the
secretory proteins and the normally transient interaction should
become more stable. Here, the associations of ER molecular chap-
erones with a model ER secretory protein is examined by Western
grp94 blot analysis of thyroglobulin (Tg) immunoprecipitates from thy-
roid cells subjected to ATP depletion. After treatment with
antimycin A, there is an increase in the amounts of ER molecular
chaperones (BiP, grp94 and ERP72) which co-immunoprecipitate
with antithyroglobulin antibody [11], suggesting that ATP deple-
tion causes stabilization of the interactions between molecular
BiP
chaperones and secretory proteins folded and assembled in the
ER. Moreover, because a number of proteins critical to the proper
functioning of polarized epithelial cells (ie, occludin, E-cadherin,
Na-K-ATPase) are folded and assembled in the ER, this suggests
that recovery from ischemic injury is likely to depend, at least in
ERp72 part, on the ability of the cell to rescue the protein-folding and -
assembly apparatus of the ER. Control media (MED) and phos-
phate buffered saline (PBS)—no ATP depletion; 1, 5, 10M
1 2 3 4 5 antimycin A—ATP-depleting conditions. (From Kuznetsov et al.
[11]; with permission.)
Acute Renal Failure: Cellular Features of Injury and Repair 16.9
Basement membrane
degrading proteinases
FIGURE 16-14
Kidney morphogenesis. Schematics demonstrate the development of the ureteric bud and
Uninduced mesenchyme metanephric mesenchyme during kidney organogenesis. During embryogenesis, mutual inductive
events between the metanephric mesenchyme and the ureteric bud give rise to primordial struc-
tures that differentiate and fuse to form functional nephrons [74-76]. Although the process has
been described morphologically, the nature and identity of molecules involved in the signaling and
regulation of these events remain unclear. A, Diagram of branching tubulogenesis of the ureteric
Condensing cells bud during kidney organogenesis. The ureteric bud is induced by the metanephric mesenchyme to
branch and elongate to form the urinary collecting system [74-76]. B, Model of cellular events
involved in ureteric bud branching. To branch and elongate, the ureteric bud must digest its way
through its own basement membrane, a highly complicated complex of extracellular matrix pro-
teins. It is believed that this is accomplished by cellular projections, “invadopodia,” which allow
for localized sites of proteolytic activity at their tips [77-81]. C, Mesenchymal cell compaction.
S-shaped body
The metanephric mesenchyme not only induces ureteric bud branching but is also induced by the
C ureteric bud to epithelialize and differentiate into the proximal through distal tubule [74–76].
(From Stuart and Nigam [80] and Stuart et al. [81]; with permission.)
FIGURE 16-15
Tubulogenesis in vitro Potential of in vitro tubulogenesis research. Flow chart indicates
relevance of in vitro models of kidney epithelial cell branching
Basic research Applied research tubulogenesis to basic and applied areas of kidney research. While
results from such studies provide critical insight into kidney devel-
opment, this model system might also contribute to the elucidation
Renal development Renal diseases of mechanisms involved in kidney injury and repair for a number
of diseases, including tubular epithelial cell regeneration secondary
Renal injury and repair to acute renal failure. Moreover, these models of branching tubulo-
genesis could lead to therapies that utilize tubular engineering as
Renal cystic diseases artificial renal replacement therapy [82].
Urogenital abnormalities
Hypertension
Artificial kidneys
16.10 Acute Renal Failure
FIGURE 16-16
Cellular response to growth factors. Schematic representation of
Cell proliferation
Mitogenesis the pleiotrophic effects of growth factors, which share several
properties and are believed to be important in the development and
morphogenesis of organs and tissues, such as those of the kidney.
Cell movement Among these properties are the ability to regulate or activate
Motogenesis
numerous cellular signaling responses, including proliferation
(mitogenesis), motility (motogenesis), and differentiation (morpho-
Growth Cell organization genesis). These characteristics allow growth factors to play critical
Morphogenesis roles in a number of complex biological functions, including
factor
embryogenesis, angiogenesis, tissue regeneration, and malignant
Cell survival transformation [83].
Antiapoptosis
DD
A B
C D
FIGURE 16-17
Motogenic effect of growth factors—hepatocyte growth factor type of cultured renal epithelial cell with HGF induced the dissoci-
(HGF) induces cell “scattering.” During development or regenera- ation of islands of cells into individual cells. This phenomenon is
tion the recruitment of cells to areas of new growth is vital. referred to as scattering. HGF was originally identified as scatter
Growth factors have the ability to induce cell movement. Here, factor, based on its ability to induce the scattering of MDCK cells
subconfluent monolayers of either Madin-Darby canine kidney [83]. Now, it is known that HGF and its receptor, the transmem-
(MDCK) C, D, or murine inner medullary collecting duct brane tyrosine kinase c-met, play important roles in development,
(mIMCD) A, B, cells were grown for 24 hours in the absence, regeneration, and carcinogenesis [83]. (From Cantley et al. [84];
A, C, or presence B, D, of 20 ng/mL HGF. Treatment of either with permission.)
Acute Renal Failure: Cellular Features of Injury and Repair 16.11
FIGURE 16-20
Development of cell lines derived from embryonic kidney. Flow
chart of the establishment of ureteric bud and metanephric mes-
enchymal cell lines from day 11.5 mouse embryo. Although the
results obtained from the analysis of kidney epithelial cells—
Pregnant SV40–transgenic mouse Madin-Darby canine kidney (MDCK) or murine inner medullary
collecting duct (mIMCD) seeded in three-dimensional extracellular
matrix gels has been invaluable in furthering our understanding of
Isolate embryos
the mechanisms of epithelial cell branching tubulogenesis, ques-
tions can be raised about the applicability to embryonic develop-
Dissect out embryonic kidney ment of results using cells derived from terminally differentiated
adult kidney epithelial cells [94]. Therefore, kidney epithelial cell
lines have been established that appear to be derived from the
Isolate metanephric mesenchyme Isolate ureteric bud ureteric bud and metanephric mesenchyme of the developing
embryonic kidney of SV-40 transgenic mice [94, 95]. These mice
have been used to establish a variety of “immortal” cell lines.
Culture to obtain immortalized cells
16.12 Acute Renal Failure
A B C
FIGURE 16-21
Ureteric bud cells undergo branching tubulogenesis in three- vitro model with the greatest relevance to early kidney develop-
dimensional extracellular matrix gels. Cell line derived from ment [94]. A, UB cells grown for 1 week in the presence of condi-
ureteric bud (UB) and metanephric mesenchyme from day 11.5 tioned media collected from cells cultured from the metanephric
mouse embryonic kidney undergo branching tubulogenesis in mesenchyme. Note the formation of multicellular cords. B, After
three-dimensional extracellular matrix gels. Here, UB cells have 2 weeks’ growth under the same conditions, UB cells have formed
been induced to form branching tubular structures in response to more substantial tubules, now with clear lumens. C, Interestingly,
“conditioned” media collected from the culture of metanephric after 2 weeks of culture in a three-dimensional gel composed
mesenchymal cells. During normal kidney morphogenesis, these entirely of growth factor–reduced Matrigel, ureteric bud cells have
two embryonic cell types undergo a mutually inductive process not formed cords or tubules, only multicellular cysts. Thus, chang-
that ultimately leads to the formation of functional nephrons ing the matrix composition can alter the morphology from tubules
[74–76]. This model system illustrates this process, ureteric bud to cysts, indicating that this model might also be relevant to renal
cells being induced by factors secreted from metanephric mes- cystic disease, much of which is of developmental origin. (From
enchymal cells. Thus, this system could represent the simplest in Sakurai et al. [94]; with permission.)
FIGURE 16-23
Mechanism of growth factor action. Proposed model for the gener-
FIGURE 16-22
alized response of epithelial cells to growth factors, which the
Signalling pathway of hepatocyte growth factor action. Diagram of depends on their environment. Epithelial cells constantly monitor
the proposed intracellular signaling pathway involved in hepatocyte their surrounding environment via extracellular receptors (ie, inte-
growth factor (HGF)–mediated tubulogenesis. Although HGF is per- grin receptors) and respond accordingly to growth factor stimula-
haps the best-characterized of the growth factors involved in epithe- tion. If the cells are in the appropriate environment, growth factor
lial cell-branching tubulogenesis, very little of its mechanism of binding induces cellular responses necessary for branching tubulo-
action is understood. However, recent evidence has shown that the genesis. There are increases in the levels of extracellular proteinases
HGF receptor (c-Met) is associated with Gab-1, a docking protein and of structural and functional changes in the cytoarchitecture
believed to be involved in signal transduction [96]. Thus, on binding that enable the cells to form branching tubule structures.
to c-Met, HGF activates Gab-1–mediated signal transduction, which,
by an unknown mechanism, affects changes in cell shape and cell
movement or cell-cell–cell-matrix interactions. Ultimately, these alter-
ations lead to epithelial cell–branching tubulogenesis.
Acute Renal Failure: Cellular Features of Injury and Repair 16.13
Growth Factor Expression Following Renal Ischemia Effect of Exogenous Administration Branching/Tubulogenic Activity
HGF Increased [97] Enhanced recovery [103] Facilatory [109,110]
EGF Unclear [98,99] Enhanced recovery [104,105] Facilatory [111]
HB-EGF Increased [100] Undetermined Facilatory [111]
TGF- Unclear Enhanced recovery [106] Facilatory [111]
IGF Increased [101] Enhanced recovery [107,108] Facilatory [112,113]
KGF Increased [102] Undetermined Undetermined
bFGF Undetermined Undetermined Facilatory [112]
GDNF Undetermined Undetermined Facilatory [114]
TGF- Increased† [98] Undetermined Inhibitory for branching [115]
PDGF Increased† [98] Undetermined No effect [112]
*Increase in endogenous biologically active EGF probably from preformed sources; increase in EGF-receptor mRNA
†Chemoattractants for macrophages and monocytes (important source of growth promoting factors)
FIGURE 16-24
Growth factors in development and renal recovery. This table tubulogenesis or to affect recovery of kidney tubules after ischemic
describes the roles of different growth factors in renal injury or in or other injury. Interestingly, growth factors that facilitate branch-
branching tubulogenesis. A large variety of growth factors have ing tubulogenesis in vitro also enhance the recovery of injured
been tested for their ability either to mediate ureteric branching renal tubules.
References
1. Zager RA, Gmur DJ, Bredl CR, et al.: Regional responses within the 13. Nigam SK, Denisenko N, Rodriguez-Boulan E, Citi S: The role of phos-
kidney to ischemia: Assessment of adenine nucleotide and catabolite phorylation in development of tight junctions in cultured renal epithelial
profiles. Biochim Biophys Acta 1990, 1035:29–36. (MDCK) cells. Biochem Biophys Res Commun 1991, 181:548–553.
2. Hays SR: Ischemic acute renal failure. Am J Med Sci 1992, 14. Nigam SK, Rodriguez-Boulan E, Silver RB: Changes in intracellular
304:93–108. calcium during the development of epithelial polarity and junctions.
3. Toback FG: Regeneration after acute tubular necrosis. Kidney Int Proc Natl Acad Sci USA 1992, 89:6162–6166.
1992, 41:226–246. 15. Stuart RO, Sun A, Panichas M, et al.: Critical role for intracellular
4. Liu S, Humes HD: Cellular and molecular aspects of renal repair in calcium in tight junction biogenesis. J Cellular Physiology 1994,
acute renal failure. Curr Opin Nephrol Hypertension 1993, 2:618–624. 159:423–433.
5. Doctor RB, Bennett V, Mandel LJ: Degradation of spectrin and ankyrin 16. Stuart RO, Nigam SK: Regulated assembly of tight junctions by pro-
in the ischemic rat kidney. Am J Physiol 1993, 264:C1003–C1013. tein kinase C. Proc Natl Acad Sci USA 1995, 92:6072–6076.
6. Doctor RB, Bacallao R, Mandel LJ: Method for recovering ATP con- 17. Stuart RO, Sun A, Bush KT, Nigam SK: Dependence of epithelial
tent and mitochondrial function after chemical anoxia in renal cell intercellular junction biogenesis on thapsigargin-sensitive intracellular
cultures. Am J Physiol 1994, 266:C1803–C1811. calcium stores. J Biol Chem 1996, 271:13636–13641.
7. Edelstein CL, Ling H, Schrier RW: The nature of renal cell injury. 18. Denker BM, Saha C, Khawaja S, Nigam SK: Involvement of a het-
Kidney Int 1997, 51:1341–1351. erotrimeric G protein subunit in tight junction biogenesis. J Biol
8. Fish EM, Molitoris BA: Alterations in epithelial polarity and the Chem 1996, 271:25750–25753.
pathogenesis of disease states. N Engl J Med 1994, 330:1580–1587. 19. Denker BM, Nigam SK: Molecular structure and assembly of the tight
9. Mandel LJ, Bacallao R, Zampighi G: Uncoupling of the molecular junction. Am J Physiol 1998, 274:F1–F9.
‘fence’ and paracellular ‘gate’ functions in epithelial tight junctions.
20. Gething M-J, Sambrook J: Protein folding in the cell. Nature 1992,
Nature 1993, 361:552–555.
355:33–45.
10. Goligorsky MS, Lieberthal W, Racusen L, Simon EE: Integrin recep-
tors in renal tubular epithelium: New insights into pathophysiology of 21. Humes HD, Cielinski DA, Coimbra T, et al.: Epidermal growth factor
acute renal failure. Am J Physiol 1993, 264:F1–F8. enhances renal tubule cell regeneration and repair and accelerates the
recovery of renal function in postischemic acute renal failure. J Clin
11. Kuznetsov G, Bush KT, Zhang PL, Nigam SK: Perturbations in matu-
Invest 1989, 84:1757–1761.
ration of secretory proteins and their association with endoplasmic
reticulum chaperones in a cell culture model for epithelial ischemia. 22. Humes HD, Beals TF, Cieslinski DA, et al.: Effects of transforming
Proc Natl Acad Sci USA 1996, 93:8584–8589. growth factor–beta, transforming growth factor-alpha, and other growth
12. Tsukamoto T, Nigam SK: Tight junction proteins become insoluble, factors on renal proximal tubule cells. Lab Invest 1991, 64:538–545.
form large complexes and associate with fodrin in an ATP depletion 23. Miller SB, Martin DR, Kissane J, Hammerman MR: Insulin-like
model for reversible junction disassembly. J Biol Chem 1997, growth factor I accelerates recovery from ischemic acute tubular
272:16133–16139. necrosis in the rat. Proc Natl Acad Sci USA 1992, 89:11876–11880.
16.14 Acute Renal Failure
24. Border W, Noble N: Transforming growth factor beta in tissue fibro- 47. Tsukita S, Oishi K, Akiyama T, et al.: Specific proto-oncogenic tyro-
sis. N Engl J Med 1994, 331:1286–1292. sine kinase of src family are enriched in cell-to-cell adherens junctions
25. Kawaida K, Matsumoto K, Shimazu H, Nakamura T: Hepatocyte where the level of tyrosine phosphorylation is elevated. J Cell Biol
growth factor prevents acute renal failure and accelerates renal regen- 1991, 113:867–879.
eration in mice. Proc Natl Acad Sci USA 1994, 91:4357–4361. 48. Citi S: Protein kinase inhibitors prevent junction dissociation induced
26. Miller S, Martin D, Kissane J, Hammerman M: Hepatocyte growth by low extracellular calcium in MDCK epithelial cells. J Cell Biol
factor accelerates recovery from acute ischemic renal injury in rats. 1992, 117:169–178.
Am J Physiol 1994, 266:F129–F134. 49. Reynolds AB, Daniel J, McCrea PD, et al.: Identification of a new
27. Miller S, Martin D, Kissane J, Hammerman M: Rat models for clini- catenin: The tyrosine kinase substrate pl20cas associates with E-cad-
cal use of insulin-like growth factor I in acute renal failure. Am J herin complexes. Molec Cell Biol 1994, 14:8333–8342.
Physiol 1994, 266:F949–F956. 50. Weber E, Berta G, Tousson A, et al.: Expression and polarized target-
28. Noiri E, Romanov V, Forest T, et al.: Pathophysiology of renal tubu- ing of a Rab3 isoform in epithelial cells. J Cell Biol 1994,
lar obstruction: Therapeutic role of synthetic RGD peptides in acute 125:583–594.
renal failure. Kidney Int 1995, 48:1375–1385. 51. Zahraoui A, Joberty G, Arpin M, et al.: A small rab GTPase is dis-
29. Rahman SN, Butt AR, DuBose TD, et al.: Differential clinical effects tributed in cytoplasmic vesicles in non-polarized cells but colocalizes
of anaritide atrial natiuretic peptide (ANP) in oliguric and non-olig- with the tight junction marker ZO-1 in polarized epithelial cells. J
uric ATN. J Am Soc Nephrol 1995, 6:474. Cell Biol 1994, 124:101–115.
30. Franklin S, Moulton M, Hammerman MR, Miller SB: Sustained 52. Citi S, Denisenko N: Phosphorylation of the tight junction protein
improvement of renal function and amelioration of symptoms in cingulin and the effects of protein kinase inhibitors and activators in
patients with chronic renal failure (CRF) treated with insulin-like MDCK epithelial cells. J Cell Sci 1995, 108:2917–2926.
growth factor I (IGF-I). J Am Soc Nephrol 1995, 6:387. 53. Nilsson M, Fagman H, Ericson LE: Ca2+-dependent and Ca2+-inde-
31. Farquhar M, Palade GE: Junctional complexes in various epithelia. J pendent regulation of the thyroid epithelial junction complex by pro-
Cell Biol 1963, 17:375–412. tein kinases. Exp Cell Res 1996, 225:1–11.
32. Anderson JM, Itallie CMV: Tight junctions and the molecular basis 54. Braakman I, Helenius J, Helenius A: Role of ATP and disulphide
for regulation of paracellular permeability. Am J Physiol 1995, bonds during protein folding in the endoplasmic reticulum. Nature
269:G467–G475. 1992, 356:260–262.
33. Citi S, Sabanay H, Jakes R, et al.: Cingulin, a new peripheral compo- 55. Bush KT, Hendrickson BA, Nigam SK: Induction of the FK506–bind-
nent of tight junctions. Nature 1988, 333:272–276. ing protein, FKBP13, under conditions which misfold proteins in the
34. Zhong Y, Saitoh T, Minase T, et al.: Monoclonal antibody 7H6 reacts endoplasmic reticulum. Biochem J 1994, 303:705–708.
with a novel tight junction–associated protein distinct from ZO-1, 56. Kuznetsov G, Chen LB, Nigam SK: Several endoplasmic reticulum
cingulin and ZO-2. J Cell Biol 1993, 120:477–483. stress proteins, including ERp72, interact with thyroglobulin during
35. Furuse M, Hirose T, Itoh M, et al.: Occludin: A novel integral mem- its matulation. J Biol Chem 1994, 269:22990–22995.
brane protein localizing at tight junctions. J Cell Biol 1993, 57. Nigam SK, Goldberg AL, Ho S, et al.: A set of ER proteins with prop-
123:1777–1788. erties of molecular chaperones includes calcium binding proteins and
36. Jesaitis LA, Goodenough DA: Molecular characterization and tissue members of the thioredoxin superfamily. J Biol Chem 1994,
distribution of ZO-2, a tight junction protein homologous to ZO-1 269:1744–1749.
and Drosophila discs–large tumor suppressor protein. J Cell Biol 58. Knittler MR, Haas IG: Interaction of BIP with newly synthesized
1994, 124:949–961. immunoglobulin light chain molecules: cycles of sequential binding
37. Balda MS, Gonzalez-Mariscal L, Matter K, et al.: Assembly of the and release. EMBO J 1992, 11:1573–1581.
tight junction: The role of diacylglycerol. J Cell Biol 1993,
59. Pelham H: Speculations on the functions of the major heat shock and
123:293–302.
glucose regulated proteins. Cell 1986, 46:959–961.
38. Furuse M, Itoh M, Hirase T, et al.: Direct association of occludin with
60. Pelham HR: Heat shock and the sorting of luminal ER proteins.
ZO-1 and its possible involvement in the localization of occludin at
Embo J 1989, 8:3171–3176.
tight junctions. J Cell Biol 1994, 127:1617–1626.
61. Ellis R, Van Der Vies S: Molecular chaperones. Annu Rev Biochem
39. Balda M, Whitney J, Flores C, et al.: Functional dissociation of para-
cellular permeability and transepithelial resistance and disruption of 1991, 60:321–347.
the apical-basolateral intramembrane diffusion barrier by expression 62. Fra A, Sitia R: The endoplasmic reticulum as a site of protein degra-
of a mutant tight junction protein. J Cell Biol 1996, 134:1031–1049. dation. Subcell Biochem 1993, 21:143–168.
40. Citi S, Sabanay H, Kendrick-Jones J, Geiger B: Cingulin: 63. Hwang C, Sinskey A, Lodish H: Oxidized redox state of glutathione
Characterization and localization. J Cell Sci 1989, 93:107–122. in the endoplasmic reticulum. Science 1992, 257:1496–1502.
41. Keon BH, Schafer S, Kuhn C, et al.: Symplekin, a novel type of tight 64. Gaut J, Hendershot L: The modification and assembly of proteins in
junction plaque protein. J Cell Biol 1996, 134:1003–1018. the endoplasmic reticulum. Curr Opin Cell Biol 1993, 5:589–595.
42. Canfield PE, Geerdes AM, Molitoris BA: Effect of reversible ATP 65. Bole DG, Hendershot LM, Kearny JF: Posttranslational association of
depletion on tight-junction integrity in LLC-PK1 cells. Am J Physiol immunoglobulin heavy chain binding protein with nascent heavy
1991, 261:F1038–F1045. chains in nonsecreting and secreting hybridomas. J Cell Biol 1986,
43. Rodriguez-Boulan E, Nelson WJ: Morphogenesis of the polarized 102:1558–1566.
epithelial cell phenotype. Science 1989, 245:718–725. 66. Gething MJ, McCammon K, Sambrook J: Expression of wild-type
44. Balda MS, Gonzalez-Mariscal L, Contreras RG, et al.: Assembly and and mutant forms of influenza hemagglutinin: The role of folding in
sealing of tight junctions: Possible participation of G-proteins, phos- intracellular transport. Cell 1986, 46:939–950.
pholipase C, protein kinase C and calmodulin. J Membrane Biol 67. Dorner AJ, Bole DG, Kaufman RJ: The relationship of N-linked gly-
1991, 122:193–202. cosylation and heavy chain–binding protein association with the secre-
45. de Almeida JB, Holtzman EJ, Peters P, et al.: Targeting of chimeric G- tion of glycoproteins. J Cell Biol 1987, 105:2665–2674.
alpha-i proteins to specific membrane domains. J Cell Sci 1994, 68. Ng DT, Randall RE, Lamb RA: Intracellular maturation and transport
107:507–515. of the SV5 type II glycoprotein hemagglutinin-neuraminidase: Specific
46. Dodane V, Kachar B: Identification of isoforms of G proteins and and transient association with GRP78-BiP in the endoplasmic reticu-
PKC that colocalize with tight junctions. J Membrane Biol 1996, lum and extensive internalization from the cell surface. J Cell Biol
149:199–209. 1989, 109:3273–3289.
Acute Renal Failure: Cellular Features of Injury and Repair 16.15
69. Rothman JE: Polypeptide chain binding proteins: catalysts of protein 93. Sakurai H, Nigam SK: TGF- selectively inhibits branching morpho-
folding and related processes in cells. Cell 1989, 59:591–601. genesis but not tubulogenesis. Am J Physiol 1997, 272:F139–F146.
70. Blount P, Merlie JP: BIP associates with newly synthesized subunits of 94. Sakurai H, Barros EJ, Tsukamoto T, et al.: An in vitro tubulogenesis
the mouse muscle nicotinic receptor. J Cell Biol 1991, system using cell lines derived from the embryonic kidney shows
113:1125–1132. dependence on multiple soluble growth factors. Proc Natl Acad Sci
71. Melnick J, Aviel S, Argon Y: The endoplasmic reticulum stress protein USA 1997, 94:6279–6284.
GRP94, in addition to BiP, associates with unassembled immunoglob- 95. Barasch J, Pressler L, Connor J, Malik A: A ureteric bud cell line
ulin chains. J Biol Chem 1992, 267:21303–21306. induces nephrogenesis in two steps by two distinct signals. Am J
72. Pind S, Riordan J, Williams D: Participation of the endoplasmic retic- Physiol 1996, 271:F50–F61.
ulum chaperone calnexin (p88, IP90) in the biogenesis of the cystic 96. Weidner K, Di Cesare S, Sachs M, et al.: Interaction between Gab1
fibrosis transmembrane conductance regulator. J Biol Chem 1994, and the c-Met receptor tyrosine kinase is responsible for epithelial
269:12784–12788. morphogenesis. Nature 1996, 384:173–176.
73. Kuznetsov G, Chen L, Nigam S: Multiple molecular chaperones com- 97. Igawa T, Matsumoto K, Kanda S, et al.: Hepatocyte growth factor
plex with misfolded large oligomeric glycoproteins in the endoplasmic may function as a renotropic factor for regeneration in rats with acute
reticulum. J Biol Chem 1997, 272:3057–3063. renal injury. Am J Physiol 1993, 265:F61–F69.
74. Saxen L: Organogenesis of the Kidney. Cambridge: Cambridge 98. Schaudies RP, Johnson JP: Increased soluble EGF after ischemia is
University Press; 1987. accompanied by a decrease in membrane-associated precursors.
75. Brenner BM: Determinants of epithelial differentiation during early Am J Physiol 1993, 264:F523–F531.
nephrogenesis. J Am Soc Nephrol 1990, 1:127–139. 99. Salido EC, Lakshmanan J, Fisher DA, et al.: Expression of epidermal
76. Nigam SK, Aperia A, Brenner BM: Development and maturation of growth factor in the rat kidney. An immunocytochemical and in situ
the kidney. In The Kidney. Edited by Brenner BM. Philadelphia: WB hybridization study. Histochemistry 1991, 96:65–72.
Saunders; 1996. 100.Homma T, Sakai M, Cheng HF, et al.: Induction of heparin-binding
77. Montesano R, Schaller G, Orci L: Induction of epithelial tubular mor- epidermal growth factor-like growth factor mRNA in rat kidney after
phogenesis in vitro by fibroblast-derived soluble factors. Cell 1991, acute injury. J Clin Invest 1995, 96:1018–1025.
66:697–711.
101.Metejka GL, Jennische E: IGF-I binding and IGF-I mRNA expression
78. Montesano R, Matsumoto K, Nakamura T, Orci L: Identification of a in the post-ischemic regenerating rat kidney. Kidney Int 1992,
fibroblast-derived epithelial morphogen as hepatocyte growth factor. 42:1113–1123.
Cell 1991, 67:901–908.
102.Ichimura T, Finch PW, Zhang G, et al.: Induction of FGF-7 after
79. Santos OFP, Nigam SK: HGF-induced tubulogenesis and branching of kidney damage: a possible paracrine mechanism for tubule repair.
epithelial cells is modulated by extracellular matrix and TGF-. Dev Am J Physiol 1996, 271:F967–F976.
Biol 1993, 160:293–302.
103.Kawaida K, Matsumoto K, Shimazu H, Nakamura T: Hepatocyte
80. Stuart RO, Barros EJG, Ribeiro E, Nigam SK: Epithelial tubulogenesis growth factor prevents acute renal failure and accelerates renal
through branching morphogenesis: Relevance to collecting system regeneration in mice. Proc Natl Acad Sci USA 1994, 91:4357–4361.
development. J Am Soc Nephrol 1995, 6:1151–1159.
104.Humes HD, Cielski DA, Coimbra T, et al.: Epidermal growth factor
81. Stuart RO, Nigam SK: Development of the tubular nephron. Semin enhances renal tubule cell regeneration and repair and accelerates the
Nephrol 1995, 15:315–326. recovery of renal function in postischemic acute renal failure. J Clin
82. Sakurai H, Nigam SK: In vitro branching tubulogenesis: Implications Invest 1989, 84:1757–1761.
for developmental and cystic disorders, nephron number, renal repair 105.Coimbra T, Cielinski DA, Humes HD: Epidermal growth factor accel-
and nephron engineering. Kidney Int 1998, 54:14–26.
erates renal repair in mercuric chloride nephrotoxicity. Am J Physiol
83. Matsumoto K, Nakamura T: Emerging multipotent aspects of hepato- 1990, 259:F438–F443.
cyte growth factor. J Biochem 1996, 119:591–600.
106.Reiss R, Cielinski DA, Humes HD: Kidney Int 1990, 37:1515–1521.
84. Cantley LG, Barros EJG, Gandhi M, et al.: Regulation of mitogenesis,
107.Miller SB, Martin DR, Kissane J, Hammerman MR: Insulin-like
motogenesis, and tubulogenesis by hepatocyte growth factor in renal
growth factor I accelerates recovery from ischemic acute tubular
collecting duct cells. Am J Phisiol 1994, 267:F271–F280.
necrosis in the rat. Proc Natl Acad Sci USA 1992, 89:11876–11880.
85. Perantoni AO, Williams CL, Lewellyn AL: Growth and branching
morphogenesis of rat collecting duct anlagen in the absence of 108.Rabkin R, Sorenson A, Mortensen D, Clark R: J Am Soc Nephrol
metanephric mesenchyme. Differentiation 1991, 48:107–113. 1992, 3:713.
86. Santos OF, Barros EJ, Yang X-M, et al.: Involvement of hepatocyte 109.Montesano R, Schaller G, Orci L: Induction of epithelial tubular
growth factor in kidney development. Dev Biol 1994, 163:525–529. morphogenesis in vitro by fibroblast-derived soluable factors.
Cell 1991, 66:697–711.
87. Barros EJG, Santos OF, Matsumoto K, et al.: Differential tubulogenic
and branching morphogenetic activities of growth factors: 110.Santos OFP, Nigam SK: Modulation of HGF-induced tubulogenesis
Implications for epithelial tissue development. Proc Natl Acad Sci and branching by multiple phosphorylation mechanisms. Dev Biol
USA 1995, 92:4412–4416. 1993, 159:535–548.
88. Rogers S, Ryan G, Hammerman MR: Insulin-like growth factors I 111.Sakurai H, Tsukamoto T, Kjelsberg CA, et al.: EGF receptor ligands
and II are produced in metanephros and are required for growth and are a large fraction of in vitro branching morphogens secreted by
development in vitro. J Cell Biol 1991, 113:1447–1453. embryonic kidney. Am J Physiol 1997, 273:F463–F472.
89. Rogers SA, Ryan G, Hammerman MR: Metanephric transforming 112.Sakurai H, Barros EJG, Tsukamoto T, et al.: An in vitro tubulogenesis
growth factor alpha is required for renal organogenesis in vitro. Am J system using cell lines derived from the embrionic kidney shows
Physiol 1992, 262:F533–F539. dependence on multiple soluble growth factors. Proc Natl Acad Sci
USA 1997, 94:6297–6284.
90. Liu Z, Wada J, Alvares K, et al.: Distribution and relevance of insulin-
like growth factor I receptor in metanephric development. Kidney Int 113.Rogers SA, Ryan G, Hammerman MR: Cell Biol 113:1447–1453.
1993, 44:1242–1250. 114.Vega QC, Worby CA, Lechner MS, et al.: Glial cell line-derived
91. Liu J, Baker J, Perkins A, et al.: Mice carrying null mutations of the neurotrophic factor activates the receptor tyrosine kinase RET and
genes encoding insulin-like growth factor I (IGF-1) and type I IGF promotes kidney morphogenesis. Proc Natl Acad Sci USA 1996,
receptor (IGF1R). Cell 1993, 75:59–72. 93:10657–10661.
92. Sakurai H, Tsukamoto T, Kjelsberg C, et al.: EGF receptor ligands are 115.Sakurai H, Nigam SK: Transforming growth factor-beta selectively
a large fraction of in vitro branching morphogens secreted by embry- inhibits branching morphogenesis but not tubulogenesis. Am J Physiol
onic kidney. Am J Physiol 1997, 273:F463–F472. 1997, 272:F139–F146.
Molecular Responses
and Growth Factors
Steven B. Miller
Babu J. Padanilam
T
he kidney possesses a remarkable capacity for restoring its
structure and functional ability following an ischemic or toxic
insult. It is unique as a solid organ in its ability to suffer an
injury of such magnitude that the organ can fail for weeks and yet
recover full function. Studying the natural regenerative process after
an acute renal insult has provided new insights into the pathogenesis
of acute renal failure (ARF) and possible new therapies. These thera-
pies may limit the extent of injury or even accelerate the regenerative
process and improve outcomes for patients suffering with ARF. In this
chapter we illustrate some of the molecular responses of the kidney to
an acute insult and demonstrate the effects of therapy with growth
factors in the setting of experimental models of ARF. We conclude by
demonstrating strategies that will provide future insights into the mol-
ecular response of the kidney to injury.
The regions of the nephron most susceptible to ischemic injury are
the distal segment (S3) of the proximal tubule and the medullary thick
ascending limb of the loop of Henle. Following injury, there is loss of
the epithelial lining as epithelial cells lose their integrin-mediated
attachment to basement membranes and are sloughed into the lumen.
An intense regenerative process follows. Normally quiescent renal
tubule cells increase their nucleic acid synthesis and undergo mitosis.
It is theorized that surviving cells situated close to or within the
denuded area dedifferentiate and enter mitotic cycles. These cells then
redifferentiate until nephron segment integrity is restored. The molec-
ular basis that regulates this process is poorly-understood. After an CHAPTER
injury, there is a spectrum of cell damage that is dependent on the type
and severity of the insult. If the intensity of the insult is limited, cells
17
become dysfunctional but survive. More severe injury results in
detachment of cells from the tubule basement membranes, resulting in
necrosis. Still other cells have no apparent damage and may prolifer-
ate to reepithelialize the damaged nephron segments. Thus, several
17.2 Acute Renal Failure
different processes are required to achieve structural and func- and 3) some damaged cells may actually die—not as a result of
tional integrity of the kidney after a toxic or ischemic insult: the initial insult but through a process of programmed cell death
1) uninjured cells must proliferate and reepithelialize damaged known as apoptosis. Figure 17-1 provides a schematic represen-
nephron segments; 2) nonlethally damaged cells must recover; tation of the renal response to an ischemic or toxic injury.
FIGURE 17-1
Schematic representation of some of the events pursuant to a stimulating cells to undergo mitosis. Nonlethally injured cells
renal insult and epithelial cell repair. Subcellular; Initial events have the potential to follow one of two pathways. In the appro-
include a decrease in cellular ATP and an increase in intracellu- priate setting, perhaps stimulated by growth factors, these cells
lar free calcium. There is blebbing of the endoplasmic reticulum may recover with restoration of cellular integrity and function
with mitochondrial swelling and dysfunction. The brush border (Pathway 2); however, if the injury is significant the cell may still
of the proximal tubules is sloughed into the tubule lumen, and die, but through a process of programmed cell death or apopto-
there is redistribution of membrane proteins with the loss of cel- sis. The third population of cells are those with severe injury
lular polarity. Cellular; At a cellular level this results in three that undergo necrotic cell death. Nephron/Kidney; With the
populations of tubule cells, depending on the severity of the reepithelialization of damaged nephron segments and cellular
insult. Some cells are intact and are poised to participate in the recovery of structural and functional integrity, renal function is
proliferative process (Pathway 1). Growth factors participate by restored. (Modified from Toback [1]; with permission.)
FIGURE 17-2
Growth regulation after an acute insult in regenerating renal tubule
epithelial cells. Under the influence of growth-stimulating factors
the damaged renal tubule epithelium is capable of regenerating
with restoration of tubule integrity and function. The growth fac-
tors may be 1) produced by the tubule epithelium itself and act
locally in an autocrine, juxtacrine or paracrine manner; 2) pro-
duced by surrounding cells to work in a paracrine manner; or 3)
presented to the regenerating area via the circulation mediated by
an endocrine mechanism. Cells at the edge of an injured nephron
Basement membrane segment are illustrated on the left. These cells proliferate in
response to the growth-stimulating factors. The middle cell is in the
process of dividing and the cell on the right is migrating into the
area of injury. (Adapted from Toback [1]; with permission.)
Molecular Responses and Growth Factors 17.3
FIGURE 17-4
Prepro-EGF DCT
Expression of messenger RNA (mRNA) for prepro–epidermal
mRNA
growth factor (EGF) in kidney. This schematic depicts the localiza-
tion of mRNA for prepro-EGF under basal states in kidney.
PCT Prepro-EGF mRNA is localized to the medullary thick ascending
limbs (MTAL) and distal convoluted tubules (DCT).
Immunohistochemical studies demonstrate that under basal condi-
tions the peptide is located on the luminal membrane with the
CTAL
active peptide actually residing within the tubule lumen. It is specu-
lated that, during pathologic states, preformed EGF is either trans-
ported or routed to the basolateral membrane or can enter the
interstitium via backleak. After a toxic or ischemic insult, expres-
sion of EGF is rapidly suppressed and can remain low for a long
time. Likewise, total renal content and renal excretion of EGF
OMCD decreases. CTAL—cortical thick ascending limb; IMCD—inner
MTAL medullary collecting duct; OMCD—outer medullary collecting
duct; and PCT—proximal convoluted tubule.
IMCD
17.4 Acute Renal Failure
FIGURE 17-5
GROWTH FACTOR PRODUCTION Production of epidermal growth factor (EGF), insulin-like growth
factor (IGF-I), and hepatocyte growth factor (HGF) by various tis-
sues. EGF, IGF-I, and HGF have all been demonstrated to improve
outcomes in various animal models of acute renal failure (ARF).
EGF IGF-I
All three growth-promoting factors are produced in the kidneys
Submandibular salivary glands Liver
and in a variety of other organs. The local production is probably
Kidney Lung
most important for recovery from an acute renal insult. The influ-
Others Kidney
ence of production in other organs in the setting of ARF has yet to
HGF Heart be determined. This chapter deals primarily with local production
Liver Muscle and actions of EGF, IGF-I, and HGF.
Spleen Other organs
Kidney
Lung
Other organs
FIGURE 17-6
EGF-receptor DCT
Receptor binding for epidermal growth factor (EGF). EGF binding
binding
in kidney under basal conditions is extensive. The most significant
specific binding occurs in the proximal convoluted (PCT) and
PCT proximal straight tubules. There is also significant EGF binding in
the glomeruli (GLOM), distal convoluted tubules (DCT), and the
entire collecting duct (OMCD, IMCD). After an ischemic renal
insult, EGF receptor numbers increase. This change in the renal
CTAL
EGF system may be responsible for the beneficial effect of exoge-
nously administered EGF is the setting of acute renal failure.
GLOM CTAL—cortical thick ascending loop.
OMCD
MTAL
IMCD
Molecular Responses and Growth Factors 17.5
PCT PCT
CTAL CTAL
GLOM GLOM
OMCD OMCD
MTAL MTAL
IMCD IMCD
FIGURE 17-10
Diagram of intracellular signaling pathways
IGF-I
mediated by the insulin-like growth factor I
IGF-IR (IGF-IR) receptor. IGF-IR when bound to
IGF-I undergoes autophosphorylation on its
tyrosine residues. This enhances its intrinsic
Other tyrosine kinase activity and phosphorylates
substrates multiple substrates, including insulin recep-
SHC tor substrate 1 (IRS-1), IRS-2, and Src
homology/collagen (SHC). IRS-1 upon
Grb2
phosphorylation associates with the p85
SOS P110 subunit of the PI3-kinase (PI3K) and phos-
p85 phorylates PI3-kinase. PI3K upon phospho-
Crk II PI3-kinase rylation converts phosphoinositide-3 phos-
signaling
IRS-1/IRS-2 phate (PI-3P) into PI-3,4-P2, which in turn
activates a serine-thronine kinase Akt (pro-
C3G Akt tein kinase B). Activated Akt kinase phos-
SYP phorylates the proapoptotic factor Bad on a
Grb2 nck BAD
serine residue, resulting in its dissociation
SOS Cell survival from B-cell lymphoma-X (Bcl-XL) . The
Phosphotyrosine
released Bcl-XL is then capable of suppress-
Ras dephosphorylation ing cell death pathways that involve the
Growth,
activity of apoptosis protease activating fac-
differentiation tor (Apaf-1), cytochrome C, and caspases.
A number of growth factors, including
Raf-1 platelet-derived growth factor (PDGF) and
MEKs
S6-kinase IGF 1 promotes cell survival. Activation of
the PI3K cascade is one of the mechanisms
Gene by which growth factors mediate cell sur-
ERKs expression
TF vival. Phosphorylated IRS-1 also associates
with growth factor receptor bound protein
EGF-R 2 (Grb2), which bind son of sevenless (Sos)
MBP
and activates the ras-raf-mitogen activated
protein (ras/raf-MAP) kinase cascade. SHC
also binds Grb2/Sos and activates the
ras/raf-MAP kinase cascade. Other sub-
strates for IGF-I are phosphotyrosine phos-
phatases and SH2 domain containing tyro-
sine phosphatase (Syp). Figure 17-7 has
details on the other signaling pathways in
this figure. MBP—myelin basic protein;
nck—an adaptor protein composed of SH2
and SH3 domains; TF—transcription factor.
17.8 Acute Renal Failure
FIGURE 17-11
HGF mRNA DCT
Expression of hepatocyte growth factor (HGF) mRNA and HGF
HGF receptor
mRNA receptor mRNA in kidney. While the liver is the major source of
circulating HGF, the kidney also produces this growth-promoting
PCT peptide. Experiments utilizing in situ hybridization, immunohisto-
chemistry, and reverse transcription–polymerase chain reaction
(RT-PCR) have demonstrated HGF production by interstitial cells
but not by any nephron segment. Presumably, these interstitial
CTAL
cells are macrophages and endothelial cells. Importantly, HGF
expression in kidney actually increases within hours of an
ischemic or toxic insult. This expression peaks within 6 to 12
hours and is followed a short time later by an increase in HGF
bioactivity. HGF thus seems to act as a renotrophic factor, partic-
ipating in regeneration via a paracrine mechanism; however, its
OMCD expression is also rapidly induced in spleen and lung in animal
MTAL
models of acute renal injury. Reported levels of circulating HGF
in patients with acute renal failure suggest that an endocrine
mechanism may also be operational.
The receptor for HGF is the c-met proto-oncogene product.
Receptor binding has been demonstrated in kidney in a variety of
sites, including the proximal convoluted (PCT) and straight
tubules, medullary and cortical thick ascending limbs (MTAL,
IMCD CTAL), and in the outer and inner medullary collecting ducts
(OMCD, IMCD). As with HGF peptide production, expression of
c-met mRNA is induced by acute renal injury.
Molecular Responses and Growth Factors 17.9
FIGURE 17-12
Pro-HGF
convertase Model of hepatocyte growth factor
Membrane bound Mature (HGF)/c-met signal transduction. In the
Pro-HGF HGF extracellular space, single-chain precursors
Matrix soluble of HGF bound to the proteoglycans at the
pro-HGF
cell surface are converted to the active form
by urokinase plasminogen activator (uPA),
uPa HGFR
Extracellular while the matrix soluble precursor is
processed by a serum derived pro-HGF
convertase. HGF, upon binding to its recep-
tor c-met, induces its dimerization as well
Cytosol as autophosphorylation of tyrosine
GTP-γas Urokinase S S Antiapoptosis residues. The phosphorylated residue binds
Raf-1 receptor BAG-1
Y
to various adaptors and signal transducers
Y PIP2
Y Y such as growth factor receptor bound pro-
SHC PLC-γ tein-2 (Grb2), p85-PI3 kinase, phospholi-
PKC λ, β, γ
DAG activation
P
pase C-gamma (PLC-gamma), signal trans-
P P Y Y
mSos1 IP3 ducer and activator of transcription-3
Grb2
(STAT-3) and Src homology/collagen (SHC)
P Y Y P via Src homology 2 (SH2) domains and
Gab 1 triggers various signal transduction path-
p85 ways. A common theme among tyrosine
MAP kinases C-SγC PI3K kinase receptors is that phosphorylation of
kinases (MEK S) STAT3 different specific tyrosine residues deter-
mines which intracellular transducer will
bind the receptor and be activated. In the
case of HGF receptor, phosphorylation of a
Focal single multifunctional site triggers a
MAP kinases adhesion
TF
Scatter pleiotropic response involving multiple sig-
(ERK5)
SRE nal transducers. The synchronous activation
of several signaling pathways is essential to
TF conferring the distinct invasive growth abil-
Nuclear
membrane ity of the HGF receptor. HGF functions as
Growth
a scattering (dissociation/motility) factor for
TF
epithelial cells, and this ability seems to be
Transcription
mediated through the activation of STAT-3.
Gene
Phosphorylation of adhesion complex
regulatory proteins such as ZO-1, beta-
catenin, and focal adhesion kinase (FAK)
may occur via activation of c-src. Another
Bcl2 interacting protein termed BAG-1
mediates the antiapoptotic signal of HGF
receptor by a mechanism of receptor associ-
ation independent from tyrosine residues.
FIGURE 17-13
DETERMINANT MECHANISMS FOR Mechanisms by which growth factors may possibly alter outcomes
OUTCOMES OF ACUTE RENAL FAILURE of acute renal failure (ARF). Epidermal growth factor, insulin-like
growth factor, and hepatocyte growth factor (HGF) have all been
demonstrated to improve outcomes when administered in the set-
ting of experimental ARF. While the results are the same, the
Mitogenic Anabolic
respective mechanisms of actions of each of these growth factors
Morphogenic Alter leukocyte function
are probably quite different. Many investigators have examined
Cell migration Alter inflammatory process
individual growth factors for a variety of properties that may be
Hemodynamic Apoptosis
beneficial in the setting of ARF. This table lists several of the prop-
Cytoprotective Others erties examined to date. Suffice it to say that the mechanisms by
which the individual growth factors alter the course of experimen-
tal ARF is still unknown.
17.10 Acute Renal Failure
+Vehicle
HGF +IGF-I *
4
↑ *
Serum creatinine, mg/dL
↑ *
↑ *
2
←→
*
←→ *
↑↑↑
0
0 2 4 6
Time after ischemia, d
FIGURE 17-15
Rationale for the use of insulin-like growth factor IGF-I in the set-
ting of acute renal failure (ARF). Of the growth factors that have FIGURE 17-16
been demonstrated to improve outcomes after acute renal injury, Serial serum creatinine values in rats with ischemic acute renal failure
the most progress has been made with IGF-I. From this table, it is (ARF) treated with insulin-like growth factor (IGF-I) or vehicle. This is
evident that IGF-I has a broad spectrum of activities, which makes the original animal experiment that demonstrated a benefit from IGF-I
it a logical choice for treatment of ARF. An agent that increased in the setting of ARF. In this study, IGF-I was administered beginning
renal plasma flow and glomerular filtration rate and was mito- 30 minutes after the ischemic insult (arrow). Data are expressed as
genic for proximal tubule cells and anabolic would address several mean ± standard error. Significant differences between groups are indi-
features of ARF. cated by asterisks.
This experiment has been reproduced, with variations, by several
groups, with similar findings. IGF-I has now been demonstrated to be
beneficial when administered prophylactically before an ischemic injury
and when started as late as 24 hours after reperfusion when injury is
established. It has also been reported to improve outcomes for a variety
of toxic injuries and is beneficial in a model of renal transplantation
with delayed graft function and in cyclosporine-induced acute renal
insufficiency. (From Miller et al. [2]; with permission.)
Molecular Responses and Growth Factors 17.11
FIGURE 17-17
280
+ Vehicle Body weights of rats with ischemic acute renal failure (ARF) treat-
+ IGF-I ed with insulin-like growth factor (IGF-I) or vehicle. Unlike epider-
* mal growth factor or hepatocyte growth factor (HGF), IGF-I is
*
anabolic even in the setting of acute renal injury. These data are
* *
Body weight, g
A B
FIGURE 17-18
Photomicrograph of kidneys from rats with acute renal failure cations, and papillary proliferations the tubule lumen of proxi-
(ARF) treated with insulin-like growth factor (IGF-I) or vehicle. mal tubules. The kidney obtained from the IGF-I–treated rat (B)
These photomicrographs are of histologic sections stained with appears almost normal, showing evidence of regeneration and
hematoxylin and eosin originating from kidneys of rats that restoration of normal renal architecture. In this experiment the
received vehicle or IGF 1 after ischemic renal injury. Kidneys histologic appearance of kidneys from the IGF-I–treated animals
were obtained 7 days after the insult. There is evidence of con- was statistically better than that of the vehicle-treated controls,
siderable residual injury in the kidney from the vehicle-treated as determined by a pathologist blinded to therapy. (From Miller
rat (A): dilation and simplification of tubules, interstitial calcifi- et al. [2]; with permission.)
17.12 Acute Renal Failure
Laron-type dwarfism
Insulin-dependent and non–insulin-dependent diabetes mellitus
Anabolic agent in catabolic states
Acute renal failure
AIDS (Protein wasting malnutrition)
Chronic renal failure
Burns
Future Directions
FIGURE 17-24
HUMAN IGF-I IN PATIENTS WITH ARF* A list of genes
whose expression
is induced at
Multicenter, double- *No difference between the groups were observed in final values or changes in values for glomerular filtration various time points
blind, randomized, by ischemic renal
placebo-controlled 1 Hour 1 Day 2 Days 5 Days References injury. The molecu-
ARF secondary to lar response of
surgery, trauma, ↑ ←→ Bardella et al. [5] the kidney to an
hypertensive ↑ ←→ Ouellette et al. [6] ischemic insult is
nephropathy, sep- ↑ ←→ Bonventre et al. [7] complex and is
sis, or drugs
←→ ↓ ↓ ↓ Witzgall et al. [8] the subject of
Treated within the investigations by
first 6 days for 14
days ↑ ↑ ↑ ↑ Safirstein et al. [9]
several laboratories.
Evaluated renal func- ↑ ←→ “ (Continued on
tion and mortality ↑ Goes et al. [10] next page)
↑ ↑ “
↑ “
↑ ↑ “
↑ ↑ Singh et al. [11]
↑ ↑ “
↑ ↑ “
↑ ↑ “
↑ ↑ ←→ ←→ Soifer et al. [12]
↑ (6 h) ↑ ↑ Firth and Ratcliffe [13]
↓ (6 h) ↓ ↓ “
(Table continued on next page)
17.14 Acute Renal Failure
Well-tolerated
FIGURE 17-25
ARF—acute renal failure. Schematic representation of differential display. In a complex
organ like the kidney, ischemic renal injury triggers altered
expression of various cell factors and vascular components.
Depending on the severity of the insult, expression of these genes
can vary in individual cells, leading to their death, survival, or
MOLECULAR RESPONSE TO RENAL
proliferation. A better understanding of the various factors and
ISCHEMIC/REPERFUSION INJURY
the signal transduction pathways transduced by them that con-
tribute to cell death can lead to development of therapeutic
Genes strategies to interfere with the process of cell death. Similarly,
Transcription factors identification of factors that are involved in initiating cell migra-
c-jun tion, dedifferentiation, and proliferation may lead to therapy
c-fos aimed at accelerating the regeneration program. To identify the
Egr-1 various factors involved in cell injury and regeneration, powerful
Kid 1 methods for identification and cloning of differentially expressed
genes are critical. One such method that has been used exten-
Cytokines
sively by several laboratories is the differential display poly-
JE
merase chain reaction (DD-PCR).
KC
In this schematic, mRNA is derived from kidneys of sham-
IL-2
operated (controls) and ischemia-injured rats, some pretreated
IL-10
with insulin-like growth factor (IGF-I). The mRNAs are reverse
IFN-
transcribed using an anchored deoxy thymidine-oligonucleotide
GM-CSF
(oligo-dT) primer (Example: dT[12]-MX, where M represent G,
MIP-2
A, or C, and X represents one of the four nucleotides). An
IL-6
anchored primer limits the reverse transcription to a subset of
IL-11
mRNAs. The first strand cDNA is then PCR amplified using an
LIF
arbitrary 10 nucleotide-oligomer primer and the anchored
PTHrP
primer. The PCR reaction is performed in the presence of
Endothelin 1
radioactive or fluorescence-labeled nucleotides, so that the
Endothelin 3
amplified fragments can be displayed on a sequencing gel. Bands
of interest can be excised from the gel and used for further char-
acterization. ARF—acute renal failure.
FIGURE 17-26
Sham ARF Schematic representation of a differential display gel in which
Sham +IGF-1 ARF
+ IGF-1
mRNA from kidneys is reverse-transcribed and polymerase chain
reaction (PCR) amplified (see Figure 17-25). The PCR amplifica-
1
tion is conducted in the presence of radioactive nucleotides. The
cDNA fragments corresponding to the 3’ end of the mRNA species
2 are displayed by running them on a sequencing gel, followed by
autoradiography. The arrows show bands corresponding to mRNA
3 transcripts that are expressed differentially 1) in response to
insulin-like growth factor (IGF-I) treatment and induction of
ischemic injury; 2) in an IGF-I–dependent manner; 3) in response
to induction of ischemic injury; and 4) to genes that are down-reg-
4 ulated after induction of ischemic injury. ARF—acute renal failure.
17.16 Acute Renal Failure
References
1. Toback GF: Regeneration after acute tubular necrosis. Kidney Int 17. Ishibashi K, et al.: Expressions of receptor for hepatocyte growth
1992, 41:226–246. factor in kidney after unilateral nephrectomy and renal injury.
2. Miller SB, Martin DR, Kissane J, Hammerman, MR: Insulin-like Biochem Biophys Res Commun 1993, 187:1454–1459.
growth factor I accelerates recovery from ischemic acute tubular 18. Safirstein R, et al.: Changes in gene expression after temporary renal
necrosis in the rat. Proc Natl Acad Sci USA 1992, 89:11876–11880. ischemia. Kidney Int 1990, 37:1515–1521.
3. Franklin SC, Moulton M, Sicard GA, et al.: Insulin-like growth factor 19. Basile DP, et al.: Increased transforming growth factor-beta 1 expres-
I preserves renal function postoperatively. Am J Physiol 1997, sion in regenerating rat renal tubules following ischemic injury. Amer
272:F257–F259. J Physiol 1996, 270:F500–F509.
4. Kopple JD, Hirschberg R, Guler H-P, et al.: Lack of effect of recombi- 20. Padanilam BJ, Hammerman MR: Ischemia-induced receptor for acti-
nant human insulin-like growth factor I (IGF-I) in patients with acute vated C kinase (RACK1) expression in rat kidneys. Amer J Physiol
renal failure (ARF). J Amer Soc Nephro 1996, 7:1375. 1997, 272:F160–F166.
5. Bardella L, Comolli R: Differential expression of c-jun, c-fos and hsp 21. Pombo CM, et al.: The stress-activated protein kinases are major
70 mRNAs after folic acid and ischemia reperfusion injury: effect of
c-Jun amino-terminal kinases activated by ischemia and reperfusion.
antioxidant treatment. Exp Nephrol 1994, 2:158–165.
J Biol Chem 1994, 269:26546–26551.
6. Ouellette AJ, et al.: Expression of two “immediate early” genes, Egr-1
22. Safirstein R: Gene expression in nephrotoxic and ischemic acute renal
and c-fos, in response to renal ischemia and during compensatory
failure [editorial]. J Am Soc Nephrol 1994, 4:1387–1395.
renal hypertrophy in mice. J Clin Invest 1990, 85:766–771.
7. Bonventre JV, et al.: Localization of the protein product of the imme- 23. Safirstein R, Zelent AZ, Price PM: Reduced renal prepro-epidermal
diate early growth response gene, Egr-1, in the kidney after ischemia growth factor mRNA and decreased EGF excretion in ARF. Kid Int
and reperfusion. Cell Regulation 1991, 2:251–60. 1989, 36:810–815.
8. Witzgall R, et al.: Kid-1, a putative renal transcription factor: regula- 24. Raju VS, Maines, MD: Renal ischemia/reperfusion up-regulates heme
tion during ontogeny and in response to ischemia and toxic injury. oxygenase-1 (HSP32) expression and increases cGMP in rat heart.
Mol Cell Biol 1993, 13:1933–1942. J Pharmacol Exp Ther 1996, 277:1814–1822.
9. Safirstein R, et al.: Expression of cytokine-like genes JE and KC is 25. Van Why SK, et al.: Induction and intracellular localization of HSP-72
increased during renal ischemia. Amer J Physiol 1991, 261:F1095–F1101. after renal ischemia. Am J Physiol 1992, 263:F769–F775.
10. Goes N, et al.: Ischemic acute tubular necrosis induces an extensive 26. Padanilam BJ, Martin DR, Hammerman MR: Insulin-like growth
local cytokine response. Evidence for induction of interferon-gamma, factor I–enhanced renal expression of osteopontin after acute
transforming growth factor-beta 1, granulocyte-macrophage ischemic injury in rats. Endocrinology 1996, 137:2133–2140.
colony–stimulating factor, interleukin-2, and interleukin-10. 27. Walker PD: Alterations in renal tubular extracellular matrix compo-
Transplantation 1995, 59:565–572. nents after ischemia-reperfusion injury to the kidney. Lab Invest 1994,
11. Singh AK, et al.: Prominent and sustained upregulation of MIP-2 and 70:339–345.
gp130 signaling cytokines in murine renal ischemic-reperfusion injury. 28. Van Why SK, et al.: Expression and molecular regulation of Na+-K+-
J Am Soc Nephrol 1997, 8:595A. ATPase after renal ischemia. Am J Physiol 1994, 267:F75–F85.
12. Soifer NE, et al.: Expression of parathyroid hormone–related protein
29. Wang Z, et al.: Ischemic-reperfusion injury in the kidney: overexpres-
in the rat glomerulus and tubule during recovery from renal ischemia.
sion of colonic H+-K+-ATPase and suppression of NHE-3. Kidney Int
J Clin Invest 1993, 92:2850–2857.
1997, 51:1106–1115.
13. Firth JD, Ratcliffe PJ: Organ distribution of the three rat endothelin
messenger RNAs and the effects of ischemia on renal gene expression. 30. McKanna JA, et al.: Localization of p35 (annexin I, lipocortin I) in
J Clin Invest 1992, 90:1023–1031. normal adult rat kidney and during recovery from ischemia. J Cell
Physiol 1992, 153:467–76.
14. Witzgall R, et al.: Localization of proliferating cell nuclear antigen,
vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for 31. Nakamura H, et al.: Subcellular characteristics of phospholipase A2
a heterogeneous genetic response among nephron segments, and a activity in the rat kidney. Enhanced cytosolic, mitochondrial, and
large pool of mitotically active and dedifferentiated cells. J Clin Invest microsomal phospholipase A2 enzymatic activity after renal ischemia
1994, 93:2175–2188. and reperfusion. J Clin Invest 1991, 87:1810–1818.
15. Basile DP, Liapis H, Hammerman MR: Expression of bcl-2 and bax in 32. Lewington AJP, Padanilam BJ, Hammerman MR: Induction of calcy-
regenerating rat renal tubules following ischemic injury. Am J Physiol clin after ischemic injury to rat kidney. Am J Physiol 1997,
1997, 272:F640–F647. 273(42):F380–F385.
16. Matejka GL, Jennische E: IGF-I binding and IGF-1 mRNA expression
in the post-ischemic regenerating rat kidney. Kidney Int 1992,
42(5):1113–1123.
Nutrition and Metabolism
in Acute Renal Failure
Wilfred Druml
A
dequate nutritional support is necessary to maintain protein
stores and to correct pre-existing or disease-related deficits in
lean body mass. The objectives for nutritional support for
patients with acute renal failure (ARF) are not much different from
those with other catabolic conditions. The principles of nutritional sup-
port for ARF, however, differ from those for patients with chronic renal
failure (CRF), because diets or infusions that satisfy minimal require-
ments in CRF are not necessarily sufficient for patients with ARF.
In patients with ARF modern nutritional therapy must include a
tailored regimen designed to provide substrate requirements with var-
ious degrees of stress and hypercatabolism. If nutrition is provided to
a patient with ARF the composition of the dietary program must be
specifically designed because there are complex metabolic abnormali-
ties that affect not only water, electrolyte, and acid-base-balance but
also carbohydrate, lipid, and protein and amino acid utilization.
In patients with ARF the main determinants of nutrient require-
ments (and outcome) are not renal dysfunction per se but the degree of
hypercatabolism caused by the disease associated with ARF, the nutri-
tional state, and the type and frequency of dialysis therapy. Pre-exist-
ing or hospital-acquired malnutrition has been identified as an impor-
tant contributor to the persisting high mortality in critically ill persons.
Thus, with modern nutritional support requirements must be met for
all nutrients necessary for preservation of lean body mass, immunocom-
petence, and wound healing for a patient who has acquired ARF—in
may instances among other complications. At the same time the spe-
cific metabolic alterations and demands in ARF and the impaired
excretory renal function must be respected to limit uremic toxicity. CHAPTER
In this chapter the multiple metabolic alterations associated with
ARF are reviewed, methods for estimating nutrient requirements are
18
discussed and, current concepts for the type and composition of nutri-
tional programs are summarized. This information is relevant for
designing nutritional support in an individual patient with ARF.
18.2 Acute Renal Failure
FIGURE 18-1
NUTRITION IN ACUTE RENAL FAILURE Nutritional goals in patients with acute renal failure (ARF). The
goals of nutritional intervention in ARF differ from those in
patients with chronic renal failure (CRF): One should not provide
Goals a minimal intake of nutrients (to minimize uremic toxicity or to
Preservation of lean body mass retard progression of renal failure, as recommended for CRF) but
Stimulation of wound healing and reparatory functions rather an optimal amount of nutrients should be provided for cor-
Stimulation of immunocompetence rection and prevention of nutrient deficiencies and for stimulation
Acceleration of renal recovery (?) of immunocompetence and wound healing in the mostly hypercata-
But not (in contrast to stable CRF) bolic patients with ARF [1].
Minimization of uremic toxicity (perform hemodialysis and CRRT as required)
Retardation of progression of renal failure
Thus, provision of optimal but not minimal amounts of substrates
FIGURE 18-2
METABOLIC PERTURBATIONS Metabolic perturbations in acute renal failure (ARF). In most
IN ACUTE RENAL FAILURE instances ARF is a complication of sepsis, trauma, or multiple
organ failure, so it is difficult to ascribe specific metabolic alter-
ations to ARF. Metabolic derangements will be determined by the
Determined by Plus acute uremic state plus the underlying disease process or by com-
plications such as severe infections and organ dysfunctions and,
Renal dysfunction (acute uremic state) Specific effects of renal
last but not least by the type and frequency of renal replacement
Underlying illness replacement therapy
therapy [1, 2].
The acute disease state, such as Nonspecific effects of extracorporeal
circulation (bioincompatibility)
Nevertheless, ARF does not affect only water, electrolyte, and acid
systemic inflammatory response
base metabolism: it induces a global change of the metabolic envi-
syndrome (SIRS)
ronment with specific alterations in protein and amino acid, carbo-
Associated complications (such as
infections) hydrate, and lipid metabolism [2].
FIGURE 18-4
ESTIMATION OF ENERGY REQUIREMENTS Estimation of energy requirements. Energy requirements of
patients with acute renal failure (ARF) have been grossly over-
estimated in the past and energy intakes of more than 50 kcal/kg
Calculation of resting energy expenditure (REE) (Harris Benedict equation): of body weight (BW) per day (ie, about 100% above resting
Males: 66.47 (13.75 BW) (5 height) (6.76 age) energy expenditure (REE) haven been advocated [6]. Adverse
Females: 655.1 (9.56 BW) (1.85 height) (4.67 age)
effects of overfeeding have been extensively documented during
the last decades, and it should be noted that energy intake must
The average REE is approximately 25 kcal/kg BW/day
not exceed the actual energy consumption. Energy requirements
Stress factors to correct calculated energy requirement for hypermetabolism:
can be calculated with sufficient accuracy by standard formulas
Postoperative (no complications) 1.0
such as the Harris Benedict equation. Calculated REE should be
Long bone fracture 1.15–1.30
multiplied with a stress factor to correct for hypermetabolic
Cancer 1.10–1.30
disease; however, even in hypercatabolic conditions such as sepsis
Peritonitis/sepsis 1.20–1.30 or multiple organ dysfunction syndrome, energy requirements
Severe infection/polytrauma 1.20–1.40 rarely exceed 1.3 times calculated REE [1].
Burns ( approxim. REE % burned body surface area) 1.20–2.00
Corrected energy requirements (kcal/d) REE stress factor
Protein metabolism
FIGURE 18-5
Protein metabolism in acute renal failure (ARF): activation of
protein catabolism. Protein synthesis and degradation rates in
acutely uremic and sham-operated rats. The hallmark of metabol-
ic alterations in ARF is activation of protein catabolism with
excessive release of amino acids from skeletal muscle and sus-
tained negative nitrogen balance [7, 8]. Not only is protein break-
down accelerated, but there also is defective muscle utilization of
amino acids for protein synthesis. In muscle, the maximal rate of
insulin-stimulated protein synthesis is depressed by ARF and pro-
tein degradation is increased, even in the presence of insulin [9].
(From [8]; with permission.)
18.4 Acute Renal Failure
FIGURE 18-6
Protein metabolism in acute renal failure (ARF): impairment of of the curves, insulin sensitivity is maintained (see also Fig. 18-14).
cellular amino acid transport. A, Amino acid transport into skele- This abnormality can be linked both to insulin resistance and to
tal muscle is impaired in ARF [10]. Transmembranous uptake of a generalized defect in ion transport in uremia; both the activity
the amino acid analogue methyl-amino-isobutyrate (MAIB) is and receptor density of the sodium pump are abnormal in adi-
reduced in uremic tissue in response to insulin (muscle tissue pose cells and muscle tissue [11]. B, The impairment of rubidium
from uremic animals, black circles, and from sham-operated ani- uptake (Rb) as a measure of Na-K-ATPase activity is tightly cor-
mals, open circles, respectively). Thus, insulin responsiveness is related to the reduction in amino acid transport. (From [10,11];
reduced in ARF tissue, but, as can be seen from the parallel shift with permission.)
FIGURE 18-7
Protein catabolism in acute renal failure (ARF). Amino acids are erated hepatic gluconeogenesis, which cannot be suppressed by
redistributed from muscle tissue to the liver. Hepatic extraction of exogenous substrate infusions (see Fig. 18-15). In the liver, protein
amino acids from the circulation—hepatic gluconeogenesis, A, and synthesis and secretion of acute phase proteins are also stimulated.
ureagenesis, B, from amino acids all are increased in ARF [12]. Circles—livers from acutely uremic rats; squares—livers from sham
The dominant mediator of protein catabolism in ARF is this accel- operated rats. (From Fröhlich [12]; with permission.).
Nutrition and Metabolism in Acute Renal Failure 18.5
FIGURE 18-9
Amino acid pools and amino acid utilization in acute renal failure extraction of amino acids observed in animal experiments,
(ARF). As a consequence of these metabolic alterations, imbal- overall amino acid clearance and clearance of most glucoplastic
ances in amino acid pools in plasma and in the intracellular com- amino acids is enhanced. In contrast, clearances of PHE, proline
partment occur in ARF. A typical plasma amino acid pattern is (PRO), and, remarkably, VAL are decreased [16, 17]. ALA—
seen [16]. Plasma concentrations of cysteine (CYS), taurine (TAU), alanine; ARG—arginine; ASN—asparagine; ASP—aspartate;
methionine (MET), and phenylalanine (PHE) are elevated, where- CIT—citrulline; GLN—glutamine; GLU—glutamate; GLY—
as plasma levels of valine (VAL) and leucine (LEU) are decreased. glycine; HIS—histidine; ORN—ornithine; PRO—proline; SER—
Moreover, elimination of amino acids from the intravascular serine; THR—threonine; TRP—tryptophan; TYR—tyrosine.
space is altered. As expected from the stimulation of hepatic (From Druml et al. [16]; with permission.)
18.6 Acute Renal Failure
Protein requirements
FIGURE 18-12
ESTIMATING THE EXTENT OF PROTEIN CATABOLISM Estimation of protein catabolism and nitrogen balance. The extent
of protein catabolism can be assessed by calculating the urea nitro-
gen appearance rate (UNA), because virtually all nitrogen arising
Urea nitrogen appearance (UNA) (g/d) from amino acids liberated during protein degradation is converted
Urinary urea nitrogen (UUN) excretion to urea. Besides urea in urine (UUN), nitrogen losses in other body
Change in urea nitrogen pool
fluids (eg, gastrointestinal, choledochal) must be added to any
change in the urea pool. When the UNA rate is multiplied by 6.25,
(UUN V) (BUN2 BUN1) 0.006 BW
it can be converted to protein equivalents. With known nitrogen
(BW2 BW1) BUN2/100
intake from the parenteral or enteral nutrition, nitrogen balance
If there are substantial gastrointestinal losses, add urea nitrogen in secretions:
can be estimated from the UNA calculation.
volume of secretions BUN2
Net protein breakdown (g/d) UNA 6.25
Muscle loss (g/d) UNA 6.25 5
V is urine volume; BUN1 and BUN2 are BUN in mg/dL on days 1 and 2
BW1 and BW2 are body weights in kg on days 1 and 2
body weight per day) was derived from a study in which, unfortu-
nately, energy intake was not kept constant [6]. In the polyuric
recovery phase in patients with sepsis-induced ARF, a nitrogen intake
of 15 g/day (averaging an amino acid intake of 1.3 g/kg body weight
per day) as compared to 4.4 g/kg per day (about 0.3 g/kg amino
acids) was superior in ameliorating nitrogen balance [26].
Several recent studies have tried to evaluate protein and amino
acid requirements of critically ill patients with ARF. Kierdorf and
associates found that, in these hypercatabolic patients receiving
continuous hemofiltration therapy, the provision of amino acids 1.5
g /kg body weight per day was more effective in reducing nitrogen
loss than infusion of 0.7 g (3.4 versus 8.1 g nitrogen per day)
[27]. An increase of amino acid intake to 1. 74 g/kg per day did not
FIGURE 18-13 further ameliorate nitrogen balance.
Amino acid and protein requirements of patients with acute renal Chima and coworkers measured a mean PCR of 1.7 g kg body
failure (ARF). The optimal intake of protein or amino acids is weight per day in 19 critically ill ARF patients and concluded that
affected more by the nature of the underlying cause of ARF and protein needs in these patients range between 1.4 and 1.7 g/kg per
the extent of protein catabolism and type and frequency of dialysis day [28]. Similarly, Marcias and coworkers have obtained a protein
than by kidney dysfunction per se. Unfortunately, only a few stud- catabolic rate (PCR) of 1.4 g/kg per day and found an inverse
ies have attempted to define the optimal requirements for protein relationship between protein and energy provision and PCR and
or amino acids in ARF: again recommended protein intake of 1.5 to 1.8 g/kg per day [29].
In nonhypercatabolic patients, during the polyuric phase of ARF Similar conclusions were drawn by Ikitzler in evaluating ARF
protein intake of 0.97 g/kg body weight per day was required to patients on intermittent hemodialysis therapy [30]. (From Kierdorf
achieve a positive nitrogen balance [25]. A similar number (1.03g/kg et al. [27]; with permission.)
18.8 Acute Renal Failure
Glucose metabolism
FIGURE 18-14
Glucose metabolism in acute renal failure (ARF): Peripheral insulin than impaired insulin sensitivity as the cause of defective glucose
resistance. ARF is commonly associated with hyperglycemia. The metabolism. The factors contributing to insulin resistance are more
major cause of elevated blood glucose concentrations is insulin or less identical to those involved in the stimulation of protein
resistance [31]. Plasma insulin concentration is elevated. Maximal breakdown (see Fig. 18-8). Results from experimental animals sug-
insulin-stimulated glucose uptake by skeletal muscle is decreased by gest a common defect in protein and glucose metabolism: tyrosine
50 %, A, and muscular glycogen synthesis is impaired, B. However, release from muscle (as a measure of protein catabolism) is closely
insulin concentrations that cause half-maximal stimulation of glu- correlated with the ratio of lactate release to glucose uptake [9].
cose uptake are normal, pointing to a postreceptor defect rather (From May et al. [31]; with permission.)
FIGURE 18-15
Glucose metabolism in acute renal failure (ARF): Stimulation of
hepatic gluconeogenesis. A second feature of glucose metabolism
(and at the same time the dominating mechanism of accelerated pro-
tein breakdown) in ARF is accelerated hepatic gluconeogenesis, main-
ly from conversion of amino acids released during protein catabolism.
Hepatic extraction of amino acids, their conversion to glucose, and
urea production are all increased in ARF (see Fig. 18-7) [12].
In healthy subjects, but also in patients with chronic renal failure,
hepatic gluconeogenesis from amino acids is readily and completely
suppressed by exogenous glucose infusion. In contrast, in ARF hepat-
ic glucose formation can only be decreased, but not halted, by sub-
strate supply. As can be seen from this experimental study, even dur-
ing glucose infusion there is persistent gluconeogenesis from amino
acids in acutely uremic dogs (•) as compared with controls dogs (o)
whose livers switch from glucose release to glucose uptake [32].
These findings have important implications for nutrition support
for patients with ARF: 1) It is impossible to achieve positive nitrogen
balance; 2) Protein catabolism cannot be suppressed by providing
conventional nutritional substrates alone. Thus, for future advances
alternative means must be found to effectively suppress protein catab-
olism and preserve lean body mass. (From Cianciaruso et al. [32];
with permission.)
Nutrition and Metabolism in Acute Renal Failure 18.9
Lipid metabolism
FIGURE 18-16
Lipid metabolism in acute renal failure (ARF). Profound alterations
of lipid metabolism occur in patients with ARF. The triglyceride con-
tent of plasma lipoproteins, especially very low-density (VLDL) and
low-density ones (LDL) is increased, while total cholesterol and in
particular high-density lipoprotein (HDL) cholesterol are decreased
[33,34]. The major cause of lipid abnormalities in ARF is impair-
ment of lipolysis. The activities of both lipolytic systems, peripheral
lipoprotein lipase and hepatic triglyceride lipase are decreased in
patients with ARF to less than 50% of normal [35].
Maximal postheparin lipolytic activity (PHLA), hepatic triglyceride
lipase (HTGL), and peripheral lipoprotein lipase (LPL) in 10 controls
(open bars) and eight subjects with ARF (black bars). However, in
contrast to this impairment of lipolysis, oxidation of fatty acids is
not affected by ARF. During infusion of labeled long-chain fatty
acids, carbon dioxide production from lipid was comparable
between healthy subjects and patients with ARF [36]. FFA—free
fatty acids. (Adapted from Druml et al. [35]; with permission.)
FIGURE 18-17
Impairment of lipolysis and elimination of artificial lipid emulsions
in acute renal failure (ARF). Fat particles of artificial fat emulsions
for parenteral nutrition are degraded as endogenous very low-den-
sity lipoprotein is. Thus, the nutritional consequence of the
impaired lipolysis in ARF is delayed elimination of intravenously
infused lipid emulsions [33, 34]. The increase in plasma triglyc-
erides during infusion of a lipid emulsion is doubled in patients
with ARF (N=7) as compared with healthy subjects (N=6). The
clearance of fat emulsions is reduced by more than 50% in ARF.
The impairment of lipolysis in ARF cannot be bypassed by using
medium-chain triglycerides (MCT); the elimination of fat emul-
sions containing long chain triglycerides (LCT) or MCT is equally
retarded in ARF [34]. Nevertheless, the oxydation of free fatty acid
released from triglycerides is not inpaired in patients with ARF
[36]. (From Druml et al. [34]; with permission.)
18.10 Acute Renal Failure
FIGURE 18-23
Micronutrients in acute renal failure (ARF): antioxidative factors.
Micronutrients are part of the organism’s defense mechanisms
against oxygen free radical induced injury to cellular components.
In experimental ARF, antioxidant deficiency of the organism
(decreased vitamin E or selenium status) exacerbates ischemic renal
injury, worsens the course, and increases mortality, whereas reple-
tion of antioxidant status exerts the opposite effect [45]. These
data argue for a crucial role of reactive oxygen species and peroxi-
dation of lipid membrane components in initiating and mediating
ischemia or reperfusion injury.
In patients with multiple organ dysfunction syndrome and associ-
ated ARF (lightly shaded bars) various factors of the oxygen radi-
cal scavenger system are profoundly depressed as compared with
healthy subjects (black bars): plasma concentrations of vitamin C,
of -carotene, vitamin E, selenium, and glutathione all are pro-
foundly depressed, whereas the end-product of lipid peroxidation,
malondialdehyde, is increased (double asterisk, P < 0.01; triple
asterisk, P < 0.001). This underlines the importance of supplemen-
tation of antioxidant micronutrients for patients with ARF.
(Adapted from Druml et al. [46]; with permission.)
18.12 Acute Renal Failure
FIGURE 18-25
A, B, Impact of nutritional interventions on renal function and Infusion of amino acids raised renal cortical protein synthesis as
course of acute renal failure (ARF). Starvation accelerates protein evaluated by 14C-leucine incorporation and depressed protein breakdown
breakdown and impairs protein synthesis in the kidney, whereas in rats with mercuric chloride–induced ARF [49]. On the other hand, in a
refeeding exerts the opposite effects [49]. In experimental animals, similar model of ARF, infusions of varying quantities of essential amino
provision of amino acids or total parenteral nutrition accelerates acids (EAA) and nonessential amino acids (NEAA) did not provide any
tissue repair and recovery of renal function [50]. In patients, protection of renal function and in fact increased mortality [52]. However,
however, this has been much more difficult to prove, and only one in balance available evidence suggests that provision of substrates may
study has reported on a positive effect of TPN on the resolution enhance tissue regeneration and wound healing, and potentially, also
of ARF [51]. renal tubular repair [49]. (From Toback et al. [50]; with permission.)
Nutrition and Metabolism in Acute Renal Failure 18.13
FIGURE 18-26
Impact of nutritional interventions on renal function in acute renal
failure (ARF). Amino acid infused before or during ischemia or
nephrotoxicity may enhance tubule damage and accelerate loss of
renal function in rat models of ARF. In part, this therapeutic para-
dox [53] from amino acid alimentation in ARF is related to the
increase in metabolic work for transport processes when oxygen
supply is limited, which may aggravate ischemic injury [54].
Similar observations have been made with excess glucose infusion
during renal ischemia. Amino acids may as well exert a protective
effect on renal function. Glycine, and to a lesser degree alanine,
limit tubular injury in ischemic and nephrotoxic models of ARF
[55]. Arginine (possibly by producing nitric oxide) reportedly acts
to preserve renal perfusion and tubular function in both nephro-
toxic and ischemic models of ARF, whereas inhibitors of nitric
oxide synthase exert an opposite effect [56,57]. In myoglobin-
induced ARF the drop in renal blood flow (black circles, ARF con-
trols) is prevented by L-arginine infusion (black triangles) [57].
(From Wakabayashi et al. [57]; with permission.)
FIGURE 18-27
Impact of endocrine-metabolic interventions on renal function and ischemic ARF, A, but also reduces the increase in BUN and
course of acute renal failure (ARF). Various other endocrine-meta- improves nitrogen balance, B, [58]. (open circles) ARF plus vehi-
bolic interventions (eg, thyroxine, human growth hormone [HGH], cle; (black circles, sham-operated rats plus vehicle; open squares,
epidermal growth factor, insulin-like growth factor 1 [IGF-1]) have ARF plus rhIGF-I; black squares, sham operated rats plus rhIGF-
been shown to accelerate regeneration after experimental ARF I.) Unfortunately, efficacy of these interventions was not uniform-
[51]. In a rat model of postischemic ARF, treatment with IGF-1 ly confirmed in clinical studies [59, 60]. (From Ding et al. [58];
starting 5 hours after induction of ARF accelerates recovery from with permission.)
18.14 Acute Renal Failure
Extent of Catabolism
Mild Moderate Severe
Excess urea appearance >6 g 6–12 g >12 g
(above nitrogen intake)
Clinical setting (examples) Drug toxicity Elective surgery Severe injury or
± infection sepsis
Mortality 20 % 60% >80%
Dialysis or hemofiltration frequency Rare As needed Frequent
Route of nutrient Oral Enteral or parenteral Enteral or parenteral
administration
Energy recommendations 25 25–30 25–35
(kcal/kg BW/d)
Energy substrates Glucose Glucose + fat Glucose fat
Glucose (g/kg BW/d) 3.0–5.0 3.0–5.0 3.0–5.0 (max. 7.0)
Fat (g/kg BW/d) 0.5–1.0 0.8–1.5
Amino acids/protein (g/kg/d) 0.6–1.0 0.8–1.2 1.0–1.5
EAA (NEAA) EAA NEAA EAA NEAA
Nutrients used Foods Enteral formulas Enteral formulas
Glucose 50%–70% Glucose 50%–70% +
fat emulsions 10% fat emulsions 10%
or 20% or 20%
EAA + specific NEAA solutions (general or “nephro”)
Multivitamin and multitrace element preparations
FIGURE 18-29
Patient classification: substrate requirements. Ideally, a nutritional program should be
designed for each individual acute renal failure (ARF) patient. In clinical practice, it has
proved useful to distinguish three groups of patients based on the extent of protein catabo-
lism associated with the underlying disease and resulting levels of dietary requirements.
Group I includes patients without excess catabolism and a UNA of less than 6 g of
nitrogen above nitrogen intake per day. ARF is usually caused by nephrotoxins (aminogly-
cosides, contrast media, mismatched blood transfusion). In most cases, these patients are
fed orally and the prognosis for recovery of renal function and survival is excellent.
Group II consists of patients with moderate hypercatabolism and a UNA exceeding
nitrogen intake 6 to 12 g of nitrogen per day. Affected patients frequently suffer from
complicating infections, peritonitis, or moderate injury in association with ARF. Tube feed-
ing or intravenous nutritional support is generally required, and dialysis or hemofiltration
often becomes necessary to limit waste product accumulation.
Group III are patients who develop ARF in association with severe trauma, burns, or
overwhelming infection. UNA is markedly elevated (more than 12 g of nitrogen above
nitrogen intake). Treatment strategies are usually complex and include parenteral nutri-
tion, hemodialysis or continuous hemofiltration plus blood pressure and ventilatory sup-
port. To reduce catabolism and avoid protein depletion nutrient requirements are high and
dialysis is used to maintain fluid balance and blood urea nitrogen below 100 mg/dL.
Mortality in this group of patients exceeds 60% to 80%, but it is not the loss of renal
function that accounts for the poor prognosis. It is superimposed hypercatabolism and the
severity of the underlying illness. (Adapted from Druml [1]; with permission.)
18.16 Acute Renal Failure
Enteral Nutrition
FIGURE 18-30
Enteral nutrition (tube feeding). The gastrointestinal tract should be used whenever
possible because enteral nutrients may help to maintain gastrointestinal function and the
mucosal barrier and thus prevent translocation of bacteria and systemic infection [61].
Even small amounts of enteral diets exert a protective effect on the intestinal mucosa.
Recent animal experiments suggest that enteral feeds may exert additional advantages in
acute renal failure (ARF) patients [63]: in glycerol-induced ARF in rats enteral feeding
improved renal perfusion, A, and preserved renal function, B. For patients with ARF who
are unable to eat because of cerebral impairment, anorexia, or nausea, enteral nutrition
should be provided through small, soft feeding tubes with the tip positioned in the stom-
ach or jejunum [61]. Feeding solutions can be administered by pump intermittently or con-
tinuously. If given continuously, the stomach should be aspirated every 2 to 4 hours until
adequate gastric emptying and intestinal peristalsis are established. To avoid diarrhea, the
amount and concentration of the solution should be increased gradually over several days
until nutritional requirements are met. Undesired, but potentially treatable side effects
include nausea, vomiting, abdominal distension and cramping and diarrhea. (From
Roberts et al. [62]; with permission.)
Nutrition and Metabolism in Acute Renal Failure 18.17
SPECIFIC ENTERAL FORMULAS FOR NUTRITIONAL SUPPORT OF PATIENTS WITH RENAL FAILURE
FIGURE 18-31
Enteral feeding formulas. There are standardized tube feeding for- with ARF. The protein content is lower and is confined to high-
mulas designed for subjects with normal renal function that can quality proteins (in part as oligopeptides and free amino acids), the
also be given to patients with acute renal failure (ARF). electrolyte concentrations are restricted. Most formulations contain
Unfortunately, the fixed composition of nutrients, including pro- recommended allowances of vitamins and minerals.
teins and high content of electrolytes (especially potassium and In part, these enteral formulas are made up of components that
phosphate) often limits their use for ARF. increase the flexibility in nutritional prescription and enable adapta-
Alternatively, enteral feeding formulas designed for nutritional tion to individual needs. The diets can be supplemented with addi-
therapy of patients with chronic renal failure (CRF) can be used. tional electrolytes, protein, and lipids as required. Recently, ready-to-
The preparations listed here may have advantages also for patients use liquid diets have also become available for renal failure patients.
18.18 Acute Renal Failure
Parenteral Nutrition
FIGURE 18-32
Parenteral solutions. Standard solutions are available with amino acids, glucose, and
lipids plus added vitamins, trace elements, and electrolytes contained in a single bag
(“total admixture” solutions, “all-in-one” solutions). The stability of fat emulsions in
such mixtures should be tested. If hyperglycemia is present, insulin can be added to the
solution or administered separately.
To ensure maximal nutrient utilization and avoid metabolic derangements as mineral
imbalance, hyperglycemia or blood urea nitrogen rise, the infusion should be started at a
slow rate (providing about 50% of requirements) and gradually increased over several days.
Optimally, the solution should be infused continuously over 24 hours to avoid marked
derangements in substrate concentrations in the presence of impaired utilization for several
nutritional substrates in patients with acute renal failure. EAA, NEAA—essential and
nonessential amino acids; TPN—total parenteral nutrition.
Nutrition and Metabolism in Acute Renal Failure 18.19
AMINO ACID SOLUTIONS FOR THE TREATMENT OF ACUTE RENAL FAILURE (“NEPHRO” SOLUTIONS)
FIGURE 18-33
Amino acid (AA) solutions for parenteral nutrition in acute renal tions or in special proportions designed to counteract the
failure (ARF). The most controversial choice regards the type of metabolic changes of renal failure (“nephro” solutions), includ-
amino acid solution to be used: either essential amino acids (EAAs) ing the amino acids that might become conditionally essential
exclusively, solutions of EAA plus nonessential amino acids in ARF.
(NEAAs), or specially designed “nephro” solutions of different Because of the relative insolubility of tyrosine in water, dipep-
proportions of EAA and specific NEAA that might become “condi- tides containing tyrosine (such as glycyl-tyrosine) are contained in
tionally essential” for ARF (see Fig. 18-11). modern nephro solutions as the tyrosine source [22, 23]. One
Use of solutions of EAA alone is based on principles established for should be aware of the fact that the amino acid analogue N-acetyl
treating chronic renal failure (CRF) with a low-protein diet and an tyrosine, which previously was used frequently as a tyrosine
EAA supplement. This may be inappropriate as the metabolic adapta- source, cannot be converted into tyrosine in humans and might
tions to low-protein diets in response to CRF may not have occurred even stimulate protein catabolism [21].
in patients with ARF. Plus, there are fundamental differences in the Despite considerable investigation, there is no persuasive evi-
goals of nutritional therapy in the two groups of patients, and conse- dence that amino acid solutions enriched in branched-chain amino
quently, infusion solutions of EAA may be sub-optimal. acids exert a clinically significant anticatabolic effect. Systematic
Thus, a solution should be chosen that includes both essential studies using glutamine supplementation for patients with ARF are
and nonessential amino acids (EAA, NEAA) in standard propor- lacking (see Fig. 18-11).
18.20 Acute Renal Failure
FIGURE 18-34
Energy substrates in total parenteral nutrition (TPN) in acute
renal failure (ARF): glucose and lipids. Because of the well-docu-
mented effects of overfeeding, energy intake of patients with ARF
must not exceed their actual energy expenditure (ie, in most cases
100% to 130% of resting energy expenditure [REE]; see Figs. 18-3
and 18-4) [2].
Glucose should be the principal energy substrate because it can be
utilized by all organs, even under hypoxic conditions, and has the
potential for nitrogen sparing. Since ARF impairs glucose tolerance,
insulin is frequently necessary to maintain normoglycemia. Any
hyperglycemia must be avoided because of the untoward associated
side effects—such as aggravation of tissue injury, glycation of pro-
teins, activation of protein catabolism, among others [2]. When
intake is increased above 5 g/kg of body weight per day infused glu-
cose will not be oxidized but will promote lipogenesis with fatty
infiltration of the liver and excessive carbon dioxide production and
hypercarbia. Often, energy requirements cannot be met by glucose
infusion without adding large amounts of insulin, so a portion of
the energy should be supplied by lipid emulsions [2].
The most suitable means of providing the energy substrates for
parenteral nutrition for patients with ARF is not glucose or lipids,
but glucose and lipids [2]. In experimental uremia in rats, TPN
with 30% of nonprotein energy as fat promoted weight gain and
ameliorated the uremic state and survival [63]. (From Wennberg
et al. [63]; with permission.)
FIGURE 18-35
Energy substrates in parenteral nutrition: lipid emulsions. Advantages of intravenous lipids
include high specific energy content, low osmolality, provision of essential fatty acids and
phospholipids to prevent deficiency syndromes, fewer hepatic side effects (such as steato-
sis, hyperbilirubinemia), and reduced carbon dioxide production, especially relevant for
patients with respiratory failure.
Changes in lipid metabolism associated with acute renal failure (ARF) should not pre-
vent the use of lipid emulsions. Instead, the amount infused should be adjusted to meet the
patient’s capacity to utilize lipids. Usually, 1 g/kg of body weight per day of fat will not
increase plasma triglycerides substantially, so about 20% to 25% of energy requirements
can be met [1]. Lipids should not be administered to patients with hyperlipidemia (ie, plas-
ma triglycerides above 350 mg/dL) activated intravascular coagulation, acidosis (pH below
7.25), impaired circulation or hypoxemia.
Parenteral lipid emulsions usually contain long-chain triglycerides (LCT), most derived
from soybean oil. Recently, fat emulsions containing a mixture of LCT and medium-chain
triglycerides (MCT) have been introduced for intravenous use. Proposed advantages
include faster elimination from the plasma owing to higher affinity to the lipoprotein
lipase enzyme, complete, rapid, and carnitine-independent metabolism, and a triglyceride-
lowering effect; however, use of MCT does not promote lipolysis, and elimination of
triglycerides of both types of fat emulsions is equally retarded in ARF [34]. (Adapted from
[34]; with permission.)
Nutrition and Metabolism in Acute Renal Failure 18.21
FIGURE 18-36
SUGGESTED SCHEDULE FOR MINIMAL Complications and monitoring of nutritional support in acute renal
MONITORING OF PARENTERAL NUTRITION failure (ARF).
Complications: Technical problems and infectious complica-
tions originating from the central venous catheter, chemical
Metabolic Status incompatibilities, and metabolic complications of parenteral
nutrition are similar in ARF patients and in nonuremic subjects.
Variables Unstable Stable However, tolerance to volume load is limited, electrolyte derange-
Blood glucose 1–6 daily Daily ments can develop rapidly, exaggerated protein or amino acid
Osmolality Daily 2 weekly intake stimulates excessive blood urea nitrogen (BUN) and waste
Electrolytes (Na+, K+, Cl+) Daily Daily product accumulation and glucose intolerance, and decreased fat
Calcium, phosphate, magnesium Daily 3 weekly clearance can cause hyperglycemia and hypertriglyceridemia.
Daily BUN increment Daily Daily Thus, nutritional therapy for ARF patients requires more fre-
Urea nitrogen appearance rate Daily 2 weekly quent monitoring than it does for other patient groups, to avoid
Triglycerides Daily 2 weekly
metabolic complications.
Monitoring: This table summarizes laboratory tests that moni-
Blood gas analysis, pH Daily 1 weekly
tor parenteral nutrition and avoid metabolic complications.
Ammonia 2 weekly 1 weekly
The frequency of testing depends on the metabolic stability of
Transaminases bilirubin 2 weekly 1 weekly
the patient. In particular, plasma glucose, potassium, and phos-
phate should be monitored repeatedly after the start of parenter-
al nutrition.
References
1. Druml W: Nutritional support in acute renal failure. In Nutrition and 14. Kuhlmann MK, Shahmir E, Maasarani E, et al.: New experimental
the Kidney. Edited by Mitch WE, Klahr S. Philadelphia: Lippincott- model of acute renal failure and sepsis in rats. JPEN 1994,
Raven, 1998. 18:477–485.
2. Druml W, Mitch WE: Metabolism in acute renal failure. Sem Dial 15. Bergström J: Factors causing catabolism in maintenance hemodialysis
1996, 9:484–490. patients. Miner Electrolyte Metab 1992, 18:280–283.
3. Om P, Hohenegger M: Energy metabolism in acute uremic rats. 16. Druml W, Bürger U, Kleinberger G, et al.: Elimination of amino acids
Nephron 1980, 25:249–253. in acute renal failure. Nephron 1986, 42:62–67.
4. Schneeweiss B, Graninger W, Stockenhuber F, et al.: Energy metabolism 17. Druml W, Fischer M, Liebisch B, et al.: Elimination of amino acids in
in acute and chronic renal failure. Am J Clin Nutr 1990, 52:596–601. renal failure. Am J Clin Nutr 1994, 60:418–423.
5. Soop M, Forsberg E, Thˆrne A, Alvestrand A: Energy expenditure in 18. Mitch WE, Chesney RW: Amino acid metabolism by the kidney.
postoperative multiple organ failure with acute renal failure. Clin Miner Electrolyte Metab 1983, 9:190–202.
Nephrol 1989, 31:139–145. 19. Laidlaw SA, Kopple JD: Newer concepts of indispensable amino
6. Spreiter SC, Myers BD, Swenson RS: Protein-energy requirements in acids. Am J Clin Nutr 1987, 46:593–605.
subjects with acute renal failure receiving intermittent hemodialysis. 20. Naschitz JE, Barak C, Yeshurun D: Reversible diminished insulin
Am J Clin Nutr 1980, 33:1433–1437. requirement in acute renal failure. Postgrad Med J 1983, 59:269–271.
7. Mitch WE: Amino acid release from the hindquarter and urea appear- 21. Druml W, Lochs H, Roth E, et al.: Utilisation of tyrosine dipeptides
ance in acute uremia. Am J Physiol 1981, 241:E415–E419. and acetyl-tyrosine in normal and uremic humans. Am J Physiol
8. Salusky IB, Flügel-Link RM, Jones MR, Kopple JD: Effect of acute 1991, 260:E280–E285.
uremia on protein degradation and amino acid release in the rat hemi- 22. Druml W, Roth E, Lenz K, et al.: Phenylalanine and tyrosine metabo-
corpus. Kidney Int 1983, 24(Suppl. 16):S41–S42. lism in renal failure. Kidney Int 1989, 36(Suppl 27):S282–S286.
9. Clark AS, Mitch WE: Muscle protein turnover and glucose uptake in 23. Fürst P. Stehle P: The potential use of dipeptides in clinical nutrition.
acutely uremic rats. J Clin Invest 1983, 72:836–845. Nutr Clin Pract 1993, 8:106–114.
10. Maroni BJ, Karapanos G, Mitch WE: System A amino acid transport 24. Hübl W, Druml W, Roth E, Lochs H: Importance of liver and kidney
in incubated muscle: Effects of insulin and acute uremia. Am J Physiol for the utilization of glutamine-containing dipeptides in man.
1986, 251:F74–F80. Metabolism 1994, 43:1104–1107.
11. Druml W, Kelly RA, Mitch WE, May RC: Abnormal cation transport 25. Hasik J, Hryniewiecki L, Baczyk K, Grala T: An attempt to evaluate
in uremia. J Clin Invest 1988, 81:1197–1203. minimum requirements for protein in patients with acute renal failure.
12. Fröhlich J, Hoppe-Seyler G, Schollmeyer P, et al.: Possible sites of inter- Pol Arch Med Wewn 1979, 61:29–36.
action of acute renal failure with amino acid utilization for gluconeoge- 26. Lopez-Martinez J, Caparros T, Perez-Picouto F: Nutrition parenteral
nesis in isolated perfused rat liver. Eur J Clin Invest 1977, 7:261–268. en enfermos septicos con fracaso renal agudo en fase poliurica. Rev
13. May RC, Kelly RA, Mitch WE: Mechanisms for defects in muscle Clin Esp 1980, 157:171–178.
protein metabolism in rats with chronic uremia: The influence of 27. Kierdorf H: Continuous versus intermittent treatment: Clinical results
metabolic acidosis. J Clin Invest 1987; 79:1099–1103. in acute renal failure. Contrib Nephrol 1991, 93:1–12.
18.22 Acute Renal Failure
28. Chima CS, Meyer L, Hummell AC, et al.: Protein catabolic rate in 47. Druml W: Impact of continuous renal replacement therapies on
patients with acute renal failure on continuous arteriovenous hemofil- metabolism. Int J Artif Organs 1996, 19:118–120.
tration and total parenteral nutrition. J Am Soc Nephrol 1993, 48. Frankenfeld DC, Badellino MM, Reynolds HN, et al.: Amino acid
3:1516–1521. loss and plasma concentration during continuous hemodiafiltration.
29. Macias WL, Alaka KJ, Murphy MH, et al.: Impact of nutritional regi- JPEN 1993, 17:551–561.
men on protein catabolism and nitrogen balance in patients with 49. Toback FG: Regeneration after acute tubular necrosis. Kidney Int
acute renal failure. JPEN 1996, 20:56–62. 1992, 41:226–246.
30. Ikizler TA, Greene JH, Wingard RL, Hakim RM: Nitrogen balance in 50. Toback FG, Dodd RC, Maier ER, Havener LJ: Amino acid adminis-
acute renal failure patients. J Am Soc Nephrol 1995, 6:466A. tration enhances renal protein metabolism after acute tubular necro-
31. May RC, Clark AS, Goheer MA, Mitch WE: Specific defects in sis. Nephron 1983, 33:238–243.
insulin-mediated muscle metabolism in acute uremia. Kidney Int 51. Abel RM, Beck CH, Abbott WM, et al.: Improved survival from acute
1985, 28:490–497. renal failure after treatment with intravenuous essential amino acids
32. Cianciaruso B, Bellizzi V, Napoli R, et al.: Hepatic uptake and release and glucose: Results of a prospective double-blind study. N Engl J
of glucose, lactate and amino acids in acutely uremic dogs. Med 1973, 288:695–699.
Metabolism 1991, 40:261–290. 52. Oken DE, Sprinkel M, Kirschbaum BB, Landwehr DM: Amino acid
33. Druml W, Laggner A, Widhalm K, et al.: Lipid metabolism in acute therapy in the treatment of experimental acute renal failure in the rat.
Kidney Int 1980, 17:14–23.
renal failure. Kidney Int 1983, 24(Suppl 16):S139–S142.
53. Zager RA, Venkatachalam MA: Potentiation of ischemic renal injury
34. Druml W, Fischer M, Sertl S, et al.: Fat elimination in acute renal fail-
by amino acid infusion. Kidney Int 1983, 24:620–625.
ure: Long-chain versus medium-chain triglycerides. Am J Clin Nutr
1992, 55:468–472. 54. Brezis M, Rosen S, Spokes K, et al.: Transport-dependent anoxic cell
injury in the isolated perfused rat kidney. Am J Pathol 1984,
35. Druml W, Zechner R, Magometschnigg D, et al.: Post-heparin lipolyt- 116:327–341.
ic activity in acute renal failure. Clin Nephrol 1985, 23:289–293.
55. Heyman SN, Rosen S, Silva P, et al.: Protective action of glycine in
36. Adolph M, Eckart J, Metges C, et al.: Oxidative utilization of lipid cisplatin nephrotoxicity. Kidney Int 1991, 40:273–279.
emulsions in septic patients with and without acute renal failure. Clin
Nutr 1995, 14(Suppl 2):35A. 56. Schramm L, Heidbreder E, Lopau K, et al.: Influence of nitric oxide
on renal function in toxic renal failure in the rat. Miner Electrolyte
37. Dobyan DC, Bulger RE, Eknoyan G: The role of phosphate in the Metab 1996, 22:168–177.
potentiation and amelioration of acute renal failure. Miner Electrolyte
57. Wakabayashi Y, Kikawada R: Effect of L-arginine on myoglobin-
Metab 1991, 17:112–115.
induced acute renal failure in the rabbit. Am J Physiol 1996,
38. Druml W, Lax F, Grimm G, et al.: Acute renal failure in the elderly— 270:F784–F789.
1975–1990. Clin Nephrol 1994, 41:342–349.
58. Ding H, Kopple JD, Cohen A, Hirschberg R: Recombinant human
39. Kurtin P, Kouba J: Profound hypophosphatemia in the course of acute insulin-like growth factor-1 accelerates recovery and reduces catabo-
renal failure. Am J Kidney Dis 1987, 10:346–349. lism in rats with ischemic acute renal failure. J Clin Invest 1993,
40. Marik PE, Bedigian MK: Refeeding hypophosphatemia in critically ill 91:2281–2287.
patients in an intensive care unit. Arch Surg 1996, 131:1043–1047. 59. Franklin SC, Moulton M, Sicard GA, et al.: Insulin-like growth factor
41. Kleinberger G, Gabl F, Gassner A, et al.: Hypophosphatemia during 1 preserves renal function postoperatively. Am J Physiol 1997,
parenteral nutrition in patients with renal failure. Wien Klin 272:F257–F259.
Wochenschr 1978, 90:169–172. 60. Hirschberg R, Kopple JD, Guler HP, Pike M: Recombinant human
42. Madl Ch, Kranz A, Liebisch B, et al.: Lactic acidosis in thiamine defi- insulin-like growth factor-1 does not alter the course of acute renal
ciency. Clin Nutr 1993, 12:108–111. failure in patients. 8th Int. Congress Nutr Metabol Renal Disease,
Naples 1996.
43. Friedman AL, Chesney RW, Gilbert EF, et al.: Secondary oxalosis as a
61. Druml W, Mitch WE: Enteral nutrition in renal disease. In Enteral
complication of parenteral alimentation in acute renal failure. Am J
and Tube Feeding. Edited by Rombeau JL, Rolandelli RH.
Nephrol 1983, 3:248–252.
Philadelphia: WB Saunders, 1997:439–461.
44. Druml W, Schwarzenhofer M, Apsner R, Hörl WH: Fat soluble vita-
62. Roberts PR, Black KW, Zaloga GP: Enteral feeding improves outcome
mins in acute renal failure. Miner Electrolyte Metab 1998, 24:220–226. and protects against glycerol-induced acute renal failure in the rat.
45. Zurovsky Y, Gispaan I: Antioxidants attenuate endotoxin-induced Am J Respir Crit Care Med 1997, 156:1265–1269.
acute renal failure in rats. Am J Kidney Dis 1995, 25:51–57. 63. Wennberg A, Norbeck HE, Sterner G, Lundholm K: Effects of intra-
46. Druml W, Bartens C, Stelzer H, et al.: Impact of acute renal failure on venous nutrition on lipoprotein metabolism, body composition,
antioxidant status in multiple organ failure syndrome. JASN 1993, weight gain and uremic state in experimental uremia in rats. J Nutr
4:314A. 1991, 121:1439–1446.
Supportive Therapies:
Intermittent Hemodialysis,
Continuous Renal
Replacement Therapies,
and Peritoneal Dialysis
Ravindra L. Mehta
O
ver the last decade, significant advances have been made in the
availability of different dialysis methods for replacement of
renal function. Although the majority of these have been
developed for patients with end-stage renal disease, more and more
they are being applied for the treatment of acute renal failure (ARF).
The treatment of ARF, with renal replacement therapy (RRT), has the
following goals: 1) to maintain fluid and electrolyte, acid-base, and
solute homeostasis; 2) to prevent further insults to the kidney; 3) to
promote healing and renal recovery; and 4) to permit other support
measures such as nutrition to proceed without limitation. Ideally, ther-
apeutic interventions should be designed to achieve these goals, taking
into consideration the clinical course. Some of the issues that need
consideration are the choice of dialysis modality, the indications for
and timing of dialysis intervention, and the effect of dialysis on out-
comes from ARF. This chapter outlines current concepts in the use of
dialysis techniques for ARF.
CHAPTER
19
19.2 Acute Renal Failure
Dialysis Methods
run) that does not need to be pretreated, the unique characteristics of
the regeneration process allow greater flexibility in custom tailoring
DIALYSIS MODALITIES FOR ACUTE RENAL FAILURE
the dialysate. In contrast to IHD, intermittent hemodiafiltration
(IHF), which uses convective clearance for solute removal, has not
been used extensively in the United States, mainly because of the high
Intermittent therapies Continuous therapies cost of the sterile replacement fluid [3]. Several modifications have
Hemodialysis (HD) Peritoneal (CAPD, CCPD) been made in this therapy, including the provision of on-line prepara-
Single-pass Ultrafiltration (SCUF) tion of sterile replacement solutions. Proponents of this modality
Sorbent-based Hemofiltration (CAVH, CVVH) claim a greater degree of hemodynamic stability and improved middle
Peritoneal (IPD) Hemodialysis (CAVHD, CVVHD) molecule clearance, which may have an impact on outcomes.
Hemofiltration (IHF) Hemodiafiltration (CAVHDF, CVVHDF) As a more continuous technique, peritoneal dialysis (PD) is an
Ultrafiltration (UF) CVVHDF alternative for some patients. In ARF patients two forms of PD have
been used. Most commonly, dialysate is infused and drained from
the peritoneal cavity by gravity. More commonly a variation of the
procedure for continuous ambulatory PD termed continuous equili-
FIGURE 19-1 brated PD is utilized [4]. Dialysate is instilled and drained manually
Several methods of dialysis are available for renal replacement thera- and continuously every 3 to six hours, and fluid removal is achieved
py. While most of these have been adapted from dialysis procedures by varying the concentration of dextrose in the solutions.
developed for end-stage renal disease several variations are available Alternatively, the process can be automated with a cycling device
specifically for ARF patients [1] . programmed to deliver a predetermined volume of dialysate and
Of the intermittent procedures, intermittent hemodialysis (IHD) is drain the peritoneal cavity at fixed intervals. The cycler makes the
currently the standard form of therapy worldwide for treatment of process less labor intensive, but the utility of PD in treating ARF in
ARF in both intensive care unit (ICU) and non-ICU settings. The vast the ICU is limited because of: 1) its impact on respiratory status
majority of IHD is performed using single-pass systems with moder- owing to interference with diaphragmatic excursion; 2) technical dif-
ate blood flow rates (200 to 250 mL/min) and countercurrent ficulty of using it in patients with abdominal sepsis or after abdomi-
dialysate flow rates of 500 mL/min. Although this method is very effi- nal surgery; 3) relative inefficiency in removing waste products in
cient, it is also associated with hemodynamic instability resulting from “catabolic” patients; and 4) a high incidence of associated peritoni-
the large shifts of solutes and fluid over a short time. Sorbent system tis. Several continuous renal replacement therapies (CRRT) have
IHD that regenerates small volumes of dialysate with an in-line evolved that differ only in the access utilized (arteriovenous [non-
Sorbent cartridge have not been very popular; however, they are a pumped: SCUF, CAVH, CAVHD, CAVHDF] versus venovenous
useful adjunct if large amounts of water are not available or in disas- [pumped: CVVH, CVVHD, CVVHDF]), and, in the principal
ters [2]. These systems depend on a sorbent cartridge with multiple method of solute clearance (convection alone [UF and H], diffusion
layers of different chemicals to regenerate the dialysate. In addition to alone [hemodialyis (HD)], and combined convection and diffusion
the advantage of needing a small amount of water (6 L for a typical [hemodiafiltration (HDF)]).
FIGURE 19-2
Schematics of different CRRT techniques. A, Schematic repre- continuous arteriovenous or venovenous hemofiltration
sentation of SCUF therapy. B, Schematic representation of (CAVH/CVVH) therapy.
(Continued on next page)
Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis 19.3
C D
FIGURE 19-3
In contrast to intermittent techniques, until recently, the terminolo- Diffusion-based techniques similar to intermittent hemodialysis
gy for continuous renal replacement therapy (CRRT) techniques (HD) are based on the principle of a solute gradient between the
has been subject to individual interpretation. Recognizing this lack blood and the dialysate. If both diffusion and convection are used
of standardization an international group of experts have proposed in the same technique the process is termed hemodiafiltration
standardized terms for these therapies [5]. The basic premise in the (HDF). In this instance, both dialysate and a replacement solution
development of these terms is to link the nomenclature to the oper- are used, and small and middle molecules can both be removed
ational characteristics of the different techniques. In general all easily. The letters UF, H, HD, and HDF identify the operational
these techniques use highly permeable synthetic membranes and characteristics in the terminology. Based on these principles, the
differ in the driving force for solute removal. When arteriovenous terminology for these techniques is easier to understand. As shown
(AV) circuits are used, the mean arterial pressure provides the in Figure 19-1 the letter C in all the terms describes the continuous
pumping mechanism. Alternatively, external pumps generally utilize nature of the methods, the next two letters [AV or VV] depict the
a venovenous (VV) circuit and permit better control of blood flow driving force and the remaining letters [UF, H, HD, HDF] represent
rates. The letters AV or VV in the terminology serve to identify the the operational characteristics. The only exception to this is the
driving force in the technique. Solute removal in these techniques is acronym SCUF (slow continuous ultrafiltration), which remains as
achieved by convection, diffusion, or a combination of these two. a reminder of the initiation of these therapies as simple techniques
Convective techniques include ultrafiltration (UF) and hemofiltra- harnessing the power of AV circuits. (Modified from Mehta [7];
tion (H) and depend on solute removal by solvent drag [6]. with permission.)
19.4 Acute Renal Failure
Operational Characteristics
Anticoagulation
Propagation
Dialysis
Initiation
Fibrin
FIGURE 19-5
Factors influencing dialysis-related thrombogenicity. One of the
major determinants of the efficacy of any dialysis procedure in acute
FIGURE 19-4 renal failure (ARF) is the ability to maintain a functioning extracor-
Pathways of thrombogenesis in extracorporeal circuits. (Modified poreal circuit. Anticoagulation becomes a key component in this
from Lindhout [8]; with permission.) regard and requires a balance between an appropriate level of anti-
coagulation to maintain patency of the circuit and prevention of
complications. Figures 19-4 and 19-5 show the mechanisms of
thrombus formation in an extracorporeal circuit and the interaction
of various factors in this process. (From Ward [9]; with permission.)
FIGURE 19-6
Heparin CRRT
Modalities for anticoagulation for continuous renal replacement
Anticoagulant Replacement Dialysate
therapy. While systemic heparin is the anticoagulant most com-
heparin solutions 1.5% dianeal
(~400µ/h) (A & B alternating) (1000mL/h)
monly used for dialysis, other modalities are available. The utiliza-
tion of these modalities is largely influenced by prevailing local
experience. Schematic diagrams for heparin, A, and citrate, B, anti-
Arterial Venous
Filter coagulation techniques for continuous renal replacement therapy
catheter catheter (CRRT). A schematic of heparin and regional citrate anticoagula-
(d)
(a) (b) (c) tion for CRRT techniques. Regional citrate anticoagulation mini-
3–way
stop cock
mizes the major complication of bleeding associated with heparin,
Ultrafiltrate but it requires monitoring of ionized calcium. It is now well-recog-
(effluent dialysate nized that the longevity of pumped or nonpumped CRRT circuits
A plus net ultrafiltrate)
is influenced by maintaining the filtration fraction at less than
20%. Nonpumped circuits (CAVH/HD/HDF) have a decrease in
efficacy over time related to a decrease in blood flow (BFR),
Citrate CRRT Dialysate Calcium whereas in pumped circuits (CVVH/HD/HDF) blood flow is main-
NA 117, K4, Mg 1., 1 mEq/10 mL tained; however, the constant pressure across the membrane results
Cl 122.5 mEq/L; (~40 mL/h) in a layer of protein forming over the membrance reducing its effi-
dextrose 0.1%–2.5% cacy. This process is termed concentration repolarization [10].
Anticoagulant Replacement zero alkali CAVH/CVVH—continuous arteriovenous/venovenous hemofiltra-
Central
4%% trisodium citrate solution zero calcium tion. (From Mehta RL, et al. [11]; with permission.)
(~170 mL/h) 0.9%% saline (1000 mL/h) line
Arterial Venous
Filter
catheter catheter
(a) (b) (d) (c)
3–way
stop cock Ultrafiltrate
(effluent dialysate
B plus net ultrafiltrate)
Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis 19.5
Solute Removal
Membrane Membrane
Blood Dialysate Blood Dialysate
Middle
molecules
Small
molecules
Diffusion Convection
Concentration gradient based transfer. Movement of water across the membrane
Small molecular weight substances (<500 Daltons) carries solute across the membrane.
A are transferred more rapidly. B Middle molecules are removed more efficiently.
FIGURE 19-7
Membrane
Blood Dialysate Mechanisms of solute removal in dialysis. The success of any dialysis
procedure depends on an understanding of the operational character-
istics that are unique to these techniques and on appropriate use of
specific components to deliver the therapy. Solute removal is achieved
by diffusion (hemodialysis), A, convection (hemofiltration), B, or a
combination of diffusion and convection (hemodiafiltration), C.
Adsorption
Several solutes are removed from circulation by
adsorption to the membrane. This process is
C influenced by the membrane structure and charge.
19.6 Acute Renal Failure
FIGURE 19-9
Dialyste flow, L/h Dialysis time Ultrafiltrate volume, Cycling Manual Comparison of weekly urea clearances with different dialysis tech-
1.5 1 4 h/d 4 h qod L/d treatment time, hrs
40 48 niques. Although continuous therapies are less efficient than inter-
352 20 15 mittent techniques, overall clearances are higher as they are utilized
Dialysate inflow, L/wk
160 96 continuously. It is also possible to increase clearances in continuous
302 techniques by adjustment of the ultrafiltration rate and dialysate
268
flow rate. In contrast, as intermittent dialysis techniques are opera-
tional at maximum capability, it is difficult to enhance clearances
except by increasing the size of the membrane or the duration of
140 therapy. CAV/CVVHDF—continuous arteriovenous/venovenous
hemodiafiltration; IHD—intermittent hemodialysis; CAVH—con-
84
72 tinuous arteriovenous hemodialysis; PD—peritoneal dialysis.
FIGURE 19-12
Nutritional assessment and support with renal replacement tech- absorption occurs form the dialysate in hemodialysis and hemodi-
niques. A key feature of dialysis support in acute renal failure is to afiltration modalities and can result in hyperglycemia. Intermittent
permit an adequate amount of nutrition to be delivered to the dialysis techniques are limited by time in their ability to allow
patient. The modality of dialysis and operational characteristics unlimited nutritional support. (From Monson and Mehta [14];
affect the nutritional support that can be provided. Dextrose with permission.)
Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis 19.9
Fluid Control
patients with acute renal failure in the
intensive care setting. In the presence of a
OPERATING CHARACTERISTICS OF CRRT:
failing kidney, fluid removal is often a chal-
FLUID REMOVAL VERSUS FLUID REGULATION
lenge that requires large doses of diuretics
with a variable response. It is often neces-
sary in this setting to institute dialysis for
Fluid Removal Fluid Regulation volume control rather than metabolic con-
Ultrafiltration rate (UFR) To meet anticipated needs Greater than anticipated needs trol. CRRT techniques offer a significant
Fluid management Adjust UFR Adjust amount of replacement fluid advantage over intermittent dialysis for
Fluid balance Zero or negative balance Positive, negative, or zero balance fluid control [14,15]; however, if not car-
Volume removed Based on physician estimate Driven by patient characteristics ried out appropriately they can result in
Application Easy, similar to intermittent hemodialysis Requires specific tools and training major complications. To utilize these thera-
pies for their maximum potential it is neces-
sary to recognize the factors that influence
fluid balance and have an understanding of
the principles of fluid management with
FIGURE 19-13 these techniques. In general it is helpful to
Operating characteristics of continuous renal replacement (CRRT): fluid removal versus consider dialysis as a method for fluid
fluid regulation. Fluid management is an integral component in the management of removal and fluid regulation.
FIGURE 19-15
COMPOSITION OF REPLACEMENT FLUID AND DIALYSATE FOR CRRT Composition of dialysate and replacement
fluids used for continuous renal replace-
ment therapy (CRRT). One of the key fea-
Replacement Fluid tures of any dialysis method is the manipu-
lation of metabolic balance. In general, this
Investigator Golper [19] Kierdorf [20] Lauer [21] Paganini [22] Mehta [11] Mehta [11] is achieved by altering composition of
Na+ 147 140 140 140 140.5 154 dialysate or replacement fluid . Most com-
Cl- 115 110 — 120 115.5 154 mercially available dialysate and replace-
HCO3- 36 34 — 6 25 — ment solutions have lactate as the base;
K+ 0 0 2 2 0 — however, bicarbonate-based solutions are
Ca2+ 1.2 1.75 3.5 4 4 — being utilized more and more [17,18].
Mg2+ 0.7 0.5 1.5 2 — —
Glucose 6.7 5.6 — 10 — —
Acetate — — 41 40 — —
Dialysate
Component (mEq/L) 1.5% Dianeal Hemosol AG 4D Hemosol LG 4D Baxter Citrate
Sodium 132 140 140 140 117
Potassium — 4 4 2 4
Chloride 96 119 109.5 117 121
Lactate 35 — 40 30 —
Acetate — 30 — — —
Calcium 3.5 3.5 4 3.5 —
Magnesium 1.5 1.5 1.5 1.5 1.5
Dextrose (g/dL) 1.5 0.8 .11 0.1 0.1–2.5
FIGURE 19-16
Replacement 17 mL/min
Prefilter Prefilter Postfilter Effect of site of delivery of replacement fluid: pre- versus postfilter
Prepump Prepump BFR 100 mL/min continuous venovenous hemofiltration with ultrafiltration rate of 1
BFR 83 mL/min BFR 117 mL/min L/hour. Replacement fluids may be administered pre- or postfilter,
depending on the circuit involved . It is important to recognize that
the site of delivery can influence the overall efficacy of the proce-
Filter dure. There is a significant effect of fluid delivered prepump or
postpump, as the amount of blood delivered to the filter is reduced
Blood pump
in prepump dilution. BFR—blood flow rate.
BFR 100 mL/min
Ultrafiltrate
FIGURE 19-17
50 Prefilter prepump 47.6 Pre- versus postfilter replacement fluid: effect on filtration fraction.
Prefilter postpump 41.6 Prefilter replacement tends to dilute the blood entering the circuit
40 35.7
Postfilter 32.2 32.2 and enhances filter longevity by reducing the filtration fraction;
30 26.3 however, in continuous venovenous hemofiltration (CVVH) circuits
%
22.6 23.9
20 19.5 the overall clearance may be reduced as the amount of solute deliv-
ered to the filter is reduced.
10
0
CVVH 1L/h CVVH 3L/h CVVH 6L/h
Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis 19.11
FIGURE 19-19
POTENTIAL APPLICATIONS FOR CONTINUOUS Potential applications for continuous renal
RENAL REPLACEMENT THERAPY replacement therapy (CRRT). CRRT tech-
niques are increasingly being utilized as sup-
port modalities in the intensive care setting
Renal Replacement Renal Support Extrarenal Applications and are particularly suited for this function.
The freedom to provide continuous fluid
Acute renal failure Fluid management Cytokine removal ? sepsis management permits the application of
Chronic renal failure Solute control Heart failure unlimited nutrition, adjustments in hemody-
Acid-base adjustments Cancer chemotherapy namic parameters, and achievement of
Nutrition Liver support steady-state solute control, which is difficult
Burn management Inherited metabolic disorders with intermittent therapies. It is thus possi-
ble to widen the indications for renal inter-
vention and provide a customized approach
for the management of each patient.
19.12 Acute Renal Failure
FIGURE 19-20
RELATIVE ADVANTAGES () AND DISADVANTAGES () OF CRRT, IHD, AND PD Advantages () and disadvantages () of
dialysis techniques. CRRT—continuous
renal replacement therapy; IHD—intermit-
Variable CRRT IHD PD tent hemodialysis; PD—peritoneal dialysis.
FIGURE 19-21
DETERMINANTS OF THE CHOICE OF TREATMENT Determinants of the choice of treatment modality for acute renal
MODALITY FOR ACUTE RENAL FAILURE failure. The primary indication for dialysis intervention can be a
major determinant of the therapy chosen because different thera-
pies vary in their efficacy for solute and fluid removal. Each tech-
Patient nique has its advantages and limitations, and the choice depends
Indication for dialysis on several factors. Patient selection for each technique ideally
Presence of multiorgan failure
should be based on a careful consideration of multiple factors [1].
The general principle is to provide adequate renal support without
Access
adversely affecting the patient. The presence of multiple organ fail-
Mobility and location of patient
ure may limit the choice of therapies; for example, patients who
Anticipated duration of therapy
have had abdominal surgery may not be suitable for peritoneal
Dialysis process
dialysis because it increases the risk of wound dehiscence and infec-
Components (eg, membrane, anticoagulation)
tion. Patients who are hemodynamically unstable may not tolerate
Type (intermittent or continuous) intermittent hemodialysis (IHD). Additionally, the impact of the
Efficacy for solute and fluid balance chosen therapy on compromised organ systems is an important
Complications consideration. Rapid removal of solutes and fluid, as in IHD, can
Outcome result in a disequilibrium syndrome and worsen neurologic status.
Nursing and other support Peritoneal dialysis may be attractive in acute renal failure that com-
Availability of machines plicates acute pancreatitis, but it would contribute to additional
Nursing support protein losses in the hypoalbuminemic patient with liver failure.
Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis 19.13
FIGURE 19-22
RECOMMENDATION FOR INITIAL DIALYSIS Recommendation for initial dialysis modality
MODALITY FOR ACUTE RENAL FAILURE (ARF) for acute renal failure (ARF). Patients with
multiple organ failure (MOF) and ARF can
be treated with various continuous therapies
Indication Clinical Condition Preferred Therapy or IHD. Continuous therapies provide better
hemodynamic stability; however, if not moni-
Uncomplicated ARF Antibiotic nephrotoxicity IHD, PD tored carefully they can lead to significant
Fluid removal Cardiogenic shock, CP bypass SCUF, CAVH volume depletion. In general, hemodynami-
Uremia Complicated ARF in ICU CVVHDF, CAVHDF, IHD cally unstable, catabolic, and fluid-over-
Increased intracranial pressure Subarachnoid hemorrhage, CVVHD, CAVHD loaded patients are best treated with continu-
hepatorenal syndrome ous therapies, whereas IHD is better suited
Shock Sepsis, ARDS CVVH, CVVHDF, CAVHDF for patients who require early mobilization
Nutrition Burns CVVHDF, CAVHDF, CVVH and are more stable. It is likely that the mix
Poisons Theophylline, barbiturates Hemoperfusion, IHD, CVVHDF of modalities used will change as evidence
Electrolyte abnormalities Marked hyperkalemia IHD, CVVHDF linking the choice of modality to outcome
ARF in pregnancy Uremia in 2nd, 3rd trimester PD becomes available. For now, it is probably
appropriate to consider all these techniques
as viable options that can be used collectively.
Ideally, each patient should have an individu-
alized approach for management of ARF.
Outcomes
FIGURE 19-23
CRRT CRRT
Efficacy of continuous renal replacement
100 IHD 6 IHD
S Creat, mg/dL
5
80 4
hemodialysis (IHD): effect on blood urea
3 nitrogen, A, and creatinine levels, B, in
60 acute renal failure.
2
40 1
0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9
Days B Days
A
FIGURE 19-24
Survivors
Blood urea nitrogen (BUN) levels in survivors and non-survivors in acute renal failure
50 Non-survivors
treated with continuous renal replacement therapy (CRRT). It is apparent that CRRT tech-
Urea, mmol/L
40 niques offer improved solute control and fluid management with hemodynamic stability,
however a relationship to outcome has not been demonstrated. In a recent retrospective
30 analysis van Bommel [24] found no difference in BUN levels among survivors and non-
20 survivors with ARF While it is clear that lower solute concentrations can be achieved with
0 1 2 3 4 5 6 CRRT whether this is an important criteria impacting on various outcomes from ARF still
Days needs to be determined. A recent study form the Cleveland Clinic suggests that the dose of
dialysis may be an important determinant of outcome allowing for underlying severity of
illness [25]. In this study the authors found that in patients with ARF, 65.4% of all IHD
treatments resulted in lower Kt/V than prescribed. There appeared to be an influence of
dose of dialysis on outcome in patients with intermediate levels of severity of illness as
judged by the Cleveland Clinic Foundation acuity score for ARF (see Fig. 19-25). Patients
receiving a higher Kt/V had a lower mortality than predicted. These data illustrate the
importance of the underlying severity of illness, which is likely to be a major determinant
of outcome and should be considered in the analysis of any studies.
19.14 Acute Renal Failure
1 Low Kt/V
0.8 High Kt/V BIOCOMPATIBLE MEMBRANES IN INTERMITTENT HEMODIALYSIS (IHD)
AND ACUTE RENAL FAILURE (ARF): EFFECT ON OUTCOMES
Survival, %
CCF score
0.6
0.4
0.2 BCM Group BICM Group Probability
0 Patients, n 72 81
0 5 10 15 20 All patients recover of renal function 46 (64%) 35 (43%) 0.001
Cleveland clinic ICU ARF score Survival 41 (57%) 37 (46%) 0.03
Patients nonoliguric before hemodialysis 39 46
FIGURE 19-25 Development of oliguria with dialysis 17 (44%) 32 (70%) 0.03
Effect of dose of dialysis in acute renal fail- Recovery of renal function 31 (79%) 21 (46%) 0.0004
ure (ARF) on outcome from ARF. Survival 28 (74%) 22 (48%) 0.003
Patients oliguric before hemodialysis 33 35
Recovery of renal function 15 (45%) 14 (40%) ns
Survival 12 (36%) 15 (43%) ns
FIGURE 19-26
Biocompatible membranes in intermittent hemodialysis (IHD) and acute renal failure (ARF):
effect on outcomes. The choice of dialysis membrane and its influence on survival from ARF
has been of major interest to investigators over the last few years. While the evidence tends to
support a survival advantage for biocompatible membranes, most of the studies were not well
controlled. The most recent multicenter study showed an improvement in mortality and recov-
ery of renal function with biocompatible membranes; however, this effect was not significant
in oliguric patients. Further investigations are required in this area. NS—not significant.
IHD CRRT
Investigator Type of Study No Mortality, % No Mortality, % Change, % P Value
Mauritz [32] Retrospective 31 90 27 70 20 ns
Alarabi [33] Retrospective 40 55 40 45 10 ns
Mehta [34] Retrospective 24 85 18 72 13 ns
Kierdorf [20] Retrospective 73 93 73 77 16 < 0.05
Bellomo [35] Retrospective 167 70 84 59 11 ns
Bellomo [36] Retrospective 84 70 76 45 25 < 0.01
Kruczynski [37] Retrospective 23 82 12 33 49 < 0.01
Simpson [38] Prospective 58 82 65 70 12 ns
Kierdorf [39] Prospective 47 65 48 60 4.5 ns
Mehta [40] Prospective 82 41.5 84 59.5 18 ns
FIGURE 19-27
Continuous renal replacement therapy (CRRT) versus intermittent major studies done in this area do not show a survival advantage for
hemodialysis (IHD): effect on mortality. Despite significant advances CRRT [29,30]. Although several investigators have not been able to
in the management of acute renal failure (ARF) over the last four demonstrate an advantage of these therapies in influencing mortality,
decades, the perception is that the associated mortality has not we believe this may represent the difficulty in changing a global out-
changed significantly [26]. Recent publications suggest that there come which is impacted by several other factors [31]. It is probably
may have been some improvement during the last decade [27]. Both more relevant to focus on other outcomes such as renal functional
IHD and peritoneal dialysis (PD) were the major therapies until a recovery rather than mortality. We believe that continued research is
decade ago, and they improved the outcome from the 100% mortali- required in this area; however, there appears to be enough evidence
ty of ARF to its current level. The effect of continuous renal replace- to support the use of CRRT techniques as an alternative that may be
ment therapy on overall patient outcome is still unclear [28] . The preferable to IHD in treating ARF in an intensive care setting.
Supportive Therapies: Intermittent Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis 19.15
Future Directions
FIGURE 19-28
Schematic for the bioartificial kidney. As experience with these techniques grows, innovations in technology
will likely keep pace. Over the last 3 years, most of the major manufacturers of dialysis equipment have devel-
oped new pumps dedicated for continuous renal replacement therapy (CRRT). Membrane technology is also
evolving, and antithrombogenic membranes are on the horizon [41]. Finally the application of these therapies
is likely to expand to other arenas, including the treatment of sepsis, congestive heart failure [42], and multi-
organ failure [43]. An exciting area of innovative research is the development of a bioartificial tubule utilizing
porcine tubular epithelial cells grown in a hollow fiber to add tubular function to the filtrative function pro-
vided by dialysis [44]. These devices are likely to be utilized in combination with CRRT to truly provide com-
plete RRT in the near future. (From Humes HD [44]; with permission.)
References
1. Mehta RL: Therapeutic alternatives to renal replacement therapy for 10. Ronco C, Brendolan A, Crepaldi C, et al.: Importance of hollow fiber
critically ill patients in acute renal failure. Semin Nephro 1994, geometry in CAVH. Contrib Nephrol 1991, 15:175–178.
14:64–82. 11. Mehta RL, McDonald BR, Aguilar MM, Ward DM: Regional citrate
2. Shapiro WB: The current status of Sorbent hemodialysis. Semin Dial anticoagulation for continuous arteriovenous hemodialysis in critically
1990, 3:40–45. ill patients. Kidney Int 1990, 38:976–981.
3. Botella J, Ghezzi P, Sanz-Moreno C, et al.: Multicentric study on 12. Grootendorst AF, Bouman C, Hoeben K, et al.: The role of continu-
paired filtration dialysis as a short, highly efficient dialysis technique. ous renal replacement therapy in sepsis multiorgan failure. Am J
Nephrol Dial Transplant 1991, 6:715–721. Kidney Dis 1996, 28(5) S3:S50–S57.
4. Steiner RW: Continuous equilibration peritoneal dialysis in acute renal 13. Kroh UF, Holl TJ, Steinhausser W: Management of drug dosing in
failure. Perit Dial Intensive 1989, 9:5–7. continuous renal replacement therapy. Semin Dial 1996, 9:161–165.
5. Bellomo R, Ronco C, Mehta RL: Nomenclature for continuous renal 14. Monson P, Mehta RL: Nutritional considerations in continuous renal
replacement therapies. Am J Kidney Dis 1996, 28(5)S3:2–7. replacement therapies. Semin Dial 1996, 9:152–160.
6. Henderson LW: Hemofiltration: From the origin to the new wave. Am 15. Golper TA: Indications, technical considerations, and strategies for
J Kidney Dis 1996, 28(5)S3:100–104. renal replacement therapy in the intensive care unit. J Intensiv Care
7. Mehta RL: Renal replacement therapy for acute renal failure: Med 1992, 7:310–317.
Matching the method to the patient. Semin Dial 1993, 6:253–259. 16. Mehta RL: Fluid management in continuous renal replacement thera-
8. Lindhout T: Biocompatability of extracorporeal blood treatment. py. Semin Dial 1996, 9:140–144.
Selection of hemostatic parameters. Nephrol Dial Transplant 1994, 17. Palevsky PM: Continuous renal replacement therapy component selec-
9(Suppl. 2):83–89. tion: replacement fluid and dialysate. Semin Dial 1996, 9:107–111.
9. Ward RA: Effects of hemodialysis on corpulation and platelets: Are 18. Thomas AN, Guy JM, Kishen R, et al.: Comparison of lactate and
we measureing membrane biocompatability? Nephrol Dial Transplant bicarbonate buffered haemofiltration fluids: Use in critically ill
1995, 10(Suppl. 10):12–17. patients. Nephrol Dial Transplant 1997, 12(6):1212–1217.
19.16 Acute Renal Failure
19. Golper TA: Continuous arteriovenous hemofiltration in acute renal 33. Alarabi AA, Danielson BG, Wikstrom B, Wahlberg J: Outcome of
failure. Am J Kidney Dis 1985, 6:373–386. continuous arteriovenous hemofiltration (CAVH) in one centre. Ups J
20. Kierdorf H: Continuous versus intermittent treatment: clinical results Med Sci 1989, 94:299–303.
in acute renal failure. Contrib Nephrol 1991, 93:1–12. 34. McDonald BR, Mehta RL: Decreased mortality in patients with acute
21. Lauer renal failure undergoing continuous arteriovenous hemodialysis.
Contrib Nephrol 1991, 93:51–56.
22. Paganini EP: Slow continuous hemofiltration and slow continuous
ultrafiltration. Trans Am Soc Artif Intern Organs 1988, 34:63–66. 35. Bellomo R, Mansfield D, Rumble S, et al.: Acute renal failure in criti-
cal illness. Conventional dialysis versus acute continuous hemodiafil-
23. Schrier RW, Abraham HJ: Strategies in management of acute renal
tration. Am Soc Artif Intern Organs J 1992, 38:654–657.
failure in the intensive therapy unit. In Current Concepts in Critical
Care: Acute Renal Failure in the Intensive Therapy Unit. Edited by 36. Bellomo R, Boyce N: Continuous venovenous hemodiafiltration com-
Bihari D, Neild G. Berlin:Springer-Verlag, 1990:193–214. pared with conventional dialysis in critically ill patients with acute
24. Van Bommel EFH, Bouvy ND, So KL, et al.: High risk surgical acute renal failure. Am Soc Artif Intern Organs J 1993, 39:794–797.
renal failure treated by continuous arterio venous hemodiafiltration: 37. Kruczynski K, Irvine-Bird K, Toffelmire EB, Morton AR: A compari-
Metabolic control and outcomes in sixty patients. Nephron 1995, son of continuous arteriovenous hemofiltration and intermittent
70:185–196. hemodialysis in acute renal failure patients in the intensive care unit.
25. Paganini EP, Tapolyai M, Goormastic M, et al.: Establishing a dialysis Am Soc Artif Intern Organs J 1993, 39:778–781.
therapy/patient outcome link in intensive care unit acute dialysis for 38. Simpson K, Allison MEM: Dialysis and acute renal failure: can mor-
patients with acute renal failure. Am J Kidney Dis 1996, tality be improved? Nephrol Dial Transplant 1993, 8:946.
28(5)S3:81–90. 39. Kierdorf H: Einfuss der kontinuierlichen Hamofiltration auf
26. Wilkins RG, Faragher EB: Acute renal failure in an intensive care unit: Proteinkatabolismus, Mediatorsubstanzen und Prognose des akuten
Incidence, prediction and outcome. Anesthesiology 1983, 38:638. Nierenversagens [Habilitation-Thesis], Medical Faculty Technical
27. Firth JD: Renal replacement therapy on the intensive care unit. Q J University of Aachen, 1994.
Med 1993, 86:75–77. 40. Mehta RL, McDonald B, Pahl M, et al.: Continuous vs. intermittent
28. Bosworth C, Paganini EP, Cosentino F, et al.: Long term experience dialysis for acute renal failure (ARF) in the ICU: Results from a ran-
with continuous renal replacement therapy in intensive care unit acute domized multicenter trial. Abstract A1044. JASN 1996, 7(9):1456.
renal failure. Contrib Nephrol 1991, 93:13–16. 41. Yang VC, Fu Y, Kim JS: A potential thrombogenic hemodialysis mem-
29. Kierdorf H: Continuous versus intermittent treatment: Clinical results branes with impaired blood compatibility. ASAIO Trans 1991,
in acute renal failure. Contrib Nephrol 1991, 93:1–12. 37:M229–M232.
30. Jakob SM, Frey FJ, Uhlinger DE: Does continuous renal replacement 42. Canaud B, Leray-Moragues H, Garred LJ, et al.: Slow isolated ultra-
therapy favorably influence the outcome of patients? Nephrol Dial filtration for the treatment of congestive heart failure. Am J Kidney
Transplant 1996, 11:1250–1235. Dis 1996, 28(5)S3:67–73.
31. Mehta RL: Acute renal failure in the intensive care unit: Which out- 43. Druml W: Prophylactic use of continuous renal replacement therapies
comes should we measure? Am J Kidney Dis 1996, 28(5)S3:74–79. in patients with normal renal function. Am J Kidney Dis 1996,
32. Mauritz W, Sporn P, Schindler I, et al.: Acute renal failure in abdomi- 28(5)S3:114–120.
nal infection: comparison of hemodialysis and continuous arteriove- 44. Humes HD, Mackay SM, Funke AJ, Buffington DA: The bioartificial
nous hemofiltration. Anasth Intensivther Notfallmed 1986, renal tuble assist device to enhance CRRT in acute renal failure. Am J
21:212–217. Kidney Dis 1997, 30(Suppl. 4):S28–S30.
Normal Vascular and
Glomerular Anatomy
Arthur H. Cohen
Richard J. Glassock
T
he topic of normal vascular and glomerular anatomy is intro-
duced here to serve as a reference point for later illustrations of
disease-specific alterations in morphology.
CHAPTER
1
1.2 Glomerulonephritis and Vasculitis
FIGURE 1-1
A, The major renal circulation. The renal artery divides into the interlobar arteries (usually
4 or 5 divisions) that then branch into arcuate arteries encompassing the corticomedullary
Interlobar junction of each renal pyramid. The interlobular arteries (multiple) originate from the
artery arcuate arteries. B, The renal microcirculation. The afferent arterioles branch from the
interlobular arteries and form the glomerular capillaries (hemi-arterioles). Efferent arteri-
Arcuate oles then reform and collect to form the post-glomerular circulation (peritubular capillar-
artery Renal ies, venules and renal veins [not shown]). The efferent arterioles at the corticomedullary
artery junction dip deep into the medulla to form the vasa recta, which embrace the collecting
Pelvis
tubules and form hairpin loops. (Courtesy of Arthur Cohen, MD.)
Pyramid
Interlobular Ureter
artery
Afferent
arteriole Interlobular
artery
Glomerulus
Arcuate
artery
Efferent
arteriole
Collecting
tubule
Interlobar
artery
B
Normal Vascular and Glomerular Anatomy 1.3
FIGURE 1-3
Microscopic view of the juxtaglomerular apparatus. The juxta-
glomerular apparatus (arrow) located immediately adjacent to the
glomerular hilus, is a complex structure with vascular and tubular
components. The vascular component includes the afferent and
efferent arterioles, and the region between them is known as the
lacis. The tubular component consists of the macula densa (arrow-
head). The juxtaglomerular apparatus is an integral component of
the renin-angiotensin system.
FIGURE 1-4
Electron micrograph of the arterioles. Modified smooth muscle
cells of the arterioles of the juxtaglomerular apparatus produce and
secrete renin. Renin is packaged in characteristic amorphous
mature granules (arrow) derived from smaller rhomboid-shaped
immature protogranules (arrowhead).
1.4 Glomerulonephritis and Vasculitis
FP
A B
FIGURE 1-5 (see Color Plate)
Microscopic view of the glomeruli. Glomeruli are spherical mesangial cells (A, arrow) and the matrix (B, arrow). The free
“bags” of capillaries emanating from afferent arterioles and con- wall of glomerular capillaries, across which filtration takes place,
fined within the urinary space, which is continuous with the consists of a basement membrane (arrowheads) covered by viscer-
proximal tubule. The capillaries are partially attached to the al epithelial cells with individual foot processes (FP) and lined by
mesangium, a continuation of the arteriolar wall consisting of endothelial cells.
FIGURE 1-6
Schematic illustration of a glomerulus and adjacent hilar structure.
Note the relationship of mesangial cells to the juxtaglomerular
apparatus and distal tubule (macula densa). Red—mesangial cells;
blue—mesangial matrix; black—basement membrane; green—vis-
ceral and parietal epithelial cells; yellow—endothelial cells. (From
Churg and coworkers [1]; with permission.)
FIGURE 1-7
Electron photomicrograph illustrating a portion of the ultra-
structure of the glomerular capillary wall. The normal width of
the lamina rara externa (LRE) plus the lamina densa (LD) plus
the lamina rara interna (LRI) equals about 250 to 300 nm. The
spaces between the foot processes (FP), having diameters of 20
to 60 nm, are called filtration slit pores. It is believed they are
the path by which filtered fluid reaches the urinary space (U).
The endothelial cells on the luminal aspect of the basement
membrane (BM) are fenestrated, having diameters from 70 to
100 nm (see Fig. 1-9). The BM (LRE plus LD plus LRI) is com-
posed of Type IV collagen and negativity charged proteoglycans
(heparan sulfate). L—lumen. (From Churg and coworkers [1];
with permission.)
Normal Vascular and Glomerular Anatomy 1.5
FIGURE 1-8
Scanning electron microscopy of the glomerulus. The surface
anatomy of the interdigitating foot processes of normal visceral
epithelial cells (podocytes) is demonstrated. These cells and their
processes cover the capillary, and ultrafiltration occurs between
the fine branches of the cells. (From Churg and coworkers [1];
with permission.)
FIGURE 1-9
Scanning electron microscopy of the glomerulus. The surface
anatomy of endothelial cells of a normal glomerulus is demonstrat-
ed. Note the fenestrated appearance. (From Churg and coworkers
[1]; with permission.)
Reference
1. Churg J, Bernstein J, Glassock RJ: Renal Disease. Classification and
Atlas of Glomerular Diseases, edn 2. New York: Igaku-Shoin; 1995.
The Primary
Glomerulopathies
Arthur H. Cohen
Richard J. Glassock
T
he primary glomerulopathies are those disorders that affect
glomerular structure, function, or both in the absence of a mul-
tisystem disorder. The clinical manifestations are predominate-
ly the consequence of the glomerular lesion (such as proteinuria,
hematuria, and reduced glomerular filtration rate). The combination
of clinical manifestations leads to a variety of clinical syndromes.
These syndromes include acute glomerulomphritis; rapidly progres-
sive glomerulonephritis; chronic renal failure; the nephrotic syndrome
or “asymptomatic” hematuria, proteinuria, or both.
CHAPTER
2
2.2 Glomerulonephritis and Vasculitis
FIGURE 2-1
CLINICAL SYNDROMES OF GLOMERULAR DISEASE Each of these syndromes arises as a consequence of disturbances of
glomerular structure and function. Acute glomerulonephritis consists
of the abrupt onset of hematuria, proteinuria, edema, and hyperten-
Acute glomerulonephritis sion. Rapidly progressive glomerulonephritis is characterized by
Rapidly progressive glomerulonephritis
features of nephritis and progressive renal insufficiency. Chronic
glomerulonephritis features proteinuria and hematuria with indolent
Chronic glomerulonephritis
progressive renal failure. Nephrotic syndrome consists of massive
Nephrotic syndrome
proteinuria (>3.5 g/d in adults), hypoalbuminemia with edema,
“Asymptomatic” hematuria, proteinuria, or both
lipiduria, and hyperlipidemia. “Asymptomatic” hematuria, protein-
uria, or both is not associated initially with renal failure or edema.
Each of these syndromes may be complicated by hypertension.
FIGURE 2-2
% % %
100 Others
Age-associated prevalence of various
5 glomerular lesions in nephrotic syndrome.
4 Lupus 10.8 This schematic illustrates the age-associat-
2 90 Amyloid
5 5.9
ed prevalence of various diseases and
1 Diabetes 1.6 glomerular lesions among children and
7 80 adults undergoing renal biopsy for evalua-
Other tion of nephrotic syndrome (Guy’s
16.0
70 proliferative Hospital and the International Study of
25.8 Kidney Disease in Children) [1]. Both the
60 MCGN 9.8 systemic and primary causes of nephrotic
syndrome are included. (Diabetes mellitus
50 with nephropathy is underrepresented
because renal biopsy is seldom needed for
Membranous 19.7
76 40
diagnosis.) The bar on the left summarizes
the prevalence of various lesions in chil-
dren aged 0 to 16 years; the bar on the
30 11.8
FSGS
right summarizes the prevalence of vari-
ous lesions in adults aged 16 to 80 years.
20 Note the high prevalence of minimal
change disease in children and the increas-
10 Minimal 22 ing prevalence of membranous glomeru-
changes
lonephritis in the age group of 16 to 60
0 years. FSGS—focal segmental glomeru-
All 5 10 15 20 30 40 50 60 70 80 All osclerosis; MCGN—mesangiocapillary
children Age at onset of NS adults glomerulonephritis. (From Cameron [1];
with permission.)
FIGURE 2-3
PRIMARY GLOMERULAR LESIONS The primary glomerular lesions.
A B
FIGURE 2-4
Light and electron microscopy in minimal change disease (lipoid Minimal change disease is considered to be the result of glomerular
nephrosis). A, This glomerulopathy, one of many associated with capillary wall damage by lymphokines produced by abnormal T
nephrotic syndrome, has a normal appearance on light microscopy. cells. This glomerulopathy is the most common cause of nephrotic
No evidence of antibody (immune) deposits is seen on immunoflu- syndrome in children (>70%) and also accounts for approximately
orescence. B, Effacement (loss) of foot processes of visceral epithe- 20% of adult patients with nephrotic syndrome. This glomerulopa-
lial cells is observed on electron microscopy. This last feature is the thy typically is a corticosteroid-responsive lesion, and usually has a
major morphologic lesion indicative of massive proteinuria. benign outcome with respect to renal failure.
100
100 12 weeks
8 weeks
Complete remission, cumulative %
80
Cumulative percentage sustained
80
60
remission
60
40
ISKDC children
Prednisone + Cyclophosphamide (11) 40
20
Prednisone (75)
Cyclophosphamide (25)
0 20
0 2 4 8 16 28 0 200 400 600
Weeks from starting treatment Days
FIGURE 2-7
100
Cyclosporine Cyclosporine in minimal change disease. One of several controlled
Cyclophosphamide trials of cyclosporine therapy in this disease is illustrated. Note the
80 relapses that occur after discontinuing cyclosporine therapy (arrow).
Cyclophosphamide was given for 2 months, and cyclosporine for 9
Overall probability
40
20
0
0 90 180 270 360 450 540 630 720
Time, d
Number of patients
Cyclosporine 36 36 36 31
Cyclophosphamide 30 29 28 26
A B
FIGURE 2-8
Light and immunofluorescent microscopy in focal segmental in the deep cortex, is affected. The abnormal glomeruli exhibit
glomerulosclerosis (FSGS). Patients with FSGS exhibit massive segmental obliteration of capillaries by increased extracellular
proteinuria (usually nonselective), hypertension, hematuria, and matrix–basement membrane material, collapsed capillary walls,
renal functional impairment. Patients with nephrotic syndrome or large insudative lesions. These lesions are called hyalinosis
often are not responsive to corticosteroid therapy. Progression to (arrow) and are composed of immunoglobulin M and comple-
chronic renal failure occurs over many years, although in some ment C3 (B, IgM immunofluorescence). The other glomeruli
patients renal failure may occur in only a few years. A, This usually are enlarged but may be of normal size. In some patients,
glomerulopathy is defined primarily by its appearance on light mesangial hypercellularity may be a feature. Focal tubular
microscopy. Only a portion of the glomerular population, initially atrophy with interstitial fibrosis invariably is present.
The Primary Glomerulopathies 2.5
FIGURE 2-9
Electron microscopy of focal segmental glomerulosclerosis. The elec-
tron microscopic findings in the involved glomeruli mirror the light
microscopic features, with capillary obliteration by dense hyaline
“deposits” (arrow) and lipids. The other glomeruli exhibit primarily
foot process effacement, occasionally in a patchy distribution.
FIGURE 2-10
Note that a variety of disease processes can lead to the lesion of
focal segmental glomerulosclerosis. Some of these are the result of
infections, whereas others are due to loss of nephron population.
Focal sclerosis may also complicate other primary glomerular dis-
eases (eg, Immunoglobulin A nephropathy).
2.6 Glomerulonephritis and Vasculitis
A B
FIGURE 2-12
Histologic variations of focal segmental glomerulosclerosis (FSGS). tubule. Some investigators have described a more favorable
Two important variants of FSGS exist. In contrast to the histologic response to steroids and a more benign clinical course.
appearance of the involved glomeruli, with the sclerotic segment in The other variant, known as collapsing glomerulopathy, most
any location in the glomerulus, the glomerular tip lesion (A) is likely represents a virulent form of FSGS. In this form of FSGS,
characterized by segmental sclerosis at an early stage of evolution, most visceral epithelial cells are enlarged and coarsely vacuolated
at the tubular pole (tip) of all affected glomeruli (arrow). and most capillary walls are wrinkled or collapsed (B). These
Capillaries contain monocytes with abundant cytoplasmic lipids features indicate a severe lesion, with a corresponding rapidly pro-
(foam cells), and the overlying visceral epithelial cells are enlarged gressing clinical course of the disease. Integral and concomitant acute
and adherent to cells of the most proximal portion of the proximal abnormalities of tubular epithelia and interstitial edema occur.
100 100
<15 y (138) 90
80 80 Without nephrotic
syndrome
Survival, %
15–59 y (68) 70
60
Survival, %
60
<15 y (62)
40 >60 y (20) 50
>15 y (60) 40
20 Minimal change disease
30
FSGS With nephrotic
0 20
syndrome
0 5 10 15 20 10
Years from onset 0
0 5 10 15 20
Years from onset
FIGURE 2-13
Evolution of focal segmental glomerulosclerosis (FSGS). This graph
compares the renal functional survival rate of patients with FSGS FIGURE 2-14
to that seen in patients with minimal change disease (in adults and The outcome of focal segmental glomerulosclerosis according to the
children). Note the poor prognosis, with about a 50% rate of renal degree of proteinuria at presentation is shown. Note the favorable
survival at 10 years. (From Cameron [2]; with permission.) prognosis in the absence of nephrotic syndrome. Spontaneous or
therapeutically induced remissions have a similar beneficial effect on
long-term outcome. (From Ponticelli, et al. [5]; with permission.)
The Primary Glomerulopathies 2.7
Membranous Glomerulonephritis
A B
C D
antigen(s) of the immune complexes are unknown. In the remain-
der, membranous glomerulonephritis is associated with well-
defined diseases that often have an immunologic basis (eg, systemic
lupus erythematosus and hepatitis B or C virus infection); some
solid malignancies (especially carcinomas); or drug therapy, such as
gold, penicillamine, captopril, and some nonsteroidal anti-inflam-
matory reagents. Treatment is controversial.
The changes by light and electron microscopy mirror one anoth-
er quite well and represent morphologic progression that is likely
dependent on duration of the disease. A, At all stages immuno-
fluorescence discloses the presence of uniform granular capillary
wall deposits of immunoglobulin G and complement C3. B, In the
early stage the deposits are small and without other capillary wall
changes; hence, on light microscopy, glomeruli often are normal in
appearance. C, On electron microscopy, small electron-dense
E deposits (arrows) are observed in the subepithelial aspects of capillary
walls. D, In the intermediate stage the deposits are partially encircled
FIGURE 2-15 (see Color Plate) by basement membrane material. E, When viewed with periodic
Light, immunofluorescent, and electron microscopy in membra- acid-methenamine stained sections, this abnormality appears as
nous glomerulonephritis. Membranous glomerulonephritis is an spikes of basement membrane perpendicular to the basement
immune complex–mediated glomerulonephritis, with the immune membrane, with adjacent nonstaining deposits. Similar features
deposits localized to subepithelial aspects of almost all glomerular are evident on electron microscopy, with dense deposits and inter-
capillary walls. Membranous glomerulonephritis is the most com- vening basement membrane (D). Late in the disease the deposits
mon cause of nephrotic syndrome in adults in developed countries. are completely surrounded by basement membranes and are under-
In most instances (75%), the disease is idiopathic and the going resorption.
2.8 Glomerulonephritis and Vasculitis
FIGURE 2-16
Evolution of deposits in membranous glomerulonephritis. This
schematic illustrates the sequence of immune deposits in red; base-
ment membrane (BM) alterations in blue; and visceral epithelial cell
changes in yellow. Small subepithelial deposits in membranous
glomerulonephritis (predominately immunoglobulin G) initially
form (A) then coalesce. BM expansion results first in spikes (B) and
later in domes (C) that are associated with foot process effacement,
as shown in gray. In later stages the deposits begin to resorb (dotted
and crosshatched areas) and are accompanied by thickening of the
capillary wall (D). (From Churg, et al. [6]; with permission.)
A B
C D
FIGURE 2-17
100
Natural history of membranous glomerulonephritis. This schematic illustrates the clinical
Dead/ESRD
80 evolution of idiopathic membranous glomerulonephritis over time. Almost half of all patients
Nephrotic syndrome
60 undergo spontaneous or therapy-related remissions of proteinuria. Another group of patients
(25–40%), however, eventually develop chronic renal failure, usually in association with per-
%
Proteinuria
40 sistent proteinuria in the nephrotic range. (From Cameron [2]; with permission.)
20 Remission
0
0 5 10 15
Years of known disease
The Primary Glomerulopathies 2.9
Membranoproliferative Glomerulonephritis
A B
at all common. The first, known as membranoproliferative
(mesangiocapillary) glomerulonephritis type I, is a primary
glomerulopathy most common in children and adolescents. The
1
same pattern of injury may be observed during the course of many
2 diseases with chronic antigenemic states; these include systemic
3 lupus erythematosus and hepatitis C virus and other infections. In
membranoproliferative glomerulonephritis type I, the glomeruli
4 are enlarged and have increased mesangial cellularity and variably
increased matrix, resulting in lobular architecture. The capillary
5 walls often are thickened with double contours, an abnormality
6 resulting from peripheral migration and interposition of
mesangium (A). Immunofluorescence discloses granular to conflu-
ent granular deposits of C3 (B), immunoglobulin G, and
immunoglobulin M in the peripheral capillary walls and mesangial
regions. The characteristic finding on electron microscopy is in the
C capillary walls. C, Between the basement membrane and endothe-
lial cells are, in order inwardly: (1) epithelial cell, (2) basement
FIGURE 2-18 (see Color Plate) membrane, (3) electron-dense deposits, (4) mesangial cell cyto-
Light, immunofluorescence, and electron microscopy in membra- plasm, (5) mesangial matrix, and (6) endothelial cell. Electron-
noproliferative glomerulonephritis type I. In these types of dense deposits also are in the central mesangial regions.
immune complex–mediated glomerulonephritis, patients often Subepithelial deposits may be present, albeit typically in small
exhibit nephrotic syndrome accompanied by hematuria and numbers. The electron-dense deposits may contain an organized
depressed levels of serum complement C3. The morphology is var- (fibrillar) substructure, especially in association with hepatitis C
ied, with at least three pathologic subtypes, only two of which are virus infection and cryoglobulemia.
2.10 Glomerulonephritis and Vasculitis
A A
B
known as dense deposit disease, the glomeruli may be lobular
or may manifest only mild widening of mesangium. A, The capil-
lary walls are thickened, and the basement membranes are
stained intensely positive periodic acid–Schiff reaction, with a
refractile appearance. B, On immunofluorescence, complement
C3 is seen in all glomerular capillary basement membranes in
a coarse linear pattern. With the use of thin sections, it can be
appreciated that the linear deposits actually consist of two thin
parallel lines. Round granular deposits are in the mesangium.
Coarse linear deposits also are in Bowman’s capsule and the
tubular basement membranes. C, Ultrastructurally, the glomeru-
lar capillary basement membranes are thickened and darkly
stained; there may be segmental or extensive involvement of
the basement membrane. Similar findings are seen in Bowman’s
capsule and tubular basement membranes; however, in the latter,
C the dense staining is usually on the interstitial aspect of that
structure. Patients with dense deposit disease frequently show
FIGURE 2-19 (see Color Plate) isolated C3 depression and may have concomitant lipodystrophy.
Light, immunofluorescence, and electron microscopy in membra- These patients also have autoantibodies to the C3 convertase
noproliferative glomerulonephritis type II. In this disease, also enzyme C3Nef.
The Primary Glomerulopathies 2.11
Serum Concentration
Lesion C3 C4 C’H50 Other
Minimal change disease Normal Normal Normal –
Focal sclerosis Normal Normal Normal –
Membranous glomerulonephritis (idiopathic) Normal Normal Normal –
Immunoglobulin A nephropathy Normal Normal Normal –
Membranoproliferative glomerulonephritis:
Type I Moderate decrease Mild decrease Mild decrease –
Type II Severe decrease Normal Mild decrease C3 nephritic factor+
Acute poststreptococcal glomerulonephritis Moderate decrease Normal Mild decrease Antistreptolysin 0 titer increased
Lupus nephritis:
(World Health Organization Class IV) Moderate to severe Moderate to severe Mild decrease anti–double-stranded DNA antibody+
decrease decrease
(World Health Organization Class V) Normal or mild decrease Normal or mild decrease Normal or mild decrease anti–double-stranded DNA antibody+
Cryoglobulinemia (hepatitis C) Normal or mild decrease Severe decrease Moderate decrease Cryoglobulins; hepatitis C ab
Amyloid Normal Normal Normal –
Vasculitis Normal or increased Normal or increased Normal Antineutrophil cytoplasmic antibody+
FIGURE 2-20
The serum complement component concentration (C3 and C4) and and secondary glomerular lesions are depicted. Note the limited
serum hemolytic complement activity (C’H50) in various primary number of disorders associated with a low C3 or C4 level.
FIGURE 2-21
CLASSIFICATION OF MEMBRANOPROLIFERATIVE Note that although there is the wide variety of underlying causes for
GLOMERULONEPHRITIS TYPE I the lesion of membranoproliferative glomerulonephritis hepatitis C,
with or without cryoglobulinemia, accounts for most cases.
Primary (Idiopathic)
Secondary
Hepatitis C (with or without cryoglobulinemia)
Hepatitis B
Systemic lupus erythematosus
Light or heavy chain nephropathy
Sickle cell disease
Sjögren’s syndrome
Sarcoidosis
Shunt nephritis
Antitrypsin deficiency
Quartan malaria
Chronic thrombotic microangiopathy
Buckley’s syndrome
2.12 Glomerulonephritis and Vasculitis
A B
mesangial regions. Little if any increased cellularity is seen, despite
the presence of deposits. In this latter instance, the term mesangial
injury glomerulonephritis is more properly applied. The disorders
are defined on the basis of the immunofluorescence findings, rather
than on the presence or absence of mesangial hypercellularity. There
are numerous disorders with this appearance; some have specific
immunopathologic or clinical features (such as immunoglobulin A
nephropathy, Henoch-Schonlein purpura, and systemic lupus erythe-
matosus). Patients with primary mesangial proliferative glomeru-
lonephritis typically exhibit the disorder in one of four ways:
asymptomatic proteinuria, massive proteinuria often in the nephrot-
ic range, microscopic hematuria, or proteinuria with hematuria. A,
On light microscopy, widening of the mesangial regions is observed,
often with diffuse increase in mesangial cellularity commonly of a
mild degree. No other alterations are present. B, Depending on the
specific entity or lesion, the immunofluorescence is of granular
C mesangial deposits. In the most common of these disorders,
immunoglobulin M is the dominant or sole deposit. Other disorders
FIGURE 2-22 (see Color Plate) are characterized primarily or exclusively by complement C3,
Light, immunofluorescence, and electron microscopy in mesangial immunoglobulin G, or C1q deposits. C, On electron microscopy the
proliferative glomerulonephritis. This heterogeneous group of disor- major finding is of small electron-dense deposits in the mesangial
ders is characterized by increased mesangial cellularity in most of regions (arrow). Foot process effacement is variable, depending on
the glomeruli associated with granular immune deposits in the the clinical syndrome (eg, whether massive proteinuria is present).
The Primary Glomerulopathies 2.13
Crescentic Glomerulonephritis
A B
C D
FIGURE 2-23 (see Color Plate)
Crescentic glomerulonephritis. A crescent is the accumulation of trophil cytoplasmic antibodies (ANCAs). The clinical manifestations
cells and extracellular material in the urinary space of a glomerulus. are typically of rapidly progressive glomerulonephritis with moder-
The cells are parietal and visceral epithelia as well as monocytes and ate proteinuria, hematuria, oliguria, and uremia. The immunomor-
other blood cells. The extracellular material is fibrin, collagen, and phologic features depend on the basic disease process. On light
basement membrane material. In the early stages of the disease, the microscopy in both AGBM antibody–induced disease and
crescents consist of cells and fibrin. In the later stages the crescents ANCA–associated crescentic glomerulonephritis, the glomeruli with-
undergo organization, with disappearance of fibrin and replacement out crescents often have a normal appearance. It is the remaining
by collagen. Crescents represent morphologic consequences of glomeruli that are involved with crescents. D, Anti-GBM disease is
severe capillary wall damage. A, In most instances, small or large characterized by linear deposits of immunoglobulin G and often
areas of destruction of capillary walls (cells and basement mem- complement C3 in all capillary basement membranes, and in
branes) are observed (arrow), thereby allowing fibrin, other high approximately two thirds of affected patients in tubular basement
molecular weight substances, and blood cells to pass readily from membranes. The ANCA-associated lesion typically has little or no
capillary lumina into the urinary space. B, Immunofluorescence fre- immune deposits on immunofluorescence; hence the term pauci-
quently discloses fibrin in the urinary space. C, The proliferating immune crescentic glomerulonephritis is used. By electron
cells in Bowman’s space ultimately give rise to the typical crescent microscopy, as on light microscopy, defects in capillary wall conti-
shape. Whereas crescents may complicate many forms of glomeru- nuity are easily identified. Both AGBM- and ANCA-associated cres-
lonephritis, they are most commonly associated with either centic glomerulonephritis can be complicated by pulmonary hemor-
antiglomerular basement membrane (AGBM) antibodies or antineu- rhage (see Fig. 2-25).
2.14 Glomerulonephritis and Vasculitis
FIGURE 2-24
Note that the serologic findings allow for a differentiation of the various forms of
primary and secondary (eg, multisystem disease) forms of crescentic glomerulonephritis.
FIGURE 2-25
Chest radiograph of alveolar hemorrhage. This patient has antiglomerular basement mem-
brane–mediated glomerulonephritis complicated by pulmonary hemorrhage (Goodpasture’s
disease). Note the butterfly appearance of the alveolar infiltrates characteristic of intrapul-
monary (alveolar) hemorrhage. Such lesions can also occur in patients with antineutrophil
cytoplasmic autoantibody–associated vasculitis and glomerulonephritis, lupus nephritis
(SLE), cryoglobulinemia, and rarely in Henoch-Schonlein purpura (HSP).
The Primary Glomerulopathies 2.15
FIGURE 2-26
↑ Serum creatinine Evaluation of rapidly progressive glomeru-
Proteinuria lonephritis. This algorithm schematically
"Nephritic" sediment
illustrates a diagnostic approach to the
various causes of rapidly progressive
Renal ultrasonography glomerulonephritis (Figure 2-24), Serologic
studies, especially measurement of circulat-
ing antiglomerular basement membrane
Normal or enlarged antibodies, antineutrophil cytoplasmic
Small kidneys Obstruction
kidneys; no obstruction antibodies, antinuclear antibodies, and
serum complement component concentra-
tions, are used for diagnosis. Serologic
Serology*
patterns (A through D)permit categoriza-
tion of probable disease entities.
Pattern type (A) (B) (C) (D)
aGBMA* + – – +
ANCA† – – + +
Goodpasture's disease Type II IC-mediated Microscopic Combined
Type I primary CrGN CGN SLE, HSP, and polyangiitis; type III form; type IV
MPGN CryoIg, type V primary crescentic primary CrGN
primary CrGN CrGN; Wegener's GN;
(idiopathic) drug-induced CrGN
A B
2.16 Glomerulonephritis and Vasculitis
Immunoglobulin A Nephropathy
A B
C D
FIGURE 2-28 (see Color Plate)
Light, immunofluorescence, and electron microscopy in immuno- to the term focal proliferative glomerulonephritis. In advanced
globulin A (IgA) nephropathy. IgA nephropathy is a chronic cases, segmental sclerosis often is present and associated with mas-
glomerular disease in which IgA is the dominant or sole component sive proteinuria. During acute episodes, crescents may be present.
of deposits that localize in the mesangial regions of all glomeruli. B, Large round paramesangial fuchsinophilic deposits often are
In severe or acute cases, these deposits also are observed in the identified with Masson’s trichrome or other similar stains (arrows).
capillary walls. This disorder may have a variety of clinical presenta- C, Immunofluorescence defines the disease; granular mesangial
tions. Typically, the presenting features are recurrent macroscopic deposits of IgA are seen with associated complement C3, and IgG
hematuria, often coincident with or immediately after an upper respi- or IgM, or both. IgG and IgM often are seen in lesser degrees of
ratory infection, along with persistent microscopic hematuria and intensity than is IgA. D, On electron microscopy the abnormalities
low-grade proteinuria between episodes of gross hematuria. typically are those of large rounded electron-dense deposits
Approximately 20% to 25% of patients develop end-stage renal (arrows) in paramesangial zones of most if not all lobules.
disease over the 20 years after onset. A, On light microscopy, Capillary wall deposits (subepithelial, subendothelial, or both) may
widening and often an increase in cellularity in the mesangial be present, especially in association with acute episodes. In addi-
regions are observed, a process that affects the lobules of some tion, capillary basement membranes may show segmental thinning
glomeruli to a greater degree than others. This feature gives rise and rarefaction.
The Primary Glomerulopathies 2.17
FIGURE 2-29
Natural history of immunoglobulin A (IgA) nephropathy. The evolution of IgA nephropa-
thy over time with respect to the occurrence of end-stage renal failure (ESRF) is illustrated.
The percentage of renal survival (freedom from ESRF) is plotted versus the time in years
from the apparent onset of the disease. Note that on average about 1.5% of patients enter
ESRF each year over the first 20 years of this nephropathy. Factors indicating an unfavor-
able outcome include elevated serum creatinine, tubulointerstitial lesions or glomeruloscle-
rosis, and moderate proteinuria (>1.0 g/d). (Modified from Cameron [2].)
A B
entity in which abnormal extracellular fibrils, typically ranging
from 10- to 20-nm thick, permeate the glomerular mesangial
matrix and capillary basement membranes. The fibrils are defined
only on electron microscopy and have an appearance, at first
glance, similar to amyloid. Congo red stain, however, is negative.
Patients with fibrillary glomerulonephritis usually exhibit protein-
uria often in the nephrotic range, with variable hematuria, hyper-
tension, and renal insufficiency. A, On light microscopy the
glomeruli display widened mesangial regions, with variable
increase in cellularity and thickened capillary walls and often with
irregularly thickened basement membranes, double contours, or
both. B, On immunofluorescence, there is coarse linear or conflu-
ent granular staining of capillary walls for immunoglobulin G and
complement C3 and similar staining in the mesangial regions.
Occasionally, monoclonal immunoglobulin G k deposits are identi-
fied; in most instances, however, both light chains are equally rep-
C resented. The nature of the deposits is unknown. C, On electron
microscopy the fibrils are roughly 20-nm thick, of indefinite length,
FIGURE 2-30 (see Color Plate) and haphazardly arranged. The fibrils permeate the mesangial
Light, immunofluorescent, and electron microscopy in nonamyloid matrix and basement membranes (arrow). The fibrils have been
fibrillary glomerulonephritis. Fibrillary glomerulonephritis is an infrequently described in organs other than the kidneys.
2.18 Glomerulonephritis and Vasculitis
A B
FIGURE 2-31 (see Color Plate)
Light, immunofluorescent, and electron microscopy in immunotac-
toid glomerulopathy. Immunotactoid glomerulopathy appears to be
an immune-mediated glomerulonephritis. On electron microscopy
the deposits are composed of multiple microtubular structures in
subepithelial or subendothelial locations, or both, with lesser
involvement of the mesangium. Patients with this disorder typically
exhibit massive proteinuria or nephrotic syndrome. This glomeru-
lopathy frequently is associated with lymphoplasmacytic disorders.
A, On light microscopy the glomerular capillary walls often are
thickened and the mesangial regions widened, with increased cellu-
larity. B, On immunofluorescence, granular capillary wall and
mesangial immunoglobulin G and complement C3 deposits are pre-
sent. The ultrastructural findings are of aggregates of microtubular
structures in capillary wall locations corresponding to granular
deposits by immunofluorescence. C, The microtubular structures
C are large, ranging from 30- to 50-nm thick, or more (arrows).
The Primary Glomerulopathies 2.19
Collagenofibrotic Glomerulopathy
A B
FIGURE 2-32 (see Color Plate)
Collagenofibrotic glomerulopathy (collagen III glomerulopathy). exhibit proteinuria and mild progressive renal insufficiency.
The collagens normally found in glomerular basement mem- For reasons that are not clear, hemolytic-uremic syndrome has
branes and the mesangial matrix are of types IV (which is domi- evolved in a small number of pediatric patients. A, On light
nant) and V. In collagenofibrotic glomerulopathy, accumulation microscopy the capillary walls are thickened and mesangial
of type III collagen occurs largely in capillary walls in a suben- regions widened by pale staining material. These features are in
dothelial location. It is likely that this disease is hereditary; how- sharp contrast to the normal staining of the capillary basement
ever, because it is very rare, precise information regarding trans- membranes, as evidenced by the positive period acid–Schiff reac-
mission is not known. Collagenofibrotic glomerulopathy origi- tion. With this stain, collagen type III is not stained and there-
nally was thought to be a variant of nail-patella syndrome. fore is much paler. Amyloid stains (Congo red) are negative.
Current evidence suggests little relationship exists between the B, On electron microscopy, banded collagen fibrils are evident
two disorders. Patients with collagen III glomerulopathy often in the subendothelial aspect of the capillary wall.
References
1. Cameron JS, Glassock RJ: The natural history and outcome of the 4. Ponticelli C: Cyclosporine versus cyclophosphamide for patients with
nephrotic syndrome. In The Nephrotic Syndrome. Edited by Cameron steroid-dependent and frequently relapsing idiopathic nephrotic syn-
JS and Glassock RJ. New York: Marcel Dekker, 1987. drome. A multi-center randomized trial. Nephrol Dial Transplant
2. Cameron JS: The long-term outcome of glomerular diseases. In 1993, 8:1326–1332.
Diseases of the Kidney Vol II, edn 6. Edited by Schrier RW, 5. Ponticelli C, Glassock RJ: Treatment of Segmental Glomerulonephritis.
Gottschalk CW. Boston: Little Brown; 1996. Oxford: Oxford Medical Publishers, 1996:110.
3. Arbeitsgemeinschaft für pediatrische nephrologie. Cyclophosphamide 6. Churg J, Bernstein J, Glassock RJ: Renal Disease. Classification and
treatment of steroid-dependent nephrotic syndrome: comparison of an Atlas of Glomerular Disease, edn 2. New York: Igaku-Shoin; 1995.
eight-week with a 12-week course. Arch Dis Child 1987, 62:1102–1106.
Heredofamilial
and Congenital
Glomerular Disorders
Arthur H. Cohen
Richard J. Glassock
T
he principal characteristics of some of the more common hered-
ofamilial and congenital glomerular disorders are described and
illustrated. Diabetes mellitus, the most common heredofamilial
glomerular disease, is illustrated in Volume IV, Chapter 1. These disor-
ders are inherited in a variety of patterns (X-linked, autosomal domi-
nant, or autosomal recessive). Many of these disorders appear to be
caused by defective synthesis or assembly of critical glycoprotein
(collagen) components of the glomerular basement membrane.
CHAPTER
3
3.2 Glomerulonephritis and Vasculitis
FIGURE 3-2
NC1 100nm Schematic of basement membrane collagen type IV. The postulated
arrangement of type IV collagen chains in a normal glomerular base-
7S ment membrane is illustrated. The joining of noncollagen (NC-1)
and 75 domains creates a lattice (chicken wire) arrangement (A). In
the glomerular basement membrane, 1 and 2 chains predominate
in the triple helix (B), but 3, 4, 5, and 6 chains are also found (not
A shown). Disruption of synthesis of any of these chains may lead to
anatomic and pathologic alternations, such as those seen in Alport’s
syndrome. Arrows indicate fibrils. (From Abrahamson and coworkers
[1]; with permission.)
-S--S-
α1 -S--S- α1
α2 -S--S- α2
-S--S-
α1 -S--S- α1
B -S--S-
FIGURE 3-3
Neurosensory hearing defect in Alport’s syndrome. In patients with adult onset Alport’s
syndrome, classic X-linked sensorineural hearing defects occur. These defects often begin
20 with an auditory loss of high-frequency tone, as shown in this audiogram. The shaded
Hearing loss, dB
area represents normal ranges. (Modified from Gregory and Atkin [2]; with permission.)
40
60
80
100
500 2K 4K 8K 10K 12K 14K 16K 18K
Frequency
Heredofamilial and Congenital Glomerular Disorders 3.3
FIGURE 3-4
Thin basement membrane nephropathy. Glomeruli with abnormal-
ly thin basement membranes may be a manifestation of benign
familial hematuria. Glomeruli with thin basement membranes
many also occur in persons who do not have a family history of
renal disease but who have hematuria, low-grade proteinuria, or
both. Although the ultrastructural abnormalities have some simi-
larities in common with the capillary basement membranes of
Alport’s syndrome, these two glomerulopathies are not directly
related. Clinically, persistent microscopic hematuria or occasional
episodic gross hematuria are important features. Nonrenal abnor-
malities are absent. On light microscopy, the glomeruli are normal;
no deposits are seen on immunofluorescence. Here, the electron
microscopic abnormalities are diagnostic; all or virtually all
glomerular basement membranes are markedly thin (<200 nm in
adults) without other features such as splitting, layering, or abnor-
mal subepithelial contours.
A B
of the enzyme -galactosidase with accumulation of sphingolipids in
many cells. In the kidney, accumulation of sphingolipids especially
affects glomerular visceral epithelial cells. Deposition of sphin-
golipids in the vascular tree may lead to premature coronary artery
occlusion (angina or myocardial infarction) or cerebrovascular insuf-
ficiency (stroke). Involvement of nerves leads to painful acropares-
thesias and decreased perspiration (anhidrosis). The most common
renal manifestation is that of proteinuria with progressive renal
insufficiency. On light microscopy, the morphologic abnormalities of
the glomeruli primarily consist of enlargement of visceral epithelial
cells and accumulation of multiple uniform small vacuoles in the
cytoplasm (arrow in Panel A). Ultrastructurally, the inclusions are
those of whorled concentric layers appearing as “zebra bodies” or
myeloid bodies representing sphingolipids (B). These structures also
may be observed in mesangial and endothelial cells and in arterial
C and arteriolar smooth muscle cells and tubular epithelia. At consider-
ably higher magnification, the inclusions are observed to consist of
FIGURE 3-5 (see Color Plate) multiple concentric alternating clear and dark layers, with a periodic-
Fabry’s disease. Fabry’s disease, also known as angiokeratoma cor- ity ranging from 3.9 to 9.8 nm. This fine structural appearance (best
poris diffusum or Anderson-Fabry’s disease, is the result of deficiency appreciated at the arrow) is characteristic of stored glycolipids (C).
3.4 Glomerulonephritis and Vasculitis
FIGURE 3-6
Electron microscopy of nail-patella syndrome. This disorder having
skeletal and renal manifestations affects the glomeruli, with accu-
mulation of banded collagen fibrils within the substance of the cap-
illary basement membrane. This accumulation appears as empty
lacunae when the usual stains with electron microscopy (lead cit-
rate and uranyl acetate) are used. However, as here, the fibrils easi-
ly can be identified with the use of phosphotungstic acid stain in
conjunction with or instead of typical stains. Note that this disor-
der differs structurally from collagen type III glomerulopathy in
which the collagen fibrils are subendothelial and not intramembra-
nous in location. Patients with nail-patella syndrome may develop
proteinuria, sometimes in the nephrotic range, with variable pro-
gression to end-stage renal failure. No distinguishing abnormalities
are seen on light microscopy.
FIGURE 3-7
Radiography of nail-patella syndrome. The
skeletal manifestations of nail-patella syn-
drome are characteristic and consist of
absent patella and absent and dystrophic
nails. These photographs illustrate absent
patella (A) and the characteristic nail
changes (B) that occur in patients with the
disorder. (From Gregory and Atkin [2];
with permission.)
A
Heredofamilial and Congenital Glomerular Disorders 3.5
A B
FIGURE 3-8 (see Color Plate)
Lecithin-cholesterol acyl transferase deficiency. Lipid accumula- membranes are irregularly thickened. Some capillary lumina may
tion occurs in this hereditary metabolic disorder, especially in contain foam cells. Although quite rare, this autosomal recessive
extracellular sites throughout glomerular basement membranes disease has been described in most parts of the world; however,
and the mesangial matrix. A, On electron microscopy the lipid it occurs most commonly in Norway. Patients exhibit proteinuria,
appears as multiple small lacunae, often with small round dense often with microscopic hematuria usually noted in childhood.
granular or membranous structures (arrows). Lipid-containing Renal insufficiency may develop in the fourth or fifth decade of
monocytes may be in the capillary lumina. B, The mesangial life and may progress rapidly. Nonrenal manifestations include
regions are widened on light microscopy, usually with expansion corneal opacification, hemolytic anemia, early atherosclerosis,
of the matrix that stains less intensely than normal. Basement and sea-blue histocytes in the bone marrow and spleen.
A B
FIGURE 3-9 (see Color Plate)
Lipoprotein glomerulopathy. Patients with this rare disease, which mesangial hypercellularity or mesangiolysis may be present. With
often is sporadic (although some cases occur in the same family), immunostaining for -lipoprotein, apolipoproteins E and B are
exhibit massive proteinuria. Lipid profiles are characterized by identified in the luminal masses. B, Electron microscopic findings
increased plasma levels of cholesterol, triglycerides, and very low indicate the thrombi consist of finely granular material with numer-
density lipoproteins. Most patients have heterozygosity for ous vacuoles (lipoprotein). Lipoprotein glomerulopathy may
apolipoprotein E2/3 or E2/4. A, The glomeruli are the sites of mas- progress to renal insufficiency over a long period of time.
sive intracapillary accumulation of lipoproteins, which appear as Recurrence of the lesions in a transplanted organ has been reported
slightly tan masses (thrombi) dilating capillaries (arrows). Segmental infrequently. Lipid-lowering agents are mostly ineffective.
3.6 Glomerulonephritis and Vasculitis
A B
FIGURE 3-10 (see Color Plate)
Nephropathic cystinosis. In older children and young adults, have occasionally enlarged and multinucleated visceral epithelial cells
compared with young children, patients with cystinosis commonly (arrow). As the disease progresses, segmental sclerosis becomes evident
exhibit glomerular involvement rather than tubulointerstitial disease. as in the photomicrograph. B, Crystalline inclusions are identified on
Proteinuria and renal insufficiency are the typical initial manifestations. electron microscopy. The crystals of cysteine are usually dissolved in
A, As the most constant abnormality on light microscopy, glomeruli processing, leaving an empty space as shown here by the arrows.
A B
FIGURE 3-11 (see Color Plate)
Finnish type of congenital nephrotic syndrome. Several disorders the kidneys is varied. Some glomeruli are small and infantile with-
are responsible for nephrotic syndrome within the first few out other alterations, whereas others are enlarged, more mature,
months to first year of life. The most common and important of and have diffuse mesangial hypercellularity. Because of the mas-
these is known as congenital nephrotic syndrome of Finnish type sive proteinuria, some tubules are microcystically dilated, a find-
because the initial descriptions emphasized the more common ing responsible for the older term for this disorder, microcystic
occurrence in Finnish families. This nephrotic syndrome is an disease. Because this syndrome is primarily a glomerulopathy,
inherited disorder in which infants exhibit massive proteinuria the tubular abnormalities are a secondary process and should
shortly after birth; typically, the placenta is enlarged. This disorder not be used to designate the name of the disease. B, On electron
can be diagnosed in utero; increased -fetoprotein levels in amni- microscopy, complete effacement of the foot processes of visceral
otic fluid is a common feature. A, The microscopic appearance of epithelial cells is observed.
Heredofamilial and Congenital Glomerular Disorders 3.7
References
1. Abrahamson D, Van der Heurel GB, Clapp WL, et al.: Nephritogenic 2. Gregory M, Atkin C: Alport’s syndrome, Fabry disease and nail-patel-
antigens in the glomerular basement membrane. In Immunologic la syndrome. In Diseases of the Kidney, Vol. I. edn 6. Edited by
Renal Diseases. Edited by Nielson EG, Couser, WG. Philadelphia: Schrier RW, Gottschalk CW. Boston: Little Brown, 1995.
Lippincott-Raven, 1997.
Infection-Associated
Glomerulopathies
Arthur H. Cohen
Richard J. Glassock
M
any glomerular diseases may be associated with acute and
chronic infectious diseases of bacterial, viral, fungal, or
parasitic origin. In many instances, the glomerular activa-
tors are transient and of little clinical consequence. In other
instances, distinct clinical syndromes such as acute nephritis or
nephrotic syndrome may be provoked. Some of the more important
infection-related glomerular diseases are illustrated here. Others dis-
eases, including human immunodeficiency virus and hepatitis, are
also discussed in Volume IV.
CHAPTER
4
4.2 Glomerulonephritis and Vasculitis
A B
streptococcus. Typically, patients with glomerulonephritis exhibit
hematuria, edema, proteinuria, and hypertension. Renal function
frequently is depressed, sometimes severely. Most patients recover
spontaneously, and a few go on to rapidly progressive or chronic
indolent disease. A, On light microscopy the glomeruli are enlarged
and hypercellular, with numerous leukocytes in the capillary lumina
and a variable increase in mesangial cellularity. The leukocytes are
neutrophils and monocytes. The capillary walls are single-con-
toured, and crescents may be present. B, On immunofluorescence,
granular capillary wall and mesangial deposits of immunoglobulin
G and complement C3 are observed (starry-sky pattern). Three pre-
dominant patterns occur depending on the location of the deposits;
these include garlandlike, mesangial, and starry-sky patterns.
C, The ultrastructural findings are those of electron-dense deposits,
characteristically but not solely in the subepithelial aspects of the
capillary walls, in the form of large gumdrop or hump-shaped
C deposits (arrow). However, electron-dense deposits also are found
in the mesangial regions and occasionally subendothelial locations.
FIGURE 4-1 (see Color Plate) Endothelial cells often are swollen, and leukocytes are not only
Light, immunofluorescent, and electron microscopy of poststrepto- found in the capillary lumina but occasionally in direct contact
coccal (postinfectious) glomerulonephritis. Glomerulonephritis may with basement membranes in capillary walls with deposits. Similar
follow in the wake of cutaneous or pharyngeal infection with a lim- findings may be observed in glomerulonephritis after infectious
ited number of “nephritogenic” serotypes of group A -hemolytic diseases other than certain strains of Streptococci.
Infection-Associated Glomerulopathies 4.3
FIGURE 4-2
Infective endocarditis and shunt nephritis. The glomerulonephritis
accompanying infective endocarditis or infected ventriculoatrial
shunts or other indwelling devices is that of a postinfectious
glomerulonephritis or membranoproliferative glomerulonephritis
type I pattern, or both (see Fig. 2-18). In reality, the changes often
are a combination of both. As shown here, this glomerulopathy is
characterized by increased mesangial cellularity, with slight lobular
architecture; occasionally thickened capillary walls, with double
contours (arrow); and leukocytes in some capillary lumina. This
glomerulus also has a small crescent.
A B
(focal segmental) glomerulosclerosis with significant tubular and
interstitial abnormalities. A, In HIVAN, many visceral epithelial
cells are enlarged, coarsely vacuolated, contain protein reabsorp-
tion droplets, and overlay capillaries with varying degrees of wrin-
kling and collapse of the walls (arrows). B, In HIVAN, the tubules
are dilated and filled with a precipitate of plasma protein, and the
tubular epithelial cells display various degenerative features
(arrow). Ultrastructural findings are a combination of those expect-
ed for the glomerulopathy as well as those common to HIV infec-
tion. Thus, the foot processes of visceral epithelial cells are effaced
and often detached from the capillary basement membranes. C,
Common in HIV infection are tubuloreticular structures, modifica-
tions of the cytoplasm of endothelial cells in which clusters of
microtubular arrays are in many cells (arrow). Some evidence sug-
gests that HIV or viral proteins localize in renal epithelial cells and
perhaps are directly or indirectly responsible for the cellular and
C functional damage. HIVAN often has a rapidly progressive down-
hill course, culminating in end-stage renal disease in as few as 4
FIGURE 4-3 (see Color Plate) months. HIVAN has a striking racial predilection; over 90% of
Human immunodeficiency virus (HIV) infection. Many forms of patients are black.
renal disease have been described in patients infected with HIV. The other glomerulopathy that may be an integral feature of HIV
Various immune complex–mediated glomerulonephritides associat- infection is immunoglobulin A nephropathy. In this setting, HIV
ed with complicating infections are known; however, several disor- antigen may be part of the glomerular immune complexes and cir-
ders appear to be directly or indirectly related to HIV itself. culating immune complexes. The morphology and clinical course
Perhaps the more common of these is known as HIV-associated generally are the same as in immunoglobulin A nephropathy occur-
nephropathy (HIVAN). This disease is a form of the collapsing ring in the non-HIV setting.
4.4 Glomerulonephritis and Vasculitis
A B
HT
C D
FIGURE 4-4 (see Color Plate)
Hepatitis C virus infection. The most common glomerulonephri- peripheral granular to confluent granular capillary wall deposits
tis in patients infected with the hepatitis C virus is membra- of immunoglobulin M (IgM) and complement C3; the same
noproliferative glomerulonephritis with, in some instances, immune proteins are in the luminal masses corresponding to
cryoglobulinemia and cryoglobulin precipitates in glomerular hyaline thrombi (arrow). C, Electron microscopy indicates the
capillaries. Thus, the morphology is basically the same as in luminal masses (HT). D, On electron microscopy the deposits
membranoproliferative glomerulonephritis type I (Fig. 2-18A–C). also appear to be composed of curvilinear or annular structures
A, With cryoglobulins, precipitates of protein representing cryo- (arrows). Hepatitis C viral antigen has been documented in the
globulin in the capillary lumina and appearing as hyaline throm- circulating cryoglobulins. Membranous glomerulonephritis with
bi (HT)are observed (arrows), often with numerous monocytes a mesangial component also has been infrequently described in
in most capillaries. B, Immunofluorescence microscopy discloses patients infected with the hepatitis C virus.
Infection-Associated Glomerulopathies 4.5
A B
the isolation of the hepatitis C virus and its separation from the
hepatitis B virus, membranoproliferative glomerulonephritis was
considered a common immune complex–mediated manifestation
of hepatitis B virus infection. However, more recent data indi-
cate that this form of glomerulonephritis is a feature of hepatitis
C virus infection rather than hepatitis B virus infection. In con-
trast, membranous glomerulonephritis, often with mesangial
deposits and variable mesangial hypercellularity, is the glomeru-
lopathy that is a common accompaniment of hepatitis B virus
infection. Hepatitis B virus surface, core, or e antigens have
been identified in the glomerular deposits. The morphology of
the glomerular capillary walls is similar to the idiopathic form
of membranous glomerulonephritis. A, Some degree of mesan-
gial widening with increased cellularity occurs in most affected
patients. B, Similarly, on immunofluorescence, uniform granular
capillary wall deposits of immunoglobulin G (IgG), complement
C3, and both light chains are disclosed (IgG). It sometimes is
C very difficult to identify mesangial deposits in this setting. C, In
addition to the expected capillary wall changes, electron micro-
FIGURE 4-5 (see Color Plate) scopy discloses deposits in mesangial regions of many lobules
Hepatitis B virus infection. Several glomerulopathies have been (the arrow indicates mesangial deposits; the arrowheads indicate
described in association with hepatitis B viral infection. Until subepithelial deposits).
Vascular Disorders
Arthur H. Cohen
Richard J. Glassock
V
ascular disorders of the kidney comprise a very heterogeneous
array of lesions and abnormalities, depending on the site of the
lesion and underlying pathogenesis. Here, three common dis-
orders are the focus: thrombotic microangiopathies, benign and
malignant nephrosclerosis, and vascular occlusive disease (atheroem-
bolism). Vasculitis and renovascular hypertension are discussed in
other chapters.
CHAPTER
5
5.2 Glomerulonephritis and Vasculitis
A B
C D
thrombocytopenic purpura, malignant hypertension, and renal
disease in progressive systemic sclerosis (scleroderma renal crises).
A, These lesions are characterized primarily by fibrin deposition in
the walls of the glomeruli (fibrin). B, This fibrin deposition is asso-
ciated with endothelial cell swelling (arrow) and thickened capillary
walls, sometimes with a double contour. Variable capillary wall
wrinkling and luminal narrowing occur. Mesangiolysis (dissolution
of the mesangial matrix and cells) is not uncommon and may be
associated with microaneurysm formation. With further endothelial
cell damage, capillary thrombi ensue. C, Arteriolar thrombi also
may be present. In arterioles, fibrin deposits in the walls and lumina
are known as thrombonecrotic lesions, with extension of this
process into the glomeruli on occasion (arrow). The arterial walls
are thickened, with loose concentric intimal proliferation. D, On
electron microscopy, the subendothelial zones of the glomerular
E capillary wall are widened (arrows). Flocculent material accumu-
lates, corresponding to mural fibrin, with associated endothelial cell
FIGURE 5-1 swelling. E, With widespread arterial thrombosis, cortical necrosis is
Light microscopy of thrombotic microangiopathies. This group a common complicating feature. The necrotic cortex consists
of disorders includes hemolytic-uremic syndrome and thrombotic of pale confluent multifocal zones throughout the cortex.
Vascular Disorders 5.3
FIGURE 5-2 (see Color Plate) FIGURE 5-3 (see Color Plate)
Microangiopathic hemolytic anemia. Bizarrely shaped and Disseminated intravascular coagulation. In disseminated intravas-
fragmented erythrocytes are commonly seen in Wright’s stained cular coagulation, fibrin thrombi are typically found in many
peripheral blood smears from patients with active lesions of glomerular capillary lumina. In contrast to the thrombotic
thrombotic microangiopathy. These abnormally shaped erythro- microangiopathies, in disseminated intravascular coagulation, fib-
cytes presumably arise when the fibrin strands within small rin is not primarily in vessel walls but in the lumina. Consequently,
blood vessels shear the cell membrane, with imperfect resolution the capillary wall thickening, endothelial cell swelling, and fibrin
of the biconcave disk shape. The resultant intravascular hemoly- accumulation in subendothelial locations are not features of this
sis causes anemia, reticulocytosis, and reduced plasma haptoglo- lesion. In the glomerulus illustrated, the fibrin is in many capillary
bin level. lumina and appears as bright fuchsin positive (red) masses.
A B
FIGURE 5-4
Benign and malignant nephrosclerosis. In benign nephrosclerosis lar pole and growing as a collar around the wrinkled ischemic
the artery walls are thickened with intimal fibrosis and luminal tufts. This collagen formation ultimately is associated with tubular
narrowing. Arteriolar walls are thickened with insudative lesions, atrophy and interstitial fibrosis.
a process affecting afferent arterioles almost exclusively. Both In malignant nephrosclerosis the changes are virtually identical
of these processes, which can be quite patchy, result in chronic to those of thrombotic microangiopathies (Fig. 5-1 C). Malignant
ischemia. A, In glomeruli, chronic ischemia is manifested by grad- nephrosclerosis may be seen in essential hypertension, scleroder-
ual capillary wall wrinkling, luminal narrowing, and shrinkage ma, unilateral renovascular hypertension (with a contralateral or
and solidification of the tufts. B, As these processes progress, col- “unprotected” kidney), and as a complicating event in many
lagen forms internal to Bowman’s capsule, beginning at the vascu- chronic renal parenchymal diseases.
5.4 Glomerulonephritis and Vasculitis
A B
instrumentation of patients with severe arteriosclerosis. Most
commonly, aortic plaques are complicated with ulceration and
often adherent fibrin, A. Portions of plaques are dislodged and
travel distally in the aorta. Because the kidneys receive a dispro-
portionately large share of the cardiac output, they are a favored
site of emboli. Typically, the emboli are in small arteries and
arterioles, although glomerular involvement with a few choles-
terol crystals in capillaries is not uncommon. Because of the
size of the crystals, it is sometimes difficult if not impossible
to identify them in glomerular capillaries in paraffin-embedded
sections. In plastic-embedded sections prepared for electron
microscopy, however, the crystals are quite easy to detect. On
light microscopy, cholesterol is represented by empty crystalline
spaces. In the early stages of the disease the crystals lie free in the
vascular lumina. In time, the crystals are engulfed by multinucle-
C ated foreign body giant cells. B, In this light microscopic photo-
graph, a few crystals are evident in the glomerular capillary lumi-
FIGURE 5-5 na and in an arteriole (arrows). C, In the electron micrograph the
Vascular occlusive disease and thrombosis. Atheroemboli (choles- elongated empty space represents dissolved cholesterol. Note that
terol emboli) are most commonly associated with intravascular no cellular reaction is evident.
Renal Interstitium and
Major Features of Chronic
Tubulointerstitial Nephritis
Garabed Eknoyan
Luan D. Truong
A
s a rule, diseases of the kidney primarily affect the glomeruli, vas-
culature, or remainder of the renal parenchyma that consists of
the tubules and interstitium. Although the interstitium and the
tubules represent separate functional and structural compartments, they
are intimately related. Injury initially involving either one of them
inevitably results in damage to the other. Hence the term tubulointersti-
tial diseases is used. Because inflammatory cellular infiltrates of variable
severity are a constant feature of this entity, the terms tubulointerstitial
diseases and tubulointerstitial nephritis have come to be used inter-
changeably. The clinicopathologic syndrome that results from these
lesions, commonly termed tubulointerstitial nephropathy, may pursue
an acute or chronic course. The chronic course is discussed here. The
abbreviation TIN is used to refer synonymously to chronic tubulointer-
stitial nephritis and tubulointerstitial nephropathy.
TIN may be classified as primary or secondary in origin. Primary
TIN is defined as primary tubulointerstitial injury without significant
involvement of the glomeruli or vasculature, at least in the early stages
of the disease. Secondary TIN is defined as secondary tubulointerstitial
injury, which is consequent to lesions initially involving either the
glomeruli or renal vasculature. The presence of secondary TIN is espe-
cially important because the magnitude of impairment in renal function
and the rate of its progression to renal failure correlate better with the CHAPTER
extent of TIN than with that of glomerular or vascular damage.
Renal insufficiency is a common feature of chronic TIN, and its diag-
6
nosis must be considered in any patient who exhibits renal insufficien-
cy. In most cases, however, chronic TIN is insidious in onset, renal insuf-
ficiency is slow to develop, and earliest manifestations of the disease are
those of tubular dysfunction. As such, it is important to maintain a high
6.2 Tubulointerstitial Disease
index of suspicion of this entity whenever any evidence of tubu- the two principal hallmarks of glomerular and vascular diseases
lar dysfunction is detected clinically. At this early stage, removal of the kidney: salt retention, manifested by edema and hyperten-
of a toxic cause of injury or correction of the underlying systemic sion; and proteinuria, which usually is modest and less than 1 to
or renal disease can result in preservation of residual renal func- 2 g/d in TIN. These clinical considerations notwithstanding, a
tion. Of special relevance in patients who exhibit renal insuffi- definite diagnosis of TIN can be established only by morphologic
ciency caused by primary TIN is the absence or modest degree of examination of kidney tissue.
10 50 100%
Extracellular space Interstitial cells
Vessels Tubules
Cortex
FIGURE 6-2
A, Electron micrograph of a rat kidney cortex, where C is the cortex. B, Schematic render-
ing, where the narrow interstitium is shown in black and the wide interstitium is shown by
dots. The relative volume of the interstitium of the cortex is approximately 7%, consisting of
about 3% interstitial cells and 4% extracellular space. The vasculature occupies another
6%; the remainder (ie, some 85% or more) is occupied by the tubules. The cortical intersti-
tial space is unevenly distributed and has been divided into narrow and wide structural
components. The tubules and peritubular capillaries either are closely apposed at several
points, sometimes to the point of sharing a common basement membrane, or are separated
by a very narrow space.
This space, the so-called narrow interstitium, has been estimated to occupy 0.6% of corti-
cal volume in rats. The narrow interstitium occupies about one-half to two-thirds of the
A cortical peritubular capillary surface area. The remainder of the cortical interstitium con-
sists of irregularly shaped clearly discernible larger areas, the so-called wide interstitium.
The wide interstitium has been estimated to occupy 3.4% of cortical volume in rats. The
capillary wall facing the narrow interstitium is significantly more fenestrated than is that
facing the wide interstitium. Functional heterogeneity of these interstitial spaces has been
proposed but remains to be clearly defined. (From Bohman [1]; with permission.)
B
Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.3
Medulla
FIGURE 6-3
Scanning electron micrograph of the inner medulla, showing a
prominent collecting duct, thin wall vessels, and abundant inter-
stitium. A gradual increase in interstitial volume from the outer
medullary stripe to the tip of the papilla occurs. In the outer stripe
of the outer medulla, the relative volume of the interstitium is
slightly less than is that of the cortex. This volume has been
estimated to be approximately 5% in rats. It is in the inner stripe
of the outer medulla that the interstitium begins to increase signifi-
cantly in volume, in increments that gradually become larger
toward the papillary tip.
The inner stripe of the outer medulla consists of the vascular bun-
dles and the interbundle regions, which are occupied principally by
tubules. Within the vascular bundles the interstitial spaces are meager,
whereas in the interbundle region the interstitial spaces occupy
some 10% to 20% of the volume. In the inner medulla the differ-
entiation into vascular bundles and interbundle regions becomes
gradually less obvious until the two regions merge. A gradual increase
in the relative volume of the interstitial space from the base of the
inner medulla to the tip of the papilla also occurs. In rats, the
increment in interstitial space is from 10% to 15% at the base to
about 30% at the tip. In rabbits, the increment is from 20% to
25% at the base to more than 40% at the tip.
Cell types
Matrix
FIGURE 6-5
Peritubular interstitium in the cortex at the interface of a tubule (T) on the left and a capillary
(C) on the right. The inset shows the same space in cross section, including the basement
membrane (BM) of the two compartments. The extracellular loose matrix is a hydrated
gelatinous substance consisting of glycoproteins and glycosaminoglycans (hyaluronic acid,
heparan sulfate, dermatan sulfate, and chondroitin sulfate) that are embedded within a
fibrillar reticulum. This reticulum consists of collagen fibers (types I, III, and VI) and
unbanded microfilaments. Collagen types IV and V are the principal components of the
basement membrane lining the tubules. Glycoprotein components (fibronectin and laminin)
of the basement membrane connect it to the interstitial cell membranes and to the fibrillar
structures of the interstitial matrix. The relative increase in the interstitial matrix of the
medulla may be important for providing support to the delicate tubular and vascular
structures in this region. (From Lemley and Kriz [2]; with permission.)
Urinary tract
Immunologic diseases obstructions Hematologic diseases Miscellaneous Hereditary diseases Endemic diseases
Systemic lupus Vesicoureteral reflux Sickle hemoglobinopathies Vascular diseases Medullary cystic disease Balkan nephropathy
erythematosus Mechanical Multiple myeloma Nephrosclerosis Hereditary nephritis Nephropathia epidemica
Sjögren syndrome Lymphoproliferative Atheroembolic disease Medullary sponge kidney
Transplanted kidney disorders Radiation nephritis Polycystic kidney disease
Cryoglobulinemia Aplastic anemia Diabetes mellitus
Goodpasture’s syndrome Sickle hemoglobinopathies
Immunoglobulin A Vasculitis
nephropathy
Amyloidosis
Pyelonephritis
Infections Drugs Heavy metals Metabolic disorders Granulomatous disease Idiopathic TIN
Systemic Analgesics Lead Hyperuricemia- Sarcoidosis
Renal Cyclosporine Cadmium hyperuricosuria Tuberculosis
Bacterial Nitrosourea Hypercalcemia- Wegener’s granulomatosis
Viral Cisplatin hypercalciuria
Fungal Lithium Hyperoxaluria
Mycobacterial Miscellaneous Potassium depletion
Cystinosis
FIGURE 6-8
Tubulointerstitial nephropathy occurs in a motley group of diseases together because of the unifying structural changes associated with
of varied and diverse causes. These diseases are arbitrarily grouped TIN noted on morphologic examination of the kidneys.
6.6 Tubulointerstitial Disease
Release of cytokines, proteinases potential mechanism of injury is that of increased tubular ammonia-
↑NH3→↑C3b→↑C5
adhesion molecules, growth factors genesis by the residual functioning but hypertrophic tubules. Increased
tubular ammoniagenesis contributes to the immunologic injury by
activating the alternate complement pathway.
↑ Recruitment of Altered glomerular permeability with consequent proteinuria
Fibroblast proliferation appears to be important in the development of TIN in primary
∆Cell balance ↑Matrix deposition antigenically
activated cells glomerular diseases. By the same token, the proteinuria that
develops late in the course of primary TIN may contribute to
the tubular cell injury and aggravate the course of the disease.
Tubular Interstitial Interstitial In primary vascular diseases TIN has been attributed to ischemic
atrophy fibrosis infiltrates injury. In fact, hypertension is probably the most common cause of
TIN. The vascular lesions that develop late in the course of primary
TIN, in turn, can contribute to the progression of TIN. (From
Tubular dysfunction Eknoyan [3]; with permission.)
↓ Capillary perfusion
FIGURE 6-10
ROLE OF TUBULAR EPITHELIAL CELLS The infiltrating interstitial cells contribute
to the course TIN. However, increasing
evidence exists for a primary role of the
Chemoattractant Pro-inflammatory tubular epithelial cells in the recruitment
cytokines cytokines Cell surface markers Matrix proteins of interstitial infiltrating cells and in per-
petuation of the process. Injured epithelial
Monocyte chemo- Interleukin-6 (IL-6), IL-8 Human leukocyte antigen Collagen I, III, IV cells secrete a variety of cytokines that
attractant peptide-1 class II have both chemoattractant and pro-inflam-
Platelet-derived growth Laminin, fibronectin
Osteopontin factor- Intercellular adhesion matory properties. These cells express a
molecule-1 number of cell surface markers that enable
Chemoattractant Granulocyte -macrophage
lipids colony-stimulating factor Vascular cell adhesion them to interact with infiltrating cells.
Endothelin-1 Transforming growth
molecule-1 Injured epithelial cells also participate in
factor-1 the deposition of increased interstitial
RANTES matrix and fibrous tissue. Listed are
Tumor necrosis factor-
cytokines, cell surface markers, and matrix
components secreted by the renal tubular
From Palmer [4]; with permission. cell that may play a role in the develop-
ment of tubulointerstitial disease.
Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.7
C
6.8 Tubulointerstitial Disease
Macrophage
Virus
Protein TNF4
IL 1
TGF–3
PDGF
Lymphocyte GM–CSF
l
IFN
na
IL 4
Sig
IL 2
DO
HLA– DR
Sig
DP
na
Proliferating TH-Cell
l
Proliferating B-cell
Epithelial cell
IL 1
IL1 PDGF
IL6
IL7
IL8 Proliferation ↑↑
ICAM–1 IIFNβ
GM-CSF
G-CSF Differentiation ↓
M-CSF
Factor x MF I – MF III Interstitial fibrosis
Proximal P (30/7.3) PMF IV – PMF VI
Fibroblast
tubulus
Synthesis ↑↑ and Secretion ↑
of collagen
Fibrosin
P 53/6.1
FIGURE 6-12
Expression of human leukocyte antigen class II and adhesion pathways have been proposed to operate at different stages of the
molecules released by injured tubular epithelial cells, as well disease process. Each of these individual pathways usually is part
as by infiltrating cells, modulate and magnify the process to of a recuperative process that works in concert in response to
repair the injury (Figure 6-10). When the process becomes unre- injury. However, it is the loss of their controlling feedback in
sponsive to controlling feedback mechanisms, fibroblasts prolifer- chronic TIN that seems to account for the altered balance and
ate and increase fibrotic matrix deposition. The precise mecha- results in persistent cellular infiltrates, progressive fibrosis, and
nism of TIN remains to be identified. A number of pathogenetic tubular degeneration.
Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.9
120 900
800
700
80 600
500
60
400
300
40
200
20
100
0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12
A Interstitial disease (total score) B Interstitial disease (total score)
FIGURE 6-14
1200
Chronic GN Relationship of inulin clearance (A), maximum urine concentration
110 Acute GN (B), and ammonium excretion in response to an acute acid load (C)
PTIN to the severity of tubulointerstitial nephritis. A close correlation
Nephrosclerosis
100 exists between the severity of chronic TIN and impaired renal
tubular and glomerular function. Repeated evaluations of kidney
90 biopsy for the extent of tubulointerstitial lesions have shown a
close correlation with renal function test results in tests performed
80 before biopsy. These tests include those for inulin clearance, maximal
Ammonium excretion, µEq/min
ability to concentrate the urine, and ability to acidify the urine. This
70 correlation has been validated in a variety of renal diseases, including
primary and secondary forms of chronic TIN. (From Shainuck and
60 coworkers [5]; with permission.)
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12
C Interstitial disease (total score)
Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.11
Drugs
Analgesic Nephropathy
diuresis has provided protection from anal-
Acetaminophen Metabolism gesic-induced renal injury. Relative to plasma
levels, both acetaminophen (paracetamol)
p–phenetidine Meth–hemoglobin
n–OH–p–acetophenetidine
Sulfhemoglobin and its excretory conjugate attain significant
(fourfold to fivefold) concentrations in the
medulla and papilla, depending on the state
Phenactin of hydration of the animal studied. The
p–acetophenetidine toxic effect of these drugs apparently is
related to their intrarenal oxidation to reac-
tive intermediates that, in the absence of
Glucoronide Paracetamol Cytochrome Reactive toxic reducing substances such as glutathione,
sulfate n–acetyl–p–aminophenol P–450 metabolites
become cytotoxic by virtue of their capacity
Glutathione to induce oxidative injury. Salicylates also
are significantly (sixfold to thirteenfold
Covalent binding to Glutathione above plasma levels) concentrated in the
cellular sulfhydryl conjugate
medulla and papilla, where they attain a
level sufficient to uncouple oxidative phos-
Mercapturic
phorylation and compromise the ability of
Cell death cells to generate reducing substances. Thus,
acid
both agents attain sufficient renal medullary
concentration to individually exert a detri-
FIGURE 6-16 mental and injurious effect on cell function,
Metabolism of acetaminophen and its excretion by the kidney. Prolonged exposure to drugs which is magnified when they are present
can cause chronic TIN. Although a number of drugs (eg, lithium, cyclosporine, cisplatin, together. By reducing the medullary tonici-
and nitrosoureas) have been implicated, the more commonly responsible agents are anal- ty, and therefore the medullary concentra-
gesics. As a rule, the lesions of analgesic nephropathy develop in persons who abuse anal- tion of drug attained, water diuresis pro-
gesic combinations (phenacetin, or its main metabolite acetaminophen, plus aspirin, with or tects from analgesic-induced cell injury. A
without caffeine). Experimental evidence indicates that phenacetin, or acetaminophen, plus direct role of analgesic-induced injury can
aspirin taken alone are only moderately nephrotoxic and only at massive doses, but that the be adduced from the improvement of renal
lesions can be more readily induced when these drugs are taken together. In all experimental function that can occur after cessation of
studies the extent of renal injury has been dose-dependent and, when examined, water analgesic abuse.
6.12 Tubulointerstitial Disease
FIGURE 6-17
Pathogenesis of renal lesion associated Course of the renal lesions in analgesic nephropathy. The intrarenal
with analgesic abuse
distribution of analgesics provides an explanation for the medullary
location of the pathologic lesions of analgesic nephropathy. The initial
Cortex– normal lesions are patchy and consist of necrosis of the interstitial cells, thin
limbs of the loops of Henle, and vasa recta of the papilla. The col-
Outer medula– patchy tubular damage
a. tubular dilatation
lecting ducts are spared. The quantities of tubular and vascular
b. increased interstitial tissue basement membrane and ground substance are increased. At this
c. casts: pigment stage the kidneys are normal in size and no abnormalities have
Stage I Papilla– possible microscopic changes occurred in the renal cortex. With persistent drug exposure the
changes extend to the outer medulla. Again, the lesions are initially
patchy, involving the interstitial cells, loops of Henle, and vascular
bundles. With continued analgesic abuse, the severity of the inner
Cortex– normal medullary lesions increases with sclerosis and obliteration of the
Outer medula– increase in changes capillaries, atrophy and degeneration of the loops of Henle and
collecting ducts, and the beginning of calcification of the necrotic
Papilla– necrosis and atrophy foci. Ultimately, the papillae become entirely necrotic, with seques-
attached or separated tration and demarcation of the necrotic tissue. The necrotic papillae
Stage II
may then slough and are excreted into the urine or remain in situ,
Cortex– where they atrophy further and become calcified. Cortical scarring,
a. atrophy area overlying characterized by interstitial fibrosis, tubular atrophy, and periglo-
necrotic papilla
merular fibrosis, develops over the necrotic medullary segments.
b. hypertrophy
The medullary rays traversing the cortex are usually spared and
become hypertrophic, thereby imparting a characteristic cortical
Papilla– atrophic, necrotic nodularity to the now shrunken kidneys. Visual observation of these
Stage III configurational changes by computed tomography scan can be
extremely useful in the diagnosis of analgesic nephropathy.
1 2 3
CLINICAL FEATURES
a a a
b b b
c c c
Female predominance, 60–85%
Age, >30 y
Personality disorders: introvert, dependent, anxiety, neurosis, family instability
Addictive habits: smoking, alcohol, laxatives, psychotropics, sedatives a—cortical nephron b—juxta medullary nephron c—midcortical nephron
Cyclosporine
A B
FIGURE 6-21
A, Chronic TIN caused by cyclosporine. The arrow indicates the epithelial cell injury. Whereas these early lesions tend to be
characteristic hyaline-type arteriolopathy of cyclosporine nephro- reversible with cessation of therapy, an irreversible interstitial
toxicity. B, Patchy nature of chronic TIN caused by cyclosporine. fibrosis and mononuclear cellular infiltrates develop with pro-
Note the severe TIN on the right adjacent to an otherwise intact longed use of cyclosporine, especially at high doses. The irre-
area on the left. Tubulointerstitial nephritis has emerged as the versible nature of TIN associated with the use of cyclosporine
most serious side effect of cyclosporine. Cyclosporine-mediated and its attendant reduction in renal function have raised concerns
vasoconstriction of the cortical microvasculature has been implicated regarding the long-term use of this otherwise efficient immuno-
in the development of an occlusive arteriolopathy and tubular suppressive agent.
6.14 Tubulointerstitial Disease
Heavy Metals
Lead Nephropathy
exposure to lead are lead-based paints; lead leaked into food dur-
ing storage or processing, particularly in illegal alcoholic beverages
(moonshine); and increasingly, through environmental exposure
(gasoline and industrial fumes). This insidious accumulation of lead
in the body has been implicated in the causation of hyperuricemia,
hypertension, and progressive renal failure. Gout occurs in over
half of cases. Blood levels of lead usually are normal. The diagnosis
is established by demonstrating increased levels of urinary lead
after infusion of 1 g of the chelating agent erthylenediamine
tetraacetic acid (EDTA).
The renal lesions of lead nephropathy are those of chronic TIN.
Cases examined early, before the onset of end-stage renal disease,
show primarily focal lesions of TIN with relatively little interstitial
cellular infiltrates. In more advanced cases the kidneys are fibrotic
and shrunken. On microscopy, the kidneys show diffuse lesions of
TIN. As expected from the clinical features, hypertensive vascular
FIGURE 6-22 changes are prominent.
Lead nephropathy. Arrows indicate the characteristic intranuclear Other heavy metals associated with TIN are cadmium, silicon,
inclusions. Exposure to a variety of heavy metals results in devel- copper, bismuth, and barium. Sufficient experimental evidence and
opment of chronic TIN. Of these metals, the more common and some weak epidemiologic evidence suggest a possible role of organic
clinically important implicated agent is lead. Major sources of solvents in the development of chronic TIN.
FIGURE 6-24
Gross appearance of the kidney as a result of arteriolonephroscle-
rosis, showing the granular and scarified cortex.
Obstruction
FIGURE 6-25 (see Color Plate)
Chronic TIN secondary to vesicoureteral reflux (VUR). Clearly
demonstrated is an area that is fairly intact (lower left corner) adja-
cent to one that shows marked damage. Urinary tract obstruction,
whether congenital or acquired, is a common cause of chronic TIN.
Clinically, superimposed infection plays a secondary, adjunctive, and
definitely aggravating role in the progressive changes of TIN. How-
ever, the entire process can occur in the absence of infection.
As clearly demonstrated in experimental models of obstruction,
mononuclear inflammatory cell infiltration is one of the earliest
responses of the kidney to ureteral obstruction. The infiltrating
cells consist of macrophages and suppressor-cytotoxic lymphocytes.
The release of various cytokines by the infiltrating cells of the
hydronephrotic kidney appears to exert a significant modulating
role in the transport processes and hemodynamic changes seen
early in the course of obstruction. With persistent obstruction,
changes of chronic TIN set in within weeks. Fibrosis gradually
becomes prominent.
FIGURE 6-26
Gross appearance of a hydronephrotic kidney caused by
vesicoureteral reflux.
6.16 Tubulointerstitial Disease
Obstructive Nephropathy
FIGURE 6-27
Glomerular lesion of advanced chronic TIN secondary to vesicoureteral
reflux in a patient with massive proteinuria. Note the segmental
sclerosis of the glomerulus and the reactive proliferation of the
visceral epithelial cells. In persons with obstructive nephropathy,
the onset of significant proteinuria (>2g/d) is an ominous sign of
progressive renal failure. As a rule, most of these patients will have
coexistent hypertension, and the renal vasculature will show changes
of hypertensive arteriolosclerosis. The glomerular changes are ischemic
in nature. In those with significant proteinuria, the lesions are those
of focal and segmental glomerulosclerosis and hyalinosis. The
affected glomeruli commonly contain immunoglobulin M and C3
complement on immunofluorescent microscopy. The role of an
immune mechanism remains unclear. Autologous (Tamm-Horsfall
protein and brush-border antigen) or bacterial antigen derivatives
have been incriminated. Adaptive hemodynamic changes (hyperfil-
tration) in response to a reduction in renal mass, by the glomeruli
of remaining intact nephrons of the hydronephrotic kidney, also
have been implicated.
Hematopoietic Diseases
Sickle Hemoglobinopathy
that of chronic TIN. By far more prevalent and severe in patients
with sickle cell disease, variable degrees of TIN also are common
in those with the sickle cell trait, sickle cell–hemoglobin C disease,
or sickle cell–thalassemia disease. The predisposing factors that lead
to a propensity of renal involvement are the physicochemical prop-
erties of hemoglobin S that predispose its polymerization in an
environment of low oxygen tension, hypertonicity, and low pH.
These conditions are characteristic of the renal medulla and therefore
are conducive to the intraerythrocyte polymerization of hemoglobin S.
The consequent erythrocyte sickling accounts for development of
the typical vascular occlusive lesions. Although some of these changes
occur in the cortex, the lesions begin and are predominantly located
in the inner medulla, where they are at the core of the focal scarring
and interstitial fibrosis. These lesions account for the common
occurrence of papillary necrosis.
Examples of tubular functional abnormalities common and detectable
early in the course of the disease are the following: impaired concen-
FIGURE 6-28 trating ability, depressed distal potassium and hydrogen secretion,
The kidney in sickle cell disease. Note the tubular deposition of tubular proteinuria, and decreased proximal reabsorption of phos-
hemosiderin. The principal renal lesion of hemoglobinopathy S is phate, and increased secretion of uric acid and creatinine.
Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.17
Hematologic Diseases
Plasma Cell Dyscrasias
FIGURE 6-29 (see Color Plate)
A, Myeloma cast nephropathy. The arrow indicates a multinucleated
giant cell. B, Light chain deposition disease. Note the changes indica-
tive of chronic TIN and light chain deposition along the tubular
basement membrane (dark purple). C, Immunofluorescent stain
for light chain deposition along the tubular basement membrane.
The renal complications of multiple myeloma are a major risk factor
in the morbidity and mortality of this neoplastic disorder. Whereas
the pathogenesis of renal involvement is multifactorial (hypercal-
cemia and hyperuricemia), it is the lesions that result from the
excessive production of light chains that cause chronic TIN. These
lesions are initiated by the precipitation of the light chain dimers in
the distal tubules and result in what has been termed myeloma cast
nephropathy. The affected tubules are surrounded by multinucleated
giant cells. Adjoining tubules show varying degrees of atrophy. The
A propensity of light chains to lead to myeloma cast nephropathy
appears to be related to their concentration in the tubular fluid,
the tubular fluid pH, and their structural configuration. This
propensity accounts for the observation that increasing the flow
rate of urine or its alkalinization will prevent or reverse the casts
in their early stages of formation.
Direct tubular toxicity of light chains also may contribute to
tubular injury. Light chains appear to be more injurious than are
light chains. Binding of human and light chains to human
and rat proximal tubule epithelial cell brush-border membrane has
been demonstrated. Epithelial cell injury associated with the
absorption of these light chains in the proximal tubules has been
implicated in the pathogenesis of cortical TIN. Another mechanism
relates to the perivascular deposition of paraproteins, either as
amyloid fibrils that are derived from chains or as fragments of
light chains that are derived from kappa chains, and produce the
so-called light chain deposition disease.
B Of the various lesions, myeloma cast nephropathy appears to be
the most common, being observed at autopsy in one third of cases,
followed by amyloid deposition, which is present in 10% of cases.
Light chain deposition is relatively rare, being present in less than
5% of cases.
C
6.18 Tubulointerstitial Disease
Metabolic Disorders
Hyperuricemia
A B
FIGURE 6-30
A, Intratubular deposits of uric acid. B, Gouty tophus in the renal hyperacidity of their urine caused by an inherent abnormality in
medulla. The kidney is the major organ of urate excretion and a the ability to produce ammonia. The acidity of urine is important
primary target organ affected in disorders of its metabolism. Renal because uric acid is 17 times less soluble than is urate. Therefore,
lesions result from crystallization of urate in the urinary outflow uric acid facilitates precipitation in the distal nephron of persons
tract or the renal parenchyma. Depending on the load of urate, who do not overproduce uric acid but who have a persistently
one of three lesions result: acute urate nephropathy, uric acid acidic urine.
nephrothiasis, or chronic urate nephropathy. Whereas any of these The previous notion that chronic renal disease was common in
lesions produce tubulointerstitial lesions, it is those of chronic patients with hyperuricemia is now considered doubtful in light of
urate nephropathy that account for most cases of chronic TIN. prolonged follow-up studies of renal function in persons with
The principal lesion of chronic urate nephropathy is due to hyperuricemia. Renal dysfunction could be documented only when
deposition of microtophi of amorphous urate crystals in the inter- the serum urate concentration was more than 10 mg/dL in women
stitium, with a surrounding giant-cell reaction. An earlier change, and more than 13 mg/dL in men for prolonged periods. The deteri-
however, probably is due to the precipitation of birefringent uric oration of renal function in persons with hyperuricemia of a lower
acid crystals in the collecting tubules, with consequent tubular magnitude has been attributed to the higher than expected occur-
obstruction, dilatation, atrophy, and interstitial fibrosis. The renal rence of concurrent hypertension, diabetes mellitus, abnormal lipid
injury in persons who develop lesions has been attributed to metabolism, and nephrosclerosis.
Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.19
Hyperoxaluria
A B
FIGURE 6-31 (see Color Plate)
A, Calcium oxalate crystals (arrow) seen on light microscopy. B, Dark chronic. As a result, interstitial fibrosis, tubular atrophy, and dilation
field microscopy. When hyperoxaluria is sudden and massive (such as result in chronic TIN with progressive renal failure. The propensity
after ethylene glycol ingestion) acute renal failure develops. Other- for recurrent calcium oxalate nephrolithiasis and consequent obstruc-
wise, in most cases of hyperoxaluria the overload is insidious and tive uropathy contribute to the tubulointerstitial lesions.
Granulomatous Diseases
Malacoplakia
hallmark of certain forms of tubulointerstitial
3 5 disease. The best-known form is that of
sarcoidosis. Interstitial granulomatous reac-
tions also have been noted in renal tuberculo-
sis, xanthogranulomatous pyelonephritis,
1 2 7 renal malacoplakia, Wegener’s granulo-
matosis, renal candidiasis, heroin abuse,
hyperoxaluria after jejunoileal bypass
surgery, and an idiopathic form in associa-
tion with anterior uveitis.
The inflammatory lesions of malacoplakia
principally affect the urinary bladder but
may involve other organs, most notably the
kidneys. The kidney lesions may be limited
to one focus or may be multifocal. In three
fourths of cases the renal involvement is
4 6 multifocal, and in one third of cases both
kidneys are involved. The lesions are nodular,
well-demarcated, and variable in size. They
FIGURE 6-32 may coalesce, developing foci of suppura-
Schematic representation of the forms and course of renal involvement by malacoplakia: tion that may become cystic or calcified.
1, normal kidney; 2, enlarged kidney resulting from interstitial nephritis without nodularity; The lesions usually are located in the cortex
3, unifocal nodular involvement; 4, multifocal nodular involvement; 5, abscess formation but may be medullary and result in papillary
with perinephric spread of malacoplakia; 6, cystic lesions; and 7, atrophic multinodular necrosis. (From Dobyan and coworkers [7];
kidney after treatment. Interstitial granulomatous reactions are a rare but characteristic with permission.)
6.20 Tubulointerstitial Disease
Endemic Diseases
in a geographic area bordering the Danube River as it traverses
Romania, Bulgaria, and the former Yugoslavia. The cause of
Balkan nephropathy is unknown; however, it has been attributed
to genetic factors, heavy metals, trace elements, and infectious
agents. The disease evolves in emigrants from endemic regions,
suggesting a role for inheritance or the perpetuation of injury
sustained before emigration.
Initially thought to be restricted to Scandinavian countries, and
thus termed Scandinavian acute hemorrhagic interstitial nephritis,
Nephropathia epidemica has been shown to have a more universal
occurrence. It therefore has been more appropriately renamed hem-
orrhagic fever with renal syndrome. As a rule the disease presents
as a reversible acute tubulointerstitial nephritis but can progress to
a chronic form. It is caused by a rodent-transmitted virus of the
Hantavirus genus of the Bunyaviridae family, the so-called Hantaan
virus. Humans appear to be infected by respiratory aerosols conta-
minated by rodent excreta. Antibodies to the virus are detected in
FIGURE 6-33 the serum, and viruslike structures have been demonstrated in the
Hemorrhagic TIN associated with Hantavirus infection. Two kidneys of persons infected with the virus.
endemic diseases in which tubulointerstitial lesions are a predomi- Tubulointerstitial nephropathy caused by viral infection also has
nant component are Balkan nephropathy and nephropathia epi- been reported in polyomavirus, cytomegalovirus, herpes simplex
demica. Endemic Balkan nephropathy is a progressive chronic virus, human immunodeficiency virus, infectious mononucleosis,
tubulointerstitial nephritis whose occurrence is mostly clustered and Epstein-Barr virus.
Hereditary Diseases
Hereditary Nephritis
A B
FIGURE 6-34
A, Interstitial foam cells in Alport’s syndrome. B, Late phase Alport’s associated epithelial cell proliferation account for cyst formation. It
syndrome showing chronic TIN and glomerular changes in a patient is the continuous growth of cysts and their progressive dilation that
with massive proteinuria. Tubulointerstitial lesions are a prominent cause pressure-induced ischemic injury, with consequent TIN of the
component of the renal pathology of a variety of hereditary diseases adjacent renal parenchyma.
of the kidney, such as medullary cystic disease, familial juvenile Tubulointerstitial lesions also are a salient feature of inherited
nephronophthisis, medullary sponge kidney, and polycystic kidney diseases of the glomerular basement membrane. Notable among
disease. The primary disorder of these conditions is a tubular defect them are those of hereditary nephritis or Alport’s syndrome, in
that results in the cystic dilation of the affected segment in some which a mutation in the encoding gene localized to the X chromo-
patients. Altered tubular basement membrane composition and some results in a defect in the -5 chain of type IV collagen.
Renal Interstitium and Major Features of Chronic Tubulointerstitial Nephritis 6.21
Papillary Necrosis
A B
FIGURE 6-35
A, Renal papillary necrosis. The arrow points to the either one or both kidneys. The lesions are bilateral in
region of a sloughed necrotic papilla. B, Whole mount of most patients. In patients with involvement of one kid-
a necrotic papilla. Arrows delineate focal necrosis princi- ney at the time of initial presentation, RPN will devel-
pally affecting the medullary inner stripe. Renal papillary op in the other kidney within 4 years, which is not
necrosis (RPN) develops in a variety of diseases that unexpected because of the systemic nature of the dis-
cause chronic tubulointerstitial nephropathy in which the eases associated with RPN. RPN may be unilateral in
lesion is more severe in the inner medulla. The basic patients in whom predisposing factors (such as infec-
lesion affects the vasculature with consequent focal or tion and obstruction) are limited to one kidney.
diffuse ischemic necrosis of the distal segments of one or Azotemia may be absent even in bilateral papillary
more renal pyramids. In the affected papilla, the sharp necrosis, because it is the total number of papillae
demarcation of the lesion and coagulative necrosis seen involved that ultimately determines the level of renal
in the early stages of the disease closely resemble those of insufficiency that develops. Each human kidney has an
infarction. The fact that the necrosis is anatomically lim- average of eight pyramids, such that even with bilateral
ited to the papillary tips can be attributed to a variety of RPN affecting one papilla or two papillae in each kid-
features unique to this site, especially those affecting the ney, sufficient unaffected renal lobules remain to main-
vasculature. The renal papilla receives its blood supply tain an adequate level of renal function.
from the vasa recta. Measurements of medullary blood As a rule, RPN is a disease of an older age group,
flow notwithstanding, it should be noted that much of the average age of patients being 53 years. Nearly half
the blood flow in the vasa recta serves the countercur- of cases occur in persons over 60 years of age. More
rent exchange mechanism. Nutrient blood supply is pro- than 90% of cases occur in persons over 40 years of
vided by small capillary vessels that originate in each age, except for those caused by sickle cell hemoglo-
given region. The net effect is that the blood supply to binopathy. RPN is much less common in children, in
the papillary tip is less than that to the rest of the medul- whom the chronic conditions associated with papil-
la, hence its predisposition to ischemic necrosis. lary necrosis are rare. However, RPN does occur in
The necrotic lesions may be limited to only a few of children in association with hypoxia, dehydration,
the papillae or may involve several of the papillae in and septicemia.
6.22 Tubulointerstitial Disease
FIGURE 6-37
Renal Papillary Necrosis – Medullary Form Schematic of the progressive stages of the
medullary form of renal papillary necrosis
Normal Lesion Pyelogram
and their associated radiologic appearance
Early focal, necrosis Normal calyx seen on intravenous pyelography. In par-
of medullary inner tial papillary necrosis the lesion begins as
stripe. focal necrosis within the substance of the
medullary inner stripe. The lesion pro-
Progressive necrosis, Normal calyx gresses by coagulative necrosis to form a
coalescence of necrotic sinus to the papillary tip, with subsequent
areas. Swelling. Mucosa extrusion or resorption of the sequestered
normal. necrotic tissue. The medullary form of
papillary necrosis is commonly encoun-
Mucosal break. Sinus
tered in persons with sickle cell hemoglo-
Sequestration
binopathy. The incidence of radiographi-
and sinus formation.
cally demonstrative papillary necrosis is
Progressive sequestration, Irregular sinus as high as 33% to 65% in such persons.
extrusion, or resorption
of necrotic tissue.
FIGURE 6-39
Spectrum of Renal Papillary Necrosis
Spectrum and overlap of diseases principally associated with renal papillary necrosis
(RPN). Although each disease can cause RPN, it is their coexistence (darkly shaded areas)
that increases the risk, which is even greater after the onset of infection (lightly shaded
Obstruction areas). In most cases of RPN, more than one of the conditions associated with RPN is pre-
sent. Thus, in most cases, the lesion seems to be multifactorial in origin. The pathogenesis
of the lesion may be considered the result of an overlapping phenomenon, in which a com-
bination of detrimental factors appear to operate in concert to cause RPN. As such,
Sickle whereas each of the conditions alone can cause RPN, the coexistence of more than one
Diabetes Infection
Hgb predisposing factor in any one person significantly increases the risk for RPN. The contri-
bution of any one of these factors to RPN would be expected to differ among individuals
and at various periods during the course of the disease. To the extent that the natural
course of RPN itself predisposes patients to development of infection of necrotic foci and
Analgesic obstruction by sloughed papillae, it may be difficult to assign a primary role for any of
abuse
these processes in an individual patient. Furthermore, the occurrence of any of these fac-
tors (necrosis, obstruction, or infection) may itself initiate a vicious cycle that can lead to
another of these factors and culminate in RPN.
References
1. Bohman S: The ultrastructure of the renal interstitium. Contemp 5. Schainuck LI, Striker GE, Cutler RE, Benditt EP: Structural-functional
Issues Nephrol 10:1–34, 1983. correlations in renal disease II. The correlations. Hum Pathol 1970,
2. Lemley KV, Kriz W: Anatomy of the renal interstitium. Kidney Int 1:631–641.
1991, 39:370–381. 6. DeBroe ME, Elseviers MM: Analgesic nephropathy. N Engl J Med
3. Eknoyan G: Chronic tubulointerstitial nephropathies. In Diseases of 1998, 338:446–451.
the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: 7. Dobyan DC, Truong LD, Eknoyan G: Renal malacoplakia reap-
Little Brown; 1997:1983–2015. praised. Am J Kidney Dis 1993, 22:243–252.
4. Palmer BF: The renal tubule in the progression of chronic renal fail- 8. Eknoyan G, Qunibi WY, Grissom RT, et al.: Renal papillary necrosis:
ure. J Invest Med 1997, 45:346–361. an update. Medicine 1982, 61:55–73.
6.24 Tubulointerstitial Disease
Selected Bibliography
Renal Interstitium Drugs
Neilson EG: Symposium on the cell biology of tubulointerstitium. Kidney Boton R, Gaviria M, Battle DC: Prevalence, pathogenesis, and treatment
Int 1991, 39:369–556. of renal dysfunction associated with chronic lithium therapy. Am J
Strutz F, Mueller GA: Symposium on Renal Fibrosis: prevention and pro- Kidney Dis 1990, 10:329–345.
gression. Kidney Int 1996, 49(suppl 54):1–90. Myer BD, Newton L: Cyclosporine induced chronic nephropathy: an obliter-
ative microvascular renal injury. J Am Soc Nephrol 1991, 2(suppl 1):4551.
Chronic Tubulointerstitial Nephritis
Eknoyan G, McDonald MA, Appel D, Truong LD: Chronic tubulointersti- Heavy Metals
tial nephritis: correlation between structural and functional findings. Batuman V: Lead nephropathy, gout, hypertension. Am J Med Sci 1993,
Kidney Int 1990, 38:736–743. 305:241–247.
Jones CL, Eddy AA: Tubulointerstitial nephritis. Ped Nephrol 1992, Batuman V, Maesaka JK, Haddad B et al.: Role of lead in gouty nephropathy.
6:572–586. N Engl J Med 1981, 304:520–523.
Nath KA: Tubulointerstitial changes as a major determinant in progression Fowler BA: Mechanisms of kidney cell injury from metals. Environ Health
of renal damage. Am J Kidney Dis 1992, 20:1–17. Perspec 1993, 100:57–63.
Hu H: A 50-year follow-up of childhood plumbism. Hypertension, renal
Pathogenesis function and hemoglobin levels among survivors. Am J Dis Child 1991,
Bohle A, Muller GA, Wehrmann M et al.: Pathogenesis of chronic renal 145:681–687.
failure in the primary glomerulopathies, renal vasculopathies and
Staessen JA, Lauwerys RR, Buchet JP et al.: Impairment of renal function
chronic interstitial nephritides. Kidney Int 1996, 49(suppl 54):2–9.
with increasing lead concentrations in the general population. N Engl J
Dodd S: The pathogenesis of tubulointerstitial disease and mechanisms of Med 1992, 327:151–156.
fibrosis. Curr Top Pathol 1995, 88:117–143.
Vedeen RP: Environmental renal disease: lead. cadmium, and Balkan
Haggerty DT, Allen DM: Processing and presentation of self and foreign endemic nephropathy. Kidney Int 34(suppl):4–8.
antigens by the renal proximal tubule. J Immunol 1992, 148:2324–2331.
Nath KA: Reshaping the interstitium by platelet-derived growth factor. Impli-
Ischemic Vascular Disease
cations for progressive renal disease. Am J Path 1996, 148:1031–1036.
Freedman BI, Ishander SS, Buckalew VM et al.: Renal biopsy findings in
Sedor JR: Cytokines and growth factors in renal injury. Semin Nephrol presumed hypertensive nephrosclerosis. Am J Nephrol 1994, 14:90–94.
1992, 12:428–440.
Meyrier A, Simon P: Nephroangiosclerosis and hypertension: things are
Wilson CB: Nephritogenic tubulointers-titial antigens. Kidney Int 1991, not as simple as you might think. Nephrol Dial Transplant 1996,
39:501–517. 11:2116–1220.
Yamato T, Noble NA, Miller DE, Border WA: Sustained expression of Schlesinger SD, Tankersley MR, Curtis JJ: Clinical documentation of end
TGF-B1 underlies development of progressive kidney fibrosis. Kidney stage renal disease due to hypertension. Am J Kidney Dis 1994,
Int 1994, 45:916–927. 23:655–660.
T
he concern of renal specialists for urinary tract infections
(UTIs) had declined with the passage of time. This trend is now
being reversed, owing to new imaging techniques and to sub-
stantial progress in the understanding of host-parasite relationships,
of mechanisms of bacterial uropathogenicity, and of the inflammatory
reaction that contributes to renal lesions and scarring.
UTIs account for more than 7 million visits to physicians’ offices and
well over 1 million hospital admissions in the United States annually
[1]. French epidemiologic studies evaluated its annual incidence at
53,000 diagnoses per million persons per year, which represents
1.05% to 2.10% of the activity of general practitioners. In the United
States, the annual number of diagnoses of pyelonephritis in females
was estimated to be 250,000 [2].
The incidence of UTI is higher among females, in whom it commonly
occurs in an anatomically normal urinary tract. Conversely, in males
and children, UTI generally reveals a urinary tract lesion that must be
identified by imaging and must be treated to suppress the cause of
infection and prevent recurrence. UTI can be restricted to the bladder
(essentially in females) with only superficial mucosal involvement, or
it can involve a solid organ (the kidneys in both genders, the prostate
in males). Clinical signs and symptoms, hazards, imaging, and treatment
of various types of UTIs differ. In addition, the patient’s background
helps to further categorize UTIs according to age, type of urinary tract
lesion(s), and occurrence in immunocompromised patients, especially
with diabetes or pregnancy. Such various forms of UTI explain the
wide spectrum of treatment modalities, which range from ambulatory,
single-dose antibiotic treatment of simple cystitis in young females, to
rescue nephrectomy for pyonephrosis in a diabetic with septic shock.
This chapter categorizes the various forms of UTI, describes progress
in diagnostic imaging and treatment, and discusses recent data on
bacteriology and immunology. CHAPTER
7
7.2 Tubulointerstitial Disease
Diagnosis
would be the only way of proving it. Urinary tract infection
(UTI) cannot be identified simply by the presence of bacteria in
a voided specimen, as micturition flushes saprophytic urethral
organisms along with the urine. Thus a certain number of colony-
forming units of uropathogens are to be expected in the urine
sample. Midstream collection is the most common method of
urine sampling used in adults. When urine cannot be studied
without delay, it must be stored at 4ºC until it is sent to the
bacteriology laboratory. The urine test strip is the easiest means
of diagnosing UTI qualitatively. This test detects leukocytes and
nitrites. Simultaneous detection of the two is highly suggestive of
UTI. This test is 95% sensitive and 75% specific, and its negative
A B C predictive value is close to 96% [3]. The test does not, however,
detect such bacteria as Staphyloccocus saprophyticus, a strain
responsible for some 3% to 7% of UTIs. Thus, treating UTI sole-
FIGURE 7-1 ly on the basis of test strip risks failure in about 15% of simple
Urine test strips. Normal urine is sterile, but suprapubic aspira- community-acquired infections and a much larger proportion of
tion of the bladder, which is by no means a routine procedure, UTIs acquired in a hospital.
FIGURE 7-3
CAUSES OF ASEPTIC LEUKOCYTURIA Leukocyturia. A significant number of leukocytes (more than 10,000
per milliliter) is also required for the diagnosis of urinary tract infec-
tion, as it indicates urothelial inflammation. Abundant leukocyturia
Self-medication before urine culture can originate from the vagina and thus does not necessarily indicate
Sample contamination by cleansing solution aseptic urinary leukocyturia [1]. Bacterial growth without leukocy-
Vaginal discharge
turia indicates contamination at sampling. Significant leukocyturia
without bacterial growth (aseptic leukocyturia) can develop from
Urinary stone
various causes, among which self-medication before urinalysis is the
Urinary tract tumor
most common.
Chronic interstitial nephritis (especially due to analgesics)
Fastidious microorganisms requiring special culture medium (Ureaplasma urealyticum,
Chlamydia, Candida)
Bacteriology
FIGURE 7-4
A. MAIN MICROBIAL STRAINS RESPONSIBLE Principal pathogens of urinary tract infection (UTI). A and B, Most
FOR URINARY TRACT INFECTION pathogens responsible for UTI are enterobacteriaceae with a high pre-
dominance of Escherichia coli. This is especially true of spontaneous
UTI in females (cystitis and pyelonephritis). Other strains are less
First Episode or Relapse Due to common, including Proteus mirabilis and more rarely gram-positive
Microbial Strain Delayed Relapse Early Reinfection microbes. Among the latter, Staphylococcus saprophyticus deserves
special mention, as this gram-positive pathogen is responsible for 5%
Escherichia coli 71%–79% 60% to 15% of such primary infections, is not detected by the leukocyte
Proteus mirabilis 1.1%–9.7% 15% esterase dipstick, and is resistant to antimicrobial agents that are
Klebsiella — 20% active on gram-negative rods.
Enterobacter 1.0%–9.2% — C, Acute simple pyelonephritis is a common form of upper UTI
Enterococcus 1.0%–3.2% — in females and results from the encounter of a parasite and a host.
Staphylococcus saprophyticus 3%–7% — In the absence of urologic abnormality, this renal infection is most-
Other species 2%–6% 5% ly due to uropathogenic strains of bacteria [5,6], a majority of
cases to community-acquired E. coli. The clinical picture consists
of fever, chills, renal pain, and a general discomfort. Tissue inva-
sion is associated with a high erythrocyte sedimentation rate and
C-reactive protein level well above 2 mg/dL.
100 Minimum
Maximum
Other E. coli
5% 60%
Percent
50
P. mirabilis
15%
Klebsiella
20%
0
E. coli P. mirabilis Klebsiella Enterococcus S. saprophyticus Other
B Enterobacter C
7.4 Tubulointerstitial Disease
Escherichia coli
Fimbriae P S Type 1
Flagella
Hemolysin
Aerobactin
+
Fe3+ Na+ Na
Erythrocyte
FIGURE 7-6
An electron microscopic view of an Escherichia coli organism
FIGURE 7-5 showing the fimbriae (or pili) bristling from the bacterial cell.
Bacterial uropathogenicity plays a major role in host-pathogen inter-
actions that lead to urinary tract infection (UTI). For Escherichia
coli, these factors include flagella necessary for motility, aerobactin
necessary for iron acquisition in the iron-poor environment of the
urinary tract, a pore-forming hemolysin, and, above all, presence of
adhesins on the bacterial fimbriae, as well as on the bacterial cell
surface. (From Mobley et al. [7]; with permission.)
FIGURE 7-8
Proteus mirabilis Staghorn calculi.
Fimbriae MR/P PMF ATF NAF Ammonium genera-
tion alkalinizes the
urine, creating
Urease
Deaminase [Keto acid]3Fe3+ conditions favorable
Flagella for build-up of
2+
Ni Amino acid
voluminous struvite
Urea NH3+CO2 stones, which can
Na+ progressively invade
IgA protease Hemolysin
the entire pyeloca-
lyceal system, form-
ing staghorn calculi.
These stones are an
Renal epithelial cell endless source of
microbes, and the
urinary tract
obstruction per-
petuates infection.
FIGURE 7-7
Proteus mirabilis is endowed with other nonfimbrial virulence factors,
including the property of secreting urease, which splits urea into NH3
and CO2.
Urinary Tract Infection 7.5
FimA
PapK ~100
FimA
Rigid fiber
PapA
Adhesins
PapH
FIGURE 7-10
Pilin
Uropathogenic strains of Escherichia coli readily adhere to epithelial
Minor subunits
Adhesin cells. This figure shows two epithelial cells incubated in urine infected
with E. coli–carrying pap adhesins. Numerous bacteria are scattered
on the epithelial cell membranes. About half of all cases of cystitis are
FIGURE 7-9 due to uropathogenic strains of E. coli–carrying adhesins. Females
Schematic representation of morphology and composition of type P with primary pyelonephritis and no urologic abnormality harbor a
and type 1 adhesive structures. Bacterial adhesins are paramount in uropathogenic strain in almost 100% of cases [5].
fostering attachment of the bacteria to the mucous membranes of the
perineum and of the urothelium. There are several molecular forms
of adhesins. The most studied is the pap G adhesin, which is located
at the tip of the bacterial fimbriae (or pili). This lectin recognizes
binding site conformations provided by oligosaccharide sequences
present on the mucosal surface [8].
FIGURE 7-11
APPROPRIATE ANTIBIOTICS FOR URINARY TRACT INFECTIONS Appropriate antibiotics for urinary tract
infections (UTI). An appropriate antibiotic
for treating UTI must be bactericidal and
Antibiotics General Indications Pregnancy Prophylaxis conform to the following general specifica-
tions: 1) its pharmacology must include, in
Aminoglycosides + +* - case of oral administration, rapid absorp-
Aminopenicillins +† + - tion and attainment of peak serum concen-
Carboxypenicillins + + -
trations; 2) its excretion must be predomi-
Ureidopenicillins + + -
nantly renal; 3) it must achieve high con-
Quinolones +‡ - +
centrations in the renal or prostate tissue;
Fluoroquinolones +§ - +
4) it must cover the usual spectrum of
Cephalosporins
First generation +¶ + +‡ enterobacteria with reasonable chance of
Second generation + + - being effective on an empirical basis.
Third generation + + - Excluding special considerations for child-
Monobactams + + - hood and pregnancy, several classes of
Carbapenem + + - antibiotics fulfill these specifications and
Cotrimoxazole + - +‡ can be used alone or in combination. The
Fosfomycin trometamole +** - - choice also depends on market availability,
Nitroturantoin +†† - +
cost, patient tolerance, and potential for
inducing emergence of resistant strains.
* Aminoglycosides should not be prescribed during pregnancy except for very severe infection and for the shortest
possible duration.
With the exception of amoxicillin plus clavulanic acid, aminopenicillins should not be prescribed as first-line treatment,
owing to the frequency of primary resistance to this class of antibiotics.
‡ According to antibiotic sensitivity tests.
§ Fluoroquinolones carry a risk of tendon rupture (especially Achilles tendon).
¶ Oral administration only.
** Single-dose treatment of cystitis.
†† Simple cystitis; not pyelonephritis or prostatitis.
7.6 Tubulointerstitial Disease
Clinical
Kidney or prostate infection is marked by fever over 38°C, chills, and pain. The patient appears acutely ill.
Laboratory
Tissue invasion is invariably accompanied by an erythrocyte sedimentation rate over 20 mm/h and serum C-reactive protein
levels over 2.0 mg/dL. Blood cultures grow in 30%–50% of cases, which in an immunocompetent host indicates simply bac-
teremia, not septicemia. This reflects easy permeability between the urinary and the venous compartments of the kidney.
Imaging
When indicated, ultrasound imaging, tomodensitometry, and scintigraphy provide objective evidence of pyelonephritis.
In case of vesicoureteral reflux, urinary tract infection necessarily involves the upper urinary tract.
FIGURE 7-17
Criteria for tissue invasion.
FIGURE 7-16
Renal abscess formation. As specified else-
where, renal abscess due to enterobacteri-
aceae (as opposed to hematogenous renal
abscess, often of staphylococcal origin) can
be considered a severe form of pyelonephritis
with renal tissue liquefaction, ending in a
walled-off cavity.
FIGURE 7-18
An episode of urinary tract infection (UTI) should prompt considera-
tion of whether it involves a normal urinary tract or, alternatively, if
it is a complication of an anatomic malformation. This is especially
true of relapsing UTI in both genders, and this hypothesis should be
systematically raised in males and in children.
Recurrent cystitis in females can be explained by hymeneal scars
that pull open the urethral outlet during intercourse. Although
rarely, other malformations that promote recurrent female cystitis
are occasionally discovered, such as urethral diverticula (arrows).
Finally, it should be recalled that recurrent or chronic cystitis in an
older woman can also reveal an unsuspected bladder tumor.
7.8 Tubulointerstitial Disease
FIGURE 7-20
Urethrocystogram of a man following acute prostatitis. In males,
acute prostatitis may reveal urethral stenosis. Urethral stenosis is a
good explanation for acute prostatitis. The beaded appearance of the
stenosis (arrow) suggests an earlier episode of gonorrheal urethritis.
A B
FIGURE 7-22
Cystogram demonstrating left ureteral reflux (A). The conse- the adjacent renal tissue. The calyceal cavities are very close to the
quences on the left kidney (B) consist of calyceal distension and a renal capsule, indicating complete cortical atrophy. This picture is
clubbed appearance due to the destruction of the papillae and of typical of chronic pyelonephritis secondary to vesicoureteral reflux.
Urinary Tract Infection 7.9
Imaging
FIGURE 7-27
When acute pyelonephritis occurs in a sound, immunocompetent
female with no history of urologic disease, imaging can be limited
to a plain abdominal film (to rule out renal and ureteral stones) and
renal ultrasonography. Ultrasonography typically discloses a swollen FIGURE 7-28
kidney with loss of corticomedullary differentiation, denoting renal The ultrasound procedure occasionally discloses the cavity of a small
inflammatory edema. Images corresponding to the infected zones renal abscess, a common complication of acute pyelonephritis, even
are more dense than normal renal tissue (arrows). in simple forms.
A B
FIGURE 7-29
Computed tomodensitometry. Simple pyelonephritis does not areas in an edematous, swollen kidney. The pathophysiology of
require much imaging; however, it should be remembered that there hypodense images has been elucidated by animal experiments in
is no correlation between the severity of the clinical picture and the the primates [11] which have shown that renal infection with
renal lesions. Therefore, a diagnosis of “simple” pyelonephritis at uropathogenic Escherichia coli induces intense vasoconstriction.
first contact can be questioned when response to treatment is not Computed tomodensitometric images of acute pyelonephritis can
clear after 3 or 4 days. This is an indication for uroradiologic imag- take various appearances. The most common findings consist of
ing, such as renal tomodensitometry followed by radiography of the one or several wedge-shaped or streaky zones of low attenuation
urinary tract while it is still opacified by the contrast medium. extending from papilla to cortex, A. Hypodense images can be
The typical picture of acute pyelonephritis observed after con- round, B. On this figure, the infected zone reaches the renal cortex
trast medium injection [10] consists of hypodensities of the infected and is accompanied with adjacent perirenal edema. Several such
(Continued on next page)
Urinary Tract Infection 7.11
C D
FIGURE 7-29 (Continued)
images can coexist in the same kidney, C.
Marked juxtacortical, circumscribed hypo-
dense zones, bulging under the renal cap-
sule, D, usually correspond to lesions close
to liquefaction and should be closely fol-
lowed, as they can lead to abscess forma-
tion and opening into the perinephric space,
E and F. (E and F from Talner et al. [10];
with permission.)
E F
FIGURE 7-30
100 Comparative sensitivity of four diagnostic imaging techniques for
acute pyelonephritis. Renal cortical scintigraphy using 99mTc-dimethyl
86
succinic acid (DMSA) or 99mTc-gluconoheptonate (GH) is very sensi-
75 tive for diagnosing acute pyelonephritis. It entails very little irradiation
as compared with conventional radiography using contrast medium.
Some nephrologists consider 99mTc-DMSA cortical scintigraphy as the
Percent
0
Renal CT scan Ultrasonography IVP
scintigraphy (intravenous
pyelography)
7.12 Tubulointerstitial Disease
A B
FIGURE 7-32
Renal pathology in acute pyelonephritis. Renal pathology of human the diabetes patient whose kidney is shown here. A, The surgically
acute pyelonephritis is quite comparable to what is observed in removed kidney is swollen, and its surface shows whitish zones.
experimental pyelonephritis in primates [11]. However, our knowl- B, A section of the same organ shows white suppurative areas (scat-
edge of renal pathology in this condition in humans is based mainly tered with small abscesses) extending eccentrically from the medulla
on the most catastrophic cases, which required nephrectomy, like to the cortex. There also were sloughed papillae (see Fig. 7-37).
A B
FIGURE 7-33
Histologic appearance of pyelonephritic kidney. A, The renal tissue comprising a majority of polymorphonuclear leukocytes, induces
is severely edematous and interspersed with inflammatory cells and tubular destruction and is accompanied by a typical infectious cast
hemorrhagic streaks. B, On another section, severe inflammation, in a tubular lumen (arrow).
Urinary Tract Infection 7.13
FIGURE 7-34
Clinical picture compatible A general algorithm for the investigation
with acute pyelonephritis (APN) and treatment of acute pyelonephritis.
Treatment of acute pyelonephritis is based
Urine culture and cytology on antibiotics selected from the list in
ESR CRP Figure 7-11. Preferably, initial treatment is
based on parenteral administration. It is
Renal Negative.
debatable whether common forms of sim-
Positive
scintigraphy Reconsider Initial
ple pyelonephritis initially require both an
and/or CT scan diagnosis of APN work-up aminoglycoside and another antibiotic.
Initial parenteral treatment for an average
No renal lesion. Renal lesions. Previous No previous of 4 days should be followed by about 10
Seek other Maintain history of history of days of oral therapy based on bacterial
infection diagnosis of APN upper UTI upper UTI sensitivity tests. It is strongly recommended
that urine culture be carried out some 30
to 45 days after the end of treatment, to
Abnormal. Yes Possible urinary Plain abdominal verify that bacteriuria has not recurred.
Call urologist IVP tract obstruction radiograph APN—acute pyelonephritis; ESR—erythro-
or stone? Ultrasonography cyte sedimentation rate; CRP—C-reactive
No protein; UTI—urinary tract infection;
Secondary APN Primary APN IVP—intravenous pyelography. (From
Treat Treat Normal Drug therapy only
cause infection Meyrier and Guibert [5]; with permission.)
Day
Start treatment with first-line antibiotics 1
Day
End treatment 15
A B
FIGURE 7-36
Renal computed tomography (CT). In addition to ultrasound the renal parenchyma, A, or bulge outward under the renal capsule,
examination, CT is the best way of detecting and localizing a risking rupture into Gerota’s space, B.
renal abscess. The abscess cavity can be contained entirely within
Urinary Tract Infection 7.15
A B
FIGURE 7-37
Urinary tract infection (UTI) in the immunocompromised host. UTI
results from the encounter of a pathogen and a host. Natural defenses
against UTI rest on both cellular and humoral defense mechanisms.
These defense mechanisms are compromised by diabetes, pregnancy,
and advanced age. Diabetic patients often harbor asymptomatic bac-
teriuria and are prone to severe forms of pyelonephritis requiring
immediate hospitalization and aggressive treatment in an intensive
care unit.
A particular complication of upper renal infection in diabetes is
papillary necrosis (see Fig. 7-32). The pathologic appearance of a
sloughing renal papilla, A. The sloughed papilla is eliminated and can
be recovered by sieving the urine, B. In other cases, the necrotic papil-
la obstructs the ureter, causing retention of infected urine and severely
aggravating the pyelonephritis. C, It can lead to pyonephrosis (ie,
C complete destruction of the kidney), as shown on CT.
FIGURE 7-38
Nonpregnant Pregnant
500 Urinary tract infection (UTI) in an immunocompromised host.
IgG Pregnancy is associated with suppression of the host’s immune
response, in the form of reduced cytotoxic T-cell activity and
reduced circulating immunoglobulin G (IgG) levels. Asymptomatic
0
bacteriuria is common during pregnancy and represents a major
1000 risk of ascending infection complicated by acute pyelonephritis.
IgA
(Continued on next page)
Antibody activity, % of control
500
0
1000
IgM
500
0
0 2 0 2
A Time of sampling, wks
7.16 Tubulointerstitial Disease
Nonpregnant Pregnant
>250
IgG
1000 250
200
500
150
0 100
1000
IgA
50
500 20
20
0
0
0
0 2 0 2 Nonpregnant Pregnant Nonpregnant Pregnant
Time of sampling, wks Serum Urine
B C
FIGURE 7-39
Acute prostatitis as visualized sonographically. Acute prostatitis
is common after urethral or bladder infection (usually by
Escherichia coli or Proteus organisms). Another cause is prostate
hematogenous contamination, especially by Staphylococcus.
Signs and symptoms of acute prostatitis, in addition to fever,
chills, and more generally the signs and symptoms of tissue inva-
sion by infection described above, are accompanied by dysuria,
pelvic pain, and septic urine. Acute prostatitis is an indication
for direct ultrasound (US) examination of the prostate by
endorectal probe. In this case of acute prostatitis in a young
male, US examination disclosed a prostatic abscess (1) compli-
cating acute prostatitis in the right lobe (2). Acute prostatitis is
an indication for thorough radiologic imaging of the whole uri-
nary tract, giving special attention to the urethra. Urethral stric-
ture may favor prostate infection (see Fig. 7-20).
Urinary Tract Infection 7.17
A B
FIGURE 7-40 (see Color Plate)
Xanthogranulomatous pyelonephritis (XPN). XPN is a special obstructive renal stone. Nephrectomy was performed. A, The
form of chronic renal inflammation caused by an abnormal obstructive renal stone is shown by an arrowhead. The renal
immune response to infected obstruction [13]. This case in a cavities are dilated. The xanthogranulomatous tissue (arrows)
middle-aged woman with a long history of renal stones is typical. consists of several round, pseudotumoral masses with a typical
For several months she complained of flank pain, fever, fatigue, yellowish color due to presence of lipids. In some instances such
anorexia and weight loss. Laboratory workup found inflammatory xanthogranulomatous tissue extends across the capsule into the
anemia and increased erythrocyte sedimentation rate and C-reactive perirenal fat and fistulizes into nearby viscera such as the colon
protein levels. Urinalysis showed pyuria and culture grew Escherichia or duodenum. B, Microscopic view of the xanthogranulomatous
coli. CT scan of the right kidney showed replacement of the renal tissue. This part of the lesion is made of lipid structures composed
tissue by several rounded, low-density areas and detected an of innumerable clear droplets.
Mononuclear
cells Interstitial
Inflammation
(nonspecific) nephritis
Michaelis-Gutmann
Defective
(MG) bodies Malakoplakia
cell function
(diagnostic)
B
Destuctive
granulomas Fibrosis teroid therapy for autoimmune disease. In 13% of the published cases,
xanthogranulomatous "pseudosarcoma" malakoplakia involved a transplanted kidney. The female-male ratio is
pyelonephritis 3:1. Lesions can involve the kidney, the bladder, or the ureter and form
A
pseudotumors. B, Histologically, malakoplakia is distinguished by
large, pale, periodic acid–Schiff–positive macrophages (von Hanse-
FIGURE 7-41 mann cells) containing calcific inclusions (Michaelis-Gutmann bodies).
Malakoplakia. Malakoplakia (or malacoplakia), like xanthogranulo- The larger ones are often free in the interstitium. Malakoplakia, an
matous pyelonephritis, is also a consequence of abnormal macrophage unusual form of chronic tubulointerstitial nephritis, must be recog-
response to gram-negative bacteria, A. Malakoplakia occurs in associ- nized by early renal biopsy and can resolve, provided treatment
ation with chronic UTI [14]. In more than 20% of cases, affected per- consisting of antibiotics with intracellular penetration is applied for
sons have some evidence of immunosuppression, especially corticos- several weeks. (B, Courtesy of Gary S. Hill, MD.)
7.18 Tubulointerstitial Disease
References
1. Stamm WE, Hooton TM: Management of urinary tract infections in 8. Roberts JA, Marklund BI, Ilver D, et al.: The Gal( 1-4)Gal–
adults. N Engl J Med 1993, 329:1328–1334. specific tip adhesin of Escherichia coli P-fimbriae is needed for
2. Pinson AG, Philbrick JT, Lindbeck GH, Schorling JB: ED management pyelonephritis to occur in the normal urinary tract. Proc Natl Acad
of acute pyelonephritis in women: A cohort study. Am J Emerg Med Sci USA 1994, 91:11889–11893.
1994, 12:271–278. 9. International Reflux Study Committee: Medical versus surgical
3. Pappas PG: Laboratory in the diagnosis and management of urinary treatment of primary vesicoureteral reflux. J Urol 1981, 125:277.
tract infections. Med Clin North Am 1991, 75:313–325. 10. Talner LB, Davidson AJ, Lebowitz RL, et al.: Acute pyelonephritis:
4. Kunin CM, VanArsdale White L, Tong HH: A reassessment of the Can we agree on terminology? Radiology 1994, 192:297–306.
importance of “low-count” bacteriuria in young women with acute 11. Roberts JA: Etiology and pathophysiology of pyelonephritis.
urinary symptoms. Ann Intern Med 1993, 119:454–460. Am J Kidney Dis 1991, 17:1–9.
5. Meyrier A, Guibert J: Diagnosis and drug treatment of acute 12. Petersson C, Hedges S, Stenqvist K, et al.: Suppressed antibody and
pyelonephritis. Drugs 1992, 44:356–367. interleukin-6 responses to acute pyelonephritis in pregnancy. Kidney
6. Meyrier A: Diagnosis and management of renal infections. Curr Opin Int 1994, 45:571–577.
Nephrol Hypertens 1996, 5:151–157. 13. Case records of the Massachusetts General Hospital. N Engl J Med
7. Mobley HLT, Island MD, Massad G: Virulence determinants of 1995, 332:174–179.
uropathogenic Escherichia coli and Proteus mirabilis. Kidney Int 14. Dobyan DC, Truong LD, Eknoyan G: Renal malacoplakia
1994, 46(Suppl. 47):S129–S136. reappraised. Am J Kidney Dis 1993, 22:243–252.
Reflux and Obstructive
Nephropathy
James M. Gloor
Vicente E. Torres
R
eflux nephropathy, or renal parenchymal scarring associated
with vesicoureteral reflux (VUR), is an important cause of
renal failure. Some studies have shown that in up to 10% of
adults and 30% of children requiring renal replacement therapy for
end-stage renal disease, reflux nephropathy is the cause of the renal
failure. Reflux nephropathy is thought to result from the combination
of VUR of infected urine into the kidney by way of an incompetent
ureterovesical junction valve mechanism and intrarenal reflux. Acute
inflammatory responses to the infection result in renal parenchymal
damage and subsequent renal scarring. Loss of functioning renal mass
prompt compensatory changes in renal hemodynamics that, over time,
are maladaptive and result in glomerular injury and sclerosis.
Clinically, reflux nephropathy may cause hypertension, proteinuria,
and decreased renal function when the scarring is extensive. The identi-
fication of VUR raises the theoretic possibility of preventing reflux
nephropathy. The inheritance pattern of VUR clearly is suggestive of a
strong genetic influence. Familial studies of VUR are consistent with
autosomal dominant transmission, and linkage to the major histocom-
patibility genes has been reported. Identification of infants with reflux
detected on the basis of abnormalities seen on prenatal ultrasound
examinations before urinary tract infection occurs may provide an
opportunity for prevention of reflux nephropathy. In persons with VUR
detected at the time of diagnosis of a urinary tract infection, avoidance
of further infections may prevent renal injury. Nevertheless, the situa-
tion is far from clear. Most children with reflux nephropathy already CHAPTER
have renal scars demonstrable at the time of the urinary tract infection
that prompts the diagnosis of VUR. Most children found to have VUR
8
do not develop further renal scarring after diagnosis, even after subse-
quent urinary tract infections. Other children may develop renal scars
in the absence of further urinary tract infections. The best treatment of
8.2 Tubulointerstitial Disease
VUR has not yet been firmly established. No clear advantage has usually is accompanied by hydronephrosis, an abnormal dilation
been demonstrated for surgical correction of VUR versus medical of the renal pelvis, and calices. However, because hydronephrosis
therapy with prophylactic antibiotics after 5 years of follow-up can occur without functional obstruction, the terms obstructive
examinations. New surgical techniques such as the submucosal nephropathy and hydronephrosis are not synonymous. Hydro-
injection of bioinert substances may have a role in select cases. nephrosis is found at autopsy in 2% to 4% of cases. Obstructive
The term obstructive nephropathy is used to describe the func- nephropathy is responsible for approximately 4% of end-stage
tional and pathologic changes in the kidney that result from renal failure. Obstruction to the flow of urine can occur anywhere
obstruction to the flow of urine. Obstruction to the flow of urine in the urinary tract and has many different causes.
FIGURE 8-1
CAUSES OF OBSTRUCTIVE NEPHROPATHY Obstructive nephropathy is responsible for
end-stage renal failure in approximately 4%
of persons. Obstruction to the flow of urine
Intraluminal Extrinsic can occur anywhere in the urinary tract.
Calculus, clot, renal papilla, fungus ball Congenital (aberrant vessels): Obstruction can be caused by luminal bod-
Congenital hydrocalycosis
ies; mural defects; extrinsic compression by
Intrinsic vascular, neoplastic, inflammatory, or other
Ureteropelvic junction obstruction
Congenital: processes; or dysfunction of the autonomic
Retrocaval ureter
Calyceal infundibular obstruction nervous system or smooth muscle of the
Neoplastic tumors:
Ureteropelvic junction obstruction urinary tract. The functional and clinical
Benign tumors:
Ureteral stricture or valves consequences of urinary tract obstruction
Benign prostatic hypertrophy
Posterior urethral valves depend on the developmental stage of the
Pelvic lipomatosis kidney at the time the obstruction occurs,
Anterior urethral valves
Cysts severity of the obstruction, and whether the
Urethral stricture
Primary retroperitoneal tumors: obstruction affects one or both kidneys.
Meatal stenosis
Mesodermal origin (eg, sarcoma)
Prune-belly syndrome
neurogenic origin (eg, neurofibroma)
Neoplastic:
Embryonic remnant (eg, teratoma)
Carcinoma of the renal pelvis, ureter, or bladder
Retroperitoneal extension of pelvic or abdominal tumors:
Polyps
Uterus, cervix
Bladder, prostate
Rectum, sigmoid colon
Metastatic tumor:
Lymphoma
Inflammatory:
Retroperitoneal fibrosis
Inflammatory bowel disease
Diverticulitis
Infection or abscess
Gynecologic:
Pregnancy
Uterine prolapse
Surgical disruption or ligation
Functional
Neurogenic bladder
Drugs(anticholinergics, antidepressants, calcium channel
blockers)
Reflux and Obstructive Nephropathy 8.3
Submucosal
ureter
FIGURE 8-3
Bladder wall
Tissue sagittal sections (upper panels) and
cystoscopic appearances (lower panels) of
the ureterovesical junction illustrating vary-
Ureter ing submucosal tunnel lengths. The length of
the submucosal segment of the distal ureter
A B C D E is an important factor in determining the
12 mm 8 mm 5 mm 2 mm 0 mm effectiveness of the ureteral valvular mecha-
nism in preventing vesicoureteral reflux
(VUR). In children without VUR, the ratio
of tunnel length to ureteral diameter is sig-
nificantly greater than in children with VUR
[5,6]. (From Kramer [7]; with permission.)
A' B' C' D' E'
Cytoscopic view
FIGURE 8-4
Simple and compound papillae are illustrated [8,9]. Two types of
renal papillae have been identified. Simple papillae are the most
common type. They have slitlike papillary duct openings on their
convex surface. These papillae are compressed by increases in
pelvic pressure, preventing urine from entering the papillary ducts
(intrarenal reflux). Compound papillae are formed by the fusion of
two or more simple papillae. In compound papillae, some ducts
open onto a flat or concave surface at less oblique angles.
Increased intrapelvic pressure may permit intrarenal reflux.
Compound papillae usually are found in the renal poles.
8.4 Tubulointerstitial Disease
FIGURE 8-6
Experimental vesicoureteric reflux in pigs: cystourethrogram show-
FIGURE 8-5 ing intrarenal reflux. Reflux of radiocontrast medium into the
Experimental vesicoureteric reflux in pigs. This pathology specimen renal parenchyma is seen. The pressure required to produce
demonstrates surgically induced vesicoureteric reflux in a 2-week- intrarenal reflux is lower in young children than it is in older chil-
old male piglet. Note that the submucosal canal of one of the dren or adults, which is consistent with the observation that reflux
ureters has been unroofed. scars occur more commonly in younger children [10].
A B C
FIGURE 8-7
Experimental vesicoureteric reflux in pigs. The polar location of scars. In urinary tract infections, reflux of urine from the renal
acute suppurative pyelonephritis and evolution of parenchymal pelvis into the papillary ducts of compound papillae predominantly
(Continued on next page)
Reflux and Obstructive Nephropathy 8.5
D E F
FIGURE 8-7 (Continued)
located in the poles (intrarenal reflux) provides bacteria access reflux nephropathy: Hemorrhagic with polymorphonuclear cell
to the renal parenchyma, resulting in suppurative pyelonephritis infiltrate (A, B); white, not retracted, with prominent mononu-
and subsequent polar scarring [11,12]. Intact (A, C, E) and coro- clear cell infiltrate (C, D), and retracted scan with prominent
nally sectioned (B, D, F) kidneys illustrating the three stages of fibrosis (E, F).
FIGURE 8-10
Integrative View of Pathogenetic Mechanisms in Reflux Nephropathy Integrative view of pathogenetic mechanisms in reflux nephropa-
thy. Abnormalities of ureteral embryogenesis may result in a defec-
Defective mesonephric mesoderm tive antireflux mechanism, permitting vesicoureteral reflux (VUR),
(ureteral bud) incomplete bladder emptying, urinary stasis, and infection.
Bacterial virulence factors modify the pathogenicity of different
Abnormal induction of bacterial strains. Bacterial surface appendages such as fimbriae may
metanephric mesoderm interact with epithelial cell receptors of the urinary tract, enhancing
High-voiding bacterial adhesion to urothelium. Endotoxin is capable of inhibit-
VUR pressures
ing ureteral peristalsis, contributing to the extension of the infec-
(In utero) +
tion into the upper urinary tract even in the absence of VUR.
IRR Inoculation of the renal parenchyma with bacteria produces an
+ acute inflammatory response, resulting in the release of inflamma-
Virulent tory mediators into the surrounding tissue. The acute inflammatory
bacterial strain response elicited by the presence of infecting bacteria is responsible
+
for the subsequent renal parenchymal injury. In addition, it is pos-
Immune sible that immune complexes, bacterial fragments, and endotoxin
Susceptible Inhibition
complexes of ureteral resulting from infection may produce a glomerulopathy.
host
Bacterial peristalsis Even in the absence of urinary tract infection, VUR associated
fragments with elevated intravesical pressure is capable of producing renal
Endotoxin
Focal exudative Toxic urine parenchymal scars. The developing kidney appears to be particular-
reaction component ly susceptible. Renal tubular distention resulting from high
Delayed intrapelvic pressure may exert an injurious effect on renal tubular
hypersensitivity epithelium. Compression of the surrounding peritubular capillary
Glomerulopathy
Pyelonephritic network by distended renal tubules may produce ischemia. During
scar micturition, elevated intravesical pressure is transmitted to the
Sterile scar
Back-pressure renal pelvis and renal tubule. This transient pressure elevation may
atrophy produce tubular disruption. Extravasation of urine into the sur-
Reduced nephron
population Diffuse interstitial rounding parenchyma results in an immune-mediated interstitial
Dysplasia fibrosis nephritis and further renal injury.
The reduction in functional renal mass produced by the interaction
Hyperfiltration High-protein diet of the pathogenetic factors listed here induces compensatory hemo-
Hypertension dynamic changes in renal blood flow and the glomerular filtration
Pregnancy rate. Over time, these compensatory changes may be maladaptive,
Glomerulosclerosis may produce hyperfiltration and glomerulosclerosis, and may even-
tuate in renal insufficiency. (From Kramer [16]; with permission.)
Progressive renal insufficiency
FIGURE 8-11
Vesicoureteral reflux and renal dysplasia. An abnormal ureteral
bud resulting from defective ureteral embryogenesis may penetrate
the metanephric blastema at a site other than that required for
optimum renal development, potentially resulting in renal dysplasia
or hypoplasia [17].
Reflux and Obstructive Nephropathy 8.7
FIGURE 8-14
Voiding cystourethrogram demonstrating bilateral grade 5 vesicoureteral reflux. Voiding
cystourethrography is performed by filling the bladder with radiocontrast material and
observing for reflux under fluoroscopy, either during the phase of bladder filling or dur-
ing micturition. Contrast material is infused through a small urethral catheter under
gravity flow.
8.8 Tubulointerstitial Disease
FIGURE 8-15
Radionuclide cystogram demonstrating bilateral vesicoureteral reflux (VUR). This method
using 99mtechnetium pertechnetate is useful in detecting VUR. Advantages of radionuclide
cystography include lower radiation exposure, less interference with overlying bowel con-
tents and bones, and higher sensitivity in detection of VUR. Radionuclide cystography is
useful in follow-up examinations of patients known to have VUR, as a screening test in
asymptomatic siblings of children with reflux and girls with urinary tract infections, and in
serial examinations of children with neuropathic bladders at risk for developing VUR.
Disadvantages of this method include less anatomic detail and inadequacy in evaluating
the male urethra, making it unsuitable for screening boys for urinary tract infections [7].
A B
FIGURE 8-16
A, Intravenous pyelogram and, B, nephrotomogram demonstrating not be visible immediately after renal infection, because scars may
grade 2 reflux nephropathy. Historically, this testing modality has not be fully developed for several years [20]. The advantages of
been the one most commonly used to evaluate reflux nephropathy intravenous pyelography in evaluating reflux nephropathy include
[7]. Irregular renal contour, parenchymal thinning, small renal size, precision in delineating renal anatomic detail and providing base-
and calyceal blunting all are radiographic signs of reflux nephropa- line measurements for future follow-up evaluations, renal growth,
thy on intravenous pyelography [17]. Radiographic changes may and scar formation.
FIGURE 8-17
A, Posterior and, B, anterior views of
99mtechnetium-dimercaptosuccinic acid
(DMSA) renal scan showing bilateral grade
2 reflux nephropathy. This nephropathy is
characterized by focal areas of decreased
radionuclide uptake predominantly affect-
ing the lower renal poles.
A B
Reflux and Obstructive Nephropathy 8.9
13
Predicted mean
12 95% predicted limits
11
10
9
Renal length, cm
8
7
6
5
4
3
2
0 2 4 6 8 10 12 5 10 15
C Months Years
A
FIGURE 8-18
Prenatal detection of vesicoureteral reflux (VUR). A,
Ultrasonography showing mild fetal hydronephrosis. B, Postnatal
voiding cystourethrogram (VCUG) showing grade 4 VUR. C,
Graph showing small renal size in the same infant. Vesicoureteral
reflux has been identified in neonates in whom prenatal ultra-
sonography examination reveals hydronephrosis [21–28]. Normal
infants do not have VUR, even when born prematurely [29,30].
The severity of reflux often is not predictable on the basis of
appearance on ultrasonography [22,31]. Hydronephrosis greater
than 4 mm and less than 10 mm in the anteroposterior dimension
on ultrasound examination after 20 weeks’ gestational age has
been termed mild fetal hydronephrosis. Mild fetal hydronephrosis
is associated with VUR in a significant percentage of infants
[26,31]. Despite the absence of a previous urinary tract infection,
many kidneys affected prenatally exhibit decreased function
[22,24,32,33]. Unlike the focal parenchymal scars seen in infection-
associated reflux nephropathy, the parenchymal abnormalities seen
in prenatal VUR are most commonly manifested by a generalized
decrease in renal size (reflux nephropathy grade 3 or 4) [34,35].
B
8.10 Tubulointerstitial Disease
FIGURE 8-19
90 83 Male Prenatal detection of vesicoureteral reflux (VUR): gender distribution versus VUR detected
80 77 after urinary tract infection (UTI). VUR detected as part of the evaluation of prenatal
Female
70 hydronephrosis is most commonly identified in boys. In an analysis of six published stud-
60 ies of VUR diagnosed in a total of 124 infants with antenatally detected hydronephrosis,
50 83% of those affected were boys [33]. Conversely, VUR detected after a UTI most com-
%
40 monly affects girls. In the International Reflux Study in Children (IRSC) and Southwest
30 23 Pediatric Nephrology Study Group (SWPNSG) investigations of VUR detected in a total of
20 17
380 children after UTI, 77% of those affected were girls [20,36].
10
0
Prenatally Detected
detected after UTI
90
50 50
50 80 Grade 1
Grade 2
70
40 Resolved VUR, % Grade 3
60
30 50
30
%
20 21 40
20 30
20
10
10
0 0
1 2 3 4 5 0 1 2 3 4 5
Vesicoureteral reflux grade Years follow-up
FIGURE 8-22
90 82 80 Grade 1 Resolution of vesicoureteral reflux (VUR) detected postnatally after
80 Grade 2 urinary tract infection at follow-up examinations over 5 years. Mild
70
Patients studied, %
Grade 3
to moderate VUR spontaneously resolves in a significant percentage
60 Grade 4–5 53
of children, whereas high-grade reflux resolves only rarely. The
50 43
40
40 Southwest Pediatric Nephrology Study Group (SWPNSG) found
31 that grades I and II VUR resolved in 80% of children with refluxing
30
20 17 16 18 20 ureters at follow-up examinations over 5 years. In the Birmingham
10 Reflux Study Group (BRSG), International Reflux Study in Children
0 (IRSC), and SWPNSG investigations of high-grade VUR (grades III
Resolution Improvement Unchanged to V) in children, improvement in reflux severity was seen in 30%
to 40% of affected ureters. Spontaneous resolution was rare and
occurred in only 16% to 17% of children with refluxing ureters at
follow-up examinations over 5 years [20,37,38].
Reflux and Obstructive Nephropathy 8.11
FIGURE 8-23
40
Unilateral Resolution of grades III to V vesicoureteral reflux (VUR) detected
35
Bilateral postnatally after urinary tract infection: bilateral versus unilateral
30 VUR. Spontaneous resolution of high-grade VUR is much more
Resolved VUR, %
18
IRSC IRSC
60 16
BRSG SWPNSG
14
50
12
40 10
30 8
6
20
4
10 2
0 0
0 I–II III IV Dilated 0 1 2 3 4 5
Vesicoureteral reflux grade Years follow-up
FIGURE 8-26
Development of new renal scars versus age at diagnosis of vesicoureteral reflux
(VUR). The frequency of new scar formation appears to be inversely related to age.
The International Reflux Study in Children (IRSC) examined children with high-grade
VUR and found that new scars developed in 24% under 2 years of age, 10% from 2
to 4 years of age, and 5% over 4 years of age [40].
8.12 Tubulointerstitial Disease
FIGURE 8-28
Effectiveness of medical versus surgical treatment: incidence of uri-
40 38 39 BRSG-Surgical nary tract infections. Vesicoureteral reflux (VUR) predisposes affected
Urinary tract infections, %
35 34 BRSG- Medical persons to urinary tract infection owing to incomplete bladder empty-
IRSC-Medical ing and urinary stasis. Medical therapy with uroprophylactic antibi-
30 28
IRSC-Surgical otics and surgical correction of VUR have as a goal the prevention of
25
21 SWPNSG
20 urinary tract infection. In three prospective studies of 400 children
15 with VUR (Southwest Pediatric Nephrology Study Group [SWPNSG],
International Reflux Study in Children [IRSC], Birmingham Reflux
10
Study Group [BRSG]) treated either medically or surgically and who
5
were observed over 5 years the rate of infection was similar, ranging
0 from 21% to 39%. The rate of infection was no different between the
group treated medically and that treated surgically [20,37,39].
FIGURE 8-29
Nonpyelonephritic
Effectiveness of medical versus surgical treatment: incidence of urinary tract infection ver-
40 UTI sus pyelonephritis in severe vesicoureteral reflux (VUR). Although the incidence of uri-
UTI versus pyelonephritis, %
35 Pyelonephritis nary tract infections (UTIs) is the same in surgically and medically treated children with
30 17 VUR, the severity of infection is greater in those treated medically. The International
25 29
Reflux Study in Children (IRSC) (European group) studied 306 children with VUR and
20 observed them over 5 years; 155 were randomized to medical therapy, and 151 had surgi-
15
cal correction of their reflux. Although the incidence of UTI statistically was no different
21 between the groups (38% in the medical group, 39% in the surgical group), children
10
treated medically had an incidence of pyelonephritis twice as high (21%) as those treated
5 10
surgically (10%) [41].
0
Medical Surgical
therapy therapy
Reflux and Obstructive Nephropathy 8.13
FIGURE 8-32
100
Frequency of hypertension versus severity of parenchymal scarring. The frequency of
80 hypertension in persons with vesicoureteral reflux–related renal scars is higher than in the
normal population. In adults with reflux nephropathy the incidence of hypertension can be
Hypertensive, %
60 correlated with the severity of renal scarring. Adding the individual grade of reflux (0–4)
for the two kidneys results in a scale ranging from 0 (no scars) to 8 (severe bilateral scar-
40 ring). Persons with cumulative scores of parenchymal scarring from 1 to 4 have a 30%
incidence of hypertension, whereas 60% of those with scarring scores ranging from 5 to 8
20
have hypertension [42,43].
0
1–4 5–8
Cumulative reflux scarring severity score
FIGURE 8-35
PGE2, PGI2 Renal hemodynamic response to mild partial ureteral obstruction. Renal blood flow and
Angiotensin II the glomerular filtration rate may not change in mild partial ureteral obstruction, despite a
RA RE significant reduction in glomerular capillary ultrafiltration coefficient (Kf). This is due to
PGC
the increase in glomerular capillary hydraulic pressure (PGC) caused by a prostaglandin
E2–induced reduction of afferent arteriolar resistance (RA) and an angiotensin II–induced
Kf elevation of efferent arteriolar resistance (RE). It is likely that other vasoactive factors,
such as thromboxane A2, also play a role, particularly in more severe ureteral obstruction
accompanied by reductions in renal blood flow and glomerular filtration rate [46].
PGE2—prostaglandin E2; PGI2—prostaglandin I2; Pt—tubule hydrostatic pressure.
Pt
300
FIGURE 8-37
Intrapelvic pressure Chronic renal hemodynamic response to complete unilateral ureter-
Renal blood flow al obstruction. During complete ureteral obstruction, renal blood
Change from baseline, %
200 Glomerular filtration rate flow progressively decreases. Renal blood flow is 40% to 50% of
normal after 24 hours, 30% at 6 days, 20% at 2 weeks, and 12%
100 at 8 weeks [48].
Baseline
–50
0 1 2 3 4 5 6 7 8
Weeks after obstruction
Leukocytes, 105/g
30
Leukocytes, 105/g
30
20
20
10
10
0
0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
A Control 4 h 12 h 24 h Control 4 h 12 h 24 h C Days Days
FIGURE 8-38
Cortex
Development of interstitial cellular infiltrates in the renal cortex
and medulla after ureteral obstruction. After ureteral obstruction
there is a rapid influx of macrophages and suppressor T lympho-
cytes in the cortex and medulla (A) that is accompanied by an
increase in urinary thromboxane B2 and a decrease in the glomeru-
lar filtration rate. The production of thromboxane A2 by the infil-
trating macrophages (B) contributes to the renal vasoconstriction
of chronic urinary tract obstruction. After release of the obstruc-
tion the cellular infiltration is slowly reversible, requiring several
days to revert to near normal levels (C) [50,51].
Medulla
B
Reflux and Obstructive Nephropathy 8.17
FIGURE 8-40
Obstruction
Recovery of renal function after relief of complete unilateral
100 ureteral obstruction of variable duration. The recovery of the ipsi-
80 lateral glomerular filtration rate after relief of a unilateral com-
plete ureteral obstruction has been best studied in dogs and
60 depends on the duration of the obstruction. Complete recovery
occurs after 1 week of obstruction. The degree of recovery after 2
40 and 4 weeks of obstruction is only of 58% and 36%, respectively.
No recovery occurs after 6 weeks of obstruction [58]. Rare
20
reports of recovery of renal function in patients with longer peri-
0 ods of unilateral ureteral obstruction may represent high-grade
0 2 4 6 8 12 14 16 18 20 22 24 partial obstruction rather than complete obstruction or may
Weeks after obstruction reflect differences in lymphatic drainage and renal anatomy
between the human and canine kidneys [59].
8.18 Tubulointerstitial Disease
FIGURE 8-42
Urinary tract obstruction Clinical manifestations of obstructive nephropathy. These manifes-
tations depend on the cause of the obstruction, its anatomic loca-
tion, its severity, and its rate of development [61,68,69].
Unilateral Bilateral or solitary kidney
0.6
RI
Hydronephrosis 0.4
without obstruction
0.2
Normal
0.0
A Time B Partial obstruction Contralateral kidney
FIGURE 8-44
Diagnosis of obstructive nephropathy by postnatal renal ultra-
sonography, showing hydronephrosis in ureteropelvic junction
obstruction. Renal ultrasonography is a sensitive test to detect
hydronephrosis. The absence of ureteral dilation is consistent with
obstruction at the level of the ureteropelvic junction.
8.20 Tubulointerstitial Disease
FIGURE 8-45
Before Furosemide After Furosemide Mercaptoacetyltriglycine-3 renal scan with furosemide in a new-
born with left ureteropelvic junction obstruction. A diuretic renal
scan using 99mtechnetium-mercaptoacetyltriglycine (99mTc-MAG-3)
showing differential renal function (47% right kidney; 53% left
kidney) at 1 to 2 minutes after radionuclide administration is seen.
A significant amount of radionuclide remains in each kidney 15
1 min. minutes after administration. After administration of furosemide,
however, the isotope is seen to disappear rapidly from the right
kidney (t1/2 of radioisotope washout in 4.9 minutes) but persists
in the hydronephrotic left kidney (t1/2 in 50.1 minutes). A t1/2 of
the radioisotope in less than 10 minutes is thought to reflect a lack
of significant obstruction. A t1/2 of over 20 minutes is suggestive
of obstruction. Intermediate values of washout are indeterminate.
The most appropriate therapy for infants with delayed renal pelvic
radioisotope washout and diagnosis of ureteropelvic junction
obstruction is controversial. Some authors advocate pyeloplasty to
alleviate the obstruction based on renal scan results, whereas oth-
5 min. ers advocate withholding surgery unless renal function deteriorates
or hydronephrosis progresses.
10 min.
15 min.
Lt Rt Lt Rt
Reflux and Obstructive Nephropathy 8.21
FIGURE 8-47
Excretory urogram of a patient with poste-
rior urethral valves. Bladder outlet obstruc-
tion results in bladder wall thickening, tra-
beculation, and formation of diverticula.
Increased intravesical pressure may result
in vesicoureteral reflux, as is seen on the
left. Obstruction resulting in increased
intrarenal pressure may result in rupture
at the level of a renal fornix, producing a
urinoma, or perirenal collection of urine,
as seen on the right.
FIGURE 8-48
Voiding cystourethrogram (VCUG) demonstrating posterior urethral valves and dilation
of the posterior urethra. Urethral valves are best detected by VCUG. The obstructing
valves are seen as oblique or perpendicular folds with proximal urethral dilation and elon-
gation. Distal to the valves the urinary stream is diminished. Alleviating the bladder outlet
obstruction is indicated, either by lysis of the valves themselves or by way of vesicostomy,
in small infants until sufficient growth occurs to make valve resection technically feasible.
8.22 Tubulointerstitial Disease
Retroperitoneal Fibrosis
A B
FIGURE 8-50
A–H, Idiopathic retroperitoneal fibrosis: computed tomography nal fibrosis, sclerosing cholangitis, Riedel’s thyroiditis, and fibrous
scans of the abdomen before (left panels, note right ureteral stent pseudotumor of the orbit. In the clinical setting, patients with idio-
and mild left ureteropyelocaliectasis) and 7 years after ureterolysis pathic retroperitoneal fibrosis exhibit systemic symptoms such as
(right panels, note omental interposition). Retroperitoneal fibrosis malaise, anorexia and weight loss, and abdominal or flank pain.
is characterized by the accumulation of inflammatory and fibrotic Renal insufficiency is often seen and is caused by bilateral ureteral
tissue around the aorta, between the renal hila and the pelvic brim. obstruction. Laboratory test results usually demonstrate anemia
Most cases are idiopathic; the remainder are associated with and an elevated sedimentation rate. The treatment is directed to the
immune-mediated connective tissue diseases, ingestion of drugs release of the ureteral obstruction, which initially can be achieved
such as methysergide, abdominal aortic aneurysms, or malignancy. by placement of ureteral stents. Administration of corticosteroids is
Idiopathic retroperitoneal fibrosis can be associated with mediasti- helpful to control the systemic manifestations of the disease and
(Continued on next page)
Reflux and Obstructive Nephropathy 8.23
C D
E F
G H
FIGURE 8-50 (Continued)
often to reduce the bulk of the tumor and relieve the ureteral the ureters from the fibrotic mass, lateralizing them, and wrapping
obstruction. Administration of corticosteroids, however, should be them in omentum to prevent repeat obstruction, is often necessary.
considered only when malignancy and retroperitoneal infection can Other immunosuppressive agents have been used rarely when the
be ruled out. As in other chronic renal diseases, administration of systemic manifestations of the disease cannot be controlled with
corticosteroids should be kept at the minimal level capable of con- safe doses of corticosteroids. In most cases the long-term outcome
trolling symptoms. Surgical ureterolysis, which consists of freeing of idiopathic retroperitoneal fibrosis is satisfactory [75–77].
8.24 Tubulointerstitial Disease
References
1. Roshani H, Dabhoiwala NF, Verbeek FJ, Lamers WH: Functional 24. Anderson PAM, Rickwood AMK: Features of primary vesicoureteric
anatomy of the human ureterovesical junction. Anat Rec 1996, reflux detected by prenatal sonography. Br J Urol 1991, 67:267–271.
245:645–651. 25. Stocks A, Richards D, Frentzen B, Richard G: Correlation of prenatal
2. Noordzij JW, Dabhoiwala NF: A view on the anatomy of the renal pelvic anteroposterior diameter with outcome in pregnancy. J
ureterovesical junction. Scand J Urol Nephrol 1993, 27:371–380. Urol 1996, 155:1050–1052.
3. Thomson AS, Dabhoiwala NF, Verbeek FJ, Lamers WH: The func- 26. Adra AM, Mejides AA, Dennaoui MS, et al.: Fetal pyelectasis: Is it
tional anatomy of the ureterovesical junction. Br J Urol 1994, always “physiological”? [abstract]. Am J Obstet Gynecol 1995,
73:284–291. 172:359.
4. Politano VA: Vesico-ureteral reflux. In Urologic Surgery, edn 2. Edited 27. Morin L, Cendron M, Garmel SH, et al.: Minimal fetal hydronephro-
by Glenn JF. New York: Harper and Row Publishers, 1975:272–293. sis: natural history and implications for treatment. Am J Obstet
5. Paquin AJ: Ureterovesical junction: the description and evaluation of Gynecol 1995, 172:354.
a technique. J Urol 1959, 82:573. 28. Zerin JM, Ritchey MJ, Chang ACH: Incidental vesicoureteral reflux
6. Stephens FD, Lenaghan D: The anatomical basis and dynamics of in neonates with antenatally detected hydronephrosis and other
vesicoureteral reflux. J Urol 1962, 87:669. abnormalities. Radiology 1993, 187:157–160.
7. Kramer, SA: Vesicoureteral reflux. In Clinical Pediatric Urology, edn 29. Peters PC, Johnson DE, Jackson JHJ: The incidence of vesicoureteral
3. Edited by Kelalis PP, King LR, Belman AB. Philadelphia: WB reflux in the premature child. J Urol 1967, 97:259–260.
Saunders Company, 1992:441–499. 30. Lich R Jr, Howerton LW Jr, Goode LS, Davis LA: The ureterovesical
8. Ransley PG, Risdon RA: Renal papillary morphology in infants and junction of the newborn. J Urol 1964, 92:436–438.
young children. Urol Res 1975, 3:111–113. 31. Marra G, Barbieri G, Moioli C, et al.: Mild fetal hydronephrosis indi-
9. Ransley PG, Risdon RA: Renal papillary morphology and intrarenal cating vesicoureteric reflux. Arch Dis Child 1994, 70:F147–150.
reflux in the young pig. Urol Res 1975, 3:105–109. 32. Wallin L, Bajc M: The significance of vesicoureteric reflux on kidney
10. Funston MR, Cremin BJ: Intrarenal reflux-papillary morphology and development assessed by dimercaptosuccinate renal scintigraphy. Br J
pressure relationships in children’s necropsy kidneys. Br J Radiol Urol 1994, 73:607–611.
1978, 51:665–670. 33. Elder JS: Commentary: importance of antenatal diagnosis of vesi-
11. Ransley PG, Risdon RA: Reflux nephropathy: effects of antimicrobial coureteral reflux. J Urol 1992, 148:1750–1754.
therapy on the evolution of the early pyelonephritic scar. Kidney Int 34. Crabbe DCG, Thomas DFM, Gordon AC, et al.: Use of 99mtech-
1981, 20:733–742. netium-dimercaptosuccinic acid to study patterns of renal damage
12. Torres VE, Kramer SA, Holley KE, et al.: Effect of bacterial immu- associated with prenatally detected vesicoureteral reflux. J Urol 1992,
nization on experimental reflux nephropathy. J Urol 1984, 131:772. 148:1229–1231.
13. Torres VE, Kramer SA, Holley KE, et al.: Interaction of multiple risk 35. Sheridan M, Jewkes F, Gough DCS: Reflux nephropathy in the first
factors in the pathogenesis of experimental reflux nephropathy in the year of life: role of infection. Pediatr Surg Int 1991, 6:214–216.
pig. J Urol 1985, 133:131–135. 36. Weiss R, Tamminen-Mobius T, Koskimies O, et al.: Characteristics at
14. Goldraich NP, Goldraich IH, Anselmi OE, Ramos OL: Reflux entry of children with severe primary vesicoureteral reflux recruited
nephropathy: the clinical picture in South Brazilian children. Control for a multicenter international therapeutic trial comparing medical
Nephrol 1984, 39:52–67. and surgical management. J Urol 1992, 148:1644–1649.
15. Scherz HC, Downs TM, Caeser R: The selective use of dimercaptosuc- 37. Taylor CM, White RHR: Prospective trial of operative vs. non-opera-
cinic acid renal scans in children with vesicoureteral reflux. J Urol tive treatment of severe vesicoureteric reflux in children: five years’
1994, 152:628–631. observation. Br Med J 1987, 295:237–241.
16. Kramer SA: Experimental vesicoureteral reflux. Dialogues Pediatr 38. Tamminen-Mobius T, Brunier E, Ebel K-D, et al.: Cessation of vesi-
Urol 1984, 7:1. coureteral reflux for 5 years in infants and children allocated to med-
ical treatment. J Urol 1992, 148:1662–1666.
17. Hinchliffe SA, Chan Y, Jones H, et al.: Renal hypoplasia and postna-
tally acquired cortical loss in children with vesicoureteral reflux. 39. Astley R, Clark RC, Corkery JJ, et al.: Prospective trial of operative
Pediatr Nephrol1992, 6:439–444. vs. non-operative treatment of severe vesicoureteric reflux: two years’
observation in 96 children. Br Med J 1983, 287:171–174.
18. Lebowitz RL, Olbing H, Parkkulainen K, et al.: International system
of radiographic grading of vesicoureteral reflux. Pediatr Radiol 1985, 40. Olbing H, Claesson I, Ebel K-D, et al.: Renal scars and parenchymal
15:105. thinning in children with vesicoureteral reflux: a 5-year report of the
International Reflux Study in Children (European branch). J Urol
19. Smellie JM, Edwards D, Hunter N, et al.: Vesico-ureteric reflux and 1992, 148:1653–1656.
renal scarring. Kidney Int 1975, 8:s65–s72.
41. Jodal U, Koskimies O, Hanson E, et al.: Infection pattern in children
20. Arant BS: Medical management of mild and moderate vesicoureteral with vesicoureteral reflux randomly allocated to operation or long-
reflux: followup studies of infants and young children. A preliminary term antibacterial prophylaxis. J Urol 1992, 148:1650–1652.
report of the Southwest Pediatric Nephrology Study Group. J Urol
1992, 148:1683–1687. 42. Goonasekera CDA, Shah V, Wade A, et al.: 15-year follow-up of renin
and blood pressure in reflux nephropathy. Lancet 1996,
21. Steele BT, Robitaille P, DeMaria J, Grignon A: Follow-up evaluation 347:640–643.
of prenatally recognized vesicoureteric reflux. J Pediatr 1989,
115:95–96. 43. Torres V, Malek RS, Svensson JP: Vesicoureteral reflux in the adult:
nephropathy, hypertension, and stones. J Urol 1983, 130:41–44.
22. Najmaldin A, Burge DM, Atwell JD: Reflux nephropathy secondary
to intrauterine vesicoureteric reflux. J Pediatr Surg 1990, 25:387–390. 44. Torres V, Velosa J, Holley KE, et al.: The progression of vesicoureteral
reflux nephropathy. Ann Intern Med 1980, 92:776–784.
23. Marra G, Barbieri G, Dell’Agnola CA, et al.: Congenital renal damage
associated with primary vesicoureteral reflux detected prenatally in 45. Chevalier RL: Effects of ureteral obstruction on renal growth. Semin
male infants. J Pediatr 1994, 124:726–730. Nephrol 1995, 15:353–360.
Reflux and Obstructive Nephropathy 8.25
46. Ichikawa I, Brenner BM: Local intrarenal vasoconstrictor-vasodilator 62. Campbell HT, Bello-Reuss E, Klahr S: Hydraulic water permeability
interactions in mild partial ureteral obstruction. Am J Physiol 1979, and transepithelial voltage in the isolated perfused rabbit cortical col-
236:F131–140. lecting tubule following acute unilateral ureteral obstruction. J Clin
47. Dal Canton A: Effects of 24-hour unilateral ureteral obstruction on Invest 1985, 75:219.
glomerular hemodynamics in rat kidney. Kidney Int 1979, 15:457. 63. Hanley MJ, Davidson K: Isolated nephron segments from rabbit mod-
48. Klahr S: Pathophysiology of obstructive nephropathy: a 1991 update. els of obstructive uropathy. J Clin Invest 1982, 69:165.
Semin Nephrol 1991, 11:156. 64. Hwang S: Transport defects of rabbit inner medullary collecting duct
49. Marin-Grez M, Fleming JT: Atrial natriuretic peptide causes pre- cells in obstructive uropathy. Am J Physiol 1993, 264:F808.
glomerular vasodilatation and post-glomerular vasoconstriction in rat 65. Hwang S: Transport defects of rabbit medullary thick ascending limb
kidney. Nature 1986, 324:473. cells in obstructive uropathy. J Clin Invest 1993, 91:21.
50. Schreiner GF, Harris KPG, Purkerson ML, Klahr S: Immunological 66. Kimura H, Mujais SK: Cortical collecting duct Na-K pump in
aspects of acute ureteral obstruction: immune cell infiltrate in the kid- obstructive uropathy. Am J Physiol 1990, 258:F1320.
ney. Kidney Int 1988, 34:487–493. 67. Muto S, Asano Y: Electrical properties of the rabbit cortical collecting
51. Diamond JR: Macrophages and progressive renal disease in experi- duct from obstructed kidneys after unilateral ureteral obstruction. J
mental hydronephrosis. Am J Kidney Dis 1995, 26:133–140. Clin Invest 1994, 94:1846.
52. Chevalier RL: Growth factors and apoptosis in neonatal ureteral 68. Davis BB, Preuss HG, Murdaugh HVJ: Hypomagnesemia following
obstruction. J Am Soc Nephrol 1996, 7:1098–1105. the diuresis of post-renal obstruction and renal transplant. Nephron
53. Ishidoya S, Morrisey J, McCracken R, Klahr S: Delayed treatment 1975, 14:275.
with enalapril halts tubulointerstitial fibrosis in rats with obstructive 69. Landsberg L: Hypernatremia complicating partial urinary tract
uropathy. Kidney Int 1996, 49:1110–1119. obstruction. N Engl J Med 1970, 283:746.
54. Morrisey J, Ishidoya S, McCracken R, Klahr S: Nitric oxide genera- 70. Whitherow RO, Whitaker RH: The predictive accuracy of antegrade
tion ameliorates the tubulointerstitial fibrosis of obstructive nephropa- pressure flow studies in equivocal upper tract obstruction. Br J Urol
thy. J Am Soc Nephrol 1996, 7:2202–2212. 1981, 53:496.
55. Ricardo SD, Ding G, Eufemio M, Diamond JR: Antioxidant expres- 71. Koff SA, Thrall JN, Keyes JW: Diuretic radionuclide urography. A
sion in experimental hydronephrosis: role of mechanical stretch and noninvasive method for evaluating nephroureteral dilatation. J Urol
growth factors. Am J Physiol 1997, 272:F789–F798. 1979, 122:451.
56. Wright EJ, McCaffrey TA, Robertson AP, et al.: Chronic unilateral ureter- 72. Whitfield HN: Furosemide intravenous urography in the diagnosis of
al obstruction is associated with interstitial fibrosis and tubular expression pelviureteric junction obstruction. Br J Urol 1979, 51:445.
of transforming growth factor-beta.Lab Invest 1996, 74:528–537. 73. Shokeir AA, Nijman RJM, El-Azab M, Provoost AP: Partial ureteral
57. Yanagisawa H: Dietary protein restriction normalized eicosanoid pro- obstruction: effect of intravenous normal saline and furosemide on the
duction in isolated glomeruli from rats with bilateral ureteral obstruc- resistive index. J Urol 1997, 157:1074–1077.
tion.Kidney Int 1994, 46:245. 74. Kaplan GW, Scherz HC: Infravesicle obstruction. In Clinical Pediatric
58. Vaughn EDJ, Gillenwater JY: Recovery following complete chronic Urology, edn 3. Edited by Kelalis PP, King LR, Belman AB.
unilateral ureteral occlusion: functional, radiographic and pathologic Philadelphia: WB Saunders Company; 1992:821–864.
alterations. J Urol 1971, 106:27–35. 75. Gilkeson GS, Allen NB: Retroperitoneal fibrosis: a true connective tis-
59. Shapiro SR: Recovery of renal function after prolonged unilateral sue disease. Rheum Dis North Am 1996, 22:23–38.
ureteral obstruction. J Urol 1976, 115:136–40. 76. Kottra JJ, Dunnick NR: Retroperitoneal fibrosis. Radiol Clin North
60. Miller TR: Urinary diagnostic studies in acute renal failure: a prospec- Am 1996, 34:1259–1275.
tive study. Ann Intern Med 1978, 89:47. 77. Massachusetts General Hospital: Case records–case 27–1996: N Engl
61. Batlle DC, Arruda JAL, Kurtzman NA: Hyperkalemic distal renal J Med 1996, 335:650–655.
tubular acidosis associated with obstructive uropathy. N Engl J Med
1981, 304:373.
Cystic Diseases
of the Kidney
Yves Pirson
Dominique Chauveau
A
kidney cyst is a fluid-filled sac arising from a dilatation in any
part of the nephron or collecting duct. A sizable fraction of all
kidney diseases—perhaps 10% to 15%—are characterized by
cysts that are detectable by various imaging techniques. In some, cysts
are the prominent abnormality; thus, the descriptor cystic (or poly-
cystic). In others, kidney cysts are an accessory finding, or are only
sometimes present, so that some question whether they are properly
classified as cystic diseases of the kidney. In fact, the commonly
accepted complement of cystic kidney diseases encompasses a large
variety of disorders of different types, presentations, and courses.
Dividing cystic disorders into genetic and “nongenetic” conditions
makes sense, not only conceptually but clinically: in the former cystic
involvement of the kidney often leads to renal failure and is most often
associated with extrarenal manifestations of the inherited defect,
whereas in the latter cysts rarely jeopardize renal function and gener-
ally are not part of a systemic disease.
In the first section of this chapter we deal with nongenetic (ie,
acquired and developmental) cystic disorders, emphasizing the imaging
characteristics that enable correct identification of each entity. Some
common pitfalls are described. A large part of the section on genetic
disorders is devoted to the most common ones (eg, autosomal-domi-
nant polycystic kidney disease), focusing on genetics, clinical manifes-
tations, and diagnostic tools. Even in the era of molecular genetics, the
diagnosis of the less common inherited cystic nephropathies relies on
proper recognition of their specific renal and extrarenal manifestations. CHAPTER
Most of these features are illustrated in this chapter.
9
9.2 Tubulointerstitial Disease
General Features
FIGURE 9-1
PRINCIPAL CYSTIC DISEASES OF THE KIDNEY Principal cystic diseases of the kidney.
Classification of the renal cystic disorders,
with the most common ones printed in bold
Nongenetic Genetic type. (Adapted from Fick and Gabow [1];
Welling and Grantham [2]; Pirson, et al. [3].)
Acquired disorders Autosomal-dominant
Simple renal cysts (solitary or multiple) Autosomal-dominant polycystic kidney disease
Cysts of the renal sinus (or peripelvic lymphangiectasis) Tuberous sclerosis complex
Acquired cystic kidney disease (in patients with von Hippel-Lindau disease
chronic renal impairment) Medullary cystic disease
Multilocular cyst (or multilocular cystic nephroma) Glomerulocystic kidney disease
Hypokalemia-related cysts Autosomal-recessive
Developmental disorders Autosomal-recessive polycystic kidney disease
Medullary sponge kidney Nephronophthisis
Multicystic dysplastic kidney X-linked
Pyelocalyceal cysts Orofaciodigital syndrome, type I
FIGURE 9-2
Characteristics of the most common renal cystic diseases detectable in the vast majority of patients. ADPKD—autosomal-dominant
by imaging techniques (ultrasonography, computed tomography, polycystic kidney disease; ARPKD—autosomal-recessive polycystic
magnetic resonance). In the context of family history and clinical kidney disease; CHF—congenital hepatic fibrosis; NPH—
findings, these allow the clinician to establish a definitive diagnosis nephronophthisis.
Cystic Diseases of the Kidney 9.3
Nongenetic Disorders
FIGURE 9-3
Solitary simple cyst. Large solitary cyst found incidentally at ultra-
sonography (longitudinal scan) in the lower pole of the right kid-
ney. Criteria for the diagnosis of simple cyst include absence of
internal echoes, rounded outline, sharply demarcated, smooth
walls, bright posterior wall echo (arrows). The latter occur because
less sound is absorbed during passage through cyst than through
the adjacent parenchyma. If these criteria are not satisfied, comput-
ed tomography can rule out complications and other diagnoses.
Prevalence, %
≥1 Cyst ≥2 Cysts* ≥3 Cysts* ≥1 Cyst in Each Kidney
Age group, y M F M F M F M F
15–29 0 0 0 0 0 0 0 0
30–49 2 1 0 1 0 1 0 1
50–69 15 7 2 1 1 1 2 1
≥70 32 15 17 8 6 3 9 3
FIGURE 9-4
Prevalence of simple renal cysts detected by ultrasonography increases with age and is higher in males. Cyst size also increases
according to age in an Australian population of 729 persons with age. Most simple cysts are located in the cortex. (From
prospectively screened by ultrasonography. The prevalence Ravine et al. [4]; with permission.)
9.4 Tubulointerstitial Disease
A B
FIGURE 9-5
A and B, Multiple simple cysts (one 7 cm in diameter in the lower Each cyst exhibits the typical features of an uncomplicated simple
pole of the left kidney and three 4 to 5 cm in diameter in the right cyst on CT: 1) homogeneous low density, unchanged by contrast
kidney) detected by contrast-enhanced computed tomography (CT). medium; 2) rounded outline; 3) very thin (most often indetectable)
Additional millimetric cysts might be suspected in both kidneys. wall; 4) distinct delineation from adjacent parenchyma.
A B
FIGURE 9-6
A, Contrast-enhanced computed tomography (CT) shows a Ultrasonographic appearance mimicked hydronephrosis. Also
simple, 3-cm wide cyst of the renal sinus (arrows) found during known as hilar lymphangiectasis or peripelvic (or parapelvic)
investigation of renal calculi. Note subcapsular hematoma cysts, this acquired disorder consists of dilated hilar lymph
(arrowheads) detected after lithotripsy. B, Contrast-enhanced channels. Its frequency is about 1% in autopsy series. Although
CT shows bilateral multiple cysts of the renal sinus, leading to usually asymptomatic, cysts of the renal sinus can cause severe
chronic compression of the pelvis and subsequent renal atrophy. urinary obstruction, B.
Cystic Diseases of the Kidney 9.5
A B
FIGURE 9-7
A, Acquired cystic kidney disease (ACKD) detected by contrast- hemodialysis and peritoneal dialysis, respectively [5]. In the early
enhanced computed tomography (CT) in a 71-year-old man on stage, kidneys are small or even shrunken and cysts are usually
hemodialysis for 4 years. A, Note the several intrarenal calcifica- smaller than 0.5 cm. Cyst numbers and kidney volume increase
tions, which are not unusual in dialysis patients. ACKD is charac- with time, as seen on this patient’s scan (B) repeated 8 years into
terized by the development of many cysts in the setting of chronic dialysis. Advanced ACKD can mimic autosomal-dominant polycys-
uremia. It can occur at any age, including childhood, whatever the tic disease. ACKD sometimes regresses after successful transplanta-
original nephropathy. The diagnosis is based on detection of at tion; it can involve chronically rejected kidney grafts. Although
least three to five cysts in each kidney in a patient who has chronic ACKD is usually asymptomatic it may be complicated by bleed-
renal failure but not hereditary cystic disease. The prevalence of ing—confined to the cysts or extending to either the collecting sys-
ACKD averages 10% at onset of dialysis treatment and subse- tem (causing hematuria) or the perinephric spaces—and associated
quently increases, to reach 60% and 90% at 5 and 10 years into with renal cell carcinoma. (Courtesy of M. Jadoul.)
FIGURE 9-8
Age <55 and > 3 years No Screening for acquired cystic kidney disease (ACKD) and renal neoplasms in patients receiv-
on RRT and good No
screening ing renal replacement therapy (RRT). The major clinical concern with ACKD is the risk of
clinical condition?
renal cell carcinoma, often the tubulopapillary type, associated with this disorder: the inci-
Yes dence is 50-times greater than in the general population. Moreover, ACKD-associated renal
No
carcinoma is more often bilateral and multicentric; however, only a minority of them evolve
Echography: into invasive carcinomas or cause metastases [5]. There is no doubt that imaging should be
ACKD? performed when a dialysis patient has symptoms such as flank pain and hematuria, the
Yes question of periodic screening for ACKD and neoplasms in asymptomatic dialysis patients
is still being debated. Using decision analysis incorporating morbidity and mortality associ-
No
Suspicion of ated with nephrectomy in dialysis patients, Sarasin and coworkers [6] showed that only the
Biennial echo
renal neoplasm? youngest patients at risk for ACKD benefit from periodic screening. On the basis of this
analysis, it has been proposed that screening be restricted to patients younger than 55 years,
Yes
who have been on dialysis at least 3 years and are in good general condition. Recognized
Enhanced CT: No risk factors for renal cell carcinoma in ACKD are male gender, uremia of long standing,
confirmed neoplasm? large kidneys, and analgesic nephropathy.
Yes
Nephrectomy
and annual
follow-up of
contralateral kidney
9.6 Tubulointerstitial Disease
FIGURE 9-9
Multilocular cyst (or multilocular cystic
nephroma) of the right kidney, detected by
ultrasonography (A) and contrast-enhanced
CT-scan (B). Both techniques show the
characteristic septa (arrow) dividing the
mass into multiple sonolucent locules. This
rare disorder is usually a benign tumor,
though some lesions have been found to
contain foci of nephroblastoma or renal
clear cell carcinoma. The imaging appear-
ance is actually indistinguishable from
those of the cystic forms of Wilms’ tumor
and renal clear cell carcinoma. (Courtesy
of A. Dardenne.)
A B
A B
FIGURE 9-10
A, contrast-enhanced computed tomography (CT) for evaluation
of a left renal stone in a 67-year-old man. A cystic mass was found
at the lower pole of the right kidney. Only careful examination
revealed that the walls of the mass (arrows) were too thick for a
simple cyst (see Fig. 9-5 for comparison). B, The echo pattern of
the mass was very heterogeneous (arrows), clearly different from
the echo-free appearance of a simple cyst (see Fig. 9-3 for compari-
son). C, Magnetic resonance imaging showed thick, irregular
walls and a hyperintense central area (arrows). At surgery, the
mass proved to be a largely necrotic renal cell carcinoma. Thus,
although renal carcinoma is not a true cystic disease, it occasional-
ly has a cystic appearance on CT and can mimic a simple cyst.
C (Courtesy of A. Dardenne.)
Cystic Diseases of the Kidney 9.7
FIGURE 9-11
Medullary sponge kidney (MSK) diagnosed by intravenous urography in 53-year-old
woman with a history of recurrent kidney stones. Pseudocystic collections of contrast medi-
um in the papillary areas (arrows) are the typical feature of MSK. They result from congen-
ital dilatation of collecting ducts (involving part or all of one or both kidneys), ranging
from mild ectasia (appearing on urography as linear striations in the papillae, or papillary
“blush”) to frank cystic pools, as in this case (giving a spongelike appearance on section of
the kidney). MSK has an estimated prevalence of 1 in 5000 [2]. It predisposes to stone for-
mation in the dilated ducts: on plain films, clustering of calcifications in the papillary areas
is very suggestive of the condition. MSK may be associated with a variety of other congeni-
tal and inherited disorders, including corporeal hemihypertrophy, Beckwith-Wiedemann
syndrome (macroglossia, omphalocele, visceromegaly, microcephaly, and mental retarda-
tion), polycystic kidney disease (about 3% of patients with autosomal-dominant polycystic
kidney disease have evidence of MSK), congenital hepatic fibrosis, and Caroli’s disease [7].
FIGURE 9-12
Multicystic dysplastic kidney (MCDK) found incidentally by
enhanced CT in a 34-year-old patient. The dysplastic kidney is
composed of cysts with mural calcifications (arrows). Note the
compensatory hypertrophy of the right kidney and the incidental
simple cysts in it. MCDK consists of a collection of cysts frequently
described as resembling a bunch of grapes and an atretic ureter. No
function can be demonstrated. Only unilateral involvement is com-
patible with life. Usually, the contralateral kidney is normal and
exhibits compensatory hypertrophy. In some 30% of cases, howev-
er, it is also affected by some congenital abnormalities such as dys-
plasia or pelviureterical junction obstruction. In fact, among the
many forms of renal dysplasia, MCDK is thought to represent a
cystic variety.
FIGURE 9-13
Intravenous urography demonstrates multiple calyceal diverticula
(arrows) in a 38-year-old woman who complained of intermittent
flank pain. Previously, the ultrasonographic appearance had sug-
gested the existence of polycystic kidney disease. Although usually
smaller than 1 cm in diameter, pyelocalyceal diverticula occasion-
ally are much larger, as in this case. They predispose to stone for-
mation. Since ultrasonography is the preferred screening tool for
cystic renal diseases, clinicians must be aware of both its pitfalls
(exemplified in this case and in the case of parapelvic cysts; see
Fig. 9-6) and its limited power to detect very small cysts.
9.8 Tubulointerstitial Disease
Genetic disorders
FIGURE 9-14
GENETICS OF ADPKD Genetics of autosomal-dominant polycystic kidney disease
(ADPKD). ADPKD is by far the most frequent inherited kidney dis-
ease. In white populations, its prevalence ranges from 1 in 400 to 1
Gene Chromosome Product Patients with ADPKD, % in 1000. ADPKD is characterized by the development of multiple
renal cysts that are variably associated with extrarenal (mainly
PKD1 16 Polycystin 1 80–90 hepatic and cardiovascular) abnormalities [1,2,3]. It is caused by
PKD2 4 Polycystin 2 10–20 mutations in at least three different genes. PKD1, the gene responsi-
PKD3 ? ? Very few ble in approximately 85% of the patients, located on chromosome
16, was cloned in 1994 [8]. It encodes a predicted protein of 460
kD, called polycystin 1. The vast majority of the remaining cases
are accounted for by a mutation in PKD2, located on chromosome
4 and cloned in 1996 [9]. The PKD2 gene encodes a predicted pro-
tein of 110 kD called polycystin 2. Phenotypic differences between
the two main genetic forms are detailed in Figure 9-19. The exis-
tence of (at least) a third gene is suggested by recent reports.
FIGURE 9-15
NH2 Autosomal-dominant polycystic kidney disease: predicted structure
of polycystin 1 and polycystin 2 and their interaction. Polycystin 1
Cysteine-rich domain
is a 4302-amino acid protein, which anchors itself to cell mem-
Leucine-rich domain branes by seven transmembrane domains [10]. The large extracel-
PKD1 domain lular portion includes two leucine-rich repeats usually involved in
C protein-protein interactions and a C-type lectin domain capable of
C L C-type lectin domain
L B binding carbohydrates. A part of the intracellular tail has the
B capacity to form a coiled-coil motif, enabling either self-assembling
Lipoprotein A domain or interaction with other proteins. Polycystin 2 is a 968-amino acid
R protein with six transmembrane domains, resembling a subunit of
E REJ domain
J voltage-activated calcium channel. Like polycystin 1, the C-termi-
nal end of polycystin 2 comprises a coiled-coil domain and is able
Transmembrane segment
to interact in vitro with PKD2 [11]. This C-terminal part of poly-
cystin 2 also includes a calcium-binding domain. On these grounds,
it has been hypothesized that polycystin 1 acts like a receptor and
Alpha helix coiled-coil signal transducer, communicating information from outside to
inside the cell through its interaction with polycystin 2. This coor-
R
E dinated function could be crucial during late renal embryogenesis.
J It is currently speculated that both polycystins play a role in the
Out
maturation of tubule epithelial cells. Mutation of polycystins could
Membrane
thus impair the maturation process, maintaining some tubular cells
in a state of underdevelopment. This could result in both sustained
In
cell proliferation and predominance of fluid secretion over absorp-
tion, leading to cyst formation (see Fig. 9-16 and references 12 and
NH2 13 for review). (From Hughes et al. [10] and Germino [12].)
HOOC
COOH
Polycystin 1 Polycystin 2
Cystic Diseases of the Kidney 9.9
FIGURE 9-17
Autosomal-dominant polycystic kidney disease (ADPKD): mecha-
nisms of intracystic fluid accumulation [13,14]. The primary mech-
Basolateral Aden
ylate Apical anism of intracystic fluid accumulation seems to be a net transfer
cycla
se of chloride into the lumen. This secretion is mediated by a
(CFTR) bumetanide-sensitive Na+-K+-2Cl- cotransporter on the basolateral
Na+ cAMP ATP
K+ Cl– side and cystic fibrosis transmembrane regulator (CFTR) chloride
2Cl– channel on the apical side. The activity of the two transporters is
PKA regulated by protein kinase A (PKA) under the control of cyclic
Bumetanide DPC
2K + adenosine monophosphate (AMP). The chloride secretion drives
+ + ATP movement of sodium and water into the cyst lumen through elec-
(Na -K -ATPase) Lumen trical and osmotic coupling, respectively. The pathway for transep-
3Na+ ADP + Pi
ithelial Na+ movement has been debated. In some experimental
H 2O conditions, part of the Na+ could be secreted into the lumen via a
Ouabain
(A P)
Q mispolarized apical Na+-K+-ATPase (“sodium pump”); however, it
H 2O
Na+ is currently admitted that most of the Na+ movement is paracellu-
lar and that the Na+-K+-ATPase is located at the basolateral side.
( AQP)
The movement of water is probably transcellular in the cells that
express aquaporins on both sides and paracellular in others [13,
14]. AQP—aquaporine; DPC—diphenylamine carboxylic acid.
9.10 Tubulointerstitial Disease
0.46
ADPKD: CLINICAL MANIFESTATIONS 1.0 (0.22-0.98)
20
FIGURE 9-18
10
Main clinical manifestations of autosomal-dominant polycystic kid-
ney disease (ADPKD). Renal involvement may be totally asympto- 0
matic at early stages. Arterial hypertension is the presenting clinical Clinical End-stage Death
finding in about 20% of patients. Its frequency increases with age. presentation renal failure
Flank or abdominal pain is the presenting symptom in another Median age
20%. The differential diagnosis of acute abdominal is detailed in
Figure 9-22. Gross hematuria is most often due to bleeding into a
cyst, and more rarely to stone. Renal infection, a frequent reason FIGURE 9-19
for hospital admission, can involve the upper collecting system, Autosomal-dominant polycystic kidney disease (ADPKD): pheno-
renal parenchyma or renal cyst. Diagnostic data are obtained by type PKD2 versus PKD1. Families with a PKD2 mutation have a
ultrasonography, excretory urography and CT: use of CT in cyst milder phenotype than those with a PKD1 mutation. In this study
infection is described in Figure 9-21. Frequently, stones are radiolu- comparing 306 PKD2 patients (from 32 families) with 288 PKD1
cent or faintly opaque, because of their uric acid content. The main patients (17 families), PKD2 patients were, for example, less likely
determinants of progression of renal failure are the genetic form of to be hypertensive, to have a history of renal infection, to suffer a
the disease (see Fig. 9-19) and gender (more rapid progression in subarachnoid hemorrhage, and to develop an abdominal hernia. As
males). Hepatobiliary and intracranial manifestations are detailed a consequence of the slower development of clinical manifestations,
in Figures 9-23 to 9-26. Pancreatic and arachnoid cysts are most PKD2 patients were, on average, 26 years older at clinical presen-
usually asymptomatic. Spinal meningeal diverticula can cause pos- tation, 14 years older when they started dialysis, and 5 years older
tural headache. ESRD—end-stage renal disease. when they died. Early-onset ADPKD leading to renal failure in
childhood has been reported only in the PKD1 variety. (Data from
Hateboer [24].)
Cystic Diseases of the Kidney 9.11
A B
C D
FIGURE 9-20
Autosomal-dominant polycystic kidney disease (ADPKD): kidney kidneys may be observed, as in this 36-year-old woman. In the early
involvement. Examples of various cystic involvements of kidneys in stage of the disease, making the diagnosis may be more difficult (see
ADPKD. Degree of involvement depends on age at presentation and Fig. 9-28 for the minimal sonographic criteria to make a diagnosis
disease severity. A, With advanced disease as in this 54-year-old of ADPKD in PKD1 families). C, D, Contrast-enhanced CT is more
woman, renal parenchyma is almost completely replaced by innu- sensitive than ultrasonography in the detection of small cysts. The
merable cysts. Note also the cystic involvement of the liver. B, presence of liver cysts helps to establish the diagnosis, as in this 38-
Marked asymmetry in the number and size of cysts between the two year-old man with PKD2 disease and mild kidney involvement.
9.12 Tubulointerstitial Disease
A B
FIGURE 9-21
Autosomal-dominant polycystic kidney disease (ADPKD): kidney antibiotherapy (fluoroquinolone). B, CT repeated 17 days later
cyst infection. Course of severe cyst infection in the right kidney of showed considerable enlargement of the infected cysts (arrows).
a patient with ADPKD who was admitted for fever and acute right Percutaneous drainage failed to control infection, and nephrectomy
flank pain. Blood culture was positive for Escherichia coli. A, CT was necessary. This case illustrates the potential severity of cyst
performed on admission showed several heterogeneous cysts in the infection and the contribution of sequential CT in the diagnosis
right kidney (arrows). Infection did not respond to appropriate and management of complicated cysts.
FIGURE 9-22
ADPKD: SPECIFIC CAUSES OF Autosomal-dominant polycystic kidney disease (ADPKD): specific
ACUTE ABDOMINAL PAIN causes of acute abdominal pain. The most frequent cause of acute
abdominal pain related to ADPKD is intracyst bleeding. Depending
on the amount of bleeding, it may cause mild, transient fever. It may
Cause Frequency Fever or may not cause gross hematuria. Cyst hemorrhage is responsible for
most high-density cysts and cyst calcifications demonstrated by CT.
Renal Spontaneous resolution is the rule. Excretory urography or enhanced
Cyst Bleeding ++++ Mild (<38°C, maximum 2 days) or none CT is needed mostly to locate obstructive, faintly opaque stones.
Stone ++ With pyonephrosis Stones may be treated by percutaneous or extracorporal lithotripsy.
Infection + High; prolonged with cyst involved Renal infection may involve the upper collecting system,
Liver Cyst renal parenchyma, or cyst. Parenchymal infection is evidenced
Infection Rare High, prolonged by positive urine culture and prompt response to antibiotherapy;
Bleeding Very Rare Mild (<38°C, maximum 2 days) or none cyst infection by the development of a new area of renal tenderness,
quite often a negative urine culture (but a positive blood culture),
and a slower response to antibiotherapy. CT demonstrates the het-
erogeneous contents and irregularly thickened walls of infected
cysts. Cyst infection warrants prolonged anti-biotherapy [3]. An
example of severe, intractable cyst infection is shown in Figure 9-21.
Cystic Diseases of the Kidney 9.13
Finding Frequency
Asymptomatic liver cysts Very common; increased prevalence with
age (up to 80% at age 60)
Symptomatic polycystic liver disease Uncommon (male/female ratio: 1/10)
Complicated cysts (hemorrhage,
infection)
Massive hepatomegaly
Chronic pain/discomfort
Early satiety
Supine dyspnea
Abdominal hernia
Obstructive jaundice
Hepatic venous outflow obstruction
Congenital hepatic fibrosis Rare (not dominantly transmitted)
Idiopathic dilatation of intrahepatic or Very rare
extrahepatic biliary tract
Cholangiocarcinoma Very rare
FIGURE 9-24
Autosomal-dominant polycystic kidney disease (ADPKD): polycys-
tic liver disease. Contrast-enhanced CT in a 32-year-old woman
FIGURE 9-23 with ADPKD, showing massive polycystic liver disease contrasting
Autosomal-dominant polycystic kidney disease (ADPKD): hepato- with mild kidney involvement.
biliary manifestations. Liver cysts are the most frequent extrarenal Massive polycystic liver disease can cause chronic pain, early
manifestation of ADPKD. Their prevalence increases dramatically satiety, supine dyspnea, abdominal hernia, and, rarely, obstructive
from the third to the sixth decade of life, reaching a plateau of 80% jaundice, or hepatic venous outflow obstruction. Therapeutic
thereafter [25, 26]. They are observed earlier and are more numer- options include cyst sclerosis and fenestration, hepatic resection,
ous and extensive in women than in men. Though usually mild and and, ultimately, liver transplantation [25, 26].
asymptomatic, cystic liver involvement occasionally is massive and
symptomatic (see Figure 9-24). Rare cases have been reported of
congenital hepatic fibrosis or idiopathic dilatation of the intrahepatic
or extrahepatic tract associated with ADPKD [25, 26].
A B
FIGURE 9-25
Autosomal-dominant polycystic kidney disease (ADPKD): ICA rupture in ADPKD is ill-defined. ICA rupture entails 30% to
intracranial aneurysm detection. Magnetic resonance angiogra- 50% mortality. It is generally manifested by subarachnoid hemor-
phy (MRA), A, and spiral computed tomography (CT) angiogra- rhage, which usually presents as an excruciating headache. In this
phy, B, in two different patients, both with ADPKD, show an setting, the first-line diagnostic procedure is CT. Management
asymptomatic intracranial aneurysm (ICA) on the posterior com- should proceed under neurosurgical guidance [27].
municating artery (arrow), A, and the anterior communicating Given the severe prognosis of ICA rupture and the possibility
artery (arrow), B, respectively. of prophylactic treatment, screening ADPKD patients for ICA has
The prevalence of asymptomatic ICA in ADPKD is 8%, as been considered. Screening can be achieved by either MRA or spi-
compared with 1.2% in the general population. It reaches 16% ral CT angiography. Current indications for screening are present-
in ADPKD patients with a family history of ICA [27]. The risk of ed in Figure 9-26. (Courtesy of T. Duprez and F. Hammer.)
9.14 Tubulointerstitial Disease
FIGURE 9-26
Age 18–40 years No Autosomal-dominant polycystic kidney disease (ADPKD): intracranial aneurysm (ICA)
and family history No
screening. On the basis of decision analyses (taking into account ICA prevalence, annual
of ICA? screening
risk of rupture, life expectancy, and risk of prophylactic treatment), it is currently pro-
Yes posed to screen for ICA 18 to 40-year-old ADPKD patients with a family history of ICA
[25, 27]. Screening could also be offered to patients in high-risk occupations and those
Brain MR angiography No
or spiral CT scan: Repeat every who want reassurance. Guidelines for prophylactic treatment are the same ones used in
ICA? 5 years the general population: the neurosurgeon and the interventional radiologist opt for either
surgical clipping or endovascular occlusion, depending on the site and size of ICA.
Yes
Conventional
angiography
Discuss management
with neurosurgeon
Presymptomatic diagnosis
Is advisable in families when early management of affected patients would be altered Age Cysts
(eg, because of history of intracranial aneurysm)
15–29 2, uni- or bilateral
Should be made available to persons at risk who are 18 years or older who request
the test 30–59 2 in each kidney
Should be preceded by information about the possibility of inconclusive results and ≥60 4 in each kidney
the consequences of the diagnosis:
If negative, reassurance Minimal number of cysts to establish a diagnosis of ADPKD in PKD1 families at risk.
If positive, regular medical follow-up, possible psychological burden,
risk of disqualification from employment and insurances
FIGURE 9-28
Autosomal-dominant polycystic kidney disease (ADPKD): ultra-
sonographic diagnostic criteria. Ultrasound diagnostic criteria for
FIGURE 9-27 the PKD1 form of ADPKD, as established by Ravine’s group on the
Autosomal-dominant polycystic kidney disease (ADPKD): presymp- basis of both a sensitivity and specificity study [4, 28]. Note that
tomatic diagnosis. Presymptomatic diagnosis is aimed at both detect- the absence of cyst before age 30 years does not rule out the diag-
ing affected persons (to provide follow-up and genetic counseling) nosis, the false-negative rate being inversely related to age. When
and reassuring unaffected ones. Until a specific treatment for ADPKD ultrasound diagnosis remains equivocal, the next step should be
is available, presymptomatic diagnosis in children is not advised either contrast-enhanced CT (more sensitive than ultrasonography
except in rare families where early-onset disease is typical. Presymp- in the detection of small cysts) or gene linkage (see Figure 9-29). A
tomatic diagnosis is recommended when a family is planned and similar assessment is not yet available for the PKD2 form. (From
when early management of affected patients would be altered. The Ravine et al. [28]; with permission.)
mainstay of screening is ultrasonography; diagnostic echographic
criteria according to age in PKD1 families are depicted in Figure 9-28,
and diagnosis by gene linkage in Figure 9-29.
Cystic Diseases of the Kidney 9.15
FIGURE 9-29
Deceased Example of the use of gene linkage to identify ADPKD gene carriers
I ? ? Unaffected among generation IV of a PKD1 family. Two markers flanking the
1 2 Affected PKD1 gene were used. The first one (3’ HVR) has six possible alle-
? Unknown status les (1 through 6) and the other (p 26.6) is biallelic (a, b). In this
family, the haplotype 2a is transmitted with the disease (see affected
persons II5, III1, and III3). Thus, IV4 has a 99% chance of being a
carrier of the mutated PKD1 gene, whereas her sisters (IV1, IV2,
II IV3) have a 99% chance of being disease free.
1 2 3 4 5
Until direct gene testing for PKD1 and PKD2 is readily available,
1 1 genetic diagnosis will rest on gene linkage. Such analysis requires
b b that other affected and unaffected family members (preferably from
III
1 2 3 two generations) be available for study. Use of markers on both
sides of the tested gene is required to limit potential errors due to
2 3 2 5 4 2
a b b a a a recombination events. Linkage to PKD1 is to be tested first, as it
accounts for about 85% of cases.
IV ? ? ? ?
1 2 3 4
2 3 3 2 3 5 2 5
b b b b b a a a
FIGURE 9-30
Life expectancy <5 yrs Autosomal-dominant polycystic kidney disease (ADPKD): renal
or contraindication to surgery Yes replacement therapy. Transplantation nowadays is considered in any
or to immunosuppressants? ADPKD patient with a life expectancy of more than 5 years and
No with no contraindications to surgery or immunosuppression.
Pretransplant workup should include abdominal CT, echocardiogra-
Pretransplant workup: phy, myocardial stress scintigraphy, and, if needed (see Figure 9-26),
Yes Eligibility for transplantation? screening for intracranial aneurysm. Pretransplant nephrectomy is
advised for patients with a history of renal cyst infection, particularly
No if the infections were recent, recurrent, or severe. Patients not eligible
History of No
cyst infection? for transplantation may opt for hemodialysis or peritoneal dialysis.
Very large kidneys Yes Although kidney size is rarely an impediment to peritoneal dialysis,
Yes or abdominal hernia?
this option is less desirable for patients with very large kidneys,
No because their volume may reduce the exchangeable surface area and
Remove the tolerance for abdominal distension. Outcome for ADPKD
kidney(s)? or
patients following renal replacement therapy is similar to that of
matched patients with another primary renal disease [29, 30].
Transplantation Peritoneal dialysis Hemodialysis
9.16 Tubulointerstitial Disease
FIGURE 9-31
CLINICAL FEATURES Tuberous sclerosis complex (TSC): clinical features. TSC is an auto-
somal-dominant multisystem disorder with a minimal prevalence of
1 in 10,000 [30, 31]. It is characterized by the development of mul-
Finding Frequency, % Age at onset, y tiple hamartomas (benign tumors composed of abnormally arranged
and differentiated tissues) in various organs. The most common
Skin manifestations are dermatologic (see Fig. 9-32) and neurologic (see
Hypomelanotic macules 90 Childhood Fig. 9-33). Renal involvement occurs in 60% of cases and includes
Facial angiofibromas 80 5–15
Forehead fibrous plaques 30 ≥5
cysts (see Fig. 9-34). Retinal involvement, occurring in 50% of
“Shagreen patches” (lower back) 30 ≥10 cases, is almost always asymptomatic. Liver involvement, occurring
Periungual fibromas 30 ≥15 in 40% of cases, includes angiomyolipomas and cysts. Involvement
Central nervous system of other organs is much rarer [31, 32].
Cortical tubers 90 Birth
Subependymal tumors 90 Birth
(may be calcified)
focal or generalized seizures 80 0–1
Mental retardation/ 50 0–5
behavioral disorder
Kidney
Angiomyolipomas 60 Childhood
Cysts 30 Childhood
Renal cell carcinoma 2 Adulthood
Eye
Retinal hamartoma 50 Childhood
Retinal pigmentary abnormality 10 Childhood
Liver (angiomyolipomas, cysts) 40 Childhood
Heart (rhabdomyoma) 2 Childhood
Lung (lymphangiomyomatosis; 1 ≥20
affects females)
B
FIGURE 9-32 (see Color Plate)
Tuberous sclerosis complex (TSC): skin involvement. Facial angiofibromas, forehead
plaque, A, and ungual fibroma, B, characteristic of TSC. Previously (and inappropriately)
called adenoma sebaceum, facial angiofibromas are pink to red papules or nodules, often
concentrated in the nasolabial folds. Forehead fibrous plaques appear as raised, soft patch-
es of red or yellow skin. Ungual fibromas appear as peri- or subungual pink tumors; they
are found more often on the toes than on the fingers and are more common in females.
Other skin lesions include hypomelanotic macules and “shagreen patches” (slightly elevated
A patches of brown or pink skin). (Courtesy of A. Bourloud and C. van Ypersele.)
Cystic Diseases of the Kidney 9.17
FIGURE 9-33
Tuberous sclerosis complex (TSC): central nervous system involvement. Brain CT shows
several subependymal, periventricular, calcified nodules characteristic of TSC. Subependymal
tumors and cortical tubers are the two characteristic neurologic features of TSC. Calcified
nodules are best seen on CT, whereas noncalcified tumors are best detected by magnetic
resonance imaging. Clinical manifestations are seizures (including infantile spasms) occur-
ring in 80% of infants, and varying degrees of intellectual disability or behavioral disorder,
reported in 50% of children [32].
A B
FIGURE 9-34
Tuberous sclerosis complex (TSC): kidney involvement. Contrast- of fat into the tumor, but it is not always possible to distinguish
enhanced CT, A, and gadolinium-enhanced T1 weighted magnetic between AML and renal cell carcinoma. The main complication of
resonance images, B, of a 15-year-old woman with TSC, show AML is bleeding with subsequent gross hematuria or potentially life-
both a large, hypodense, heterogeneous tumor in the right kidney threatening retroperitoneal hemorrhage.
(arrows) characteristic of angiomyolipoma (AML) and multiple Cysts seem to be restricted to the TSC2 variety (see Fig. 9-35)
bilateral kidney cysts. Kidney cysts had been detected at birth. [33]. Their extent varies widely from case to case. Occasionally,
AML is a benign tumor composed of atypical blood vessels, polycystic kidneys are the presenting manifestation of TSC2 in early
smooth muscle cells, and fat tissue. While single AML is the most childhood: in the absence of renal AML, the imaging appearance is
frequent kidney tumor in the general population, multiple and bilat- indistinguishable from ADPKD. Polycystic kidney involvement leads
eral AMLs are characteristic of TSC. In TSC, AMLs develop at a to hypertension and renal failure that reaches end stage before age
younger age in females; frequency and size of the tumors increase 20 years. Though the frequency of renal cell carcinoma in TSC is
with age. Diagnosis of AML by imaging techniques (ultrasonography small, the incidence is increased as compared with that of the gener-
[US], CT, magnetic resonance imagine [MRI]) relies on identification al population. (Courtesy of J. F. De Plaen and B. Van Beers.)
9.18 Tubulointerstitial Disease
FIGURE 9-37
Von Hippel-Lindau disease (VHL): central nervous system involve-
ment. Gadolinium-enhanced brain magnetic resonance image of a
patient with VHL, shows a typical cerebellar hemangioblastoma,
appearing as a highly vascular nodule (arrow) in the wall of a cyst
(arrowheads) located in the posterior fossa. Hemangioblastomas are
benign tumors whose morbidity is due to mass effect. Cerebellar
hemangioblastomas may present with symptoms of increased
intracranial pressure. Spinal cord involvement may be manifested
as syringomyelia. (Courtesy of S. Richard.)
Cystic Diseases of the Kidney 9.19
FIGURE 9-40
Von Hippel-Lindau disease (VHL): adrenal gland involvement.
FIGURE 9-39 Gadolinium-enhanced abdominal magnetic resonance image of a
Von Hippel-Lindau disease (VHL): kidney involvement. Contrast- patient with VHL shows bilateral pheochromocytoma (arrows).
enhanced CT of a patient with VHL, showing the polycystic aspect Renal lesions include cysts and solid carcinomas (arrow heads).
of the kidneys. Renal involvement of VHL includes cysts (simple, Pheochromocytoma may be the first manifestation of VHL. It
atypical, and cystic carcinoma) and renal cell carcinoma [36, 37]. tends to cluster within certain VHL families [36]. (Courtesy of
The latter is the leading cause of death from VHL. Occasionally, H. Neumann.)
polycystic kidney involvement may mimic autosomal-dominant
polycystic kidney disease. Both cystic involvement and sequelae
of surgery can lead to renal failure. Nephron-sparing surgery is
recommended [37].
9.20 Tubulointerstitial Disease
FIGURE 9-41
Von Hippel-Lindau disease (VHL): pancreas involvement. Contrast-
enhanced abdominal CT in a patient with VHL shows multiple cysts
in both pancreas (especially the tail, arrows) and kidneys. The major-
ity of pancreatic cysts are asymptomatic. When they are numerous
and large, they can induce diabetes mellitus or steatorrhea. Other,
rare pancreatic lesions include microcystic adenoma, islet cell tumor,
and carcinoma.
FIGURE 9-42
VHL: SCREENING PROTOCOL Von Hippel-Lindau disease. As most manifestations of VHL are
potentially treatable, periodic examination of affected patients is
strongly recommended. Though genetic testing is now very useful
Study Affected persons Relatives at risk for presymptomatic identification of affected persons, it must be
remembered that a mutation in the VHL gene currently is detected
Physical examination Annual Annual in only 70% of families. For persons at risk in the remaining families,
24-h Urine collection for Annual Annual a screening program is also proposed.
metadrenaline and
normetadrenaline
Funduscopy Annual Annual (age 5 to 60)
Gadolinium MRI brain scan Every 3 y (from age 10) Every 3 y (age 15 to 60)
Abdomen Annual gadolinium MRI Annual echography or
gadolinium MRI
(age 15 to 60)
FIGURE 9-43
Medullary cystic disease (MCD). Contrast-enhanced CT in a 35-
year-old man with MCD. Multiple cysts are seen in the medullary
area. Two daughters were also found to be affected. MCD is a very
rare autosomal-dominant disorder characterized by medullary cysts
detectable by certain imaging techniques (preferably computed
tomography) and progressive renal impairment leading to end-
stage disease between 20 and 40 years of age. Dominant inheri-
tance and early detection of kidney cysts distinguish MCD from
autosomal-recessive nephronophthisis (see Fig. 9-48), even though
the two may be indistinguishable on histologic examination.
Cystic Diseases of the Kidney 9.21
THERE IS A WHITE
BOX PLACED OVER
HANDWRITTEN
TYPE.
A
B
multiple cysts, typically small cortical ones. This cystic pattern was
verified in the nephrectomy specimen, B, obtained 8 months later
at the time of kidney transplantation, and GCKD was confirmed
by histopathologic examination with Masson’s trichrome stain.
C, Cysts consisted of a dilatation of Bowman’s space surrounding
a primitive-looking glomerulus.
C GCKD may be sporadic or genetically dominant. Among the
familial cases, some patients are infants who have early-onset auto-
FIGURE 9-44 somal-dominant polycystic disease. In others (children or adults) the
Glomerulocystic kidney disease (GCKD). Contrast-enhanced CT, A, disease is unrelated to PKD1 and PKD2 and may or not progress to
in a 23-year-old woman with the sporadic form of GCKD shows end-stage renal failure [38]. (Courtesy of D. Droz.)
FIGURE 9-45
ARPKD: CLINICAL MANIFESTATIONS Autosomal-recessive polycystic kidney disease (ARPKD): clinical man-
ifestations. ARPKD is characterized by the development of cysts origi-
nating from collecting tubules and ducts, invariably associated with
Renal congenital hepatic fibrosis. Its prevalence is about 1 in 40,000 [39].
Antenatal (ultrasonographic changes) In the most severe cases, with marked oligohydramnios and an empty
Oligohydramnios with empty bladder
bladder, the diagnosis may be suspected as early as the 12th week of
Increased renal volume and echogenicity
gestation. Some neonates die from either respiratory distress or renal
failure. In most survivors, the disease is recognized during the first
Neonatal period
year of life. The ultrasonographic (US) kidney appearance is depicted
Dystocia and oligohydramnios
in Figure 9-46. Excretory urography shows medullary striations
Enlarged kidneys
owing to tubular ectasia. Kidney enlargement may regress with time.
Renal failure
End-stage renal failure develops before age 25 in 70% of patients.
Respiratory distress with pulmonary hypoplasia (possibly fatal)
Liver involvement consists of portal fibrosis (see Fig. 9-47) and
Infancy of childhood
intrahepatic bilary ectasia, frequently resulting in portal hypertension
Nephromegaly (may regress with time)
(leading to hypersplenism and esophageal varices) and less often in
Hypertension (often severe in the first year of life) cholangitis, respectively. US may show dilatation of the biliary ducts,
Chronic renal failure (slowly progressive, with a 60% probability of renal survival at and even cysts. The respective severity of kidney and liver involve-
15 years of age and 30% at 25 years of age)
ment vary widely between families and even in a single kindred.
Hepatic
A comparison of the diagnostic features of autosomal-dominant
Portal fibrosis
polycystic kidney disease (ADPKD) and ARPKD is summarized in
Intrahepatic biliary tract ectasia
Figure 9-2. Renal US of the parents of a child with ARPKD is, of
course, normal. It should be noted that congenital hepatic fibrosis is
found in rare cases of ADPKD with early-onset renal disease. The
gene responsible for ARPKD has been mapped to chromosome 6.
There is no evidence of genetic heterogeneity [40].
9.22 Tubulointerstitial Disease
FIGURE 9-46
A and B, Autosomal-recessive polycystic
kidney disease (ARPKD): renal imaging. On
ultrasonography of a child with ARPKD
the kidneys appear typically enlarged and
uniformly hyperechogenic (owing to the
presence of multiple small cysts), and
demarcations of cortex, medulla, and sinus
are lost. The ultrasonographic appearance
is different in older children, because cysts
can grow and become round; then they
resemble the appearance of ADPKD. Figure
9-2 describes how to differentiate the two
conditions. (Courtesy of P. Niaudet.)
A B
FIGURE 9-49
NPH: EXTRARENAL INVOLVEMENT Nephronophthisis (NPH): extrarenal involvement. Extrarenal involve-
ment occurs in 20% of NPH cases. The most frequent finding is
tapetoretinal degeneration (known as Senior-Loken syndrome), which
Retinitis pigmentosa (Senior-Loken syndrome) often results in early blindness or progressive visual impairment.
Multiple organ involvement, including Other rare manifestations include liver (hepatomegaly, hepatic fibro-
Liver fibrosis
sis), bone (cone-shaped epiphysis), and central nervous system (mental
retardation, cerebellar ataxia) abnormalities, quite often in association.
Other rare features
Skeletal changes (cone-shaped epiphyses)
Cerebellar ataxia
Mental retardation
A B
FIGURE 9-50
Orofaciodigital syndrome (OFD). Contrast-enhanced CT, Characteristic dysmorphic features include oral (hyperplastic
A, and the hands, B, of a 26-year-old woman with OFD type 1 frenulum, cleft tongue, cleft palate or lip, malposed teeth), facial
(OFD1) [43]. Multiple cysts involve both kidneys. Note that (asymmetry, broad nasal root), and digit (syn-brachy-polydacty-
they are smaller and more uniform than in ADPKD and that ly) abnormalities. Mental retardation is present in about half the
renal contours are preserved. Some cysts were also detected in cases. Kidneys may be involved by multiple (usually small) cysts,
liver and pancreas (arrow). Syndactyly was surgically corrected, mostly of glomerular origin; renal failure occurs between the
and the digits of the hands are shortened (brachydactyly). second and the seventh decade of life. Recognition of the dys-
OFD1 is a rare X-linked, dominant disorder, diagnosed morphic features is the key to the diagnosis [44, 45]. (Courtesy
almost exclusively in females, as affected males die in utero. of F. Scolari.)
References
1. Fick GM, Gabow PA: Hereditary and acquired cystic disease of the 6. Sarasin FP, Wong JB, Levey AS, Meyer KB: Screening for acquired
kidney. Kidney Int 1994, 46:951–964. cystic kidney disease: A decision analytic perspective. Kidney Int
2. Welling LW, Grantham JJ: Cystic and developmental diseases of the 1995, 48:207–219.
kidney. In The Kidney. Edited by Brenner M. Philadelphia:WB 7. Hildebrandt F, Jungers P, Grünfeld JP: Medullary cystic and medullary
Saunders Company; 1996:1828–1863. sponge renal disorders. In Diseases of the Kidney. Edited by Schrier
RW, Gottschalk CW. Boston: Little Brown; 1997:499–520.
3. Pirson Y, Chauveau D, Grünfeld JP: Autosomal dominant polycystic
kidney disease. In Oxford Textbook of Clinical Nephrology. Edited 8. The European Polycystic Kidney Disease Consortium: The polycystic
kidney disease 1 gene encodes a 14 kb transcript and lies within a
by Davison AM, Cameron JS, Grünfeld JP, et al. Oxford:Oxford duplicated region on chromosome 16. Cell 1994, 77:881–894.
University Press; 1998:2393–2415.
9. Mochizuki T, Wu G, Hayashi T, et al.: PKD2, a gene for polycystic
4. Ravine D, Gibson RN, Donlan J, Sheffield LJ: An ultrasound renal kidney disease that encodes an integral membrane protein. Science
cyst prevalence survey: Specificity data for inherited renal cystic dis- 1996, 272:1339–1342.
eases. Am J Kidney Dis 1993, 22:803–807. 10. Hughes J, Ward CJ, Peral B, et al.: The polycystic kidney disease 1
5. Levine E: Acquired cystic kidney disease. Radiol Clin North Am (PKD1) gene encodes a novel protein with multiple cell recognition
1996, 34:947–964. domains. Nature Genet 1995, 10:151–160.
9.24 Tubulointerstitial Disease
11. Qian F, Germino FJ, Cai Y, et al.: PKD1 interacts with PKD2 through 30. Culleton B, Parfrey PS: Management of end-stage renal failure and
a probable coiled-coil domain. Nature Genet 1997, 16:179–183. problems of transplantation in autosomal dominant polycystic kidney
12. Germino GG: Autosomal dominant polycystic kidney disease: a two- disease. In Polycystic Kidney Disease. Edited by Watson ML, Torres
hit model. Hospital Pract 1997, 81–102. VE. Oxford:Oxford University Press; 1996:450–461.
13. Grantham JJ: The etiology, pathogenesis, and treatment of autosomal 31. Torres VE: Tuberous sclerosis complex. In Polycystic Kidney Disease.
dominant polycystic kidney disease: Recent advances. Am J Kidney Edited by Watson ML, Torres VE. Oxford:Oxford University Press;
Dis 1996, 28:788–803. 1996:283–308.
14. Devuyst O, Beauwens R: Ion transport and cystogenesis: The para- 32. Huson SM, Rosser EM: The Phakomatoses. In Principles and Practice
digm of autosomal dominant polycystic kidney disease. Adv Nephrol of Medical Genetics. Edited by Rimoin DL, Connor JM, Pyeritz RE.
1998, (in press). New York:Churchill Livingstone; 1997: 2269–2302.
15. Parfrey PS, Barrett BJ: Hypertension in autosomal dominant polycys- 33. Sampson JR, Maheshwar MM, Aspinwall R, et al.: Renal cystic dis-
tic kidney disease. Curr Opin Nephrol Hypertens 1995, 4:460–464. ease in tuberous sclerosis: Role of the polycystic kidney disease 1
gene. Am J Human Genet 1997, 61:843–851.
16. Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J
Med 1993, 329:332–342. 34. Jones AC, Daniells CE, Snell RG, et al.: Molecular genetic and pheno-
typic analysis reveals differences between TSC1 and TSC2 associated
17. Torres WE, Wilson DM, Hattery RR, Segura JW: Renal stone disease
familial and sporadic tuberous sclerosis. Hum Molec Genet 1997,
in autosomal dominant polycystic kidney disease. Am J Kidney Dis
6:2155–2161.
1993, 22:513–519.
35. Michels V: Von Hippel-Lindau disease. In Polycystic Kidney Disease.
18. Choukroun G, Itakura Y, Albouze G, et al.: Factors influencing pro-
Edited by Watson ML, Torres VE. Oxford:Oxford University Press;
gression of renal failure in autosomal dominant polycystic kidney dis-
1996:309–330.
ease. J Am Soc Nephrol 1995, 6:1634–1642.
36. Neumann HPH, Zbar B: Renal cysts, renal cancer and von Hippel-
19. Schievink WI, Torres VE, Wiebers DO, Huston J III: Intracranial arterial
Lindau disease. Kidney Int 1997, 51:16–26.
dolichoectasia in autosomal dominant polycystic kidney disease. J Am
Soc Nephrol 1997, 8:1298–1303. 37. Chauveau D, Duvic C, Chretien Y, et al.: Renal involvement in von
Hippel-Lindau disease. Kidney Int 1996, 50:944–951.
20. Torra R, Nicolau C, Badenas C, et al.: Ultrasonographic study of pan-
creatic cysts in autosomal dominant polycystic kidney disease. Clin 38. Sharp CK, Bergman SM, Stockwin JM, et al.: Dominantly transmitted
Nephrol 1997, 47:19–22. glomerulocystic kidney disease: A distinct genetic entity. J Am Soc
Nephrol 1997, 8:77–84.
21. Schievink WI, Huston J III, Torres VA, Marsh WR: Intracranial cysts
in autosomal dominant polycystic kidney disease. J Neurosurg 1995, 39. Gagnadoux MF, Broyer M: Polycystic kidney disease in children. In
83:1004–1007. Oxford Textbook of Clinical Nephrology. Edited by Davison AM,
Cameron JS, Grünfeld JP, et al. Oxford:Oxford University Press;
22. Gabow PA: Autosomal dominant polycystic kidney disease—more
1998:2385–2393.
than a renal disease. Am J Kidney Dis 1990, 16:403–413.
40. Zerres K, Mücher G, Bachner L, et al.: Mapping of the gene for auto-
23. Schievink WI, Torres VE: Spinal meningeal diverticula in autosomal
somal recessive polycystic kidney disease (ARPKD) to chromosome
dominant polycystic kidney disease. Lancet 1997, 349:1223–1224.
6p21-cen. Nature Genet 1994, 7:429–432.
24. Hateboer N, Dijk M, Torra R, et al.: Phenotype PKD2 vs. PKD1;
41. Antignac C, Arduy CH, Beckmann JS, et al.: A gene for familial juve-
results from the European concerted action. J Am Soc Nephrol 1997,
nile nephronophthisis (recessive medullary cystic kidney disease) maps
8:373A.
to chromosome 2p. Nature Genet 1993, 3:342–345.
25. Chauveau D, Pirson Y, Le Moine A, et al.: Extrarenal manifestations
42. Hildebrandt F, Otto E, Rensing C, et al.: A novel gene encoding an
in autosomal dominant polycystic kidney disease. Adv Nephrol 1997,
SH3 domain protein is mutated in nephronophthisis type 1. Nature
26:265–289.
Genet 1997, 17:149–153.
26. Torres VE: Polycystic liver disease. In Polycystic Kidney Disease.
43. Konrad M, Saunier S, Heidet L, et al.: Large homozygous deletions of
Edited by Watson ML, Torres VE. Oxford: Oxford University Press;
the 2q13 region are a major cause of juvenile nephronophthisis. Hum
1996:500–529.
Molec Genet 1996, 5: 367–371.
27. Pirson Y, Chauveau D: Intracranial aneurysms in autosomal dominant
44. Scolari F, Valzorio B, Carli O, et al.: Oral-facial-digital syndrome type
polycystic kidney disease. In Polycystic Kidney Disease. Edited by
I: An unusual cause of hereditary cystic kidney disease. Nephrol Dial
Watson ML, Torres VE. Oxford:Oxford University Press;
Transplant 1997, 12:1247–1250.
1996:530–547.
45. Feather SA, Winyard PJD, Dodd S, Woolf AS: Oral-facial-digital syn-
28. Ravine D, Gibson RN, Walker RG, et al.: Evaluation of ultrasono-
drome type 1 is another dominant polycystic kidney disease: Clinical,
graphic diagnostic criteria for autosomal dominant polycystic kidney
radiological and histopathological features of a new kindred. Nephrol
disease 1. Lancet 1994, 343:824–827.
Dial Transplant 1997, 12:1354–1361.
29. Pirson Y, Christophe JL, Goffin E: Outcome of renal replacement
therapy in autosomal dominant polycystic kidney diseases. Nephrol
Dial Transplant 1996, 11 (suppl. 6):24–28.
Toxic Nephropathies
Jean-Louis Vanherweghem
T
ubular interstitial structures of the kidney are particularly vul-
nerable in face of toxic compounds. High concentration of the
toxics in de medulla as well as medullary hypoxia and renal
hypoperfusion could explain this particularity. Clinical nephrotoxici-
ty involves toxins of diverse origin. The culprits are often registered
and non registered drugs either prescribed or purchased over the
counter. Other major causes result from occupational and industrial
exposures. Sometimes, the identification of the nephrotoxin requires
astuteness and long investigations especially in cases of environmental
toxins or prolonged intake of unregulated drugs or natural products.
A correct diagnosis of the causes is, however, the key for future pre-
vention of renal diseases. The diagnosis of “chronic interstitial nephri-
tis of unknown origin” should, therefore, no longer be used.
CHAPTER
10
10.2 Tubulointerstitial Disease
Exposure to Nephrotoxins
FIGURE 10-1
TOXIC CAUSES OF CHRONIC Chronic exposure to drugs, occupational hazards, or environmental
TUBULOINTERSTITIAL RENAL DISEASES toxins can lead to chronic interstitial renal diseases. The following
are the major causes of chronic interstitial renal diseases: occupation-
al exposure to heavy metals; abuse of over-the-counter analgesics;
Metals (Environmental or Occupational Exposure) misuse of germanium; chronic intake of mesalazine for intestinal dis-
Lead orders, lithium for depression, and cyclosporine in renal and nonre-
Cadmium
nal diseases; and environmental or iatrogenic exposure to fungus or
plant nephrotoxins (ochratoxins, aristolochic acids).
Drugs or Additives (Use, Misuse, or Abuse)
Lithium
Germanium
Analgesics
Cyclosporine
Mesalazine
Fungus and Plant Toxins (Environmental or Iatrogenic Exposure)
Ochratoxins
Aristolochic acids
Exposure to Metals
FIGURE 10-2
30
Occupational exposure to metals and risks for chronic renal fail-
25 ure. Comparison of the occupational histories of 272 patients with
(95% confidence intervals)
0
Mercury Tin Chromium Copper Lead Cadmium
Lead nephropathy
Environmental Gout
Eating paint from lead-painted furniture, woodwork, and toys in children Arterial hypertension
Lead-contaminated flour Renal failure (interstitial type)
Home lead-contaminated drinking water from lead pipes
Drinking of moonshine whiskey
Occupational
Lead-producing plants: lead smelters, battery plants FIGURE 10-4
Gout and hypertension are the major clinical manifestations of lead
nephropathy. The prominent feature of early hyperuricemia in lead
nephropathy may explain the confusion between lead nephropathy
FIGURE 10-3 and gout nephropathy. Lead urinary excretion after ethylenedi-
Lead nephropathy associated with environmental and occupational amine tetraacetic acid (EDTA)–lead mobilization testing may help
exposure. Epidemiologic observations have established the relation- with the correct diagnosis [3].
ship between lead exposure and renal failure in association with
children eating lead paint in their homes, chronic ingestion of lead-
contaminated flour, lead-loaded drinking water in homes, and
drinking of illegal moonshine whiskey [2,3]. Occupational expo-
sure in lead-producing industries also has been associated with a
higher incidence of renal dysfunction.
FIGURE 10-5
Days 1 2 3 Ethylenediamine tetraacetic acid (EDTA)–lead mobilization test in lead nephropathy.
EDTA (calcium disodium acetate) for detecting lead nephropathy. This test consists of a
24-hour urinary lead excretion over 3 consecutive days after administration of 2 g of EDTA
by intramuscular route on the first day in divided doses 12 hours apart. Persons without
8 AM 8 PM excessive lead exposure excrete less than 0.6 mg of lead during the day after receiving 2 g
of EDTA parenterally. In the presence of renal failure, the excretion is delayed; however,
EDTA 1 g 1g the cumulative total remains less than 0.6 mg over 3 days (From Batuman and coworkers
[3]; with permission.)
IM IM
Urinary Lead,
collection mg
FIGURE 10-6
120 I II 1500 Ethylenediamine tetraacetic acid (EDTA)–
Creatinine clearance, mL/min
50 III
II
C 0
Cadmium nephropathy
FIGURE 10-7
110 Decrease in renal function after 25-year exposure to cadmium (Cd). In workers exposed to
Glomerular filtration rate,
105 cadmium for an average time of 25 years, a progressive decrease in renal function occurs
mL/min/1.73 m2
100 during a 5-year follow-up period, despite removal from cadmium exposure 10 years earlier.
95 On average, the glomerular filtration rate was shown to be decreased to 31 mL/min/1.73
90 m2 after 5 years instead of the expected age-related value of 5 mL/min/1.73 m2. (Adapted
85 from Roels and coworkers [5].)
80
Expected values
75 Cd exposure
70
5 6 7 8 9 10 11
Removal from Cd exposure, y
Graph values
I II III IV
NEP 43 53 50 76
CC16 16 17 25 124
RBP 80 122 132 594
ß2-m 73 112 102 834
FIGURE 10-8
* Tubular markers in cadmium workers. Impairment of renal proximal
NEP 834
800 CC16
tubular epithelium induced by cadmium can be documented by an
RBP
increase in urinary excretion of urinary neutral endopeptidase 24.11
Creatinine, µg/g
ß2–m *
594
(NEP), an enzyme of the proximal tubule brush borders, as well as
600 by an increase in microproteinuria: Clara cell protein (CC16),
*P < 0.05
200 retinol-binding protein (RBP) and 2-microglobulin (2-m). The data
*
were obtained from 106 healthy persons working in cadmium smelt-
* ing plants. These markers could be used for the screening of cadmi-
um workers. (Adapted from Nortier and coworkers [6].)
0
I II III IV
I II III IV
Creatinine
103 103 90* 79*
clearance, mL/min
Urinary Cd,
0.55 1.34 3.28* 8.45*
µg/g/creatinine
Toxic Nephropathies 10.5
Lithium nephropathy
LITHIUM NEPHROTOXICITY
FIGURE 10-9
Lithium acts both distally and proximally to antidiuretic hor-
mone–induced generation of cyclic adenosine monophosphatase.
Polyuria and polydipsia can occur in up to 40% of patients on
lithium therapy and are considered harmless and reversible.
However, nephrogenic diabetes insipidus may persist months after FIGURE 10-10 (see Color Plate)
lithium has been discontinued [7]. Lithium also induces an impair- Lithium nephropathy. A 22-year-old female patient was on mainte-
ment of distal urinary acidification. Chronic renal failure secondary nance lithium therapy (lithium carbonate 750 mg/d) for 5 years.
to chronic interstitial fibrosis may appear in up to 21% of patients She presented with polyuria (6500 mL/d) and moderate renal fail-
on maintenance lithium therapy for more than 15 years [8]. ure (creatinine clearance, 60 mL/min). Proteinuria was not present,
However, these observations are still a matter of debate [7]. and the urinary sediment was unremarkable. A renal biopsy
showed focal interstitial fibrosis with scarce inflammatory cell infil-
trate, tubular atrophy, and characteristic dilated tubule (microcyst
formation). Half of the glomeruli (not shown) were sclerotic.
(Magnification 125, periodic acid–Schiff reaction.)
Germanium nephropathy
FIGURE 10-11
CIRCUMSTANCES OF CHRONIC RENAL FAILURE Germanium (atomic number, 32; atomic weight, 72.59) is con-
SECONDARY TO GERMANIUM SUPPLEMENTS tained in soil, plants, and animals as a trace metal. It is widely
used in the industrial fields because of its semiconductive capacity.
The increased use of natural remedies and trace elements to pro-
Ge-dioxyde elixir, food additives, or capsules (used to improve health tect, improve, or restore the health has lead regular supplementa-
in normal persons [Japan]) tion with germanium salts either through food addition or by the
Ge-lactate-citrate (used to rebuild the immune system) in patients means of elixirs and capsules. The chronic supplementation by
with HIV infection (Switzerland) germanium salts was at the origin of the development of chronic
Ge-lactate-citrate (used to improve health) in patients with cancer renal failure secondary to a tubulointerstitial nephritis [9–12].
(the Netherlands)
Ge-dioxyde elixir (used to restore health) in patients with chronic
hepatitis (Japan)
10.6 Tubulointerstitial Disease
A B
FIGURE 10-12
Light microscopy of renal tissue in a patient with chronic renal Renal tubular epithelial cells show numerous dark small inclu-
failure secondary to the chronic intake of germanium, showing sions. B, Periodic acid–Schiff reaction. (Magnification, 350).
focal tubular atrophy and focal interstitial lymphocyte infiltra- (From Hess and coworkers [12]; with permission).
tion. A, Hematoxylin and eosin stain. (Magnification 162.)
Exposure to Analgesics
Normal papilla
Swollen
Forniceal erosion
Detachment
Calcification
FIGURE 10-13
Analgesic nephropathy and papillary necrosis. The characteristic
feature of analgesic nephropathy is the papillary necrosis process
that begins with swollen papillae and continues with forniceal ero-
sion, detachment, and calcification of necrotic papillae.
FIGURE 10-14
Pathology of analgesic nephropathy. Nephrectomy showing a kid-
ney reduced in size with necrosed and calcified papillae.
Toxic Nephropathies 10.7
FIGURE 10-16
Classic analgesic nephropathy is a slowly progressive disease
resulting from the daily consumption over several years of mix-
tures containing analgesics usually combined with caffeine,
codeine, or both. Caffeine and codeine create psychological depen-
dence. Most cases of analgesic nephropathy occur in women. In
80% of the cases, analgesics were taken for persistent headache.
FIGURE 10-15 Gastrointestinal complaints are also frequent, as are urinary tract
Radiologic appearance of papillary necrosis in analgesic nephropa- infections. Evidence of clinical papillary necrosis (fever and pain)
thy. The pyelogram was obtained by pyelostomy. It shows a swollen is present in 20% of cases. Calcifications of papillae (detected by
papilla (upper calyx), forniceal erosions (middle calyx), and detach- computed tomography scan) are present in 65% of persons who
ment of papilla, or filling defect (lower calyx). abuse analgesics [13].
FIGURE 10-17
EPIDEMIOLOGY OF ANALGESIC NEPHROPATHY Worldwide epidemiology of analgesic nephropathy. The frequency
AMONG ESRD PATIENTS of analgesic nephropathy in patients with end-stage renal diseases
(ESRD) varies greatly within and among countries [14–16]. The
highest prevalence rates of end-stage renal disease from analgesic
Australia 20% nephropathy occur in South Africa (22%), Switzerland and Australia
Belgium 18% (20%), Belgium (18%), and Germany (15%). In Belgium, the preva-
Canada 6%
lence is 36% in the north and 10% in the south. In Great Britain,
the rate is 1% nationwide; in Scotland it is 26%. In United States,
Germany 15%
the rate is 5% nationwide, 13% in North Carolina, and 3% in
South Africa 22%
Washington, DC. In Canada, the rate is 6% nationwide.
Switzerland 20%
United Kingdom 1%
United States 5%
FIGURE 10-18
25 Prevalence of analgesic nephropathy versus
Prevalence (EDTA, 1989)
Analgesic nephropathy nephropathy with unknown cause. Cross-
20
Unknown cause national comparisons in Europe indicate
15 that the proportion of cases of end-stage
renal disease attributed to analgesics varies
%
in
a
m
nce
ds
y
d
al
Ital
rlan
Spa
tug
giu
rlan
rm
Fra
Au
Bel
the
Ge
Sw
Ne
.
analgesic components
A, The risk factor for end-stage renal
2000
disease of unknown cause is increased in
relationship to the cumulative intake of
10.0
95% confidence intervals
A SP A
FIGURE 10-20
D. PERCENTAGES OF SENSITIVITY AND SPECIFICITY High performance of computed tomography (CT) scan for diagnos-
ing analgesic nephropathy. Three criteria may be used to diagnose
analgesic nephropathy by CT scan: decrease in renal size, measured
Criteria Sensitivity, % Specificity, % by the sum of both sides of the rectangle enclosing the kidney at
the level of the renal vessels (A); indentations counted at the level
Decrease in renal size 95 10 at which most indentations are present (more than three are quali-
Bumpy contours 50 90 fied of bumpy contours) (B); and papillary calcifications (C).
Papillary calcifications 87 97 Percentages of sensitivity and specificity are given for the three cri-
teria (D). Example of papillary calcifications on CT scan (E). RA—
renal artery; RV—renal vein; SP—spine. (Adapted from Elseviers
and De Broe [19]; with permission).
E
Toxic Nephropathies 10.9
FIGURE 10-21
HONCOCH3 NCOCH3 O OH
Malignancies of the urinary tract and their association with anal-
gesic nephropathy. Malignancies of the renal pelvis and ureters were
reported in up to 9% of patients with analgesic nephropathy. This
high prevalence can be explained by the appearance of carcinogenic
OC2H5 O O OH substances in the major pathways of the metabolism of phenacetin.
N-hydroxy- Probable carcinogenic substances are indicated by a plus sign.
p-ocetophenetidine
OH
[OH]
HNCOCH3 NH2 H 2N O OH
OH
H NH2
FIGURE 10-22
Malignant uroepithelial tumors of the
upper urinary tract in patients with anal-
gesic nephropathy. A, Pyelogram showing
a filling defect, indicating a tumor of the
renal pelvis. B, Retrograde pyelography
showing a long malignant stricture of
the ureter, causing ureteral dilation and
hydronephrosis. (Courtesy of W Lornoy,
MD, OL Vrouwziekenhuis, MD.)
B
10.10 Tubulointerstitial Disease
Exposure to Cyclosporine
Inactive
metabolites Sympathetic Endothelium Cytosol
Liver
cytochrome nervous Thromboxane calcium
P450 system Endothelin
Chronic
Renal vasoconstruction renal failure
Inhibition
Ketoconazole
Verapamil Sodium chloride
Diltiazem retention
Erythromycin
Hypertension
FIGURE 10-23
Toxicity of cyclosporine. Cyclosporine is a neutral fungal FIGURE 10-24
hydrophobic 11-amino acid cyclic polypeptide. Cyclosporine is
Cyclosporine and hypertension. Hypertension can develop in 10%
metabolized by hepatic cytochrome P450 to multiple less active
to 80% of patients treated with cyclosporine, depending on dosage
and less toxic metabolites. Drugs that inhibit cytochrome P450
and length of the exposure. Cyclosporine increases cytosol calcium
enzymes such as ketoconazole, verapamil, diltiazem, and ery-
and, thus, enhances arteriolar smooth muscle responsiveness to
thromycin increase the concentration of cyclosporine and may
vasoconstrictive stimuli. Vasoconstrictive effects of cyclosporine
thus precipitate renal side effects [20,21].
also are mediated by enhanced thromboxane action, sympathetic
nerve stimulation, and release of endothelin. Renal vasoconstric-
tion results in salt retention and hypertension. In chronic exposure
to cyclosporine, hypertension also is a part of cyclosporine-induced
chronic renal failure [22].
FIGURE 10-25
Mechanisms of cyclosporine renal injury Pathogenesis of cyclosporine nephropathy. Chronic administration of cyclosporine may
induce sustained renal vasoconstriction. Impairment of renal blood flow leads to tubuloin-
Cyclosporine terstitial fibrosis. Cyclosporine increases the recruitment of renin-containing cells along the
afferent arteriole. Hyperplasia of the juxtaglomerular apparatus increases angiotensin II
levels that, in turn, stimulate tumor growth factor- (TGF-) secretion, resulting in inter-
Sustained Renin stitial fibrosis [20].
vasoconstriction
Angiotensin II
Interstitial
fibrosis
Toxic Nephropathies 10.11
100 CyA, 7.5 mg/kg 100 CyA, 9.3 mg/kg 100 CyA, 10 to 6 mg/kg
Glomerular filtration rate,
% of normal values
% of normal values
60 60 60
40 40 40
20 20 20
0 0 0
0 8 Weeks 0 13 Months 0 36 Months
A Psoriasis B Autoimmune diseases C Cardiac transplantations
FIGURE 10-26
100 CyA, 5 mg/kg Cyclosporine (CyA) nephrotoxicity in nonrenal diseases. A, Patients treated with
cyclosporine (7.5 mg/kg) for psoriasis experienced a median decrease to 84% of the initial
Glomerular filtration rate,
80 values in the glomerular filtration rate after 8 weeks of therapy. B, Of patients treated with
% of normal values
60
cyclosporine (9.3 mg/kg) for autoimmune diseases, 21% showed cyclosporine nephropathy
on biopsy, with a decrease to 60% of the initial values in renal function. C, Patients with
40 cardiac transplantation treated with high doses of cyclosporine (10 to 6 mg/kg) developed
a reduction to 57% of the initial values in renal function 36 months after transplantation.
20 Patients treated with azathioprine did not show any reduction in renal function. D,
0
Patients receiving cyclosporine (5 mg/kg) for uveitis for 2 years showed a decrease in
0 24 Months glomerular filtration rate to 65% of the initial values. (Panel A adapted from Ellis and
D Uveitis coworkers [23]; panel B adapted from Feutren and Mihatsch [24]; panel C adapted from
Myers and Newton [25]; and panel D adapted from Deray and coworkers [26].)
A B
FIGURE 10-27
Morphology of cyclosporine nephropathy on renal biopsy of a periodic acid–Schiff reaction). B, A striped form of interstitial
patient with cardiac transplantation. Two different types of lesions fibrosis characterized by irregularly distributed areas of stripes of
are seen in cyclosporine nephropathy. A, Arteriolopathy: Hyalin, interstitial fibrosis and tubular atrophy in the renal cortex. Tubules
paucicellular thickening of the intima with focal wall necrosis in other areas were normal (magnification x 100 periodic
results in narrowing of the vascular lumen (magnification 300 acid–Schiff reaction).
10.12 Tubulointerstitial Disease
10.6
10
C.P. man born
Seerum creatinine, mg/dL
6
4.9
4.2 4.0 3.9
4 IBD diagnosis
32 mg/d
2 1.1 Renal biopsy Renal biopsy
Methyl- 16 mg/d
Oral Pentasa® 500 mg/d, 3 x per day Hemodialysis prednisolone
0
De , 1994
1, 4
Jan 1994
1
96
994
4
995
96
De , 1994
De 2, 199
199
199
199
, 19
, 19
2, 1
6, 1
t 3,
rch
23,
y1
c1
c2
v2
c2
c3
rch
Oc
Ma
Ma
Feb
De
No
Ma
B C
FIGURE 10-28
Aminosalicylic acid and chronic tubulointerstitial nephritis. A, A of the interstitium tubular atrophy, and fibrosis. Several atrophic
36-year-old man suffering from Crohn’s disease exhibited severe tubules are surrounded by one or more layers of -smooth mus-
renal failure after 23 months of treatment with 5-aminosalicylic cle actin positive cells. The patient had normal renal function on
acid (5-ASA, or Pentasa, Hoechst Marion Roussel, Kansas City, beginning treatment with 5-ASA. After 5 years of 5-ASA therapy,
MO). B, The first renal biopsy showing widening and massive the patient demonstrated severe impaired renal function. The
cellular infiltration of the interstitium, tubular atrophy, and rela- association between the use of 5-ASA and development of chron-
tive spacing of glomeruli. C, The second renal biopsy 8 months, ic tubulointerstitial nephritis in patients with inflammatory bowel
after discontinuation of the drug and moderate improvement of disease (IBD) has gained recognition in recent years [27,28].
the renal function, again showing important cellular infiltration (Courtesy of ME De Broe, MD.)
Toxic Nephropathies 10.13
Exposure to Ochratoxins
FIGURE 10-29
Ochratoxin A
Ochratoxin nephropathy. Ochratoxin A is a mycotoxin produced by various species of
COOH OH O Aspergillus and Penicillium. Ochratoxins contaminate foods (mainly cereals) for humans as
well as for cattle. Ochratoxins are mutagenic, oncogenic, and nephrotoxic. Ochratoxins are
– CH2- CH-NH-CO- responsible for chronic nephropathy in pigs and also may be the cause of endemic Balkan
CH3 nephropathy and some chronic interstitial nephropathies seen in North Africa and France [29].
CI
Contamination of cereals
Chronic nephropathy in pigs
Endemic Balkan nephropathy
Chronic interstitial nephritis in Tunisia
Chronic interstitial nephritis in France (?)
R. Danube
Austria
Hungary CLINICAL FEATURES OF BALKAN NEPHROPATHY
Slovenia
R. Sava
Croatia
R. S Romania Residence in an endemic area
ava Slavonski
Brod Occupational history of farming
Bneljina Oravita Progressive renal failure
Belgrade Turn Severin
Bosnia and Microproteinuria of tubular type
Herezgovina Lazarevac be
Paracin anu Unremarkable urinary sediment
R. D
Sarajevo Mikhaylovgrad Small and shrunken kidneys
Nis
Yugoslavia Vratsa Associated urothelial tumors
Italy Sofia Bulgaria
Macedonia
FIGURE 10-31
Albania Clinical features in Balkan nephropathy. Balkan nephropathy is
characterized by progressive renal failure in residents (generally
Greece farmers) living in endemic areas for over 10 years. The urinary
sediment is unremarkable and no proteinuria is seen, except for
a microproteinuria of tubular type. The kidneys are small and
shrunken. Urothelial cancers are frequently associated with Balkan
nephropathy [29,30].
FIGURE 10-30
Endemic Balkan nephropathy. Endemic nephropathy is encoun-
tered in some well-defined areas of the Balkans. Distribution (dark
areas) is along the affluents of the Danube, in a few areas on the
plains and low hills owing to high humidity and rainfall. (From
Stefanovic and Polenakovic [30]; with permission.)
10.14 Tubulointerstitial Disease
A B
FIGURE 10-32
Pathology of Balkan nephropathy. Balkan nephropathy is characterized hyperplasia of the myocythial cells with narrowing of the lumen of the
by pure interstitial fibrosis with marked tubular atrophy (A) and by vessel (B) (From Stefanovic and M. Polenakovic [30]; with permission).
FIGURE 10-33
Pathology of ochratoxin nephropathy. In addition to interstitial
fibrosis, large hyperchromatic nuclei in tubular epithelial cells are
shown by the arrow (interstitial caryomegalic nephropathy).
(Masson trichrome stain, magnification x 160.) The renal biopsy
was obtained from a woman from France who had renal failure
(creatinine clearance 40 mL/min) without significant proteinuria
and urinary sediment abnormalities. Ochratoxin levels were 367
and 1810 ng/mL, respectively, in the patient’s blood and urine.
(From Godin and coworkers [29].)
80 74.2
12.8
Cereal samples contaminated
70
per million inhabitants
60
by ochratoxin, %
10
50
40
30
20
1.6
10 3.2
0 0
Endemic Nonendemic Endemic Nonendemic
Areas of Balkan nephropathy Areas of Balkan nephropathy
31 32
30 cion of a new cause of renal disease. The relationship between this
24 new renal disease and the recent introduction of Chinese herbs
(namely, Stephania tetrandra) in a slimming regimen was estab-
20
15 lished [32]. The withdrawal from the market of this herb has
decreased the incidence of interstitial nephritis in Brussels, Belgium.
10 7
5
1 1
0
1989 1990 1991 1992 1993 1994 1995 1996
Year
FIGURE 10-37
A. CHINESE HERBAL MEDICINE Role of Aristolochia in Chinese herbs nephropathy. Stephania tetran-
dra was the Chinese herb chronologically associated with the develop-
ment of Chinese herbs nephropathy. However, tetrandrine, the alka-
Chinese Name Western name Chemical Marker loid characterizing Stephania tetrandra was not found in the capsules
taken by the patients. In fact, confusion between Stephania tetrandra
Han fang-ji Stephania tetrandra Tetrandrine and Aristolochia fang chi was done in the delivery of Chinese herbs in
Guang fang-ji Aristolochia fang chi Aristolochic acid Belgium [33]. Chinese characters and the pingin name of Stephania
tetrandra (Han fang-ji) are identical to that of Aristolochia fang chi
(Guang fang-ji). Investigations conducted on batches of Stephania
tetrandra powders distributed in Belgium have shown that most of
them contained aristolochic acids (characteristic of Aristolochia) and
30
30 not tetrandrine (From Vanhaelen and coworkers [33] and P Daenens,
Katholiek Universiteit Leuven, Belgium, report of expertise 1996.)
(Number of batches)
Chinese herbs
20
10
7
5
4
0
+A, +T +A, –T –A, +T –A, –T
+A, aristolochic acid present
–A, aristolochic acid absent
+T, tetrandrine present
B –T, tetrandine absent
10.16 Tubulointerstitial Disease
FIGURE 10-38
DNA ADDUCTS FORMED BY DNA aristolochic acid adducts in kidney tissues of patients with
ARISTOLOCHIC ACID IN RENAL TISSUE Chinese herbs nephropathy. The role of Aristolochia in the pathogen-
esis of Chinese herbs nephropathy was confirmed by the demonstra-
tion of DNA aristolochic acid adducts (a biomarker of aristolochic
Chinese Herb Nephropathy (n = 5) Controls (n = 6) acids exposure) in renal tissue of patients with Chinese herbs
nephropathy, whereas these adducts were absent in the renal tissue
0.7–5.3 per 107 nucleotides 0 of control cases. (Adapted from Schmeiser and coworkers [34].)
A B
FIGURE 10-41 (see Color Plate)
Pathology of Chinese herb nephropathy. The major pathologic extensive interstitial fibrosis with relative sparing of glomeruli.
lesion consists of extensive interstitial fibrosis with atrophy (Masson trichrome stain, magnification 50.) B, A normal
and loss of the tubules, predominantly located in superficial glomerulus surrounded by a paucicellular interstitial fibrosis
cortex [38,39]. A, A low-power view of transition between and atrophic tubules. (Masson’s trichrome stain, magnification
superficial cortex (left) and deep cortex (right) shows an 300.)
Toxic Nephropathies 10.17
log ug/24 h
log ug/24 h
ug/24 h
30 3
20
20 2
10 10 1
0 0 0
Controls Normal Renal End-stage Controls Normal Renal End-stage Controls Normal Renal End-stage
renal function failure renal disease renal function failure renal disease renal function failure renal disease
A After exposure to Chinese herbs B After exposure to Chinese herbs C After exposure to Chinese herbs
FIGURE 10-42
5
RBP A–D, Microproteinuria and neutral endopeptidase enzymuria in Chinese herbs nephropathy.
Proximal tubular injury in Chinese herbs nephropathy is demonstrated by a significant
4 increase in urinary excretion of microproteins (Clara cell protein, CC16; 2-microglobulin
log ug/24 h
3 [2-m] and retinol binding protein [RBP]) as well as a decrease in urinary excretion of neu-
tral endopeptidase (NEP) a marker of the brush border tubular mass. (Adapted from Nortier
2
and coworkers [40].)
1
0
Controls Normal Renal End-stage
renal function failure renal disease
D After exposure to Chinese herbs
FIGURE 10-43
Chinese herbs nephropathy and renal pelvic carcinoma. Urothelial cancers are associated
with Chinese herbs nephropathy [36,37]. Shown is a filling defect (arrow) in the renal
pelvis in an antegrade pyelogram obtained from a patient with Chinese herbs nephropathy
and hematuria. (From Vanherweghem and coworkers [37]; with permission).
10.18 Tubulointerstitial Disease
A B
FIGURE 10-44
Pathology of urothelial tumors associated with Chinese herbs is shown in Fig. 10-40). A, Part of the urothelial proliferation.
nephropathy. Microscopic pattern is shown of a lower urothe- Plurifocal thickening of the urothelium is present. (Hematoxylin
lial tumor obtained by ureteronephrectomy of a native kidney and eosin stain x 50.) B, In situ transitional cell carcinoma
in a patients with transplantation who has Chinese herbs with high mitotic rate. (Magnification x 400 periodic acid–
nephropathy (the macroscopic appearance of the nephrectomy Schiff reaction.)
0.7
Controls, n = 23 TOXIC CHRONIC INTERSTITIAL NEPHROPATHIES
0.6 Steroids, n = 12 WITH UROTHELIAL CANCERS
1/P creatinine ratio
0.5
0.4
Analgesic nephropathy (phenetidin compounds)
0.3 Balkan nephropathy (ochratoxins)
0.2 Chinese herbs nephropathy (aristolochic acids)
0.1
–6 –3 0 3 6 9 12
Months
FIGURE 10-46
Of interest is the association between chronic renal interstitial
FIGURE 10-45
fibrosis and urothelial cancers. This association appears, at least,
Effects of steroids on the evolution of renal failure in Chinese herbs in three chronic toxic nephropathies: analgesic nephropathy,
nephropathy. Steroid therapy was shown to decrease the evolution Balkan nephropathy, and Chinese herbs nephropathy. This associ-
of renal failure in a subgroup of patients with Chinese herbs ation indicates that nephrotoxins promoting interstitial fibrosis
nephropathy [41]. The evolution is shown of the 1/P creatinine (analgesics, ochratoxins, and aristolochic acids) also may be
ratio of patients with Chinese herbs nephropathy, 12 of whom oncogenic substances.
were treated with steroids as compared with 23 not treated with
steroids (control group). In the control group the 1/P creatinine
curve was limited to 6 months of follow-up because at 12 months,
17 of the 23 patients were on renal replacement therapy. (From
Vanherweghem and coworkers [41]; with permission.)
Toxic Nephropathies 10.19
References
1. Nuyts GD, Van Vlem E, Thys J, et al.: New occupational risk factors 22. Luke RG: Mechanism of cyclosporine-induced hypertension. Am J
for chronic renal failure. Lancet 1995, 346:7–11. Hypertens 1991, 4:468-471.
2. Nuyts GD, Daelemans RA, Jorens PG, et al.: Does lead play a role in 23. Ellis CN, Fradin MS, Messana JM, et al.: Cyclosporine for plaque-
the development of chronic renal disease? Nephrol Dial Transplant type psoriasis. N Engl J Med 1991, 324:277–284.
1991, 6:307–315. 24. Feutren G, Mihatsch MJ: Risk factors for cyclosporine-induced
3. Batuman V, Maesaka JK, Haddad B, et al.: The role of lead in gout nephropathy in patients with autoimmune diseases. N Engl J Med
nephropathy. N Engl J Med 1981, 304:520–523. 1992, 326: 1654–1660.
4. Sanchez-Fructuoso AI, Torralbo A, Arroyo M, et al.: Occult lead 25. Myers BD, Newton L: Cyclosporin induced chronic nephropathy: an
intoxication as a cause of hypertension and renal failure. Nephrol obliterative renal injury. J Am Soc Nephrol 1991, 2:S45–S52.
Dial Transplant 1996, 11:1775–1780. 26. Deray G, Benhmida M, Le Hoang P, et al. Renal function and blood
5. Roels HA, Lauwerys RR, Buchet JP, et al.: Health significance of cad- pressure in patients receiving long-term, low-dose cyclosporine therapy
mium induced renal dysfunction: a five year follow up. Br J Ind Med for idiopathic autoimmune uveitis. Ann Intern Med 1992, 117:578–583.
1989, 46:755–764. 27. World MJ, Stevens PE, Ashton MA, Rainford DJ: Mesalazine-associ-
6. Nortier J, Bernard A, Roels H, et al.: Urinary neutral endopeptidase ated interstitial nephritis. Nephrol Dial Transplant 1996, 11:614–621.
in workers exposed to cadmium: interaction with cigarette smoking. 28. De Broe ME, Stolear JC, Nouwen EJ, Elseviers MM: 5-Aminosalicylic
Occup Environ Med 1997, 54:432–436. acid (5-ASA) and chronic tubulointerstitial nephritis in patients with
7. Walker RG: Lithium nephrotoxicity. Kidney Int 1993, 44(suppl chronic inflammatory bowel disease: Is there a link? Nephrol Dial
42):S93–S98. Transplant 1997; 12:1839–1841.
8. Bendz H, Aurell M, Balldin J, et al.: Kidney damage in long-term lithi- 29. Godin M, Fillastre JP, Simon P, et al.: L’ochratoxine est-elle néphro-
um patients: a cross-sectional study of patients with 15 years or more toxique chez l’homme ? In Actualités Néphrologiques. Edited by
on lithium. Nephrol Dial Transplant 1994, 9:1250–1254. Brentano JL, Bach JF, Kreis H, Grunfeld JP. Paris:
9. Sanai T, Okuda S, Onoyama K, et al.: Germanium dioxide-induced Flammarion–Medecine Sciences; 1996:225–250.
nephropathy: a new type of renal disease. Nephron 1990, 54:53–60. 30. Stefanovic V, Polenakovic MH: Balkan nephropathy: kidney disease
10. Van Der Spoel JI, Stricker BH, Esseveld MR, Schipper MEI: Dangers beyond the Balkans? Am J Nephrol 1991, 11:1–11.
of dietary germanium supplements. Lancet 1990, 336:117. 31. Krogh P, Hald B, Plestina R, Ceovic S: Balkan (endemic) nephropathy
11. Takeuchi A, Yoshizawa N, Oshima S, et al.: Nephrotoxicity of germa- and foodborn ochratoxin A: preliminary results of a survey of food-
nium compounds: report of a case and review of the literature. stuffs. Acta Path Microbiol Scand Sect B 1977, 85:238–240.
Nephron 1992, 60:436–442. 32. Vanherweghem JL, Depierreux M, Tielemans C, et al.: Rapidly pro-
12. Hess B, Raisin J, Zimmermann A, et al.: Tubulointerstitial nephropa- gressive interstitial renal fibrosis in young women: association with
thy persisting 20 months after discontinuation of chronic intake of slimming regimen including Chinese herbs. Lancet 1993,
germanium lactate citrate. Am J Kidney Dis 1993, 21:548–552. 341:387–391.
13. Elseviers MM, Bosteels V, Cambier P, et al.: Diagnostic criteria of 33. Vanhaelen M, Vanhaelen-Fastre R, But P, Vanherweghem JL:
analgesic nephropathy in patients with end-stage renal failure: Identification of aristolochic acid in Chinese herbs. Lancet 1994,
results of the Belgian study. Nephrol Dial Transplant 1992, 343:174.
7:479–486. 34. Schmeiser HH, Bieler CA, Wiessler M, et al.: Detection of DNA-
14. Drukker W, Schwarz A, Vanherweghem JL: Analgesic nephropathy: adducts formed by aristolochic acid in renal tissue from patients with
an underestimated cause of end-stage renal disease. Int J Artif Organs Chinese herbs nephropathy. Cancer Res 1996, 56:2025–2028.
1986, 9:216–243. 35. Vanherweghem JL: Association of valvular heart disease with Chinese
15. Klag MJ, Whelton PK, Perneger TV: Analgesics and chronic renal dis- herbs nephropathy. Lancet 1997, 350:1858.
ease. Curr Opinion Nephrol Hypertens 1996, 5:236–241. 36. Cosijns JP, Jadoul M, Squifflet JP: Urothelial malignancy in nephropa-
16. Vanherweghem JL, Even-Adin D: Epidemiology of analgesic thy due to Chinese herbs. Lancet 1994, 344:118.
nephropathy in Belgium. Clin Nephrol 1982, 17:129–133. 37. Vanherweghem JL, Tielemans C, Simon J, Depierreux M: Chinese
17. Perneger TV, Whelton PK, Klag MJ: Risk of kidney failure associated herbs nephropathy and renal pelvic carcinoma. Nephrol Dial
with the use of acetaminophen, aspirin, and nonsteroidal anti-inflam- Transplant 1995, 10:270–273.
matory drugs. N Engl J Med 1994, 331:1675–1679. 38. Depierreux M, Van Damme B, Vanden Houte K, Vanherweghem JL:
18. Elseviers MM, De Broe ME: Analgesic nephropathy in Belgium is Pathologic aspects of a newly described nephropathy related to the
related to the sales of particular analgesic mixtures. Nephrol Dial prolonged use of Chinese herbs. Am J Kidney Dis 1994, 24:172–180.
Transplant 1994, 9:41–46. 39. Cosijns JP, Jadoul M, Squifflet JP et al.: Chinese herbs nephropathy: a
19. Elseviers MM, De Schepper A, Corthouts R, et al.: High diagnostic clue to Balkan endemic nephropathy? Kidney Int 1994,
performance of CT scan for analgesic nephropathy in patients with 45:1680–1688.
incipient to severe renal failure. Kidney Int 1995, 48:1316–1323. 40. Nortier JL, Deschodt-Lankman MM, Simon S, et al. Proximal tubular
20. Shihab FS: Cyclosporine nephropathy: pathophysiology and clinical injury in Chinese herbs nephropathy: monitoring by neutral endopep-
impact. Sem Nephrol 1996, 16:536–547. tidase enzymuria. Kidney Int 1997, 51:288–293.
21. Bennett WM, De Mattos A, Meyer MM, et al.: Chronic cyclosporine 41. Vanherweghem JL, Abramowicz D, Tielemans C, Depierreux M:
nephropathy: The Achilles’ heel of immunosuppressive therapy. Effects of steroids on the progression of renal failure in chronic inter-
Kidney Int 1996, 50:1089–1100. stitial renal fibrosis: a pilot study in Chinese herbs nephropathy. Am J
Kidney Dis 1996, 27:209–215.
Metabolic Causes of
Tubulointerstitial Disease
Steven J. Scheinman
A
variety of metabolic conditions produce disease of the renal
interstitium and tubular epithelium. In many cases, disease
reflects the unique functional features of the nephron, in
which the ionic composition, pH, and concentration of both the
tubular and interstitial fluid range widely beyond the narrow con-
fines seen in other tissues. Recent genetic discoveries have offered
new insights into the molecular basis of some of these conditions, and
have raised new questions. This chapter discusses nephrocalcinosis,
the relatively nonspecific result of a variety of hypercalcemic and
hypercalciuric states, as well as the renal consequences of hyperox-
aluria, hypokalemia, and hyperuricemia.
CHAPTER
11
11.2 Tubulointerstitial Disease
FIGURE 11-1
The recent discovery of the calcium-sensing
receptor and increased understanding of its
expression along the nephron have provided
explanations for many of the known effects
of hypercalcemia to cause clinical distur-
bances in renal tubular function [1]. In the
parathyroid gland the calcium-sensing recep-
tor allows the cell to sense extracellular levels
of calcium and transduce that signal to regu-
late parathyroid hormone production and
release. In the nephron, expression of the
calcium receptor can be detected on the api-
cal surface of cells of the papillary collecting
Hypercalcemia duct, where calcium inhibits antidiuretic
inhibits reabsorption hormone action. Thus, hypercalcemia impairs
of NaCl, Ca, and Mg urinary concentration and leads to isotonic
polyuria. The most intense expression of the
calcium receptor is in the thick ascending
limb of the loop of Henle, particularly the
cortical portion, where the calcium receptor
protein is located on the basolateral side of
the cells; this explains the known effects of
hypercalcemia in inhibiting reabsorption of
calcium, magnesium, and sodium chloride
in the thick ascending limb [2]. In addition,
Hypercalcemia
inhibits hypercalcemia causes hypercalciuria through
reabsorption an increased filtered calcium load and
of water suppression of parathyroid hormone release
with a consequent reduction in calcium
reabsorption. Ca—calcium; Mg—magne-
sium; NaCl—sodium chloride.
FIGURE 11-2
RENAL EFFECTS OF CALCIUM Hypercalcemia leads to renal vasoconstriction and a reduction in
the glomerular filtration rate. However, no expression of the calci-
um-sensing receptor has been reported so far in renal vascular or
Hypercalcemia glomerular tissue. Calcium receptor expression is present in the
Collecting duct proximal convoluted tubule, on the basolateral side of cells of the
Resistance to vasopressin, leading to isotonic polyuria
distal convoluted tubule, and on the basolateral side of macula
densa cells. Functional correlates of calcium receptor expression
Thick ascending limb of the loop of Henle
at these sites are not yet clear [3].
Impaired sodium chloride reabsorption, leading to modest salt wasting
Hypercalciuria leads to microscopic hematuria and, in fact, is
Inhibition of calcium transport, leading to hypercalciuria
the most common cause of microscopic hematuria in children. The
Inhibition of magnesium transport, leading to hypomagnesemia
mechanism is presumed to involve microcrystallization of calcium
Renal vasculature
salts in the tubular lumen. Conflicting effects of calcium on urinary
Arteriolar vasoconstriction acidification have been reported in clinical settings in which other
Reduction in ultrafiltration coefficient factors, such as parathyroid hormone levels, may explain the obser-
Hypercalciuria vations. whether or not it is the result of renal tubular acidosis,
Microscopic hematuria Nephrocalcinosis often is associated with impaired urinary acidifica-
Nephrocalcinosis tion, whether or not it is the result of renal tubular acidosis.
Impaired urinary acidification
Metabolic Causes of Tubulointerstitial Disease 11.3
FIGURE 11-3
CAUSES OF NEPHROCALCINOSIS Nephrocalcinosis represents calcification of the renal parenchyma. It
is primarily medullary in most cases except in dystrophic calcification
associated with inflammatory, toxic, or ischemic disease. Nephro-
Medullary (total) 97.6 calcinosis can be seen in association with chronic or severe hypercal-
Primary hyperparathyroidism 32.4 cemia or in a variety of hypercalciuric states. The spectrum of causes
Distal renal tubular acidosis 19.5
of nephrocalcinosis is described by Wrong [3]. The numbers represent
the percentage of the total of 375 patients. It is likely that the case mix
Medullary sponge kidney 11.3
is affected to some extent by Wrong’s interests in, eg, renal tubular
Idiopathic hypercalciuria 5.9
acidosis (RTA) and Dent’s disease, but this is by far the largest pub-
Dent’s disease 4.3
lished series. As in other studies, the most important causes of
Milk-alkali syndrome 3.2
nephrocalcinosis are primary hyperparathyroidism, distal RTA, and
Oxalosis 3.2
medullary sponge kidney. The primary factor predisposing patients
Hypomagnesemia-hypercalciuria 1.6 to renal calcification in many of these conditions is hypercalciuria,
Sarcoidosis 1.6 as occurs in idiopathic hypercalciuria, Dent’s disease, milk-alkali
Renal papillary necrosis 1.6 syndrome, sarcoidosis, hypervitaminosis D, and often in distal RTA.
Hypervitaminosis D 1.6 In distal RTA and milk-alkali syndrome, relative or absolute urinary
Other* 4.0 alkalinity promote precipitation of calcium phosphate crystals in the
Undiscovered causes 6.7 tubular lumena, and hypocitraturia is an important contributing
Cortical (total) 2.4 factor in distal RTA. Causes of cortical nephrocalcinosis in this study
included acute cortical necrosis, chronic glomerulonephritis, and
chronic pyelonephritis.
Adapted from Wrong [3]; with permission.
* Other causes include Bartter syndrome, idiopathic Fanconi syndrome, hypothy-
roidism, and severe acute tubular necrosis.
FIGURE 11-7
Noncontrast
abdominal
radiograph in a
24-year-old man
with X-linked
nephrolithiasis
(Dent’s disease).
The patient had
recurrent calcium
nephrolithiasis
beginning in child-
hood and developed
end-stage renal
disease requiring
dialysis at 40 years
of age. Extensive
medullary calcinosis
is evident.
FIGURE 11-6
Nephrocalcinosis. Ultrasound image of right kidney in a patient
with primary hyperparathyroidism. Echogenicity of the renal
cortex is comparable to that of the adjacent liver. The dense
nephrocalcinosis is entirely medullary. (Courtesy of Robert
Botash, MD.)
Metabolic Causes of Tubulointerstitial Disease 11.5
FIGURE 11-8
Syndromes of X-linked nephrolithiasis have been Rickets occurs early in childhood in some patients but
reported under various names, including Dent’s disease is absent in most patients with X-linked nephrolithiasis
in the United Kingdom, X-linked recessive hypophos- (Dent’s disease). In a few families, all affected males have
phatemic rickets in Italy and France, and a syndrome of had rickets. In other families, rickets is present in only
low molecular weight (LMW) proteinuria with hyper- one of several males sharing the same mutation. At pre-
calciuria and nephrocalcinosis in Japanese schoolchild- sent, the variability of this feature and other features of
ren. Mutations in a gene encoding a voltage-gated chlo- the disease is unexplained and may reflect dietary or envi-
ride channel (ClC-5) are present in all of these syn- ronmental factors or the participation of other genes in
dromes, establishing that they represent variants of one the expression of the phenotype.
disease [10]. The disease occurs most often in boys, Females who are carriers often have mild to moder-
with microscopic hematuria, proteinuria, and hypercal- ate LMW proteinuria. This abnormality can be used
ciuria. Many but not all have recurrent nephrolithiasis clinically as a screening test, but LMW protein excre-
from an early age. Affected males excrete extremely tion will not be abnormal in all heterozygous females.
large quantities of LMW proteins, particularly 2- Approximately half of women who are carriers have
microglobulin and retinol-binding protein. Other defects hypercalciuria, but other biochemical abnormalities are
of proximal tubular function, including hypophos- rare. Although symptomatic nephrolithiasis and even
phatemia, aminoaciduria, glycosuria, or hypokalemia, renal insufficiency have been reported in female carri-
occur variably and often intermittently. Many affected ers, they are very uncommon.
males have mild to moderate polyuria and nocturia, and The gene for ClC-5 that is mutated in X-linked nephro-
they often exhibit this symptom on presentation. lithiasis (Dent’s disease) is expressed in the endosomal
Urinary acidification is usually normal, and patients do vacuoles of the proximal tubule; it appears to be impor-
not have acidosis in the absence of advanced renal tant in acidification of the endosome. Thus, defective
insufficiency. Nephrocalcinosis is common by the endosomal function would explain the LMW proteinuria.
teenage years, and often earlier. Renal failure is common The mechanism of hypercalcinuria remains unexplained
and often progresses to end-stage renal disease by the at present. This gene belongs to the family of voltage-
fourth or fifth decade, although some patients escape it. gated chloride channels that includes ClC-Kb, one of the
Renal biopsy documents a nonspecific pattern of inter- gene mutations in some patients with Bartter syndrome.
stitial fibrosis and tubular atrophy, with glomerular scle- To date, 32 mutations have been reported in 40 families,
rosis that is probably secondary [11]. and nearly all are unique [11].
11.6 Tubulointerstitial Disease
HYPEROXALURIA
FIGURE 11-9
Oxalate is a metabolic end-product of limited solubility in physiologic from either exposure to metabolic precursors of oxalate or pyri-
solution. Thus, the organism is highly dependent on urinary excretion, doxine deficiency. Normally, dietary sources of oxalate account for
which involves net secretion. Normal urine is supersaturated with only approximately 10% of urinary oxalate. Restriction of dietary
respect to calcium oxalate. Crystallization is prevented by a number of oxalate can be effective in some patients with kidney stones who
endogenous inhibitors, including citrate. A mild excess of oxalate load, are hyperoxaluric, but even conscientious adherence to dietary
as occurs with excessive dietary intake, contributes to nephrolithiasis. restriction is disappointing in many patients who may have mild
A more severe oxalate overload, as in type 1 primary hyperoxaluria, metabolic hyperoxaluria, an entity that probably exists but is poorly
can lead to organ damage through tissue deposition of calcium oxalate understood. Intestinal absorption of oxalate can be enhanced
and possibly through the toxic effects of glyoxalate [12]. markedly in patients with bowel disease, particularly inflammatory
Two types of primary hyperoxaluria (PH) have been identified bowel disease or after extensive bowel resection or jejunoileal bypass.
(Fig. 11-10), of which type 1 (PH1) is much more common. PH1 In this setting, several mechanisms have been described including a)
results from absolute or functional deficiency of the liver-specific enhanced oxalate solubility as a consequence of binding of calcium
enzyme alanine:glyoxalate aminotransferase (AGT). This deficiency to fatty acids in patients with fat malabsorption; b) a direct effect
leads to calcium oxalate nephrolithiasis in childhood, with nephro- of malabsorbed bile salts to enhance absorption of oxalate by
calcinosis and progressive renal failure. Because the kidney is the intestinal mucosa, and c) altered gut flora with reduction in the
main excretory route for oxalate, in the face of excessive oxalate population of oxalate-metabolizing bacteria [4,12]. Because of
production even mild degrees of renal insufficiency can lead to the important role of the colon in absorbing oxalate, ileostomy
systemic deposition of oxalate in a wide variety of tissues. It is inter- abolishes enteric hyperoxaluria [4].
esting that the liver itself is spared from calcium oxalate deposition. Excessive endogenous production of oxalate occurs in patients
Clinical consequences include heart block and cardiomyopathy, ingesting large quantities of ascorbic acid, which may increase the
severe peripheral vascular insufficiency and calcinosis cutis, and bone risk of nephrolithiasis. In the setting of acute exposure to large
pain and fractures. Many of these conditions are exacerbated by the quantities of metabolic precursors, such as ingestion of ethylene
effects of end-stage renal disease. In contrast, PH2 is much more rare glycol or administration of glycine or methoxyflurane, tubular
than is PH1. Patients with PH2 have recurrent nephrolithiasis. obstruction by calcium oxalate crystals can lead to acute renal
Nephrocalcinosis, renal failure, and systemic oxalosis have not been failure. Pyridoxine deficiency is associated with increased oxalate
reported in PH2. The metabolic defect in PH2 appears to be a func- excretion clinically in humans and experimentally in animals; it
tional deficiency of D-glycerate dehydrogenase (DGDH) [12]. can contribute to mild hyperoxaluria. In all patients with primary
Secondary causes of hyperoxaluria include dietary excess, enteric hyperoxaluria, a trial of pyridoxine therapy should be given,
hyperabsorption, and enhanced endogenous production resulting because some patients will have a beneficial response.
Metabolic Causes of Tubulointerstitial Disease 11.7
A B
FIGURE 11-11
Sequential biopsies of a transplanted kidney documenting progressive and eosin. Panels A–C show specimens viewed by polarization
recurrence of renal oxalosis. This patient with primary hyperoxaluria microscopy, all at the same low-power magnification, from biop-
type I received renal transplantation, without liver transplantation, at sies taken after transplantation within the first year (A), third
24 years of age. Panels A–D show tissue stained with hematoxylin year (B),
(Continued on next page)
11.8 Tubulointerstitial Disease
C D
radial array of oxalate crystals and phagocytosis of small crystals by
multinucleated giant cells (E).
Conservative treatment of PH1 is of limited efficacy. Dietary
Multinucleated restriction has little effect on the course of the disease. High-dose
giant cells pyridoxine should be tried in all patients, but many patients do not
Ox Oxalate crystals respond. Strategies to prevent calcium oxalate stone formation
Ox include a high fluid intake (recommended in all patients), magnesium
oxide (because magnesium increases the solubility of calcium oxalate
Ox Ox salts), and inorganic phosphate. Lithotripsy or surgery may be neces-
Ox sary but do not alter the progression of nephrocalcinosis [12,13].
Ox Hemodialysis is superior to peritoneal dialysis in its ability to
remove oxalate, but neither one is able to maintain a rate of
oxalate removal sufficient to keep up with the production rate in
Ox
patients with PH1. Once end-stage renal disease develops, hemo-
dialysis does not prevent the progression of systemic oxalosis. In
some patients, renal transplantation accompanied by an aggressive
E program of management has been followed by a good outcome for
years [14]. However, oxalosis often recurs in the transplanted kid-
ney, particularly if any degree of renal insufficiency develops for
FIGURE 11-11 (Continued) any reason. In recent years, liver transplantation has been used
and fifth year (C), following renal transplantation. Deposition of with success, with or without renal transplantation, and offers the
oxalate crystals became progressively more severe with time, and the prospect of definitive cure. Results of liver transplantation are best
kidney failed after 5 years. Panel D illustrates a higher-power magni- in patients who have not yet developed significant renal insufficien-
fication, without polarization, of the biopsy at 5 years, showing a cy [12]. (Courtesy of Paul Shanley, MD.)
Metabolic Causes of Tubulointerstitial Disease 11.9
FIGURE 11-12
Uric acid contributes to the risk of kidney stones in several ways. Pure dialysis because of the higher clearance rates for uric acid. Frequent
uric acid stones occur in patients with hyperuricosuria, particularly hemodialysis, even multiple times per day, may be necessary to pre-
when the urine is acidic. Thus, therapy involves both allopurinol and vent extreme hyperuricemia and facilitate recovery of renal func-
alkalinization with potassium alkali salts. Hyperuricosuria also pro- tion. A modification of continuous arteriovenous hemodialysis has
motes calcium oxalate stone formation. In these patients, calcium recently been reported to be effective in management of these
nephrolithiasis can be prevented by therapy with allopurinol. The patients [16].
mechanism may involve heterogenous nucleation of calcium oxalate Chronic gouty nephropathy is a term referring to deposition of
by uric acid microcrystals, binding of endogenous inhibitors of calci- sodium urate crystals in the renal interstitium, with an accompanying
um crystallization, or “salting out” of calcium oxalate by urate [4]. destructive inflammatory reaction. As a specific entity with intrarenal
Acute uric acid nephropathy occurs most often in the setting of tophi, gouty nephropathy appears to have become uncommon. It
brisk cell lysis from cytotoxic therapy or radiation for myeloprolif- appears clear that long-standing hyperuricemia alone is not sufficient
erative or lymphoproliferative disorders or other tumors highly to cause this condition in most patients, and that renal failure in
responsive to therapy. Uric acid nephropathy can uncommonly patients with hyperuricemia or gout is almost always accompanied
occur spontaneously in malignancies or other states of high uric by other predisposing conditions, particularly hypertension or expo-
acid production. Examples are infants with the Lesch-Nyhan syn- sure to lead [17].
drome who have excessive uric acid production resulting from defi- Familial hyperuricemic nephropathy is an entity that now has been
ciency of hypoxanthine-guanine phosphoribosyltransferase deficiency reported in over 40 kindreds. It is characterized by recurrent gout,
and, rarely, adults with gout who become volume-contracted and often occurring in youth and even childhood; hyperuricemia; and
whose urine is concentrated and acidic. The mechanism involves renal failure. Histopathology reveals interstitial inflammation and
intratubular obstruction by crystals of uric acid in the setting of an fibrosis, almost always without evidence of urate crystal deposition,
acute overwhelming load of uric acid, particularly in acidic urine. In although this has been found in two patients. In contrast to gouty
recent years, the widespread use of an effective prophylactic regimen nephropathy, hypertension usually is absent until renal failure is
for chemotherapy has made acute uric acid nephropathy much less advanced. The hyperuricemia appears to reflect decreased renal
common [15]. This regimen includes preparation of the patient with excretion of urate rather than overproduction of urate. Although
high-dose allopurinol, volume-expanding the patient to maintain a hyperuricemia precedes and is disproportionate to any degree of
dilute urine, and alkaline diuresis. In patients whose tumor lysis renal failure, the role, if any, that uric acid plays in the pathogenesis
leads to hyperphosphatemia, however, it is important to discontinue of the renal failure remains unclear. These is no consensus among
urinary alkalinization or else calcium phosphate precipitation may authors regarding the potential value of allopurinol in this disease.
occur. Occasionally, patients will develop renal failure despite these The inheritance follows an autosomal dominant pattern, but, beyond
measures. In such patients, hemodialysis is preferable to peritoneal this, the genetics of the disease are not understood [18,19].
11.10 Tubulointerstitial Disease
References
1. Hebert SC: Extracellular calcium-sensing receptor: implications for 11. Scheinman SJ: X-linked hypercalciuric nephrolithiasis: clinical syn-
calcium and magnesium handling in the kidney. Kidney Int 1996, dromes and chloride channel mutations. Kidney Int 1998, 53:3–17.
50:2129–2139. 12. Danpure CJ, Purdue PE: Primay hyperoxaluria. In The Metabolic and
2. Riccardi D, Hall A, Xu J, et al.: Localization of the extracellular Ca2+ Molecular Bases of Inherited Disease, edn 6. Edited by Scriver CR, et
(polyvalent) cation-sensing receptor in kidney. Am J Physiol (Renal al. New York: McGraw-Hill; 1995:2385–2424.
Fluid Electrolyte Physiol), 1998, in press. 13. Scheinman JI: Primary hyperoxaluria. Miner Electrolyte Metab 1994,
3. Wrong OM: Nephrocalcinosis. In The Oxford Textbook of Clinical 20:340–351.
Nephrology. Edited by Davison AM, et al. London: Oxford 14. Katz A, Freese D, Danpure CJ, et al.: Success of kidney transplanta-
University Press; 1997:1378–1396. tion in oxalosis is unrelated to residual hepatic enzyme activity.
4. Coe FL, Parks JH, Asplin JR: The pathogenesis and treatment of Kidney Int 1992, 42:1408–1411.
kidney stones. N Engl J Med 1992, 327:1141–1152. 15. Razis E, Arlin ZA, Ahmed T, et al.: Incidence and treatment of tumor
5. Buckalew VM: Nephrolithiasis in renal tubular acidosis. J Urol 1989, lysis syndrome in patients with acute leukemia. Acta Haematol 1994,
141:731–737. 91:171–174.
6. Simon DB, Karet FE, Hamdan JM, et al.: Bartter’s syndrome, 16. Pichette V, Leblanc M, Bonnardeaux A, et al.: High dialysate flow
hypokalaemic alkalosis with hypercalciuria, is caused by mutations in rate continuous arteriovenous hemodialysis: a new approach for the
the Na-K-2Cl cotransporter NKCC2. Nature Genet 1996, 13:183–188. treatment of acute renal failure and tumor lysis syndrome. Am J
7. Simon DB, Karet FE, Rodriguez-Soriano J, et al.: Genetic heterogene- Kidney Dis 1994, 23:591–596.
ity of Bartter’s syndrome revealed by mutations in the K+ channel, 17. Beck LH: Requiem for gouty nephropathy. Kidney Int 1986,
ROMK. Nature Genet 1996, 14:152–156. 30:280–287.
8. Simon DB, Bindra RS, Mansfield TA, et al.: Mutations in the chloride 18. Puig JG, Miranda ME, Mateos FA, et al. Hereditary nephropathy
channel gene, CLCNKB, cause Bartter’s syndrome type III. Nature associated with hyperuricemia and gout. Arch Intern Med 1993,
Genet 1997, 17:171–178. 153:357–365.
9. Simon DB, Nelson-Williams C, Bia MJ, et al.: Gitelman’s variant of 19. Reiter L, Brown MA, Edmonds J: Familial hyperuricemic nephropathy.
Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by Am J Kidney Dis 1995, 25:235–241.
mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genet
1996, 12:24–30.
10. Lloyd SE, Pearce SHS, Fisher SE, et al.: A common molecular basis
for three inherited kidney stone diseases. Nature 1996, 379:445–449.
Renal Tubular Disorders
Lisa M. Guay-Woodford
I
nherited renal tubular disorders involve a variety of defects in renal
tubular transport processes and their regulation. These disorders
generally are transmitted as single gene defects (Mendelian traits),
and they provide a unique resource to dissect the complex molecular
mechanisms involved in tubular solute transport. An integrated
approach using the tools of molecular genetics, molecular biology,
and physiology has been applied in the 1990s to identify defects in
transporters, channels, receptors, and enzymes involved in epithelial
transport. These investigations have added substantial insight into the
molecular mechanisms involved in renal solute transport and the
molecular pathogenesis of inherited renal tubular disorders. This
chapter focuses on the inherited renal tubular disorders, highlights
their molecular defects, and discusses models to explain their under-
lying pathogenesis.
CHAPTER
12
12.2 Tubulointerstitial Disease
Renal Glucosuria
FIGURE 12-2
400 Physiology and pathophysiology of glucose titration curves. Under
Tmax
normal physiologic conditions, filtered glucose is almost entirely
Observed curve reabsorbed in the proximal tubule by way of two distinct sodium-
coupled glucose transport systems. In the S1 and S2 segments, bulk
Threshold
reabsorption of glucose load occurs by way of a kidney-specific
200 high-capacity transporter, the sodium-glucose transporter-2 (SGLT2)
[1]. The residual glucose is removed from the filtrate in the S3 seg-
ment by way of the high-affinity sodium-glucose transporter-1
Glucose reabsorption, mg/min 1.73m2
Aminoacidurias
FIGURE 12-3
Over 95% of the filtered amino acid load is normally reabsorbed in Cystine actually is a neutral amino acid that shares a common
the proximal tubule. The term aminoaciduria is applied when more carrier with the dibasic amino acids lysine, arginine, and ornithine.
than 5% of the filtered load is detected in the urine. Aminoaciduria The transport of all four amino acids is disrupted in cystinuria. The
can occur in the context of metabolic defects, which elevate plasma rarer disorder, lysinuric protein intolerance, results from defects in
amino acid concentrations and thus increase the glomerular filtered the basolateral transport of dibasic amino acids but not cystine.
load. Aminoaciduria can be a feature of generalized proximal tubu- Increased intracelluar concentrations of lysine, arginine, and
lar dysfunction caused by toxic nephropathies or Fanconi’s syn- ornithine are associated with disturbances in the urea cycle and
drome. In addition, aminoaciduria can arise from genetic defects in consequent hyperammonemia [7].
one of the several amino acid transport systems in the proximal Disorders involving the transport of neutral amino acids include
tubule. Three distinct groups of inherited aminoacidurias are distin- Hartnup disease, blue diaper syndrome, methioninuria, iminogly-
guished based on the net charge of the target amino acids at neutral cinuria, and glycinuria. Several neutral amino acid transporters
pH: acidic (negative charge), basic (positive charge), and neutral have been cloned and characterized. Clinical data suggest that
(no charge) [5]. Hartnup disease involves a neutral amino acid transport system
Acidic aminoaciduria involves the transport of glutamate and in both the kidney and intestine, whereas blue diaper syndrome
aspartate and results from a defect in the high-affinity sodium- involves a kidney-specific tryptophan transporter [5]. Methioninuria
potassium–dependent glutamate transporter [6]. It is a clinically appears to involve a separate methionine transport system in the
benign disorder. proximal tubule. Case reports describe seizures, mental retardation,
Four syndromes caused by defects in the transport of basic and episodic hyperventilation in affected patients [8]. The patho-
amino acids or cystine have been described: cystinuria, lysinuric physiologic basis for this phenotype is unclear. Iminoglycinuria
protein intolerance, isolated cystinuria, and isolated lysinuria. and glycinuria are clinically benign disorders.
Renal Tubular Disorders 12.5
FIGURE 12-4
ROSENBERG CLASSIFICATION OF CYSTINURIAS In this autosomal recessive disorder the apical
transport of cystine and the dibasic amino
acids is defective. Differences in the urinary
Category Phenotype Intestinal transport defect excretion of cystine in obligate heterozygotes
and intestinal amino acid transport studies in
I homozygotes have provided the basis for
Heterozygote No abnormality defining three distinct phenotypes of cystin-
Homozygote Cystinuria, basic aminoaciduria, cystine stones Cystinine, basic amino acids
uria [9]. Genetic studies have identified
II
mutations in the gene (SCL3A1) encoding a
Heterozygote Excess excretion of cystine and basic amino acids
Homozygote Cystinuria, basic aminoaciduria, cystine stones Basic amino acids only high-affinity transporter for cystine and the
III dibasic amino acids in patients with type I
Heterozygote Excess excretion of cystine and basic amino acids cystinuria [10,11]. In patients with type III
Homozygote Cystinuria, basic aminoaciduria, cystine stones None cystinuria, SCL3A1 was excluded as the
disease-causing gene [12]. A second cystin-
uria-susceptibility gene recently has been
From Morris and Ives [5]; with permission.
mapped to chromosome 19 [13].
FIGURE 12-5
Urinary cystine crystals. Excessive urinary excretion of cystine (250 to
1000 mg/d of cystine/g of creatinine) coupled with its poor solubility
in urine causes cystine precipitation with the formation of characteris-
tic urinary crystals and urinary tract calculi. Stone formation often
causes urinary tract obstruction and the associated problems of renal
colic, infection, and even renal failure. The treatment objective is to
reduce urinary cystine concentration or to increase its solubility.
High fluid intake (to keep the urinary cystine concentration below
the solubility threshold of 250 mg/L) and urinary alkalization are the
mainstays of therapy. For those patients refractory to conservative
management, treatment with sulfhydryl-containing drugs, such as
D-penicillamine, mercaptopropionylglycine, and even captopril can
be efficacious [14,15].
12.6 Tubulointerstitial Disease
Vitamin D—1,25-dihydroxy-vitamin D3
FIGURE 12-6
Several inherited disorders have been described that result in isolated Pi); and associated metabolic bone disease, eg, rickets in children or
renal phosphate wasting. These disorders include X-linked hypo- osteomalacia in adults [5]. These disorders can be distinguished on
phosphatemic rickets (HYP), hereditary hypophosphatemic rickets the basis of the renal hormonal response to hypophosphatemia, the
with hypercalciuria (HHRH), hypophosphatemic bone disease (HBD), biochemical profile, and responsiveness to therapy. In addition, the
autosomal dominant hypophosphatemic rickets (ADHR), autosomal rare disorder XLRH is associated with nephrolithiasis. The clinical
recessive hypophosphatemic rickets (ARHR), and X-linked recessive features of the two most common disorders HYP and HHRH are
hypophosphatemic rickets (XLRH). These inherited disorders share contrasted here. Whereas both disorders have defects in renal Pi
two common features: persistent hypophosphatemia caused by reabsorption, the renal hormonal response to hypophosphatemia is
decreased renal tubular phosphate (Pi) reabsorption (expressed as impaired in HYP but not in HHRH. Indeed, in children with
decreased ratio of plasma concentration at which maximal phosphate HHRH, phosphate supplementation alone can improve growth rates,
reabsorption occurs [TmP] to glomerular filtration rate [GFR], resolve the radiologic evidence of rickets, and correct all biochemical
[TmP/GFR], a normogram derivative of the fractional excretion of abnormalities except the reduced TmP GFR [5].
Fanconi’s Syndrome
FIGURE 12-8
INHERITED FANCONI’S SYNDROME Fanconi’s syndrome is characterized by two components: general-
ized dysfunction of the proximal tubule, leading to impaired net
reabsorption of bicarbonate, phosphate, urate, glucose, and amino
Disorder OMIM number* acids; and vitamin D–resistant metabolic bone disease [20]. The
clinical manifestations in patients with either the hereditary or
Idiopathic 227700, 227800 acquired form of Fanconi’s syndrome include polyuria, dehydra-
Cystinosis 219800, 219900, 219750 tion, hypokalemia, acidosis, and osteomalacia (in adults) or
Hepatorenal tyrosinemia (tyrosinemia type I) 276700 impaired growth and rickets (in children). Inherited Fanconi’s syn-
Hereditary fructose intolerance 229600 drome occurs either as an idiopathic disorder or in association with
Galactosemia 230400 various inborn errors of metabolism.
Glycogen storage disease type I 232200
Wilson’s disease 277900
Oculocerebrorenal (Lowe’s) syndrome 309000
Vitamin-D–dependent rickets 264700
CO2 + H2O
CA2
H2CO3
Bartter-like Syndromes
FIGURE 12-13
CLINICAL FEATURES DISTINGUISHING BARTTER-LIKE SYNDROMES Familial hypokalemic, hypochloremic meta-
bolic alkalosis, or Bartter’s syndrome, is not
a single disorder but rather a set of closely
Classic Bartter’s Gitelman’s Antenatal Bartter’s related disorders. These Bartter-like syn-
Feature syndrome syndrome syndrome dromes share many of the same physiologic
derangements but differ with regard to the
Age at presentation Infancy, early childhood Childhood, adolescence In utero, infancy age of onset, presenting symptoms, magni-
Prematurity, polyhydramnios +/- - ++ tude of urinary potassium and prostaglandin
Delayed growth ++ - +++
excretion, and extent of urinary calcium
Delayed cognitive development +/- - +
excretion. At least three clinical phenotypes
Polyuria, polydipsia ++ + +++
have been distinguished: classic Bartter’s
Tetany Rare ++ -
syndrome, the antenatal hypercalciuric
Serum magnesium Low in 20% Low in about 100% Low-normal to normal
Urinary calcium excretion Normal to high Low Very high
variant (also called hyperprostaglandin E
Nephrocalcinosis +/- - ++ syndrome), and hypocalciuric-hypomagne-
Urine prostaglandin excretion High Normal Very high semic Gitelman’s syndrome [25].
Clinical response to +/- - Often life-saving
indomethacin
FIGURE 12-14
Lumen Interstitium Transport systems involved in transepithelial sodium-chloride trans-
port in the thick ascending limb (TAL). Clinical data suggest that
Ca2+ the primary defect in the antenatal and classic Bartter syndrome
AA sensing
receptor variants involves impaired sodium chloride transport in the TAL.
Na+ 3Na+ Under normal physiologic conditions, sodium chloride is transported
K+ across the apical membrane by way of the bumetanide-sensitive
2Cl– 2K+
sodium-potassium-2chloride (Na-K-2Cl) cotransporter (NKCC2).
K+
This electroneutral transporter is driven by the low intracellular sodi-
20 HETE
Cl– um and chloride concentrations generated by the sodium-potassium
K+
Ca2+ pump and the basolateral chloride channels and potassium-chloride
Cl– cotransporter. In addition, apical potassium recycling by way of the
ATP
low-conductance potassium channel (ROMK) ensures the efficient
functioning of the Na-K-2Cl cotransporter. The activity of the ROMK
ATP cAMP V2R
Stimulatory channel, in turn, is regulated by a number of cell messengers, eg,
EP3 calcium (Ca2+) and adenosine triphosphate (ATP), as well as by the
Inhibitory
PGE2 calcium-sensing receptor (CaR), prostaglandin EP3 receptor, and vaso-
pressin receptor (V2R) by way of cAMP-dependent pathways and
arachidonic acid (AA) metabolites, eg, 20-hydroxy-eicosatetraenoic
Vte + Ca2+
Mg2+ acid (20-HETE). The positive transluminal voltage (Vte) drives the
paracellular reabsorption of calcium ions and magnesium ions
(Mg2+) [25]. cAMP—cyclic adenosine monophosphate; PGE2—
prostaglandin E2; PKA—protein kinase A.
FIGURE 12-15
Defective Defective Defective Proposed pathogenic model for the antenatal
NKCC2 ROMK CIC-Kb and classic variants of Bartter’s syndrome.
Gene defect
Genetic studies have identified mutations in
Pathophysiology
the genes encoding the bumetanide-sensitive
Defective NaCl ↓ Voltage-driven sodium-potassium-2chloride cotransporter
transport in TAL paracellular (NKCC2), luminal ATP–regulated potas-
reabsorption of
Ca2+ and Mg2+
sium channel (ROMK), and kidney-specific
Volume ↑ NaCl delivery to chloride channel (ClC-K2). These findings
contraction the distal nephron support the theory of a primary defect in
thick ascending limb (TAL) sodium-chloride
(Na-Cl) reabsorption in, at least, subsets of
↑ Renin
patients with the antenatal or classic variants
of Bartter’s syndrome. In the proposed model
↑ Angiotensin II (AII) the potential interrelationships of the com-
plex set of pathophysiologic phenomena are
Hypercalciuria illustrated. The resulting clinical manifesta-
↑ Kallikrein ↑ Aldosterone ↑ H+ and K+ Hypermagnesuria tions are highlighted in boxes [25]. Ca2+—
secretion calcium ion; H+—hydrogen ion; K+—potas-
sium ion; Mg2+—magnesium ion; PGE2—
Normotension prostaglandin E2.
Blunted vascular
response to AII and Metabolic alkalosis Impaired
norepinephrine Hypokalemia vasopressin-
stimulated
urinary
↑ PGE2 concentration
Hyposthenuria
Fever
↑ Urinary ↑ Bone
prostaglandins reabsorption
Renal Tubular Disorders 12.11
FIGURE 12-16
Defective NCCT Proposed pathogenic model for Gitelman’s
Gene defect
syndrome. The electrolyte disturbances
Pathophysiologic model
evident in Gitelman’s syndrome also are
DefectiveHypercalciuria
NaCl transport in DCT observed with administration of thiazide
? diuretics, which inhibit the sodium-chloride
(Na-Cl) cotransporter in the distal convoluted
tubule (DCT). In families with Gitelman’s
Volume ↑ NaCl delivery to Cl– efflux mediates ↓ Na+-dependent
contraction Mg2+ reabsorption syndrome, genetic studies have identified
the distal nephron cell hyperpolarization defects in the gene encoding the thiazide-
in DCT
sensitive cotransporter (NCCT) protein.
↑ Renin
The proposed pathogenic model is predicated
on loss of function of the NCCT protein
↑ Angiotensin II (AII) and, thus, most closely applies to those
patients who inherit Gitelman’s syndrome
↑ Aldosterone ↑ H+ and K+ secretion ↑ Ca2+ reabsorption as an autosomal recessive trait. Given that
the physiologic features of this syndrome
Metabolic alkalosis are virtually indistinguishable in familial
Hypocalciuria Hypermagnesuria and sporadic cases, it may be reasonable
hypokalemia
to propose the same pathogenesis for all
patients with Gitelman’s syndrome. How-
ever, it is important to caution that evidence
for NCCT mutations in sporadic cases has
not yet been established [25]. Ca2+—calci-
um ion; Cl-—chloride ion; H+—hydrogen ion;
K+—potassium ion; Mg2+—magnesium ion;
Na+—sodium ion.
Pseudohypoparathyroidism
FIGURE 12-17
Pseudohypoparathyroidism applies to a heterogeneous group of hered- Pseudohypoparathyroidism type Ia (Albright’s hereditary osteo-
itary disorders whose common feature is resistance to parathyroid dystrophy) is associated with a myriad of physical abnormalities
hormone (PTH). Affected patients are hypocalcemic and hyperphos- and resistance to multiple adenylate cyclase–coupled hormones,
phatemic, despite elevated plasma PTH levels. Hypocalcemia and most notably thyrotropin and gonadotropin [27]. The molecular
hyperphophatemia result from the combined effects of defective PTH- defect in a guanine nucleotide–binding protein (Gs) blocks the
mediated calcium reabsorption in the distal convoluted tubule and coupling of PTH and other hormone receptors to adenylate cyclase.
reduced formation of 1,25-dihydroxy-vitamin D3. The latter leads to The molecular defect has not been identified in type Ib, although
defects in renal phosphate excretion, calcium mobilization from bone, specific resistance to PTH suggests a defect in the PTH receptor.
and gastrointestinal calcium reabsorption. Differences in clinical fea- Oral supplementation with 1,25 dihydroxy-vitamin D3 and, if
tures and urinary cyclic adenosine monophosphate response to infused necessary, oral calcium, is used to correct the hypocalcemia and
PTH provide the basis for distinguishing three distinct subtypes of minimize PTH-induced bone disease [26]. Pseudohypoparathroid-
pseudohypoparathyroidism (type Ia, type Ib, and type II) [26]. ism type II may be an acquired disease.
12.12 Tubulointerstitial Disease
FIGURE 12-19
Low-renin hypertension Algorithm for evaluating patients with low-
renin hypertension. Glucocorticoid-remedial
aldosteronism (GRA), Liddle’s syndrome,
and apparent mineralocorticoid excess (AME)
+ Family history – Family history can be distinguished from one another by
characteristic urinary steroid profiles [31].
K+—potassium ion; PE—physical examina-
tion; TH18oxoF/THAD—ratio of urinary
Abnormal PE Normal PE 18-oxotetrahydrocortisol (TH18oxoF) to
Serum K+ urinary tetrahydroaldosterone (normal:
0–0.4; GRA patients: >1); THF + allo-
THF/THE—ratio of the combined urinary
Virilization Hypogonadism
tetrahydrocortisol and allotetrahydrocortisol
Low
High-normal Low-normal to urinary tetrahydrocortisone (normal:
serum K+
11β-hydroxylase 17α-hydroxylase <1.3; AME patients: 5–10-fold higher).
Gordon's deficiency deficiency
syndrome
TH180x0F Negligible urinary THF + alloTHF
Urinary THAD aldosterone THE
steroid profile:
800 dipsia, and hyposthenuria despite often elevated AVP levels [17].
(From Robertson et al. [36]; with permission.)
600
400
200 NDI
0 1 2 3 4 5 10 15
Plasma AVP, pg/mL
Urolithiases
amino acid transport in the proximal tubule.
Cystinuria is the leading single gene cause of
INHERITED CAUSES OF UROLITHIASES
inheritable urolithiasis in both children and
adults [41,42]. Three Mendelian disorders,
Dent’s disease, X-linked recessive nephrolithi-
Disorder Stone characteristics Treatment asis, and X-linked recessive hypophospha-
Cystinuria Cystine High fluid intake, urinary alkalization temic rickets cause hypercalciuric urolithiasis.
Sulfhydryl-containing drugs These disorders involve a functional loss of
Dent’s disease Calcium-containing High fluid intake, urinary alkalization the renal chloride channel ClC-5 [43]. The
X-linked recessive nephrolithiasis Calcium-containing High fluid intake, urinary alkalization common molecular basis for these three
X-linked recessive hypophos- Calcium-containing High fluid intake, urinary alkalization inherited kidney stone diseases has led to
phatemic rickets speculation that ClC-5 also may be involved
Hereditary renal hypouricemia Uric acid, calcium oxalate High fluid intake, urinary alkalization in other renal tubular disorders associated
Allopurinol with kidney stones. Hereditary renal hypour-
Hypoxanthine-guanine phospho- Uric acid High fluid intake, urinary alkalization icemia is an inborn error of renal tubular
ribosyltransferase deficiency Allopurinol transport that appears to involve urate reab-
Xanthinuria Xanthine High fluid intake, dietary purine restriction sorption in the proximal tubule [16].
Primary hyperoxaluria Calcium oxalate High fluid intake, dietary oxalate restriction In addition to renal transport deficiencies,
Magnesium oxide, inorganic phosphates defects in metabolic enzymes also can cause
urolithiases. Inherited defects in the purine
salvage enzymes hypoxanthine-guanine phos-
phoribosyltransferase (HPRT) and adenine
FIGURE 12-23 phosphoribosyltransferase (APRT) or in the
Urolithiases are a common urinary tract abnormality, afflicting 12% of men and 5% of women catabolic enzyme xanthine dehydrogenase
in North America and Europe [40]. Renal stone formation is most commonly associated with (XDH) all can lead to stone formation [44].
hypercalciuria. Perhaps in as many as 45% of these patients, there seems to be a familial Finally, defective enzymes in the oxalate
predisposition. In comparison, a group of relatively rare disorders exists, each of which is metabolic pathway result in hyperoxaluria,
transmitted as a Mendelian trait and causes a variety of different crystal nephropathies. The oxalate stone formation, and consequent
most common of these disorders is cystinuria, which involves defective cystine and dibasic loss of renal function [45].
Acknowledgment
The author thanks Dr. David G. Warnock for critically reviewing this manuscript.
References
1. Wells R, Kanai Y, Pajor A, et al.: The cloning of a human cDNA with 7. Oynagi K, Sogawa H, Minawi R,et al.: The mechanism of hyperam-
similarity to the sodium/glucose cotransporter. Am J Physiol 1992, monemia in congenital lysinuria. J Pediatr 1979, 94:255.
263:F459–F465. 8. Smith A, Strang L: An inborn error of metabolism with the urinary
2. Hediger M, Coady M, Ikeda T, Wright E: Expression cloning and excretion of -hydroxybutric acid and phenyl-pyruvic acid. Arch Dis
cDNA sequencing of the Na/glucose co-transporter. Nature 1987, Child 1958, 33:109.
330:379–381. 9. Rosenberg LE, Downing S, Durant JL, Segal S: Cystinuria: biochemi-
3. Woolf L, Goodwin B, Phelps C: Tm-limited renal tubular reabsorption cal evidence for three genetically distinct diseases. J Clin Invest 1966,
and the genetics of renal glycosuria. J Theor Biol 1966, 11:10–21. 45:365–371.
4. Meuckler M: Facilitative glucose transporters. Euro J Biochem 1994, 10. Pras E, Arber N, Aksentijevich I, et al.: Localization of a gene causing
219:713–725. cystinuria to chromosome 2p. Nature Genet 1994, 6:415–419.
5. Morris JR, Ives HE: Inherited disorders of the renal tubule. In The 11. Calonge MJ, Gasparini P, Chillaron J, et al.: Cystinuria caused by
Kidney. Edited by Brenner B, Rector F. Philadelphia: WB Saunders, mutations in rBAT, a gene involved in the transport of cystine. Nature
1996:1764–1827. Genet 1994, 6:420–425.
6. Kanai Y, Hediger M: Primary structure and functional characteriza- 12. Calonge M, Volpini V, Bisceglia L, et al.: Genetic heterogeneity in
tion of a high affinity glutamate transporter. Nature 1992, cystinuria: the SLC3A1 gene is linked to type I but not to type III
360:467–471. cystinuria. Proc Am Acad Sci USA 1995, 92:9667–9671.
12.16 Tubulointerstitial Disease
13. Wartenfeld R, Golomb E, Katz G, Bale S, et al.: Molecular analysis of 30. White P, Mune T, Rogerson F, et al.: 11--hydroxysteroid dehydroge-
cystinuria in Libyan Jews: exclusion of the SLC3A1 gene and mapping nase and its role in the syndrome of apparent mineralocorticoid
a new locus on 19q. Am J Med Genet 1997, 60:617–624. excess. Pediatr Res 1997, 41:25–29.
14. Stephens AD: Cystinuria and its treatment: 25 years’ experience at St. 31. Yiu V, Dluhy R, Lifton R, Guay-Woodford L: Low peripheral plasma
Bartholomew’s Hospital. J Inherited Metab Dis 1989, 12:197–209. renin activity as a critical marker in pediatric hypertension. Pediatr
15. Perazella M, Buller G: Successful treatment of cystinuria with captopril. Nephrol 1997, 11:343–346.
Am J Kidney Dis 1993, 21:504–507. 32. Chang S, Grunder S, Hanukoglu A, et al.: Mutations in subunits of
16. Grieff M: New insights into X-linked hypophosphatemia. Curr Opin the epithelial sodium channel cause salt wasting with hyperkalemic
Nephrol Hypertens 1997, 6:15–19. acidosis, pseudohypoaldosteronism type 1. Nature Genet 1996,
17. Robertson GL: Vasopressin in osmotic regulation in man. Annu Rev 12:248–253.
Med 1974, 25:315. 33. Kuhle U: Pseudohypoaldosteronism: mutation found, problem solved?
18. Econs M, Drezner M: Tumor-induced osteomalacia: unveiling a new Mol Cell Endocrinol 1997, 133:77–80.
hormone. N Engl J Med 1994, 330:1679–1681. 34. Gordon R: Syndrome of hypertension and hyperkalemia with normal
19. The HYP Consortium: A gene (PEX) with homologies to endopepti- glomerular filtration rate. Hypertension 1986, 8:93–102.
dases is mutated in patients with X-linked hypophosphatemic rickets. 35. Mansfield T, Simon D, Farfel Z, et al.: Multilocus linkage of familial
Nature Genet 1995, 11:130–136. hyperkalaemia and hypertension, pseudohypoaldosteronism type II,
20. Bergeron M, Gougoux A, Vinay P: The renal Fanconi syndrome. In to chromosomes 1q31-42 and 17p11-q2. Nature Genet 1997,
The Metabolic and Molecular Bases of Inherited Diseases. Edited by 16:202–205.
Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill, 36. Robertson GL, et al: Development and clinical application of a new
1995:3691–3704. method for the radioimmunoassay of arginine vasopressin in human
21. Sly W, Hu P: The carbonic anhydrase II deficiency syndrome: osteo- plasma. J Clin Invest 1973, 52:2340–2352.
petrosis with renal tubular acidosis and cerebral calcification. In The 37. Bichet D, Osche A, Rosenthal W: Congenital nephrogenic diabetes
Metabolic and Molecular Bases of Inherited Diseases. Edited by insipidus. JASN 1997, 12:1951–1958.
Scriver CH, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 38. van Lieburg A, Verdijk M, Knoers N, et al.: Patients with autosomal
1965:3581–3602. recessive nephrogenic diabetes insipidus homozygous for mutations
22. Bastani B, Gluck S: New insights into the pathogenesis of distal renal in the aquaporin 2 water channel gene. Am J Hum Genet 1994,
tubular acidosis. Miner Electrolyte Metab 1996, 22:396–409. 55:648–652.
23. Bruce L, Cope D, Jones G, et al.: Familial distal renal tubular acidosis 39. Bichet D, Arthus M-F, Lonergan M, et al.: Autosomal dominant and
is associated with mutations in the red cell anion exchanger (band 3, autosomal recessive nephrogenic diabetes insipidus: novel mutations
AE1) gene. J Clin Invest 1997, 100:1693–1707. in the AQP2 gene. J Am Soc Nephrol 1995, 6:717A.
24. Jarolim P, Shayakul C, Prabakaran D, et al.: Autosomal dominant dis- 40. Coe F, Parks J, Asplin J: The pathogenesis and treatment of kidney
tal renal tubular acidosis is associated in three families with heterozy- stones. N Engl J Med 1992, 327:1141–1152.
gosity for the R589H mutation in the AE1 (band 3) Cl-/HCO-3
41. Segal S, Thier S: Cystinuria. In The Metabolic and Molecular Bases of
exchanger. J Biol Chem, 1998, 273:6380–6388.
Inherited Diseases. Edited by Scriver CH, Beaudet AL, Sly WS, Valle
25. Guay-Woodford L: Bartter syndrome: unraveling the pathophysiologic D. York: McGraw-Hill; 1995:3581–3602.
enigma. Am J Med, 1998, 105:151–161.
42. Polinsky MS, Kaiser BA, Baluarte HJ: Urolithiasis in childhood.
26. Spiegel A, Weinstein L: Pseudohypoparathyroidism. In The Metabolic Pediatr Clin North Am 1987, 34:683–710.
and Molecular Bases of Inherited Diseases. Edited by Scriver CH,
Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill; 43. Lloyd S, Pearce S, Fisher S, et al.: A common molecular basis for three
1995:3073–3085. inherited kidney stone diseases. Nature 1996, 379:445–449.
27. Van Dop C: Pseudohypoparathyroidism: clinical and molecular 44. Cameron J, Moro F, Simmonds H: Gout, uric acid and purine metab-
aspects. Semin Nephrol 1989, 9:168–178. olism in paediatric nephrology. Pediatr Nephrol 1993, 7:105–118.
28. Lifton RP, Dluhy RG, Powers M., et al.: A chimaeric 11--hydroxy- 45. Danpure C, Purdue P: Primary Hyperoxaluria. In The Metabolic and
lase aldosterone synthase gene causes glucocorticoid-remediable aldos- Molecular Bases of Inherited Diseases. Edited by Scriver CH, Beaudet
teronism and human hypertension. Nature 1992, 355:262–265. AL, Sly WS, Valle D. New York: McGraw-Hill; 1995:2385–2424.
29. Shimkets RA, Warnock DG, Bositis CM, et al.: Liddle’s syndrome:
heritable human hypertension caused by mutations in the subunit
of the epithelial sodium channel. Cell 1994, 79:407–414.
The Kidney in Blood
Pressure Regulation
L. Gabriel Navar
L. Lee Hamm
D
espite extensive animal and clinical experimentation, the
mechanisms responsible for the normal regulation of arterial
pressure and development of essential or primary hyperten-
sion remain unclear. One basic concept was championed by Guyton
and other authors [1–4]: the long-term regulation of arterial pressure
is intimately linked to the ability of the kidneys to excrete sufficient
sodium chloride to maintain normal sodium balance, extracellular fluid
volume, and blood volume at normotensive arterial pressures.
Therefore, it is not surprising that renal disease is the most common
cause of secondary hypertension. Furthermore, derangements in renal
function from subtle to overt are probably involved in the pathogenesis
of most if not all cases of essential hypertension [5]. Evidence of gener-
alized microvascular disease may be causative of both hypertension and
progressive renal insufficiency [5,6]. The interactions are complex
because the kidneys are a major target for the detrimental consequences
of uncontrolled hypertension. When hypertension is left untreated, pos-
itive feedback interactions may occur that lead progressively to greater
hypertension and additional renal injury. These interactions culminate
in malignant hypertension, stroke, other sequelae, and death [7].
In normal persons, an increased intake of sodium chloride leads to
appropriate adjustments in the activity of various humoral, neural,
and paracrine mechanisms. These mechanisms alter systemic and
renal hemodynamics and increase sodium excretion without increasing
arterial pressure [3,8]. Regardless of the initiating factor, decreases in
sodium excretory capability in the face of normal or increased sodium CHAPTER
intake lead to chronic increases in extracellular fluid volume and
blood volume. These increases can result in hypertension. When the
1
derangements also include increased levels of humoral or neural factors
that directly cause vascular smooth muscle constriction, these effects
increase peripheral vascular resistance or decrease vascular capacitance.
Under these conditions the effects of subtle increases in blood volume
are compounded because of increases in the blood volume relative to
1.2 Hypertension and the Kidney
the capacitance, often referred to as the effective blood volume. extrinsic influences and intrarenal derangements can lead to
Through the mechanism of pressure natriuresis, however, the reduced sodium excretory capability. Many factors also exist
increases in arterial pressure increase renal sodium excretion, that alter cardiac output, total peripheral resistance, and cardio-
allowing restoration of sodium balance but at the expense of vascular capacitance. Accordingly, hypertension is a multifactorial
persistent elevations in arterial pressure [9]. In support of this dysfunctional process that can be caused by a myriad of different
overall concept, various studies have demonstrated strong conditions. These conditions range from stimulatory influences
relationships between kidney disease and the incidence of that inappropriately enhance tubular sodium reabsorption to
hypertension. In addition, transplantation studies have shown overt renal pathology, involving severe reductions in filtering
that normotensive recipients from genetically hypertensive capacity by the renal glomeruli and associated marked reduc-
donors have a higher likelihood of developing hypertension tions in sodium excretory capability. An understanding of the
after transplantation [10]. normal mechanisms regulating sodium balance and how
This unifying concept has helped delineate the cardinal role derangements lead to altered sodium homeostasis and hyperten-
of the kidneys in the normal regulation of arterial pressure as sion provides the basis for a rational approach to the treatment
well as in the pathophysiology of hypertension. Many different of hypertension.
200 C A
B
HEMODYNAMIC DETERMINANTS
160 Isolated systolic hypertension 180
(61 y)
Arterial pressure, mm Hg
Aortic pressure,
160
140
mm Hg
400 (56 y)
20
Therefore,
Arterial pressure - right atrial pressure
0 500 600 700 800 900 Cardiac output =
A B Arterial volume, mL Total peripheral resistance
and:
Mean arterial pressure =
FIGURE 1-1 Cardiac output total peripheral resistance
Aortic distensibility. The cyclical pumping nature of the heart places a heavy demand on
the distensible characteristics of the aortic tree. A, During systole, the aortic tree is rapidly
filled in a fraction of a second, distending it and increasing the hydraulic pressure. B, The
distensibility characteristics of the arterial tree determine the pulse pressure (PP) in response to FIGURE 1-2
a specific stroke volume. The normal relationship is shown in curve A, and arrows designate Hemodynamic determinants of arterial
the PP. A highly distensible arterial tree, as depicted in curve B, can accommodate the stroke pressure. During the diastolic phase of the
volume with a smaller PP. Pathophysiologic processes and aging lead to decreases in aortic dis- cardiac cycle, the elastic recoil characteris-
tensibility. These decreases lead to marked increases in PP and overall mean arterial pressure tics of the arterial tree provide the kinetic
for any given arterial volume, as shown in curve C. Decreased distensibility is partly responsi- energy that allows a continuous delivery of
ble for the isolated systolic hypertension often found in elderly persons. Recordings of actual blood flow to the tissues. Blood flow is
aortic pressure and flow profiles in persons with normotension and systolic hypertension are dependent on the arterial pressure gradient
shown in panel A [11,12]. (Panel B Adapted from Vari and Navar [4] and Panel A from and total peripheral resistance. Under nor-
Nichols et al. [12].) mal conditions the right atrial pressure is
near zero, and thus the arterial pressure is
the pressure gradient. These relationships
apply for any instant in time and to time-
integrated averages when the mean pressure
is used. The time-integrated average blood
flow is the cardiac output that is normally
5 to 6 L/min for an adult of average weight
(70 to 75 kg).
The Kidney in Blood Pressure Regulation 1.3
FIGURE 1-3
Dietary Insensible losses Urinary Volume determinants of arterial pressure.
intake (skin, respiration, fecal) excretion The two major determinants of arterial
+ – – Arterial baroreflexes pressure, cardiac output and total peripheral
Atrial reflexes
Renin-angiotensin-aldosterone
resistance, are regulated by a combination
Adrenal catecholamines of short- and long-term mechanisms. Rapidly
Vasopressin Neurohumoral adjusting mechanisms regulate peripheral
Net sodium and Natriuretic peptides systems vascular resistance, cardiovascular capacitance,
fluid balance Endothelial factors: and cardiac performance. These mechanisms
nitric oxide, endothelin
kallikrein-kinin system include the neural and humoral mechanisms
Prostaglandins and other eicosanoids listed. On a long-term basis, cardiac output
ECF volume
is determined by venous return, which is
Arterial Total peripheral regulated primarily by the mean circulatory
(Autoregulation)
pressure resistance pressure. The mean circulatory pressure
Blood Interstitial depends on blood volume and overall cardio-
volume fluid volume vascular capacitance. Blood volume is closely
linked to extracellular fluid (ECF) volume
and sodium balance, which are dependent
Mean circulatory Venous Cardiac Heart rate and on the integration of net intake and net
pressure return output contractility
losses [13]. (Adapted from Navar [3].)
Cardiovascular
capacitance
+
Na+ and Cl– 4
Quantity of Extracellular concentrations
÷ =
NaCl in ECF fluid volume in ECF volume
– 3
FIGURE 1-4
A, Relationship between net sodium balance and extracellular fluid B, Relationship between the ECF volume and blood volume. Under
(ECF) volume. Sodium balance is intimately linked to volume balance normal conditions a consistent relationship exists between the total
because of powerful mechanisms that tightly regulate plasma and ECF volume and blood volume. This relationship is consistent as
ECF osmolality. Sodium and its accompanying anions constitute the long as the plasma protein concentration and, thus, the colloid
major contributors to ECF osmolality. The integration of sodium osmotic pressure are regulated appropriately and the microvasculature
intake and losses establishes the net amount of sodium in the body, maintains its integrity in limiting protein leak into the interstitial
which is compartmentalized primarily in the ECF volume. The quotient compartment. The shaded area represents the normal operating
of these two parameters (sodium and volume) determines the sodium range [13]. A chronic increase in the total quantity of sodium chloride
concentration and, thus, the osmolality. Osmolality is subject to very in the body leads to a chronic increase in ECF volume, part of
tight regulation by vasopressin and other mechanisms. In particular, which is proportionately distributed to the blood volume compartment.
vasopressin is a very powerful regulator of plasma osmolality; how- When accumulation is excessive, disproportionate distribution to
ever, it achieves this regulation primarily by regulating the relative the interstitium may lead to edema. Chronic increases in blood
solute-free water retention or excretion by the kidney [13–15]. The volume increase mean circulatory pressure (see Fig. 1-3) and lead
important point is that the osmolality is rapidly regulated by adjusting to an increase in arterial pressure. Therefore, the mechanisms
the ECF volume to the total solute present. Corrections of excesses regulating sodium balance are primarily responsible for the
in extracellular fluid volume involve more complex interactions that chronic regulation of arterial pressure. (Panel B adapted from
regulate the sodium excretion rate. Guyton and Hall [13].)
1.4 Hypertension and the Kidney
Low sodium intake arterial pressure and sodium excretion under conditions of normal,
4 A high, and low sodium intake are shown. When renal function is
2 4 normal and responsive to sodium regulatory mechanisms, steady
Elevated
3 sodium intake state sodium excretion rates are adjusted to match the intakes.
2
These adjustments occur with minimal alterations in arterial pressure,
C
5 as exemplified by going from point 1 on curve A to point 2 on
Normal 1
1 curve B. Similarly, reductions in sodium intake stimulate sodium-
sodium intake
Reduced 3 retaining mechanisms that prevent serious losses, as exemplified by
0 point 3 on curve C. When the regulatory mechanisms are operating
60 80 100 120 140 160 180 200 appropriately, the kidneys have a large capability to rapidly adjust
Renal arterial pressure, mm Hg
the slope of the pressure natriuresis relationship. In doing so, the
kidneys readily handle sodium challenges with minimal long-term
FIGURE 1-5 changes in extracellular fluid (ECF) volume or arterial pressure. In
Arterial pressure and sodium excretion. In principle, sodium balance contrast, when the kidney cannot readjust its pressure natriuresis
can be regulated by altering sodium intake or excretion by the kidney. curve or when it inadequately resets the relationship, the results are
However, intake is dependent on dietary preferences and usually is sodium retention, expansion of ECF volume, and increased arterial
excessive because of the abundant salt content of most foods. There- pressure. Failure to appropriately reset the pressure natriuresis is
fore, regulation of sodium balance is achieved primarily by altering illustrated by point 4 on curve A and point 5 on curve C. When
urinary sodium excretion. It is therefore of major significance that, this occurs the increased arterial pressure directly influences sodium
for any given set of conditions and neurohumoral environment, excretion, allowing balance between intake and excretion to be
acute elevations in arterial pressure produce natriuresis, whereas reestablished but at higher arterial pressures. (Adapted from Navar [3].)
FIGURE 1-6
150 Intrarenal responses to changes in arterial pressure at different levels of sodium intake.
Filtered sodium load,
The renal autoregulation mechanism maintains the glomerular filtration rate (GFR) during
µmol/min/g
100
Low changes in arterial pressure, GFR, and filtered sodium load. These values do not change
50 Normal significantly during changes in arterial pressure or sodium intake [3,16]. Therefore, the
High changes in sodium excretion in response to arterial pressure alterations are due primarily
0 to changes in tubular fractional reabsorption. Normal fractional sodium reabsorption is
very high, ranging from 98% to 99%; however, it is reduced by increased sodium chloride
100
intake to effect the large increases in the sodium excretion rate. These responses demon-
Fractional sodium
strate the importance of tubular reabsorptive mechanisms in modulating the slope of the
reabsorption, %
98
pressure natriuresis relationship. (Adapted from Navar and Majid [9].)
96
94
92
8
Fractional sodium
6
excretion, %
0
75 100 125 150 175
Renal arterial pressure, mm Hg
The Kidney in Blood Pressure Regulation 1.5
FIGURE 1-8
Renal autoregulatory mechanism. Because the glomerular filtration rate (GFR) is so
Glomerular filtration rate,
0.6
responsive to changes in the glomerular forces, highly efficient mechanisms have been
developed to maintain a stable intrarenal hemodynamic environment [16]. These powerful
mL/min•g
0.4
mechanisms adjust vascular smooth muscle tone in response to various extrinsic disturbances.
0.2 During changes in arterial pressure, renal blood flow and the GFR are autoregulated with
high efficiency as a consequence of adjustments in the vascular resistance of the preglomerular
0 arterioles. Although efferent resistance also can be regulated by other mechanisms, it does
not participate significantly over most of the autoregulatory range. The GFR, filtered sodium
20 RA
load, and the intrarenal pressures are maintained stable in the face of various extrarenal
Vascular resistance,
mm Hg•min•g/mL
0
5
Renal blood flow,
4
mL/min•g
3
2
1
0
0 50 100 150 200
Renal arterial pressure, mm Hg
1.6 Hypertension and the Kidney
Macula densa:
Preglomerular Vascular effector
Sensor mechanism
resistance (afferent arteriole)
Transmitter
A B
High sodium intake, glomerular pressure and GFR of that nephron decrease. The shaded
ECF volume expansion area in the normal relationship represents the normal operating
level of the TGF mechanism. This mechanism helps stabilize the
20 filtered load and the solute and sodium load to the distal nephron
segment. The responsiveness of the TGF mechanism is modulated
Normal by changes in sodium intake and in extracellular fluid (ECF) volume
status. At high sodium intake and ECF volume expansion the sensi-
tivity of the TGF mechanism is low, thus allowing greater spillover
10
Low sodium intake of salt to the distal nephron. During low sodium intake and other
Decreased ECF volume conditions associated with ECF volume contraction, the sensitivity
of the TGF mechanism is markedly increased to minimize spillover
into the distal nephron and maximize sodium retention. The hor-
0 monal and paracrine mechanisms responsible for regulating TGF
0 10 20 30 40 sensitivity are discussed subsequently.
C Late proximal perfusion rate, nL/min The myogenic mechanism is intrinsic to the vessel wall and
responds to changes in wall tension to regulate vascular smooth
muscle tone. Preglomerular arteries and afferent arterioles but not
FIGURE 1-9 efferent arterioles exhibit myogenic responses to changes in wall
Tubuloglomerular feedback (TGF) and myogenic mechanisms. Two tension [16,20]. The residual autoregulatory capacity that exists
mechanisms are responsible for efficient renal autoregulation: the during blockade of the tubuloglomerular feedback mechanism
TGF and myogenic mechanisms. The TGF mechanism is explained indicates that the myogenic mechanism contributes about half to
here. A, Increases in distal tubular flow past the macula densa generate the autoregulatory efficiency of the renal vasculature. (Figure
signals from the macula densa cells to the afferent arterioles to elicit adapted from Navar [3].)
The Kidney in Blood Pressure Regulation 1.7
PKA
Ca2+
SR
Ca2+-Cal Active MLCK Phosphorylated Tension
PKC MLC development
Calmodulin MLCK MLC Actin
FIGURE 1-10
Cellular mechanisms of vascular smooth muscle contrac- tone are identified. Ad Cy—adenylate cyclase;
tion. The vascular resistances of different arteriolar ANP—atrial natriuretic protein; Cal—calmodulin;
segments are ultimately regulated by the contractile cGMP—cyclic GMP; DAG—1,2-diacylglycerol; Gq,
tone of the corresponding vascular smooth muscle Gi, Gs—G proteins; IP3—inositol 1,4,5-triphosphate;
cells. Shown are the various membrane activation MLC—myosin light chain; MLCK—myosin light chain
mechanisms and signal transduction events leading to kinase; PGE2—prostaglandin E2; PGI2—prostaglandin
a change in cytosolic calcium ions (Ca2+), cyclic AMP I2; PKA—protein kinase A; PKC—protein kinase C;
(cAMP), and phosphorylation of myosin light chain PLC—phospholipase C; PTH—parathyroid hormone;
kinase. Many of the circulating hormones and paracrine R—receptor; SR—sarcoplasmic reticulum; TXA2 —
factors that increase or decrease vascular smooth muscle thromboxane A2. (Adapted from Navar et al. [16].)
FIGURE 1-11
Differential activating mechanisms in afferent and efferent arterioles.
The relative contributions of the activation pathways are different
in afferent and efferent arterioles. Increases in cytosolic Ca2+ in
afferent arterioles appear to be primarily by calcium ion (Ca2+)
entry by way of receptor- and voltage-dependent Ca2+ channels.
The efferent arterioles are less dependent on voltage-dependent
Ca2+ channels. These differential mechanisms in the renal vasculature
are exemplified by comparing the afferent and efferent arteriolar
responses to angiotensin II before and after treatment with Ca2+
channel blockers. A, These experiments were done using the
juxtamedullary nephron preparation that allows direct visualization
of the renal microcirculation [21]. AA—afferent arteriole;
ArA—arcuate artery; PC—peritubular capillaries; V—vein;
VR—vasa recta.
(Continued on next page)
A
1.8 Hypertension and the Kidney
0.1 nM 10 nM 0.1 nM 10 nM
10
B Control Angiotensin II Control Angiotensin II
FIGURE 1-13
Renal Shear Endothelial Vascular dilation Nitric oxide in mediation of pressure natriuresis. Several recent studies
arterial stress nitric oxide but counteracted have demonstrated that nitric oxide also directly affects tubular sodi-
pressure release by autoregulation um transport and may be an important mediator of the changes
induced by arterial pressure in sodium excretion, as described in Figure
Sodium excretion, normal
FIGURE 1-14
DCT
Tubular transport processes. Sodium excretion is the difference
PCT
between the very high filtered load and net tubular reabsorption
60% rate such that, under normal conditions less than 1% of the filtered
sodium load is excreted. The percentage of reabsorption of the filtered
7%
load occurring in each nephron segment is shown. The end result is
CCD that normally less than 1% of the filtered load is excreted; however,
PST the exact excretion rate can be changed by many mechanisms. Despite
the lesser absolute sodium reabsorption in the distal nephron seg-
ments, the latter segments are critical for final regulation of sodium
2% –3% excretion. Therefore, any factor that changes the delicate balance
TALH OMCD
30%
existing between the hemodynamically determined filtered load and
the tubular reabsorption rate can lead to marked alterations in
sodium excretion. ALH—thin ascending limb of the loop of Henle;
DLH IMCD
CCD—cortical collecting duct; DCT—distal convoluted tubule;
ALH DLH—thin descending limb of the loop of Henle; IMCD—inner
medullary collecting duct; OMCD—outer medullary collecting
duct; PCT—proximal convoluted tubule; PST—proximal straight
< 1% tubule; TALH—thick ascending limb of the loop of Henle.
Filtered NA+ load = Plasma Na × Glomerular filtration rate
= 140 mEq/L × 0.120 L/min
= 16.8 mEq/min × 1440 min/d
= 24,192 mEq/min
Urinary Na+ excretion = 200 mEq/d
Fractional Na excretion = 0.83%
Fractional Na reabsorption = 99.17%
FIGURE 1-15
Peritubular capillary Proximal tubule reabsorptive mechanisms. The proximal tubule is
Lateral responsible for reabsorption of 60% to 70% of the filtered load of
intercellular ∆P
space ∆π Na K sodium. Reabsorption is accomplished by a combination of both
active and passive transport mechanisms that reabsorb sodium and
(–) other solutes from the lumen into the lateral spaces and interstitial
Na compartment. The major driving force for this reabsorption is the
basolateral sodium-potassium ATPase (Na+-K+ ATPase) that transports
Active [K ] +
Na
K
Na+ out of the proximal tubule cells in exchange for K+. As in most
transcellular
K
cells, this maintains a low intracellular Na+ concentration and a
Na+ high intracellular K+ concentration. The low intracellular Na+
Cells (–) concentration, along with the negative intracellular electrical
potential, creates the electrochemical gradient that drives most of
Paracellular
[Na+] the apical transport mechanisms. In the late proximal tubule, a lumen
(passive) to interstitial chloride concentration gradient drives additional net
Tubule lumen
solute transport. The net solute transport establishes a small
osmotic imbalance that drives transtubular water flow through
both transcellular and paracellular pathways. In the tubule, water
and solutes are reabsorbed isotonically (water and solute in equivalent
proportions). The reabsorbed solutes and water are then further
reabsorbed from the lateral and interstitial spaces into the peritubular
capillaries by the colloid osmotic pressure, which establishes
a predominant reabsorptive force as discussed in Figure 1-7.
P—transcapillary hydrostatic pressure gradient; π—transcapillary
colloid osmotic pressure gradient.
1.10 Hypertension and the Kidney
FIGURE 1-17
Lumen Thick ascending
limb cells Sodium transport mechanisms in the thick ascending limb of the
Furosemide Cell Regulation of reabsorbtion loop of Henle. The major sodium chloride reabsorptive mechanism
_ Stimulation in the thick ascending limb at the apical membrane is the sodium-
ATP Antidiuretic hormone
potassium-chloride cotransporter. This electroneutral transporter is
Na 3Na+ β-adrenergic agents
2Cl-
inhibited by furosemide and other loop diuretics and is stimulated
2 K+ Mineralocorticoids
K+ Inhibition
by a variety of factors. Potassium is recycled across the apical
or ADP
NH4+ Hypertonicity membrane into the lumen, creating a positive voltage in the lumen.
+10mv _
Prostaglandin E2 An apical sodium-hydrogen exchanger also exists that may function
K+ CI Acidosis to reabsorb some sodium bicarbonate. The sodium-potassium
Calcium ATPase (Na+-K+ ATPase) at the basolateral membrane again is the
driving force. The basolateral chloride channel and possibly other
Na+
chloride cotransporters are important in mediating chloride efflux
H+ across the basolateral membrane. Sodium and chloride are reab-
sorbed without water in this segment because water is impermeable
across the apical membrane of the thick ascending limb. Thus, the
tubular fluid osmolality in this nephron segment is hypotonic.
The Kidney in Blood Pressure Regulation 1.11
FIGURE 1-18
Distal tubule and Mechanisms of sodium chloride reabsorption in the distal tubule. The distal convoluted
connecting tubule cells
Thiazides tubule and subsequent connecting tubule have a variety of sodium transport mechanisms.
_ The distal tubule has predominantly a sodium chloride cotransporter, which is inhibited
by thiazide diuretics. In the connecting tubule, sodium channels and a sodium-hydrogen
Na ATP exchange mechanism also are present. Amiloride inhibits sodium channel activity. Again
_
Cl 3Na+ the sodium-potassium ATPase (Na+-K+ ATPase) on the basolateral membrane provides
2 K+ most of the driving force for sodium reabsorption.
Na+ ADP
Amiloride
Na+
H+
FIGURE 1-19
Collecting duct principal cell
Mechanism of sodium chloride reabsorption in collecting duct cells.
Lumen Cell Sodium transport in the collecting duct is mainly via amiloride-
Regulation of reabsorbtion
Stimulation sensitive sodium channels in the apical membrane. Some evidence for
ATP Aldosterone other mechanisms such as an electroneutral sodium-chloride cotrans-
Na+ 3Na+ Antidiuretic hormone port mechanism and a different sodium channel also has been
2 K+ Inhibition reported. Again, the basolateral sodium-potassium ATPase (Na+-K+
ADP Prostaglandins ATPase) creates the driving force for overall sodium transport.
_ Nitric oxide
Atrial natriuretic peptide There are some differences between the cortical collecting duct and
Bradykinin the deeper inner medullary collecting duct (IMCD). In the cortical
Amiloride collecting duct, sodium transport occurs in the predominant principal
K+ Na+_ cell type interspersed between acid-base transporting intercalated
2CI cells. The principal cell also is an important site of potassium
K+
(IMCD) secretion by way of apical potassium channels and water transport
via antidiuretic sensitive water channels. Regulation of sodium
channels may involve either insertion (from subapical compartments)
or activation of preexisting sodium channels.
1.12 Hypertension and the Kidney
Medulla
NTS
Normal Glossopharyngeal
firing rate, impulses/s
nerve
∆I
Baroreceptor
Afferents
Resetting NA
Carotid DN –
sinus
∆P
Efferents Bulbospinal
Vagus pathway epinephrine
Arterial nerve
100 pressure
Arterial pressure, mm Hg
Atrial
receptors Aortic
arch
Preganglionic
Heart sympathetics
rate (acetylcholine)
Postganglionic
Sympathetics Adrenal
medulla
Vascular smooth Norepinephrine
muscle
Kidney
↓ RBF
TPR ↓ GFR Epinephrine
↑Reabsorption
↓Na+ excretion
FIGURE 1-20
Neural and sympathetic influences. The neural reflexes serve as the so by enhancing cardiac performance and stimulating vascular
principal mechanisms for the rapid regulation of arterial pressure. smooth muscle tone, leading to increased total peripheral resis-
The neural reflexes also exert a long-term role by influencing sodium tance and decreased capacitance. The direct effects of the sympa-
excretion. The pathways and effectors of the arterial baroreflex thetic nervous system on kidney function lead to decreased sodium
and atrial pressure-volume reflex are depicted. The arrows indicate excretion caused by decreases in filtered load and increases in
increased or decreased activity in response to an acute reduction in tubular reabsorption [26].
arterial pressure which is sensed by the baroreceptors in the aortic The decreases in the glomerular filtration rate (GFR) and
arch and carotid sinus. filtered sodium load are due to increases in both afferent and
The insert depicts the relationship between the arterial blood efferent arteriolar resistances and to decreases in the filtration
pressure and baroreflex primary afferent firing rate. At the normal coefficient (see Fig. 1-7). Sympathetic activation also enhances
level of mean arterial pressure of approximately 100 mm Hg, the proximal sodium reabsorption by stimulating the sodium-hydrogen
sensitivity (I/P) is set at the maximum level. After chronic resetting (Na+-H+) exchanger mechanism (see Fig. 1-16) and by increasing
of the baroreceptors, the peak sensitivity and threshold of activation the net chloride reabsorption by the thick ascending limb of the
are shifted to a higher level of arterial pressure. loop of Henle. The indirect effects include stimulation of renin
The cardiovascular reflexes involve high-pressure arterial recep- secretion and angiotensin II formation, which, as discussed next,
tors in the aortic arch and carotid sinus and low-pressure atrial also stimulates tubular reabsorption. I—change in impulse firing;
receptors. In response to decreases in arterial pressure or vascular P—change in pressure; DN—dorsal motor nucleus; NA—nucleus
volume, increased sympathetic stimulation participates in short- ambiguous; NTS—nucleus tractus solitarii; RBF—renal blood flow;
term control of arterial pressure. This increased stimulation does TPR—total peripheral resistance. (Adapted from Vari and Navar [4].)
The Kidney in Blood Pressure Regulation 1.13
FIGURE 1-21
Angiotensinogen Renin-angiotensin system. The renin-angio-
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Val-Tyr-Ser-R tensin system serves as one of the most
powerful regulators of arterial pressure
Renin
and sodium balance. In response to various
stimuli that compromise blood volume,
Angiotensin I extracellular fluid (ECF) volume, or arterial
NaCl Arterial ECF Stress
intake pressure volume trauma Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu pressure—or those associated with stress
and trauma—three major mechanisms are
Angiotensin-
converting activated. These mechanisms stimulate renin
Macula densa mechanism enzyme, release by the cells of the juxtaglomerular
Baroreceptor mechanism chymase (heart) apparatus that act on angiotensinogen to
Sympathetic nervous system
form angiotensin I. Angiotensinogen is an
Angiotensin II
2 globulin formed primarily in the liver
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe and to a lesser extent by the kidney. Angio-
Juxtaglomerular apparatus Renin
Cytosolic Ca2+ Angiotensinases tensin I is a decapeptide that is rapidly
cAMP release converted by angiotensin-converting
enzyme (ACE) and to a lesser extent by
Metabolites AT1, AT2, AT? chymase (in the heart) to angiotensin II, an
Receptor binding and octapeptide. Recent studies have indicated
Angiotensin (1–7) Biologic actions that other angiotensin metabolites such as
Angiotensin (2–8)
Angiotensin (3–8) angiotensin (2–8), angiotensin (1–7), and
Inactive fragments angiotensin (3–8) have biologic actions.
Adrenal Kidney Intestine Central nervous Peripheral nervous Vascular smooth Heart Growth
cortex system system muscle factors
Adrenergic
Aldosterone Vasoconstriction facilitation Contractility
transport effects Sympathetic
discharge Proliferation
Distal
nephron Proximal and Thirst, salt appetite Vasoconstriction
reabsorption distal sodium + water
Reabsorption by Vasopressin release
intestine
Water reabsorption
Maintain or increase Total peripheral Cardiac
extracellular fluid volume resistance output Hypertrophy
FIGURE 1-22
Multiple actions of angiotensin. Angiotensin II and interacts with the sympathetic nervous system by
some of the other angiotensin II metabolites have a facilitating adrenergic transmission and has long-term
myriad of actions on many different vascular beds actions on vascular smooth muscle proliferation by
and organ systems. Angiotensin II exerts short- and interacting with growth factors. Angiotensin II exerts
long-term actions, including vasoconstriction and several important effects on the kidney that contribute
stimulation of aldosterone release. Angiotensin II also to sodium conservation. (Adapted from Navar [3].)
1.14 Hypertension and the Kidney
FIGURE 1-23
Enhance proximal
tubular reabsorption Angiotensin II actions on renal hemodynamics. Systemic and
intrarenal angiotensin II exert powerful vasoconstrictive actions on
PT the kidney to decrease renal blood flow and sodium excretion. At
the level of the glomerulus, angiotensin II is a vasoconstrictor of
both afferent (AA) and efferent arterioles (EA) and decreases the
filtration coefficient Kf. Angiotensin II also directly inhibits renin
BS
Decrease Kf release by the juxtaglomerular apparatus. Increased intrarenal
angiotensin II also is responsible for the increased sensitivity of the
tubuloglomerular feedback mechanism that occurs with decreased
sodium chloride intake (see Fig. 1-9) [17,27,28]. BS—Bowman’s
GC space; GC—glomerular capillaries; PC—peritubular capillaries;
PT—proximal tubule; TAL—thick ascending limb; TGF—tubu-
loglomerular feedback mechanism. (Adapted from Arendshorst and
Navar [17].)
Afferent arteriolar
PC vasoconstriction
Efferent Increased
arteriolar TAL
sensitivity
vasoconstriction of TGF
mechanism
AA
FIGURE 1-24
Angiotensin II actions on tubular transport. Angiotensin II receptors
are located on both the luminal and basolateral membranes of the
Angiotensin proximal and distal nephron segments. The proximal effect has
Angiotensin
been studied most extensively. Activation of angiotensin II-AT1
receptors leads to increased activities of the sodium-hydrogen
G (Na+-H+) exchanger and the sodium-bicarbonate (Na+-HCO-3)
PLA _ _ + cotransporter. These increased activities lead to augmented volume
_
H+ + HCO3 reabsorption. Higher angiotensin II concentrations can inhibit the
cAMP
Tubule Na+ Na+ tubular sodium reabsorption rate; however, the main physiologic
lumen role of angiotensin II is to enhance the reabsorption rate [28].
cAMP—cyclic AMP; G—G protein; PLA—phospholipase A.
(Adapted from Mitchell and Navar [28].)
K+
Na+
The Kidney in Blood Pressure Regulation 1.15
Reabsorption 60
A. SYNERGISTIC RENAL ACTIONS OF ANGIOTENSIN II Proximal
55
Glomerular pressure, mm Hg
SNGFR
Enhancement of proximal reabsorption rate
50
Stimulation of apical amiloride-sensitive Na-H exchanger
Stimulation of basolateral Na-HCO3 cotransporter
Distal 45
Sustained changes
in distal volume delivery
and sodium delivery 40
Increased sensitivity of afferent arteriole to signals from macula densa cells
35
30
0 10 20 30 40
B End proximal fluid flow, nL/min
Proximal reabsorption 60
55 FIGURE 1-25
Glomerular pressure, mm Hg
SNGFR
A–C, Synergistic effects of angiotensin II on proximal reabsorption
50 and tubuloglomerular feedback mechanisms. The actions of
angiotensin II on proximal nephron reabsorption and the ability
Distal 45 of angiotensin II to enhance the sensitivity of the tubuloglomerular
delivery feedback (TGF) mechanism prevent a compensatory increase in
40 glomerular filtration rate caused by the reduced distal tubular flow.
These actions allow elevated angiotensin II levels to exert a
35 sustained reduction in sodium delivery to the distal nephron
segment. This effect is shown here by the shift of operating levels
30 to a lower proximal fluid flow under the influence of elevated
0 10 20 30 40 angiotensin II [27]. The effects of angiotensin II to enhance TGF
C End proximal fluid flow, nL/min
sensitivity allow the glomerular pressure (GP) and nephron filtra-
tion rate to be maintained at a reduced distal volume delivery rate
that would occur as a consequence of the angiotensin II effects on
reabsorption. SNGFR—single nephron glomerular filtration rate.
(Panels B and C adapted from Mitchell et al. [27].)
FIGURE 1-26
Lumen Principal cell Effects of aldosterone on distal nephron sodium reabsorption.
A, Mechanism of action of aldosterone. Angiotensin II also is
a very powerful regulator of aldosterone release by the adrenal
Mitochondria
ATP gland. The increased aldosterone levels synergize with the direct
3Na+
Na+ effects of angiotensin II to enhance distal tubule sodium reabsorp-
Proteins 2 K+ tion. Aldosterone increases sodium reabsorption and potassium
ADP
secretion in the distal segments of the nephron by binding to the
mRNA cytoplasmic mineralocorticoid receptor (MR). On binding, the
receptor complex migrates to the nucleus where it induces
transcription of a variety of messenger RNAs (mRNAs). The
K+ mRNAs encode for proteins that stimulate sodium reabsorption
Nucleus Aldosterone by increasing sodium-potassium ATPase (Na+-K+ ATPase) protein
MR _ Spironolactone and activity at basolateral membranes, increasing mitochondrial
ATP formation, and increasing the sodium and potassium channels
at the luminal membrane [29]. Growing evidence also exists for
A nongenomic actions of aldosterone to activate sodium entry
pathways such as the amiloride-sensitive sodium channel [30].
(Continued on next page)
1.16 Hypertension and the Kidney
10 Aldosterone blockade can be blocked by drugs such as spironolactone that bind directly
to the mineralocorticoid receptor.
8
4 Normal
0
0 20 40 60 80 100
B Distal nephron length, %
FIGURE 1-27
Lumen Principal cell Syndrome of apparent mineralocorticoid excess and hypertension.
Aldosterone increases sodium reabsorption and potassium secretion
Mitochondria
in the distal segments of the nephron by binding to the cytoplasmic
ATP mineralocorticoid receptor (MR). Cortisol, the glucocorticoid that
3Na+
Na+ circulates in plasma at much higher concentrations than does aldos-
Proteins 2 K+ terone, also binds to MR. However, cortisol normally is prevented
ADP
from this by the action of 11--hydroxysteroid dehydrogenase (11-
mRNA -OHSD), which metabolizes cortisol to cortisone in mineralocorti-
coid-sensitive cells. A deficiency or defect in this enzyme has been
MR Aldosterone found to be responsible for a rare form of hypertension in persons
K+ with the hereditary syndrome of apparent mineralocorticoid excess.
Nucleus
Cortisone Cortisol In these persons, cortisol binds to the MR receptor, causing sodium
retention and hypertension [31]. This enzyme also is blocked by gly-
II-β_OHSD defect or cyrrhizic acid (in some forms of licorice) and carbenoxolone. The
glycyrrhizic acid or diuretic spironolactone acting by way of inhibition of MR is able to
carbenoxolone
block this excessive action of cortisol on the MR receptor.
FIGURE 1-28
Lumen Principal cell Hyperaldosteronism and glucocorticoid-remediable aldosteronism.
Hypertension can result from increased aldosterone or from
Mitochondria ATP
increases in other closely related steroids derived from abnormal
3Na+
adrenal metabolism (11--hydroxylase deficiency and 17--
Na+ hydroxylase deficiency). The most common cause is an aldos-
Proteins 2K+
ADP terone-producing adenoma; bilateral hyperplasia of the adrenal
Primary
hyperaldosteronism zona glomerulosa is the next most common cause. In glucocorti-
mRNA Adrenal enzymatic coid-remediable aldosteronism, a DNA crossover mutation results
disorder
Adenoma in a chimeric gene in which aldosterone production is regulated by
Glucorticoid-remediable adrenocorticotropic hormone (ACTH). Increases in aldosterone
K+ aldosteronism
also can result secondarily from any state of increased renin such
MR
Nucleus as renal artery stenosis, which leads to increased circulating con-
Aldosterone centrations of angiotensin II and stimulation of aldosterone release
[31]. MR—mineralocorticoid receptor; mRNA—messenger RNA.
The Kidney in Blood Pressure Regulation 1.17
FIGURE 1-29
Excess epithelial sodium channel activity in Liddle’s syndrome. The
epithelial sodium channel responsible for sodium reabsorption in
Lumen Cell much of the distal portions of the nephron is a complex of three
Liddle's homologous subunits, , , and each with two membrane-span-
syndrome ning domains. Liddle’s syndrome, an autosomal dominant disorder
Na+ ATP
δ pp 3Na+ causing low renin-aldosterone hypertension often with hypokalemia,
δ pp 2 K+ results from mutated or subunits. These mutations increase the
β
β ADP sodium reabsorptive rate by way of these channels by keeping them
α pp Liddle's
α syndrome open longer, increasing sodium channel density on the membranes,
K+ or both. The specific problem appears to reside with proline (P)-rich
domains in the carboxyl terminal region of or that are involved
in regulation of the channel membrane localization or activity. The
net result is excess sodium reabsorption and a reduced capability to
increase sodium excretion in response to volume expansion [31,32].
Na Cl
Gitleman's
syndrome Aldosterone
Sodium Renin Atrial
excretion Tubular sodium natriuretic peptide
Na+ reabsorption
L Vascular
B Na+- Vasodilation
_ 2Cl Pseudohypoaldosteronism resistance
Cl K+ K+
FIGURE 1-33
Kallikrein-kinin system
Kallikrein-kinin system. Plasma and tissue kallikreins are function-
Low molecular weight kininogen High molecular weight kininogen ally different serine protease enzymes that act on kininogens (inac-
tive 2 glycoproteins) to form the biologically active kinins
Tissue kallikrein Plasma kallikrein (bradykinin and lysyl-bradykinin [kallidin]). Kidney kallikrein and
kininogen are localized in the distal convoluted and cortical collect-
Bradykinin
ing tubules. Release of kallikrein into the tubular fluid and intersti-
Kininase I Kininase II (ACE)
NEP tium can be stimulated by prostaglandins, mineralocorticoids,
angiotensin II, and diuretics. B1 and B2 are the two major
Des Arg-bradykinin Kinin degradation products bradykinin receptors that exert most of the vascular actions.
B2-receptor Although glomerulus and distal nephron segments contain both B1
Endothelium-dependent and B2 receptors, most of the renal vascular and tubular effects
B1-receptor Nitric oxide appear to be mediated by B2-receptor activation [16,17,43,44].
PGE2 Bradykinin and kallidin elicit vasodilation and stimulate nitric
oxide, prostaglandin E2 (PGE2) and I2 (PGI2), and renin release
Vasodilation natriuresis [45,46]. Kinins are inactivated by the same enzyme that converts
angiotensin I to angiotensin II, angiotensin-converting enzyme
(ACE). The kallikrein-kinin system is stimulated by sodium deple-
tion, indicating it serves as a mechanism to dampen or offset the
effects of enhanced angiotensin II levels [47,48]. Des Arg—
bradykinin; NEP—neutral endopeptidase.
The Kidney in Blood Pressure Regulation 1.19
FIGURE 1-34
10
Decreased Normal Vasopressin. Vasopressin is synthesized by the paraventricular and supraoptic nuclei of
Plasma vasopressin, pg/mL
8 ECF ECF the hypothalamus. Vasopressin is stored in the posterior pituitary gland and released in
volume volume
response to osmotic or volume-dependent baroreceptor stimuli, or both. Atrial filling
6 inhibits vasopressin release. Increases in plasma osmolality increase vasopressin release;
4
Increased however, the relationship is shifted by the status of extracellular fluid (ECF) volume, with
ECF
volume decreases in the ECF volume increasing the sensitivity of the relationship. Stress and trauma
2 also increase vasopressin release [15]. Therefore, when ECF volume and blood volume are
diminished, vasopressin is released to help guard against additional losses of body fluids.
0
(Adapted from Navar [8].)
260 280 300 320 340
Plasma osmolality, mOsm/kg
FIGURE 1-35
Collecting duct Plasma membrane Tubule Vasopressin receptors. Vasopressin exerts its cellular actions through
principal cell lumen
two major receptors. Activation of V1 receptors leads to vascular
ATP smooth muscle constriction and increases peripheral resistance.
Adenylate
cyclase Vasopressin stimulates inositol 1,4,5-triphosphate and calcium ion
cAMP + PPi
(Ca2+) mobilization from cytosolic stores and also increases Ca2+
GTP entry from extracellular stores as shown in Figure 1-10. The vaso-
Gα Protein kinase A constrictive action of vasopressin helps increase total peripheral
G
resistance and reduces medullary blood flow, which enhances the
GTP H 2O concentrating ability of the kidney. V2 receptors are located pri-
Aquaporin 2 marily on the basolateral side of the principal cells in the collecting
Gα water
Circulating channels duct segment. Vasopressin activates heterotrimeric G proteins that
vasopressin G GDP
activate adenylate cyclase, thus increasing cyclic AMP levels. Cyclic
V2 Aquaporin 2 AMP (cAMP) activates protein kinase A, which increases the density
of water channels in the luminal membrane. Water channels (aqua-
porin proteins) reside in subapical vesicles and on activation fuse
with the apical membrane. Thus, vasopressin markedly increases
the water permeability of the collecting duct and allows conservation
of fluid and excretion of a concentrated urine. An intact vasopressin
system is essential for the normal regulation of urine concentration
by the kidney that, in turn, is the major mechanism for coupling
the solute to solvent ratio (osmolality) of the extracellular fluid.
As discussed in Figure 1-4, this tight coupling allows the conflu-
ence of homeostatic mechanisms regulating sodium balance
with those regulating extracellular fluid volume. G and
G—proteins; PPi— inorganic pyrophosphate. (Adapted from
Vari and Navar [4].)
1.20 Hypertension and the Kidney
Hypertensinogenic Process
either one or more of the physiologic mechanisms described in
Initial increase in Initial increase this chapter fails to respond appropriately to intravascular expan-
vascular resistance in volume sion or some pathophysiologic process causes excess production of
one or more sodium-retaining factors such as mineralocorticoids or
Neurogenic or Volume angiotensin II [51,52]. Through mechanisms delineated earlier,
humoral stimuli overexpansion leads to increased cardiac output that results in over-
perfusion of tissues; the resultant autoregulatory-induced increases
Vasoconstrictor Renal volume Effective blood in peripheral resistance contribute further to an increase in total
Cardiac output
effects retention volume peripheral resistance and elevated arterial pressure [2,53,54].
Hypertension also can be initiated by excess vasoconstrictor
Tissue blood flow
influences that directly increase peripheral resistance, decrease
cardiovascular capacitance, or both. Examples of this type of
Capacitance
Autoregulatory hypertension are enhanced activation of the sympathetic nervous
resistance system and overproduction of catecholamines such as that occurring
adjustments
with a pheochromocytoma [45,54,55]. When hypertension caused
Increased vascular resistance by a vasoconstrictor influence persists, however, it must also exert
significant renal vasoconstrictor and sodium-retaining actions.
Increased arterial Without a renal effect the elevated arterial pressure would cause
blood pressure pressure natriuresis, leading to a compensatory reduction in extra-
cellular fluid volume and intravascular volume. Thus, the elevated
systemic arterial pressure would not be sustained [2,8,54]. Derange-
FIGURE 1-36 ments that activate both a vasoconstrictor system and produce
Overview of mechanisms mediating hypertension. From a patho- sodium-retaining effects, such as inappropriate elevations in the
physiologic perspective, the development of hypertension requires activity of the renin-angiotensin-aldosterone system, lead to an
either a sustained absolute or relative overexpansion of the blood even more powerful hypertensinogenic mechanism that is not easily
volume, reduction of the capacitance of the cardiovascular system, counteracted [27]. These dual mechanisms are why the renin-
or both [4,49,50]. One type of hypertension is due primarily to angiotensin system has such a critical role in the cause of many
overexpansion of either the actual or the effective blood volume forms of hypertension, leaving only the option to increase arterial
compartment. In such a condition of volume-dependent hypertension, pressure and elicit a pressure natriuresis. (Adapted from Navar [3].)
FIGURE 1-37
180
Angiotensin II + Predominance of the renin-angiotensin-aldosterone mechanisms. Collectively, the various
Mean arterial pressure,
160 Aldosterone mechanisms discussed provide overlapping influences responsible for the highly efficient
regulation of sodium balance, extracellular fluid (ECF) volume, blood volume, and arterial
140
mm Hg
12
Angiotensin II + increased release of atrial natriuretic peptide and reduced activity of the sympathetic sys-
10 Aldosterone tem) could not overcome the hypertensinogenic influence of maintained aldosterone or
mmol/kg BW
8
6 aldosterone plus angiotensin II as long as renal perfusion pressure was not allowed to
4 Aldosterone increase. Thus, under conditions of increased activity of the renin-angiotensin system, an
2 increased renal arterial pressure seems essential to reestablish sodium balance.
0 In conclusion, regardless of the specific intrarenal mechanism involved, the net effect of a
long-term hypertensinogenic derangement is a reduced capability for sodium excretion at
0 1 2 3 4 5 normotensive arterial pressures that cannot be completely compensated by other neural,
Reduced renal pressure, d humoral, or paracrine mechanisms, leaving only the option to increase arterial pressure
and elicit a pressure natriuresis. (Adapted from Seeliger et al. [56].)
The Kidney in Blood Pressure Regulation 1.21
References
1. Guyton AC: Blood pressure control: special role of the kidneys and 24. Stoos BA, Garcia NH, Garvin JL: Nitric oxide inhibits sodium reab-
body fluids. Science 1991, 252:1813–1816. sorption in the isolated perfused cortical collecting duct. J Am Soc
2. Cowley AW Jr: Long-term control of arterial blood pressure. Physiol Nephrol 1995, 6:89–94.
Rev 1992, 72:231–300. 25. Stoos BA, Carretero OA, Garvin JL: Endothelial-derived nitric oxide
3. Navar LG: The kidney in blood pressure regulation and development inhibits sodium transport by affecting apical membrane channels in
of hypertension. Med Clin North Am 1997, 81:1165–1198. cultured collecting duct cells.J Am Soc Nephrol 1994, 4:1855–1860.
4. Vari RC, Navar LG: Normal regulation of arterial pressure. In 26. DiBona GF, Kopp UC: Neural control of renal function.Physiol Rev
Principles and Practice of Nephrology, edn 2. Edited by Jacobson HR, 1997, 77:75–197.
Striker GE, Klahr GE. St. Louis: Mosby-Yearbook; 1995:354–361. 27. Mitchell KD, Braam B: Navar LG: Hypertensinogenic mechanisms
5. Luke RG: Essential hypertension: a renal disease? A review and mediated by renal actions of renin-angiotensin system. Hypertension
update of the evidence. Hypertension 1993, 21:380–390. 1992, 19(suppl I):I-18–I-27.
6. Freedman BI, Iskandar SS, Appel RG: The link between hypertension 28. Mitchell KD, Navar LG: Intrarenal actions of angiotensin II in the
and nephrosclerosis. Am J Kidney Dis 1995, 25:207–221. pathogenesis of experimental hypertension. In Hypertension:
Pathophysiology, Diagnosis, and Management, edn 2. Edited by
7. Tepel M, Zidek W: Hypertensive crisis: pathophysiology, treatment
Laragh JH, Brenner BM. New York: Raven Press; 1995:1437–1450.
and handling of complications. Kidney Int 1998, 53(suppl 64):S-2–S-5.
29. O’Neil RG: Aldosterone regulation of sodium and potassium trans-
8. Navar LG: Regulation of body fluid balance. In Edema. Edited by
port in the cortical collecting duct. Sem Nephrol 1990, 10:365–374.
Staub NC, Taylor AE. New York: Raven Press; 1984:319–352.
30. Wehling M, Eisen C, Christ M: Membrane receptors for aldosterone:
9. Navar LG, Majid DSA: Interactions between arterial pressure and
a new concept of nongenomic mineralocorticoid action. NIPS 1993,
sodium excretion. Curr Opin Nephrol Hypertens 1996, 5:64–71.
8:241–244.
10. Rettig R, Schmitt B, Pelzl B, Speck T: The kidney and primary hyper-
31. Lifton RP: Molecular genetics of human blood pressure variation.
tension: contributions from renal transplantation studies in animals
Science 1996, 272:676–680.
and humans. J Hypertens 1993, 11:883–891.
32. Warnock DG: Liddle syndrome: an autosomal dominant form of
11. Folkow B: Pathophysiology of hypertension: differences between
human hypertension. Kidney Int 1998, 53:18–24.
young and elderly. J Hypertens 1993, 11(suppl 4):S21–S24.
33. Jamison RL, Canaan-Kuhl S, Pratt R: The natriuretic peptides and
12. Nichols WW, Nicolini FA, Pepine CJ: Determinants of isolated systolic
their receptors. Am J Kidney Dis 1992, 20:519–530.
hypertension in the elderly. J Hypertens 1992, 10(suppl 6):S73–S77.
34. Paul RV, Kirk KA, Navar LG: Renal autoregulation and pressure natri-
13. Guyton AC, Hall JE: Integration of renal mechanisms for control of
uresis during ANF-induced diuresis. Am J Physiol 1987, 253:F424–F431.
blood volume and extracellular fluid volume. In Textbook of Medical
Physiology, edn 9. Philadelphia: WB Saunders; 1994:367–383. 35. Knepper MA, Lankford SP, Terada Y: Renal tubular actions of ANF.
Can J Physiol Pharmacol 1991, 69:1537–1545.
14. Bankir L, Bouby N, Trinh-Trang-Tan M-M: The role of the kidney in
the maintenance of water balance. In Bailliere’s Clinical Endocrinology 36. Jensen KT, Carstens J, Pedersen EB: Effect of BNP on renal hemody-
and Metabolism. Water and Salt Homeostasis in Health and Disease. namics, tubular function and vasoactive hormones in humans. Am J
Edited by Baylis PH. London: Bailliere; 1989:249–311. Physiol (Renal Fluid Electrolyte Physiol 43) 1998, 274:F63–F72.
15. Baylis PH: Regulation of vasopressin secretion. In Bailliere’s Clinical 37. Capdevila JH, Falck JR, Estabrook RW: Cytochrome P450 and the
Endocrinology and Metabolism: International Practice and Research. arachidonate cascade. FASEB J 1992, 6:731–736.
Edited by Baylis PH. London: Bailliere Tindall; 1989:313–330. 38. Smith WL: Prostanoid biosynthesis and mechanisms of action. Am J
16. Navar LG, Inscho EW, Majid DSA, et al.: Paracrine regulation of the Physiol (Renal Fluid Electrolyte Physiol 32) 1992, 263:F181–F191.
renal microcirculation. Physiol Rev 1996, 76:425–536. 39. Frazier LW, Yorio T: Eicosanoids: their function in renal epithelia ion
17. Arendshorst WJ, Navar LG: Renal circulation and glomerular hemo- transport. Proceedings of the Society for Experimental Biology and
dynamics. In Diseases of the Kidney, edn 6. Edited by Schrier RW, Medicine 1992, 201:229–243.
Gottschalk CW. Boston: Little-Brown; 1997:59–106. 40. Breyer MD, Jacobson HR, Breyer RM: Functional and molecular aspects
18. Braam B, Mitchell KD, Koomans HA: Navar LG: Relevance of the of renal prostaglandin receptors. J Am Soc Nephrol 1996, 7:8–17.
tubuloglomerular feedback mechanism in pathophysiology. J Am Soc 41. McGiff JC: Cytochrome P-450 metabolism of arachidonic acid. Ann
Nephrol 1993, 4:1257–1274. Rev Pharmacol Toxicol 1991, 31:339–369.
19. Briggs JP, Schnermann J: Control of renin release and glomerular 42. Imig JD, Zou A-P, Stec DE, et al.: Formation and actions of 20-
vascular tone by the juxtaglomerular apparatus. InHypertension: hydroxyeicosatetraenoic acid in rat renal arterioles. Am J Physiol
Pathophysiology, Diagnosis, and Management, edn 2. Edited by (Regulat Integrative Comp Physiol 39) 1996, 270:R217–R227.
Laragh JH, Brenner BM. New York: Raven Press, 1995:1359–1385. 43. Bhoola KD, Figueroa CD, Worthy K: Bioregulation of kinins:
20. Carmines PK, Inscho EW, Gensure RC: Arterial pressure effects on kallikreins, kininogens, and kininases. Pharmacol Rev 1992, 44:1–80.
preglomerular microvasculature of juxtamedullary nephrons. Am J 44. El-Dahr SS: Development biology of the renal kallikrein-kinin system.
Physiol (Renal Fluid Electrolyte Physiol 27) 1990, 258:F94–F102. Pediatr Nephrol 1994, 8:624–631.
21. Casellas D, Navar LG: In vitro perfusion of juxtamedullary nephrons 45. Carretero OA, Scicli AG: Local hormonal factors (intracrine,
in rats. Am J Physiol (Renal Fluid Electrolyte Physiol 15) 1984, autocrine, and paracrine) in hypertension. Hypertension 1991, 18
246:F349–F358. (suppl I):I-58–I-69.
22. Carmines PK, Navar LG: Disparate effects of Ca channel blockade on 46. Siragy HM, Jaffa AA, Margolius HS: Bradykinin B2 receptor modulates
afferent and efferent arteriolar responses to ANG II. Am J Physiol renal prostaglandin E2 and nitric oxide. Hypertension 1997, 29:757–762.
(Renal Fluid Electrolyte Physiol 25) 1989, 256:F1015–F1020.
47. Margolius HS: Kallikreins and kinins: molecular characteristics and
23. Navar LG, Inscho EW, Imig JD, Mitchell KD: Heterogenous activa- cellular and tissue responses. Diabetes 1996, 45:S14–S19.
tion mechanisms in the renal microvasculature. Kidney Int 1998,
54(suppl 67):S17–S21.
1.22 Hypertension and the Kidney
48. Siragy HM: Evidence that intrarenal bradykinin plays a role in regula- 53. Coleman TG, Guyton AC: Hypertension caused by salt loading in the
tion of renal function. Am J Physiol (Endocrinol Metab28) 1993, dog. Circ Res 1969, XXV:153–160.
265:E648–E654. 54. Guyton AC, Hall JE, Coleman TG, et al.: The dominant role of the
49. Ploth DW, Navar LG: Physiologic control of arterial blood pressure kidneys in long-term arterial pressure regulation in normal and hyper-
and mechanisms of hypertension. In Clinical Approaches to High tensive states. In Hypertension: Pathophysiology, Diagnosis, and
Blood Pressure in the Young. Edited by Kotchen TA, Kotchen JM. Management, edn 2. Edited by Laragh JH, Brenner BM. New York:
Boston: John Wright, PSG; 1983:23–78. Raven Press; 1995, 78:1311–1326.
50. Guyton AC, Manning RA, Normon RA, et al.: Current concepts and 55. Julius S, Nesbitt S: Sympathetic overactivity in hypertension: a moving
perspectives of renal volume regulation in relationship to hyperten- target. Am J Hypertens 1996, 9:113S–120S.
sion. J Hypertens 1986, 4(suppl 4):S49–S56. 56. Seeliger E, Boemke W, Corea M, et al.: Mechanisms compensating Na
51. DeWardener HE: The primary role of the kidney and salt intake in the and water retention induced by long-term reduction of renal perfusion
aetiology of essential hypertension: part II. Clin Sci 1990, 79:289–297. pressure. Am J Physiol (Regulat Integrative Comp Physiol 42) 1997,
52. Hamlyn JM, Blaustein MP: Sodium chloride, extracellular fluid vol- 273:R646–R654.
ume, and blood pressure regulation. Am J Physiol (Renal Fluid
Electrolyte Physiol 20) 1986, 251:F563–F575.
Renal Parenchymal Disease
and Hypertension
Stephen C. Textor
H
ypertension and parenchymal disease of the kidney are closely
interrelated. Most primary renal diseases eventually disturb
sodium and volume control sufficiently to produce clinical
hypertension. Both on theoretical and practical grounds, many authors
argue that any sustained elevation of blood pressure depends ultimately
on disturbed renal sodium excretion, ie, altered pressure natriuresis.
Hence, some investigators argue that a clinical state of hypertension
represents de facto evidence of disturbed (or “reset”) renal function
even before changes in glomerular filtration can be measured.
Many renal insults further induce inappropriate activation of vasoactive
systems such as the renin-angiotensin system, adrenergic sympathetic
nerve traffic, and endothelin. These mechanisms may both enhance
vasoconstriction and act as mediators of additional tissue injury by
altering the activity of inflammatory cytokines and promoters of inter-
stitial fibrosis.
Arterial hypertension itself accelerates many forms of renal disease
and hastens the progression to advanced renal failure. Recent studies
have firmly established the importance of blood pressure reduction as
a means to slow the progression of many forms of renal parenchymal
injury, particularly those characterized by massive proteinuria. Over
the long term, damage to the heart and cardiovascular system resulting
from hypertension represents the major causes of morbidity and mor-
tality for patients with end-stage renal disease.
Here are illustrated the roles of renal parenchymal disease in sustaining
hypertension and of arterial pressure reduction in slowing the progression
of renal injury. As discussed, parenchymal renal disease may refer to
either unilateral (uncommon) or bilateral conditions. CHAPTER
2
2.2 Hypertension and the Kidney
FIGURE 2-1
FORMS OF UNILATERAL RENAL Forms of unilateral renal parenchymal diseases related to hypertension. Many unilateral
PARENCHYMAL DISEASE RELATED abnormalities, such as congenital malformations, renal agenesis, reflux nephropathy, and
TO HYPERTENSION stone disease, do not commonly produce hypertension. However, some unilateral lesions
can produce blood pressure elevation. Data for each of these are based primarily on
demonstrating unilateral secretion of renin and resolution with unilateral nephrectomy. It
Renal artery stenosis should be emphasized that unilateral renal disease does not reduce the overall glomerular
Atherosclerosis and fibromuscular lesions (Chapter X) filtration rate beyond that expected in patients with a solitary kidney. It follows that addi-
Small vessel disease tional reductions in the glomerular filtration rate must reflect bilateral renal injury.
Vasculitis
Atheroembolic renal infarction
Thrombosis and infarction
Traumatic injury
Renal fracture
Perirenal fibrosis (“Page” kidney)
Radiation injury
Arteriovenous malformation or fistulas
Other diseases
Renal carcinoma
Enlarging renal cyst
Multiple renal cysts
Renin-secreting tumors (rare)
FIGURE 2-2
Angiogram and nephrogram of a persistent fractured kidney. The kidney damage shown here
produced hypertension in a young woman 2 years after a motor vehicle accident. Measurement
of renal vein renins confirmed unilateral production of renin from the affected side. Blood
pressure control was achieved with blockade of the renin-angiotensin system using an
angiotensin II receptor antagonist (losartan). Many traumatic injuries to the kidney produce
temporary hypertension when a border of viable but underperfused renal tissue remains.
60
nephropathy (DN) and membranoproliferative glomerulonephritis
(MPGN), in which 70% to 80% of patients are affected. Minimal
50 change nephropathy (MCN) is a notable exception. Tubulointerstitial
40 disorders such as analgesic nephropathy, medullary cystic diseases,
and chronic reflux nephropathies are less commonly affected.
30 APKD—adult-onset polycystic kidney disease; CIN—chronic intersti-
20 tial nephritis; FSGN—focal segmental glomerulonephritis; MGN—
membranous glomerulonephritis. (Data from Smith and Dunn [1].)
10
0
CIN APKD MCN IgA MGN DN MPGN FSGN
Renal Parenchymal Disease and Hypertension 2.3
FIGURE 2-4
100 Prevalence of hypertension requiring therapy as a function of the degree of chronic renal
*n=255 patients
90 failure in the Modification of Diet in Renal Disease (MDRD) trial on progressive renal
Mean GFR=18.5 mL/min/1.73 m2
80 failure. The mean age of these patients was 52 years, with glomerular disease (25%) and
70 Mean GFR=39 mL/min/1.73 m2 polycystic disease (24%) being the most common renal diagnoses in this trial. In Study B,
60 more than 90% of patients were treated with antihypertensive agents, including diuretics,
to achieve an overall average blood pressure of 133/81 mm Hg. In general, the more
50
severe the level of renal dysfunction, the more antihypertensive therapy is required to
%
40 NHANES estimates
achieve acceptable blood pressures. Patients with glomerular filtration rates (GRFs) below
30 10 mL/min were hypertensive in 95% of cases. NHANES—National Health and Nutrition
20 Examination Survey. (Data from Klahr and coworkers [2].)
10
0
MDRD: MDRD: US
Study B* Study A Population
FIGURE 2-5
Early
Hypertension in acute renal disease. Acute renal failure is defined as transient increases in
80
Late serum creatinine above 5.0 mg/dL. During the course of acute renal failure, worsening of
70 preexisting levels or newly detected hypertension (>140/90 mm Hg) is common and almost
Prevalence of hypertension, %
60
universally observed in patients with acute glomerulonephritis (GN). Many of these
patients have lower pressures as the course of acute renal injury subsides, although resid-
50 ual abnormalities in renal function and sediment may remain. Blood pressure returns to
40 normal in some but not all of these patients. Overall, 39% of patients with acute renal
failure develop new hypertension. IN—interstitial nephritis. (Adapted from Rodriguez-
30 Iturbe and coworkers [3]; with permission.)
20
10
0
Acute GN Acute IN
7 7
6 6
Intake and output of water and salt
t
blat
G o ld
5 5 Normal
ys
ne
(x normal)
(x normal)
kid
4 D 4
ted
High intake
ula
tim
3 3
n
e-s
F
nsio
High intake
Normal
ron
hyp tial
ass G
erte
ste
E
n
2 2 lm
E s se
do
ena
Al
r
of
Normal intake A B Normal intake A B ss D
1 1 Lo
C
Low intake Low intake H
C
0 0
0 50 100 150 200 0 50 100 150 200
A Arterial pressure, mm Hg B Arterial pressure, mm Hg
FIGURE 2-8
A, The relationship between renal artery perfusion pressure and as “loss of renal mass.” Similar effects are observed in conditions
sodium excretion (which defines “pressure natriuresis”) has been with disturbed hormonal effects on sodium excretion (aldos-
the subject of extensive research. Essential hypertension is charac- terone-stimulated kidneys) or reduced renal blood flow as a
terized by higher renal perfusion pressures required to achieve result of an arterial stenosis (“Goldblatt” kidneys). In all of these
daily sodium balance. B, Distortion of this relationship routinely instances, higher arterial pressures are required to maintain
occurs in patients with parenchymal renal disease, illustrated here sodium balance.
Renal Parenchymal Disease and Hypertension 2.5
200
Hemodialysis Cumulative daily
130 40
Percentage of body weight, kg
sodium intake
Sodium, mEq
122 30
–800
Sodium losses during
hemodialysis or ultrafiltration
118
–1200
Net sodium loss
F S S M T W TH F S S M
Days –1600
Total net loss of
10.0 sodium=1741 mEq
activity, mg/mL/h
Uremic
Plasma renin
control F S S M T W TH F S S M T
5.0 subjects B Days
Captopril, 25 mg
Sequential steps were undertaken to achieve net negative sodium
and volume losses by means of restricting sodium intake (10 mEq/d)
and initiating ultrafiltration to achieve several liters of negative
140
balance with each treatment. A negative balance of nearly 1700 mEq
was required before evidence of achieving dry weight was observed,
specifically a reduction of blood pressure. Measured levels of plasma
100 renin activity gradually increased during sodium removal, and blood
A
pressure became dependent on the renin-angiotensin system, as
defined by a reduction in blood pressure after administration of the
FIGURE 2-9 angiotensin-converting enzyme inhibitor captopril. Achieving adequate
Sodium expansion in chronic renal failure. The degree of sodium reduction of both extracellular fluid volume and sodium is essential
expansion in patients with chronic renal failure can be difficult to to satisfactory control of blood pressure in patients with renal failure.
ascertain. A, Shown are data regarding body weight, plasma renin B, Daily and cumulative sodium balance.
FIGURE 2-10
Angiotensin II inhibitor, µg/kg/min
5 10 50 100 10 10
Interaction between sodium balance and angiotensin-dependence in malignant hypertension.
Studies in a patient with renal dysfunction and accelerated hypertension during blockade
pressure, mm Hg
between angiotensin and sodium. Reduction of blood pressure induced by the angiotensin
150
II antagonist was reversed during saline infusion with a positive sodium balance and reduction
in circulating plasma renin activity. Administration of a loop diuretic (L40 [furosemide],
100
40 mg intravenously) induced net sodium losses, restimulated plasma renin activity, and
restored sensitivity to the angiotensin II antagonist. Such observations further establish the
Plasma renin Cumulative sodium
reciprocal relationship between the sodium status and activation of the renin-angiotensin
balance, mEq
200 system [5]. (From Brunner and coworkers [5]; with permission.)
100
0
activity, ng/mL/hr
100
50
0
0 1 11 35 38 41 65 67
Hours
2.6 Hypertension and the Kidney
FIGURE 2-11
15 s A, Sympathetic neural activation in chronic
Normal
renal disease. Adrenergic activity is dis-
person turbed in chronic renal failure and may par-
ticipate in the development of hypertension.
Microneurographic studies in patients
undergoing hemodialysis demonstrate
enhanced neural traffic (panel A) that
Hemodialysis,
relates closely to peripheral vascular tone [6].
bilateral
nephrectomy Studies in patients in whom native kidneys
are removed by nephrectomy demonstrate
normal levels of neural traffic, suggesting that
afferent stimuli from the kidney modulate
Hemodialysis, no
central adrenergic outflow. B, Delayed onset
nephrectomy
hypertension in denervated rats. Panel B
shows evidence from experimental studies in
denervated animals subjected to deoxycortico-
sterone–salt hypertension. The role of the
renal nerves in modifying the development
of hypertension is supported by studies of
Neurogram
renal denervation that show a delayed onset
of hypertension, although no alteration in
Electrocardiogram the final level of blood pressure was achieved.
NS—not significant. (Panel A from
A 3s Converse and coworkers [6]; with permis-
sion. Panel B from Katholi and coworkers
[7]; with permission.)
200 Sham
Renal denervated
Systolic blood pressure, mm Hg
190
180
170
160
150
140
130
120
110 NS NS <0.01 <0.001 <0.001 <0.01 <0.05 <0.05 <0.05 NS
0 5 10 15 20 25 30 35
B Deoxycorticosterone acetate–salt administration, d
Renal Parenchymal Disease and Hypertension 2.7
FIGURE 2-12
MAJOR CANDIDATE MECHANISMS THAT MAY Major candidate mechanisms that may elevate peripheral vascular
ELEVATE PERIPHERAL VASCULAR RESISTANCE resistance in renal parenchymal disease. Some data support each of
IN RENAL PARENCHYMAL DISEASE these pathways, although rarely does one mechanism predominate.
Experimental studies suggest that endothelin-1 may magnify interstitial
fibrosis and contribute to hypertension in some models; however,
Increased vasoconstrictors Impaired or relatively inadequate vasodilators rarely is the effect major [8,9]. Most levels of vasodilators, including
nitric oxide, prostacyclin, and atrial natriuretic peptide, are normal
Renin-angiotensin system Nitric oxide: inadequate compensation or elevated in patients with renal disease. The vasodilators appear
Endothelin Vasodilator prostaglandins: prostacyclin 2 to buffer the vasoconstrictive actions of angiotensin II, which may
Prostanoids: thromboxane Natriuretic peptides: atrial natriuretic peptide be increased abruptly if the vasodilator is removed, as occurs with
Arginine vasopressin Kallikrein-kinin system inhibition of cyclo-oxygenase with the use of nonsteroidal anti-
Endogenous digitalis-like inflammatory drugs.
substance: ouabain (?)
Mean ±SEM
200 Horizontal bars=mean values
160
60 *† *† 120
40 80 *
†
20 Normal
40
0 0
A Pretransplantation 12 mo 24 mo B Basal Day 45 Basal Day 45
FIGURE 2-13
Urinary endothelin in renal disease. A, Urinary endothelin levels in diminished glomerular filtration rate. With time, however, these
patients with cyclosporine-induced renal dysfunction and hypertension changes lose the feature of reversibility [11]. B, Renal ablation.
before and after liver transplantation. These patients had near-normal Urinary endothelin levels in rats exposed to reduced renal mass
kidney function before liver transplantation, after which their glomeru- achieved by 5/6 nephrectomy. As in humans, plasma levels of
lar filtration rates decreased from 85 to 55 mL/min, on average. These endothelin were dissociated from urinary levels, and injected
data underscore the observation that the kidney itself is a rich source endothelin was not excreted. These results suggest that urinary levels
of vasoactive materials and that renal excretion of substances such as were of renal origin. These studies further support the concept that the
endothelin is independent of circulating blood levels [10]. Endothelin has diminished nephron number elicits production of potent vasoactive
properties that both facilitate vasoconstriction and enhance mitogenic and inflammatory materials that may accelerate irreversible parenchy-
and fibrogenic responses, perhaps accelerating interstitial fibrosis in mal injury. (Panel A from Textor and coworkers [10]; with permis-
the kidney. Early withdrawal of cyclosporine leads to reversal of a sion. Data in panel B from Benigni and coworkers [12].)
2.8 Hypertension and the Kidney
Increased glomerular
pressure FIGURE 2-15
Many pharmacologic agents affect blood pressure levels or the
effectiveness of antihypertensive therapy. Shown here are several
FIGURE 2-14 agents that commonly lead to worsening hypertension and are like-
Mechanisms of glomerular injury in hypertension and progressive ly to be administered to patients with renal disease.
renal failure. This schematic diagram summarizes the general mech-
anisms by which disturbances linked to elevated arterial pressure in
patients with parenchymal renal disease may lead to further tissue
injury. Hemodynamic changes lead to increased glomerular perfusion
pressures, whereas local activation of growth factors, angiotensin,
and probably several other factors both worsen peripheral resistance
and increase tissue fibrotic mechanisms. (From Smith and Dunn [1].)
160 Control
*
pressure, mL/min
10 µg L–NAME
pressure, mm Hg
120 *
Mean arterial
150 * 50 µg L–NAME
Blood
90 140 *
*
60 130
30 120
1 min
Heart rate, bpm
280
110
240
flow, mL/min
Results=means±standard error
Renal plasma
FIGURE 2-16
rate, mL/min
1.2
*
Increase in arterial pressure induced by inhibition of nitric oxide. *
1.0 *
A, Intra-arterial pressure in rabbits during N-nitro-L-arginine * *
methyl ester (L-NAME) infusion. B, Decrease in renal plasma flow 0.8
and glomerular filtration rate in the blood pressures of rats during
nitric oxide inhibition.
B Control 60' 120' 180'
(Continued on next page)
Renal Parenchymal Disease and Hypertension 2.9
19
Urinary sodium
120
Urinary flow
80
*
60
C Control 60' 120' 180'
Percentage of total
25
Death: Congestive heart failure 20
Blood pressure
Overall mortality
15
A
10
5
FIGURE 2-18
Based on average blood pressure values, a strong direct relationship 0
was found between arterial pressure and left ventricular hypertrophy, B Left ventricular Systolic Left ventricular
chamber dilation dysfunction hypertrophy
left ventricular chamber dilation (by echocardiography), and systolic
dysfunction in patients undergoing dialysis for end-stage renal disease.
After prolonged follow-up, blood pressures fell with the onset of
congestive heart failure and manifest coronary artery disease. With
the onset of cardiac failure, there appeared to be an inverse rela-
tionship between arterial pressure and mortality. From the outset,
the strongest predictor of congestive heart failure was elevated
blood pressure. (Adapted from Foley and coworkers [17].)
FIGURE 2-19
250 Around-the-clock ambulatory blood pressure
Awake: 156/101 mm Hg Nocturnal: 167/100 mm Hg
monitoring in a patient with renal disease.
Loss of diurnal blood pressure patterns
Blood pressure, mm Hg
1.0
0.9
0.8
0.7
1/Creatinine
0.6
0.5
0.4
0.3
0.2
0.1
0.0
May Feb Nov Aug May Jan Oct Jul
1979 1982 1984 1987 1990 1993 1995 1998
B Date
A
FIGURE 2-20 (see Color Plate)
Hypertension accelerates the rate of progressive renal failure in blood pressure level at approximately 240/130 mm Hg. The biopsy
patients with parenchymal renal disease. A, Photomicrograph of specimen shows the following features of malignant nephrosclerosis:
malignant phase hypertension. Regardless of the cause of renal disease, these patients develop vascular and glomerular injury, which can
untreated hypertension leads to more rapid loss of remaining nephrons progress to irreversible renal failure. Before the introduction of antihy-
and decline in glomerular filtration rates. A striking example of pertensive drug therapy, patients with malignant phase hypertension
pressure-related injury may be observed in patients with malignant routinely proceeded to uremia. Effective antihypertensive therapy can
phase hypertension. This image is an open biopsy specimen obtained slow or reverse this trend in some but not all patients. B, Progressive
from a patient with papilledema, an expanding aortic aneurysm, and renal failure in malignant hypertension over 8 years.
100
0.12 n=11,912 men White=300,645
SBP>180
P<0.001 Black=20,222 83.1
0.10 N=332,544 men
80
Incidence per 100,000 person-years, %
Proportion with ESRD
0.08
60
0.06
165<SBP≤180 40 37.21
32.37
0.04 27.34 26.18
20 15.83
0.02 14.22
SBP≤165 9.1
5.43 5.41
0.00 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 <117 117–123 124–130 131–140 >140
A Years from beginning therapy to ESRD B Systolic blood pressure, mm Hg
FIGURE 2-21
Blood pressure levels and rates of end-stage renal disease (ESRD). A, follow-up period [18]. Similarly, follow-up studies after 16 years of
Line graph showing Kaplan-Meier estimates of ESRD rates; 15-year more than 300,000 men in MRFIT demonstrated a progressive increase
follow-up. B, Age-adjusted 16-year incidence of all-cause ESRD in in the risk for ESRD, most pronounced in blacks [19]. These data
men in the Multiple Risk Factor Intervention Trial (MRFIT). Large- suggest that blood pressure levels predict future renal disease. However,
scale epidemiologic studies indicate a progressive increase in the risk it remains uncertain whether benign essential hypertension itself
for developing ESRD as a function of systolic blood pressure levels. induces a primary renal lesion (hypertensive renal disease nephroscle-
Follow-up of nearly 12,000 male veterans in the United States rosis) or acts as a catalyst in patients with other primary renal disease,
established that systolic blood pressure above 165 mm Hg at the initial otherwise not detected at initial screening. SBP—systolic blood
visit was predictive of progressively higher risk of ESRD over a 15-year pressure. (Panel A from Perry and coworkers [18]; with permission.)
2.12 Hypertension and the Kidney
50
0 0
40
Ccr, mL/min
–3 –3
3 –15 –15
Study A: mean GFR: 39 mL/min/1.73 m2
N=585: range: 25–55 mL/min
2 –18 –18
Cr-1/s,
86 92 98 107
1 Mean follow-up MAP, mm Hg
–400 –200 0 +200 +400
Days
FIGURE 2-23
Blood pressure, proteinuria, and the rate of renal disease progression:
FIGURE 2-22 results from the Modification of Diet in Renal Disease (MDRD)
Rates of progression in glomeruloneophritis. The decrease in glomeru- trial. Shown are rates of decrease of glomerular filtration rate
lar filtration rate is illustrated. The rates of decline decreased con- (GFR) for patients enrolled in the MDRD trial, depending on level
siderably with administration of antihypertensive drug therapy. of achieved treated blood pressure during the trial [21]. A component
Among other mechanisms, the decrease in arterial pressure lowers of this trial included strict versus conventional blood pressure control.
transcapillary filtration pressures at the level of the glomerulus [20]. The term strict was defined as target mean arterial pressure (MAP)
This effect is correlated with a reduction in proteinuria and slower of under 92 mm Hg. The term conventional was defined as MAP
development of both glomerulosclerosis and interstitial fibrosis. A of under 107 mm Hg. The rate of decline in GFR increased at higher
distinctive feature of many glomerular diseases is the massive pro- levels of achieved MAP in patients with significant proteinuria
teinuria and nephron loss associated with high single-nephron (>3.0 g/d). No such relationship was evident over the duration of
glomerular filtration, partially attributable to afferent arteriolar this trial (mean, 2.2 years) for patients with less severe proteinuria.
vasodilation. The appearance of worsening proteinuria (>3 g/d) is These data emphasize the importance of blood pressure in deter-
related to progressive renal injury and development of renal failure. mining disease progression in patients with proteinuric nondiabetic
Reduction of arterial pressure can decrease urinary protein excre- renal disease. No distinction was made in this study regarding the
tion and slow the progression of renal injury. Ccr—creatinine clear- relative benefits of specific antihypertensive agents. (From Peterson
ance rate; Cr-1/s—reciprocal creatinine, expressed as 1/creatinine. and coworkers [21]; with permission.)
(From Bergstrom and coworkers [20]; with permission.)
FIGURE 2-25
CLASSES OF ANTIHYPERTENSIVE AGENTS USED The current classification of agents applied for chronic treatment
IN TREATMENT OF CHRONIC RENAL DISEASE of hypertension as summarized in the report by the Joint National
Committee on Prevention, Detection, Evaluation and Treatment of
High Blood Pressure [23]. Attention must be given to drug accu-
Diuretics: mulation and limitations of individual drug efficacy as glomerular
Thiazide class filtration rates decrease in chronic renal disease. Potassium levels
Loop diuretics
may increase during administration of potassium-sparing agents
and medications that inhibit the renin-angiotensin system, especial-
Potassium-sparing agents
ly in patients with impaired renal function [24].
Adrenergic inhibitors
Peripheral agents, eg, guanethidine
Central -agonists, eg, clonidine, methyldopa, and guanfacine
-Blocking agents, eg, doxazosin
-Blocking agents
Combined - blocking agents, eg, labetalol
Vasodilators
Hydralazine
Minoxidil
Classes of calcium-channel blocking agents
Verapamil
Diltiazem
Dihydropyridine
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
4
60 Conventional Mean
Strict ±SEM
n=87 patients 3
Rate of change in GFR, mL/min/1.73 m2/y
55 Bars=95% confidence
intervals for GFR
estimates 2
GFR, mL/min/1.73 m2/y
50
45 1
40 0
35 –1
30 –2
25 –3
–6 0 6 12 18 24 30 36 42 48 Strict Conventional
A Time, mo B Blood pressure control group
FIGURE 2-26
Strict blood pressure control and progression of hypertensive these patients were low. It should be emphasized that entry criteria
nephrosclerosis. Whether vigorous blood pressure reduction reduces excluded patients with diabetes and massive proteinuria. Initial
progression of early parenchymal renal disease in blacks with studies from the African American Study of Kidney Disease trial
nephrosclerosis is not yet certain. A and B, A randomized prospective confirm that biopsy findings in most patients with clinical features of
trial comparing strict (panel A) blood pressure control (defined as hypertension were considered consistent with primary hypertensive
diastolic blood pressure [DBP] <80 mm Hg) with conventional (panel disease [26]. Whether lower than normal levels of blood pressure in
B) levels of diastolic control between 85 and 95 mm Hg for more these patients will prevent progression to end-stage renal disease over
than 3 years could not identify a reduction in rates of disease progres- longer time periods remains to be determined. GFR—glomerular
sion [25]. Of patients, 68 of 87 were black. Rates of progression in filtration rate. (From Toto and coworkers [25]; with permission.)
2.14 Hypertension and the Kidney
FIGURE 2-27
100
Angiotensin-converting enzyme (ACE)
90 inhibitors and chronic renal disease.
Progression of type I diabetic nephropathy
80 to renal failure was reduced in the ACE
inhibitor arm of a trial comparing conven-
dialysis or transplantation, %
Patients who died or needed
70
tional antihypertensive therapy with a
60 regimen containing the ACE inhibitor
captopril. All patients in this trial had
50
significant proteinuria (>500 mg/d). The
P=0.002 most striking effect of the ACE inhibitor
40
regimen was seen in patients with higher
30 serum creatinine levels (>1.5 mg/dL) as
shown in the top two lines. It should be
20
noted that calcium channel blocking drugs
10 were excluded from this trial and the ACE
inhibitor arm had somewhat lower arterial
0 P=0.14
pressures during treatment. These data offer
support to the concept that ACE inhibition
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
lowers intraglomerular pressures, reduces
Years of follow-up
Creatinine ≥1.5 mg/dL proteinuria, and delays the progression of
Placebo 49 48 44 40 33 23 16 7 1 diabetic nephropathy by more mechanisms
Captopril 53 53 52 51 48 36 25 17 8 than can be explained by pressure reduction
Creatinine <1.5 mg/dL alone. (Data from Lewis and coworkers [27].)
Placebo 153 150 148 146 138 98 84 52 25
Captopril 154 154 152 150 147 104 78 47 29
2.6 2.6
Benazepril: n=583 patients; creatinine=1.5–4.0 Benazepril: n=583 patients; creatinine=1.5–4.0 117
Placebo Placebo
262
2.2 2.2
2.0 2.0
0 1 2 3 0 1 2 3
A Years B Years
FIGURE 2-28
Angiotensin-converting enzyme (ACE) inhibition in nondiabetic renal data support a role for ACE inhibition, the results are considerably
disease. A and B, Shown here are serum creatinine levels from the less convincing than are those for diabetic nephropathy. These results
12-month (panel A) and 36-month (panel B) cohorts followed in the argue that some groups may not experience major benefit from ACE
benazepril trial. In this trial, 583 patients were randomized to therapy inhibition over the short term. Preliminary reports from recent studies
with or without benazepril [28]. Slight reductions in the rates of limited to patients with proteinuria suggest that rates of progression
increase in creatinine and of stop points in the ACE inhibitor group were substantially reduced by treatment with ramipril [29]. (From
occurred; however, these reductions were modest. Whereas these Maschio and coworkers [28]; with permission.)
Renal Parenchymal Disease and Hypertension 2.15
FIGURE 2-29
CONCLUSIONS AND RECOMMENDATIONS OF THE SIXTH REPORT OF Conclusions and Recommendations of the
THE JOINT NATIONAL COMMITTEE ON PREVENTION, DETECTION, Sixth Report of the Joint National
EVALUATION AND TREATMENT OF HIGH BLOOD PRESSURE, 1997 Committee (JNC) on Prevention, Detection,
Evaluation and Treatment of High Blood,
1997 [23]. The JNC Committee has empha-
1. Hypertension may result from renal disease that reduces functioning nephrons. sized the importance of vigorous blood
2. Evidence shows a clear relationship between high blood pressure and end-stage renal disease. pressure control with any agents needed,
3. Blood pressure should be controlled to ≤130/85 mm Hg (<125/75 mm Hg) in patients with proteinuria
rather than specific classes of medication.
in excess of 1 g/24 h. Angiotensin-converting enzyme inhibitors
4. Angiotensin-converting enzyme inhibitors work well to lower blood pressure and slow progression of renal failure. in proteinuric disease are the exception.
References
1. Smith MC, Dunn MJ: Hypertension in renal parenchymal disease. In 16. Whitworth JA: Renal parenchymal disease and hypertension. In
Hypertension: Pathophysiology, Diagnosis and Management. Edited by Clinical Hypertension. Edited by Robertson JIS. Amsterdam: Elsevier,
Laragh JH, Brenner BM. New York: Raven Press; 1995:2081–2102. 1992:326–350.
2. Klahr S, Levey AS, Beck GJ, et al.: The effects of dietary protein 17. Foley RN, Parfrey PS, Harnett JD, et al.: Impact of hypertension on
restriction and blood-pressure control on the progression of chronic cardiomyopathy, morbidity and mortality in end-stage renal disease.
renal disease. N Engl J Med 1994, 330:877–884. Kidney Int 1996, 49:1379–1385.
3 Rodriguez-Iturbe B, Baggio B, Colina-Chouriao J, et al.: Studies on the 18. Perry HM, Miller JP, Fornoff JR, et al.: Early predictors of 15-year
renin-aldosterone system in the acute nephritic syndrome. Kidnet Int end-stage renal disease in hypertensive patients. Hypertension 1995,
1981, 445–453 25(part 1):587–594.
4. Curtiss JJ, Luke RG, Dustan HP, et al.: Remission of essential hyperten- 19. Klag MJ, Whelton PK, Randall BL, et al.: End-stage renal disease in
sion after renal transplantation. N Engl J Med 1983, 309:1009–1015. African-American and White men. JAMA 1997, 277:1293–1298.
5. Brunner HR, Gavras H, Laragh JH: Specific inhibition of the renin- 20. Bergstrom J, Alvestrand A, Bucht H, Guttierrez A: Progression of chronic
angiotensin system: a key to understanding blood pressure regulation. renal failure in man is retarded with more frequent clinical follow-ups
Prog Cardiovasc Dis 1974; 17:87–98. and better blood pressure control. Clin Nephrol 1986, 25:1–6.
6. Converse RL, Jacobsen TN, Toto RD, et al.: Sympathetic overactivity in 21. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure control, pro-
patients with chronic renal failure. N Engl J Med1992, 327:1912–1918. teinuria and the progression of renal disease. Ann Intern Med 1995;
123:754–762.
7. Katholi RE, Nafilan AJ, Oparil S: Importance of renal sympathetic
tone in the development of DOCA-salt hypertension in the rat. 22. Brazy PC, Stead WW, Fitzwilliam JF: Progression of renal insufficiency:
Hypertension 1980, 2:266–273. role of blood pressure. Kidney Int 1989, 35:670–674.
23. JNC Committee: Sixth Report of the Joint National Committee on
8. Benigni A, Zoja C, Cornay D, et al.: A specific endothelin subtype A
Prevention, Detection, Evaluation and Treatment of High Blood Pressure.
receptor antagonist protects against injury in renal disease progression.
Bethesda, MD: National Institutes of Health Publication; 1997.
Kidney Int 1993, 44:440–444.
24. Textor SC: Renal failure related to ACE inhibitors. Semin Nephrol
9. Levin ER: Mechanisms of disease: endothelins. N Engl J Med 1995,
1997, 17:67–76.
333:356–363.
25. Toto RD, Mitchell HC, Smith RD, et al.: “Strict” blood pressure control
10. Textor SC, Burnett JC, Romero JC, et al.: Urinary endothelin and renal and progression of renal disease in hypertensive nephrosclerosis.
vasoconstriction with cyclosporine or FK506 after liver transplantation. Kidney Int 1995, 48:851–859.
Kidney Int 1995, 47:1426–1433.
26. Fogo A, Breyer JA, Smith MC, et al.: Accuracy of the diagnosis of
11. Sandborn WJ, Hay JE, Porayko MK, et al.: Cyclosporine withdrawal for hypertensive nephrosclerosis in African-Americans: a report from the
nephrotoxicity in liver transplant recipients does not result in sustained African American Study of Kidney Disease (ASSK) trial. Kidney Int
improvement in kidney function and causes cellular and ductopenic 1997; 51:244–252.
rejection. Hepatology 1994, 19:925–932.
27. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-
12. Benigni A, Perico N, Gaspari F, et al.: Increased renal endothelin pro- converting-enzyme inhibition on diabetic nephropathy. N Engl J Med
duction in rats with renal mass reduction. Am J Physiol 1991, 1993, 329:1456–1462.
260:F331–F339.
28. Maschio G, Alberti D, Janin G, et al.: Effect of the angiotensin-converting
13. Rees DD, Palmer RMJ, Moncada S: Role of endothelium-derived nitric enzyme inhibitor benazepril on the progression of chronic renal insuf-
oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A ficiency. N Engl J Med 1996, 334:939–945.
1989, 86:3375–3378.
29. Ruggenenti P, Perna A, Mosconi M, et al.: The angiotensin converting
14. Lahera V, Salom MG, Miranda-Guardiola F, et al.: Effects of N-nitro- enzyme inhibitor ramipril slows the rate of GFR decline and the pro-
L-arginine methyl ester on renal function and blood pressure. Am J gression to end-stage renal failure in proteinuric, non-diabetic chronic
Physiol 1991, 261:F1033–F1037. renal diseases [abstract]. J Am Soc Nephrol 1997, 8:147A.
15. Gaston RS, Schlessinger SD, Sanders PW, et al.: Cyclosporine inhibits 30. Giatras I, Lau J, Levey AS: Effect of angiotensin-converting enzyme
the renal response to L-arginine in human kidney transplant recipients. inhibitors on the progression of non-diabetic renal disease: a meta-
J Am Soc Nephrol 1995, 5:1426–1433. analysis of randomized trials. Ann Intern Med 1997, 127:345.
Renovascular Hypertension
and Ischemic Nephropathy
Marc A. Pohl
T
he major issues in approaching patients with renal artery steno-
sis relate to the role of renal artery stenosis in the management
of hypertension, ie, “renovascular hypertension,” and to the
potential for vascular compromise of renal function, ie, “ischemic
nephropathy.” Ever since the original Goldblatt experiment in 1934,
wherein experimental hypertension was produced by renal artery
clamping, countless investigators and clinicians have been intrigued by
the relationship between renal artery stenosis and hypertension. Much
discussion has focused on the pathophysiology of renovascular hyper-
tension, the renin angiotensin system, diagnostic tests to detect pre-
sumed renovascular hypertension, and the relative merits of surgical
renal revascularization (SR), percutaneous transluminal renal angio-
plasty (PTRA), and drug therapy in managing patients with renal
artery stenosis and hypertension. Hemodynamically significant renal
artery stenosis, when bilateral or affecting the artery to a solitary func-
tioning kidney, can also lead to a reduction in kidney function
(ischemic nephropathy). This untoward observation may be reversed
by interventive maneuvers, eg, surgical renal revascularization, PTRA,
or renal artery stenting. The syndrome of “ischemic renal disease” or
“ischemic nephropathy” now looms as an important clinical condi-
tion and has attracted the fascination of nephrologists, vascular sur-
geons, and interventional cardiologists and radiologists.
The detection of renal artery stenosis in a patient with hyperten-
sion usually evokes the assumption that the hypertension is due to the
renal artery stenosis. However, renal artery stenosis is not synony-
mous with “renovascular hypertension.” On the basis of autopsy
studies and clinical angiographic correlations, high-grade atheroscle- CHAPTER
rotic renal artery stenosis (ASO-RAS) in patients with mild blood
pressure elevation or in patients with normal arterial pressure is well
3
recognized. The vast majority of patients with ASO-RAS who have
hypertension have essential hypertension, not renovascular hyperten-
sion. These hypertensive patients with ASO-RAS are rarely cured of
their hypertension by interventive procedures that either bypass or
3.2 Hypertension and the Kidney
dilate the stenotic lesion. Thus, it is critical to distinguish chronic subcapsular hematoma, and unilateral ureteral obstruction
between the anatomic presence of renal artery stenosis, in may also be associated with hypertension that is relieved when
which a stenotic lesion is present but not necessarily causing the affected kidney is removed. These clinical analogues of the
hypertension, and the syndrome of renovascular hypertension experimental Page kidney reflect the syndrome of renovascular
in which significant arterial stenosis is present and sufficient to hypertension (RVHT), but without main renal artery stenosis.
produce renal tissue ischemia and initiate a pathophysiologic Takayasu’s arteritis and atheroembolic renal disease are additional
sequence of events leading to elevated arterial pressure. In the examples of RVHT without main renal artery stenosis.
final analysis, proof that a patient has the entity of “renovas- Accordingly, the anatomic presence of renal artery stenosis
cular hypertension” rests with the demonstration that the should not be equated with renovascular hypertension and the
hypertension, presumed to be “renovascular,” can be eliminat- syndrome of RVHT need not reflect renal artery stenosis.
ed or substantially ameliorated following removal of the steno- This chapter reviews the types of renal arterial disease asso-
sis by surgical or endovascular intervention, or by removing ciated with RVHT, the pathophysiology of RVHT, clinical
the kidney distal to the stenosis. features and diagnostic approaches to renal artery stenosis and
Although the great majority of patients diagnosed as having RVHT, evolving concepts regarding ischemic nephropathy, and
renovascular hypertension have this syndrome because of main renal management considerations in patients with renal artery stenosis,
artery stenosis, hypertension following unilateral renal trauma, presumed RVHT, and ischemic renal disease.
FIGURE 3-1
CLASSIFICATION OF RENAL Classification of renal artery disease. Two main types of renal arterial lesions form the
ARTERY DISEASE anatomic basis for renal artery stenosis. Atherosclerotic renal artery disease (ASO-RAD)
is the most common cause of renal artery disease, accounting for 60% to 80% of all renal
artery lesions. The fibrous dysplasias are the other major category of renal artery disease,
Disease Incidence, %* and as a group account for 20% to 40% of renal artery lesions. Arterial aneurysm and
arteriovenous malformation are rarer types of renal artery disease.
Atherosclerosis 60–80
Fibrous dysplasia 20–40
Medial (30%)
Perimedial (5%)
Intimal (5%)
First author Year Months of follow-up, n/n Patients, n Progression, n (%) Total occlusion
Wollenweber 1968 12/88 30 21 (70) NA
Meaney 1968 6/120 39 14 (36) 3 (8)
Dean 1981 6/102 35 10 (29) 4 (11)
Schreiber 1984 12/60 85 37 (44) 14 (I6)
Tollefson 1991 15/180 48 34 (71) 7 (15)
Total 237 116 (49) 28 (14)
FIGURE 3-3
Natural history of atherosclerotic renovascular disease. cumulative incidence of progession of lesions with less than
Retrospective studies, based on serial renal angiograms, suggest 60% reduction in lumen diameter progressing to more than 60%
that atherosclerotic renal artery disease (ASO-RAD) is a progres- reduction in lumen diameter was 30% at 1 year, 44% at 2 years,
sive disorder. This figure summarizes retrospective series on the and 48% at 3 years. Progression to total occlusion occurred only
natural history of ASO-RAD. A large series from the Cleveland in arteries with a baseline reduction in lumen diameter of more
Clinic in nonoperated patients indicated progression of renal artery than 60%. The cumulative incidence of progression to total
obstruction in 44%; progression to total occlusion occurred in occlusion in patients with baseline stenosis of 60% or greater
16% of these patients. Reduction in ipsilateral renal size is associ- was 4% at 1 year, 4% at 2 years, and 7% at 3 years. Blood
ated with angiographic evidence of progression in contrast to pressure control and serum creatinine were not predictors of
patients with nonprogressive (angiographically) ASO-RAD. progression. The risk of renal parenchymal atrophy over time in
Zierler and coworkers have prospectively studied the progres- kidneys with ASO-RAD has also been described. (Table adapted
sion of ASO-RAD by sequential duplex ultrasonography. The from Rimmer and Gennari [2]; with permission.)
FIGURE 3-5
Arteriogram and schematic diagrams of
medial fibroplasia. A, Right renal arteri-
ogram demonstrating weblike stenosis
with interposed segments of dilatation
(large beads) typical of medial fibroplasia
(“string of beads” lesion). B, Schematic
diagram of medial fibroplasia.
The lesion of medial fibroplasia characteris-
tically affects the distal half of the main renal
artery, frequently extending into the branches,
is often bilateral, and angiographically gives
the appearance of multiple aneurysms (“string
B of beads”). Histologically, this beaded lesion
is characterized by areas of proliferation of
fibroblasts of the media surrounded by
fibrous connective tissue (stenosis) alternating
with areas of medial thinning (aneurysms).
Inspection of the renal angiogram in panel A
indicates that the width of areas of aneurys-
mal dilatation is wider than the nonaffected
proximal renal artery, an angiographic clue
to medial fibroplasia. (Panel A from Pohl [1];
A with permission.)
FIGURE 3-6
Arteriogram and schematic diagram of peri-
medial fibroplasia. A, Selective right renal
arteriogram shows a tight stenosis in the
mid portion of the renal artery with a small
string of beads appearance, typical of peri-
medial fibroplasia. B, Schematic diagram of
perimedial fibroplasia.
Perimedial fibroplasia, accounting for
10% to 25% of the fibrous renal artery dis-
eases, is also observed almost exclusively in
women. The stenotic lesion occurs in the
mid and distal main renal artery or branches
B and may be bilateral. Angiographically, serial
A stenoses are observed with small beads, which
are smaller in diameter than the unaffected
portion of the renal artery. This highly
stenotic lesion may progress to total occlu-
sion; collateral blood vessels and renal atro-
phy on the involved side are frequently
observed. Pathologically, the outer layer of
the media varies in thickness and is densely
fibrotic, producing a severe reduction in
lumen diameter (panel B). Renal artery dis-
section and/or thrombosis are common.
(Panel A from Pohl [1]; with permission.)
Renovascular Hypertension and Ischemic Nephropathy 3.5
FIGURE 3-7
Arteriogram and schematic diagram of
intimal fibroplasia. A, Selective right renal
arteriogram demonstrating a localized,
highly stenotic, smooth lesion involving the
distal renal artery, from intimal fibroplasia.
B, Schematic diagram of intimal fibroplasia.
Intimal fibroplasia occurs primarily in
children and adolescents and angiographi-
cally gives the appearance of a localized,
highly stenotic, smooth lesion, with post-
stenotic dilatation. It may occur in the prox-
imal portion of the renal artery as well as
B in the mid and distal portions of the renal
A artery, is progressive, and is occasionally
associated with dissection or renal infarc-
tion. Pathologically, idiopathic intimal fibro-
plasia is due to a proliferation of the intimal
lining of the arterial wall. Intimal fibroplasia
of the renal artery may also occur as an
event secondary to atherosclerosis or as a
reactive intimal fibroplasia consequent to an
inciting event such as prior endarterectomy
or balloon angioplasty. (Panel A from Pohl
[1]; with permission.)
FIGURE 3-11
Two-kidney hypertension One-kidney hypertension Schematic representation of two types of experimental hypertension.
The discussion so far of the pathophysiology of renovascular
hypertension has focused on the two-kidney, one-clip model of
renovascular hypertension (“two-kidney hypertension”), wherein the
artery to the “contralateral kidney” is patent and the “contralateral”
nonaffected kidney is present. Elevated peripheral renin activity,
normal plasma volume, and hypokalemia are typically associated
with the elevated arterial pressure. There is another type of “reno-
Blood Renin Volume Blood Renin Volume vascular hypertension” known as “one-kidney” hypertension,
pressure pressure wherein in the experimental model, one renal artery is constricted
High Normal Normal High and the contralateral kidney is removed. Although there is an initial
increase in renin release responsible for the early rise in blood pressure
in “one-kidney” hypertension as in “two-kidney” hypertension, the
absence of an unclipped contralateral kidney allows for sodium
retention early in the course of this one-kidney, one-clip (1K,1C)
model. Renin levels are suppressed to normal levels in conjunction
with high blood pressure which is maintained by salt and water
retention. Thus, extracellular fluid volume expansion is a prime
feature of “one-kidney” hypertension.
3.8 Hypertension and the Kidney
FIGURE 3-12
A. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR Lesions producing the syndrome of reno-
HYPERTENSION (“TWO-KIDNEY HYPERTENSION”)* vascular hypertension. A, Two-kidney
hypertension. The most common clinical
counterpart to “two-kidney” hypertension
Unilateral atherosclerotic renal arterial disease is unilateral renal artery stenosis due to either
Unilateral fibrous renal artery disease atherosclerotic or fibrous renal artery disease.
Renal artery aneurysm
Unilateral renal trauma, with development
of a calcified fibrous capsule surrounding
Arterial embolus
the injured kidney causing compression of
Arteriovenous fistula (congenital and traumatic)
the renal parenchyma, may produce reno-
Segmental arterial occlusion (traumatic)
vascular hypertension; this clinical situation is
Pheochromocytoma compressing renal artery
analogous to the experimental Page kidney,
Unilateral perirenal hematoma or subcapsular hematoma (compressing renal parenchyma)
wherein cellophane wrapping of one of two
kidneys causes hypertension, which is
*Implies contralateral (nonaffected) kidney present. relieved by removal of the wrapped kidney.
B, One-kidney hypertension. Clinical
counterparts of experimental one-kidney,
one-clip (“one kidney”) hypertension
B. LESIONS PRODUCING THE SYNDROME OF RENOVASCULAR include renal artery stenosis to a solitary
HYPERTENSION (“ONE-KIDNEY HYPERTENSION”)* functioning kidney, bilateral renal arterial
stenosis, aortic coarctation, Takayasu’s
arteritis, fulminant polyarteritis nodosa,
Stenosis to a solitary functioning kidney atheroembolic renal disease, and renal
Bilateral renal arterial stenosis artery stenosis in a transplanted kidney.
Aortic coarctation In some parts of the world, eg, China and
Vasculitis (polyarteritis nodosa and Takayasu’s arteritis) India, Takayasu’s arteritis is a frequent
Atheroembolic disease
cause of renovascular hypertension.
FIGURE 3-15
Renal duplex ultrasound for diagnosis of renal artery stenosis. Duplex ultrasound scanning
of the renal arteries is a noninvasive screening test for the detection of renal artery stenosis.
It combines direct visualization of the renal arteries (B-mode imaging) with measurement
of various hemodynamic factors in the main renal arteries and within the kidney (Doppler),
thus providing both an anatomic and functional assessment. Unlike other noninvasive screening
tests (eg, captopril renography), duplex ultrasonography does not require patients to dis-
continue any antihypertensive medications before the test. The study should be performed
while the patient is fasting. The white arrow indicates the aorta and the black arrow the left
renal artery, which is stenotic. Doppler scans (bottom) measure the corresponding peak systolic
velocities in the aorta and in the renal artery. The peak systolic velocity in the left renal artery
was 400 cm/s, and the peak systolic velocity in the aorta was 75 cm/s. Therefore, the renal-
aortic ratio was 5.3, consistent with a 60% to 99% left renal artery stenosis. (From Hoffman
and coworkers [4]; with permission.)
3.10 Hypertension and the Kidney
FIGURE 3-16
COMPARISON OF DUPLEX ULTRASOUND Comparison of duplex ultrasound with arteriography. A total of
WITH ARTERIOGRAPHY 102 consecutive patients with both duplex ultrasound scanning of
the renal arteries and renal arteriography were prospectively studied.
All patients in this study had difficult-to-control hypertension,
Percent stenosis by arteriogram unexplained azotemia, or associated peripheral vascular disease,
Percent stenosis giving them a high pretest likelihood of renovascular hypertension.
by ultrasound 0–59 60–79 80–99 100 Total Sixty-two of 63 arteries that showed less than 60% stenosis by formal
0–59 62 0 1 1 64 arteriography, were identified by duplex ultrasound scanning.
60–99 1 31 67 0 99 Twenty-two of 23 arteries with total occlusion on arteriography
100 0 1 1 22 24 were correctly identified by duplex ultrasound. Thirty-one of 32
Total 63 32 69 23 187 arteries with 60% to 79% stenosis using arteriography were identified
as having 60% to 99% stenosis on duplex ultrasound and 67 of 69
arteries with 80% to 99% stenosis on arteriography were detected
Sensitivity, 0.98.
to have 60% to 99% stenosis on ultrasound. A current limitation
Specificity, 0.98.
of duplex ultrasound is the inability to consistently distinguish
Positive predictive value, 0.99. between more than and less than 80% stenosis (considered to be
Negative predictive value, 0.97. the magnitude of stenosis required for hemodynamic significance
of the lesion). Nevertheless, duplex ultrasound is currently highly
sensitive and specific in patients with a high likelihood of renovascular
disease in detecting patients with more or less than 60% renal artery
stenosis. Accessory renal arteries are difficult to identify by ultra-
sound and remain a limitation of this test. (Adapted from Olin
and coworkers [5]; with permission.)
1.0
1.0
0.8
0.8
Relative acidity
Relative acidity
0.6
0.6
0.4 0.4
0.2 0.2
Bladder Bladder
Right kidney Right kidney
Left kidney Left kidney
0 0
0 8 16 24 32 40 48 0 8 16 24 32 40 48
A Time, min B Time, min
FIGURE 3-19
Captopril renography. A, TcDPTA time-activity curves during asymmetry of renal size and function and on specific, captopril-
baseline. B, TcDPTA time-activity curves after captopril adminis- induced changes in the renogram, including delayed time to maximal
tration. These curves represent a captopril renogram in a patient activity (≥11 minutes), significant asymmetry of the peak of each
with unilateral left renal artery stenosis. This diagnostic test has been kidney, marked cortical retention of the radionuclide, and marked
used to screen for renal artery stenosis and to predict renovascular reduction in the calculated glomerular filtration rate of the kidney
hypertension. Captopril renography appears to be highly sensitive ipsilateral to the stenosis. One must interpret the clinical and reno-
and specific for detecting physiologically significant renal artery graphic data with caution, as protocols are complex and diagnostic
stenosis. Scintigrams and time-activity curves should both be analyzed criteria are not well standardized. Nevertheless, captopril renogra-
to assess renal perfusion, function, and size. If the renogram following phy appears to be an improvement over the captopril provocation
captopril administration is abnormal (panel B, demonstrating delayed test, with many reports indicating sensitivity and specificity from
time to maximal activity and retention of the radionuclide in the right 80% to 95% in predicting an improvement in blood pressure
kidney), another renogram may be obtained without captopril for following intervention. (Adapted from Nally and coworkers [7];
comparison. The diagnosis of renal artery stenosis is based on with permission.)
3.12 Hypertension and the Kidney
Ischemic Nephropathy
FIGURE 3-21
Aortogram in a 62-year-old white woman demonstrating subtotal occlusion of the left
main renal artery supplying an atrophic left kidney and high-grade ostial stenosis of the
proximal right renal artery from atherosclerosis. This patient presented in 1977 with a
recent appearance of hypertension and a blood pressure of 170/115 mm Hg. Three years
previously, when diagnosed with polycythemia vera, an IVP was normal. She was fol-
lowed closely between 1974 and 1977 by her physician and was always normotensive
until the hypertension suddenly appeared. A repeat rapid sequence IVP demonstrated a
reduction in the size of the left kidney from 14 cm in height (1974) to 11.5 cm in height
(1977). The serum creatinine was 2.6 mg/dL. The renal arteriogram shown here indi-
cates high-grade bilateral renal artery stenosis with the left kidney measuring 11.5 cm
in height, and the right kidney measuring 14.5 cm in height. Renal vein renins were
obtained and lateralized strongly to the smaller left kidney. The blood pressure was
well controlled with inderal and chlorthalidone. Right aortorenal reimplantation was
undertaken solely to preserve renal function. Postoperatively the serum creatinine fell to
1.5 mg/dL and remained at this level for the next 13 years. Blood pressure continued to
require antihypertensive medication, but was controlled to normal levels with inderal
and chlorthalidone.
Renovascular Hypertension and Ischemic Nephropathy 3.13
12.0
11.0
10.0
9.0
8.0
Serum creatinine, mg/dL
Pt. 7
7.0 Pt. 8
6.0
Pt. 3
5.0
Pt. 6
A
4.0
3.0 Pt. 2
Pt. 1
Pt. 4
2.0
Pt. 3
1.0
0
Admission Medical Surgery or
therapy angioplasty
FIGURE 3-22
Effects of medical therapy and surgery or angioplasty on serum
creatinine levels. This figure describes eight patients hospitalized
because of severe hypertension and renal insufficiency. With med-
ical management of the hypertension (antihypertensive drug thera-
py), four of the eight patients developed substantial worsening of B
their renal function as measured by serum creatinine; three of these
four patients demonstrated improvement following surgery or FIGURE 3-23
angioplasty. The other four patients (patients one to four) did not Improved renal function demonstrated by intravenous pyelography
demonstrate a worsening serum creatinine level with medical thera- following left renal revascularization. A, preoperative IVP (5-minute
py; but three of these four patients showed improved renal func- film) in a 65-year-old white man with a 15-year history of hyperten-
tion following surgery or angioplasty. (Adapted from Ying and sion; serum creatinine 2.6 mg/dL. Note poorly functioning left kidney,
coworkers [9]; with permission.) which measured 11.5 cm in height. B, post operative IVP (5-minute
film) obtained following left aortorenal saphenous vein bypass grafting
to the left kidney. Note the prompt function and increased height
(14.0 cm) of the revascularized left kidney versus the preoperative
IVP. (From Novick and Pohl [10]; with permission.)
The clinical story of the patient in Figure 3-21, the benefits of
surgical renal revascularization or pecutaneous transluminal renal
angioplasty (Fig. 3-22), and the radiographic evidence of improved
renal function after renal revascularization (Fig. 3-23) are examples
of ischemic nephropathy. Two definitions of ischemic nephropathy
are suggested herein: 1) clinically significant reduction in renal
function due to compromise of the renal circulation; and 2) clinically
significant reduction in glomerular filtration rate due to hemody-
namically significant obstruction to renal blood flow, or renal failure
due to renal artery occlusive disease.
3.14 Hypertension and the Kidney
FIGURE 3-24
ATHEROSCLEROTIC RENAL ARTERY STENOSIS IN 395 PATIENTS Atherosclerotic renal artery stenosis in
WITH GENERALIZED ATHEROSCLEROSIS OBLITERANS AND IN patients with generalized atherosclerosis
PATIENTS WITH CORONARY ARTERY DISEASE obliterans and in patients with coronary
artery disease (CAD). Atherosclerotic renal
artery stenosis is common in older patients
Patients, n Percent of patients with >50% stenosis with and without hypertension simply as a
consequence of generalized atherosclerosis
Abdominal aortic aneurysm 109 38 obliterans. Approximately 40% of consecu-
Aorto-occlusive disease 21 33 tively studied patients undergoing arteriography
Lower extremity disease 189 39* for routine evaluation of abdominal aortic
Suspected renal artery stenosis 76 70† aneurysm, aorto-occlusive disease, or lower
Coronary artery disease 76 29† extremity occlusive disease have associated
817 20‡ renal artery stenosis (more than 50% unilateral
renal artery stenosis) and nearly 30% of
*50% in diabetic patients. patients undergoing coronary angiography
†Data from Vetrovec and coworkers [12]. may have incidentally detected unilateral
‡Data from Harding [13]. renal artery stenosis. Approximately 4%
to 13% of patients with CAD or peripheral
vascular disease have more than 75% bilateral
renal artery stenosis. Correlations of hyper-
cholesterolemia and cigarette smoking with
renal artery atherosclerosis are not unequiv-
ocally clear, but they probably represent
risk factors for renal artery atherosclerosis
just as they represent risk factors for
atherosclerosis in other vascular beds.
(Adapted from Olin and coworkers [11];
with permission.)
FIGURE 3-25
CLINICAL PRESENTATIONS OF Clinical presentations of ischemic renal disease. The clinical presen-
ISCHEMIC RENAL DISEASE tation of a patient likely to develop renal failure from atheroscle-
rotic ischemic renal disease is that of an older (more than 50 years)
individual demonstrating progressive azotemia in conjunction with
Acute renal failure, frequently precipitated by a reduction in blood pressure antihypertensive drug therapy, risk factors for generalized athero-
(ie, angiotensin-converting enzyme inhibitors plus diuretics) sclerosis obliterans, known renal artery disease, refractory hyper-
Progressive azotemia in a hypertensive patient with known renal artery stenosis tension, and generalized atherosclerosis. Acute renal failure precipi-
treated medically tated by a reduction in blood pressure below a “critical perfusion
Progressive azotemia in a patient (usually elderly) with refractory hypertension pressure,” and particularly with the use of angiotensin converting-
Unexplained progressive azotemia in an elderly patient enzyme inhibitors (ACEI) or angiotensin II receptor blockers plus
Hypertension and azotemia in a renal transplant patient diuretics, strongly suggests severe intrarenal ischemia from arterio-
lar nephrosclerosis and/or severe main renal artery stenosis.
Unexplained progressive azotemia in an elderly patient with clinical
signs of vascular disease with minimal proteinuria and a bland urinary
sediment also suggest ischemic nephropathy. (Adapted from
Jacobson [14]; with permission.)
Renovascular Hypertension and Ischemic Nephropathy 3.15
FIGURE 3-26
Mild stenosis (less than 50%) due to athero-
sclerotic disease of the left main renal artery
(panel A) that has progressed to high-grade
(75% to 99%) stenosis on a later arteri-
ogram (panel B). Underlying the concept
of renal revascularization for preservation
of renal function is the notion that athero-
sclerotic renal artery disease (ASO-RAD)
is a progressive disorder. The sequential
angiograms in Figures 3-26 and 3-27 show
angiographic progression of ASO-RAD over
time. In patients demonstrating progressive
renal artery stenosis by serial angiography, a
decrease in kidney function as measured by
serum creatinine and a decrease in ipsilateral
kidney size correlate significantly with pro-
gressive occlusive disease. Patients demon-
strating more than 75% stenosis of a renal
artery are at highest risk for progression to
complete occlusion. (From Novick [15];
A B with permission.)
A B
FIGURE 3-27
A, Normal right main renal artery and minimal atherosclerotic stenosis of the right main renal artery (arrow) and total occlusion
irregularity of left main renal artery on initial (1974) aortogram. of left main renal artery (arrow). (From Schreiber and coworkers
B, Repeat aortography (1978) showed progression to moderate [16]; with permission.)
3.16 Hypertension and the Kidney
FIGURE 3-30
This abdominal aortogram reveals com-
plete occlusion of the left main renal artery
(panel A) with filling of the distal renal
artery branches from collateral supply on
delayed films (panel B). The observation
of collateral circulation when the main
renal artery is totally occluded proximally
suggests viable renal parenchyma. (From
Novick and Pohl [10]; with permission.)
A B
Renovascular Hypertension and Ischemic Nephropathy 3.17
FIGURE 3-33
Severe atherosclerosis involving the abdominal aorta, renal, and iliac arteries. This abdominal
aortogram demonstrates a ragged aorta, total occlusion of the right main renal artery, and
subtotal occlusion of the proximal left main renal artery. Such patients are at high-risk for
atheroembolic renal disease following aortography, selective renal arteriography, pecutaneous
transluminal renal angioplasty, renal artery stenting, or surgical renal revascularization.
FIGURE 3-35
Pathologic specimen of kidney demonstrating atheroembolic renal
disease (AERD). Microemboli of atheromatous material are readily
identified by the characteristic appearance of cholesterol crystal
inclusions that appear in a biconvex needle-shaped form. In routine
paraffin-embedded histologic sections, the cholesterol is not seen
because the methods used in preparing sections dissolve the crystals;
the characteristic biconvex clefts in the glomeruli (or blood vessels)
persist, allowing easy identification. Several patterns of renal failure
in patients with AERD are recognized: 1) insult (eg, abdominal
aortogram) leads to end-stage renal disease (ESRD) over weeks
to months; 2) insult leads to chronic stable renal insufficiency;
3) multiple insults (repeated angiographic procedures) lead to a
step-wise rise in serum creatinine eventuating in end-stage renal
failure; and 4) insult leading to ESRD over several weeks to
months with recovery of some renal function allowing for
discontinuance of dialysis.
FIGURE 3-36
Renal biopsy demonstrating severe arteriolar nephrosclerosis.
Arteriolar nephrosclerosis is intimately associated with hypertension.
The histology of the kidney in arteriolar nephrosclerosis shows
considerable variation in intensity and extent of the arteriolar
lesions. Thickening of the vessel wall, edema of the smooth muscle
cells, hypertrophy of the smooth muscle cells, and hyaline degenera-
tion of the vessel wall may be apparent depending on the severity of
the nephrosclerosis. In addition to the vascular lesions of arteriolar
nephrosclerosis there are abnormalities of glomeruli, tubules, and
interstitial areas that are believed to be secondary to the ischemia
that results from arteriolar insufficiency. Arteriolar nephrosclerosis
is observed in patients with longstanding hypertension; the more
severe the hypertension, the more severe the arteriolar nephrosclerosis.
Arteriolar nephrosclerosis may also be seen in elderly normotensive
individuals and is frequently observed in elderly patients with gener-
alized atherosclerosis or essential hypertension.
FIGURE 3-37
Schematic representation of ischemic nephropathy. Patients with atherosclerotic renal artery
Atherosclerosis Nephrosclerosis
disease (ASO-RAD) often have coexisting renal parenchymal disease with varying degrees of
nephrosclerosis (small vessel disease) or atheroembolic renal disease. Whether or not the renal
insufficiency is solely attributable to renal artery stenosis, nephrosclerosis, or atheroembolic renal
disease is difficult to determine. The term “ischemic nephropathy” is more complex than being
Atheroembolism
simply due to atherosclerotic renal artery stenosis. In addition, in the azotemic patient with ASO-
RAD, one should exclude other potential or contributing causes of renal insufficiency such as
obstructive uropathy, primary glomerular disease (suggested by heavy proteinuria), drug-related
renal insufficiency (eg, nonsteroidal anti-inflammatory drugs), and uncontrolled blood pressure.
Renovascular Hypertension and Ischemic Nephropathy 3.19
4% FIGURE 3-38
Miscellaneous Distribution of endstage renal disease diagnoses. Atherosclerotic renal artery disease (ASO-
11%
Other RAD) has been claimed to contribute to the ESRD population. This diagram from the US
Renal Data System Coordinating Center 1994 report indicates that 29% of calendar year
12% 1991 incident patients entered ESRD programs because of “hypertension (HBP).” No reno-
CGN 36% vascular disease diagnosis is listed. Crude estimates of the percentage of patients entering
DM
ESRD programs because of ASO-RAD range from 1.7% to 15%. Precise bases for making
5% these estimates are both unclear and confounded by the high likelihood of coexisting arterio-
Urology 29% lar nephrosclerosis, type II diabetic nephropathy, and atheroembolic renal disease. ASO-RAD
High blood as a major contributor to the ESRD population is probably small on a percentage basis, occu-
3% pressure
Cyst pying some portion of the ESRD diagnosis “hypertension (HBP).” For dialysis-dependent
patients with ASO-RAD, predictors of recovery of renal function following renal revascular-
ization and allowing for discontinuance of dialysis (temporary or permanent) include 1) bilat-
eral (vs unilateral) renal artery stenosis, 2) a relatively fast rate of decline of estimated
glomerular filtration rate (less than 6 months) prior to initiation of dialysis; and 3) mild-to-
moderate arteriolar nephrosclerosis angiographically.
FIGURE 3-40
INCREASING COMORBIDITY IN PATIENTS Comorbidity in patients undergoing renovascular surgery. Patients
UNDERGOING RENOVASCULAR SURGERY presenting for renovascular surgery or endovascular renal revascu-
larization are at high-risk for complications during intervention
because of age, and frequently associated coronary, cerebrovascular,
Comorbidity, % or peripheral vascular disease. As the population ages, the percentage
of patients being considered for interventive maneuvers on the
Condition 1970–1980 1980–1993 renal artery has increased significantly. Approximately 30% of
Angina 21.4 29.9 patients currently undergoing interventive approaches to renal
Prior MI 16.3 27.0 artery disease have angina, or have had a previous myocardial
CHF 12.2 23.7* infarction. Congestive heart failure, cerebrovascular disease (eg, carotid
Cerebrovascular disease 11.2 24.8* artery stenosis), diabetes mellitus, and claudication are frequent
Diabetes 7.1 18.1* comorbid conditions in these patients. Their aortas are often laden
Claudication 35.7 56.4* with extensive atherosclerotic plaque (Fig. 3-33), making angiographic
investigation or endovascular renal revascularization hazardous.
(Adapted from Hallet and coworkers [17]; with permission.)
*P <0.001.
3.20 Hypertension and the Kidney
FIGURE 3-42
Schematic diagram of alternate bypass
procedures. A, Hepatorenal bypass to
right kidney. B, Splenorenal bypass to left
kidney. C, Ileorenal bypass to left kidney.
D, Autotransplantation.
A B
C D
Renovascular Hypertension and Ischemic Nephropathy 3.21
A B
FIGURE 3-43
Percutaneous transluminal renal angioplasty (PTRA) of the renal artery. PTRA of the renal artery has emerged as an important inter-
A, High-grade (more than 75%) nonostial atherosclerotic stenosis of the ventional modality in the management of patients with renal
left main renal artery in a patient with a solitary functioning kidney (right artery stenosis. PTRA is most successful and should be the initial
renal artery totally occluded). Note gradient of 170 mm Hg across the interventive therapeutic maneuver for patients with the medial
stenotic lesion. B, Balloon angioplasty of the left main renal artery was fibroplasia type of fibrous renal artery disease (eg, Fig.3-5A).
successfully performed with reduction in the gradient across the stenotic Excellent technical success rates have also been attained for
lesion from 170 mm Hg pre-PTRA to 15 mm Hg post-PTRA. Repeat nonostial atherosclerotic lesions of the main renal artery, as
aortogram 3 years later demonstrated patency of the left renal artery. shown here.
FIGURE 3-44
High-grade athero-
sclerotic renal artery
stenosis at the
ostium of the right
main renal artery in
a 68-year-old man
with a totally
occluded left main FIGURE 3-45
renal artery. Several Palmaz stent, expanded. Because percutaneous transluminal renal
attempts at balloon angioplasty (PTRA) has suboptimal long-term benefits for athero-
dilatation were sclerotic ostial renal artery stenosis, endovascular stenting has gained
unsuccessful. Over wide acceptance. Renal artery stenting may be performed at the time
the subsequent 10 of the diagnostic angiogram, or at some time thereafter, depending
days, severe renal on the physician’s preference and the risk to the patient of repeated
insufficiency devel- angiographic procedures. From a technical standpoint, indications
oped (serum creati- for renal artery stenting include 1) as a primary procedure for ostial
nine increasing from atherosclerotic renal artery disease (ASO-RAD), 2) technical difficul-
2.0 to 12.0 mg/dL) ties in conjunction with attempted PTRA, 3) post-PTRA dissection,
requiring dialysis. 4) post-PTRA abrupt occlusion, and 5) restenosis following PTRA.
Renal function never It is unclear what the long-term patency and restenosis rates will be
improved and the for renal artery stenting for ostial disease. Preliminary observations
patient remained suggest that the 1-year patency rate for stents is approximately twice
on dialysis. that for PTRA.
3.22 Hypertension and the Kidney
FIGURE 3-46
Abdominal aortogram in a 63-year-old male, 6 months following placement of a Palmaz
stent. Note wide patency of the left main renal artery.
FIGURE 3-47
Surgical revascularization vs percutaneous transluminal renal The “percent success” for PTRA and surgical revascularization
angioplasty (PTRA) for renal artery disease. A, Success rates for depicted above are estimates, and reflect primarily “technical” success
atherosclerotic renal artery disease (ASO-RAD). B, Success rates for both nonostial and ostial lesions in ASO-RAD. Technical success
for fibrous renal artery disease. Success of either PTRA or surgi- rates for surgical revascularization are high, approximating 90%,
cal renal revascularization is viewed in terms of “technical” suc- with little difference in the technical success rates between ostial
cess and “clinical” success. For PTRA, technical success reflects and nonostial lesions. For PTRA, technical success rates are much
a lumen patency with less than 50% residual stenosis (ie, suc- higher for nonostial lesions. There is a high rate of restenosis at 1
cessful establishment of a patent lumen). For surgical revascular- year (≈50% to 70%) for ostial ASO-RAD, which has promoted the
ization, technical success is the demonstration of good blood use of renal artery stents for these lesions.
flow to the revascularized kidney determined during surgery, or The success rates of surgical renal revascularization and PTRA
postoperatively by DPTA renal scan or other immediate postop- for stenosis of the main renal artery in fibrous renal artery disease
erative imaging procedures. Technical success with either PTRA are comparable, approximately 90%. Hypertension is more pre-
or surgical revascularization is rarely defined by postoperative dictably improved with surgical revascularization and PTRA in
angiography. “Clinical” success may be defined as improved fibrous renal artery disease in comparison with ASO-RAD. Technical
blood pressure or improvement in kidney function, and/or reso- success rates with surgical renal revascularization are high for
lution of flash pulmonary edema. Technical and clinical success- branch fibrous renal artery disease, but long-term technical and
es do not necessarily occur together because technical success clinical success rates are not available for PTRA of branch lesions
may be apparent, but without improvement in blood pressure due to fibrous dysplasia. NA—not available. (Adapted from Pohl
or renal function. [18]; with permission.)
Renovascular Hypertension and Ischemic Nephropathy 3.23
References
1. Pohl MA: Renal artery stenosis, renal vascular hypertension and ischemic 11. Olin JW, Melia M, Young JR, et al.: Prevalence of atherosclerotic
nephropathy. In Diseases of the Kidney, edn 6. Edited by Schrier RW, renal artery stenosis in patients with atherosclerosis elsewhere. Am J
Gottschalk CW. Boston: Little, Brown & Co; 1997: 1367–1427. Med 1990, 88:46N–51N.
2. Rimmer JM, Gennari FJ: Atherosclerotic renovascular disease and 12. Vetrovec GW, Landwehr DM, Edwards VL: Incidence of renal artery
progressive renal failure. Ann Intern Med 1993, 118:712–719. stenosis in hypertensive patients undergoing coronary angiography. J
3. Brown JJ, Davies DL, Morton JJ, et al.: Mechanism of renal hyper- Intervent Cardiol 1989, 2:69–76.
tension. Lancet 1976, 1:1219–1221. 13. Harding MB, Smith LR, Himmelstein SI, et al.: Renal artery stenosis:
4. Hoffmann U, Edwards JM, Carter S, et al.: Role of duplex scanning prevalence and associated risk factors in patients undergoing routine
for the detection of atherosclerotic renal artery disease. Kidney Int cardiac catheterization. J Am Soc Nephrol 1992, 2:1608–1616.
1991, 39:1232–1239. 14. Jacobson HR: Ischemic renal disease: an overlooked clinical entity?
5. Olin JW, Piedmonte MR, Young JR, et al.: The utility of duplex [clinical conference]. Kidney Int 1988, 34:729–743.
ultrasound scanning of the renal arteries for diagnosing significant 15. Novick AC: Patient selection for intervention to preserve renal
renal artery stenosis. Ann Intern Med 1995, 122:833–838. function in ischemic renal disease. In Renovascular Disease. Edited
6. Muller FB, Sealey JE, Case DB, et al.: The captopril test for identifying ren- by Novick AC, Scoble J, Hamilton G. London: WB Saunders;
ovascular disease in hypertensive patients. Am J Med 1986, 80:633–644. 1996:323–335.
7. Nally JV, Olin JW , Lammert MD: Advances in noninvasive screening for 16. Schreiber MJ, Pohl MA, Novick AC: The natural history of athero-
renovascular hypertension disease. Cleve Clin J Med 1994, 61:328–336. sclerotic and fibrous renal artery disease. Urol Clin North Am 1984,
8. Mann SJ, Pickering TG: Detection of renovascular hypertension: state 11:383–392.
of the art: 1992. Ann Intern Med 1992, 117:845–853. 17. Hallett JW Jr, Textor SC, Kos PB, et al.: Advanced renovascular
9. Ying CY, Tifft CP, Gavras H, Chobanian AV: Renal revascularization hypertension and renal insufficiency: trends in medical comorbidity
in the azotemic hypertensive patient resistant to therapy. N Engl J and surgical approach from 1970 to 1993. J Vasc Surg 1995,
Med 1984, 311:1070–1075. 21:750–759.
10. Novick AC, Pohl MA: Atherosclerotic renal artery occlusion extend- 18. Pohl MA: Renovascular hypertension: An internist’s point of view. In
ing into branches: successful revascularization in situ with a branched Hypertension. Edited by Punzi HA, Flamenbaum W. Mt. Kisco, NY:
saphenous vein graft. J Urol 1979, 122:240–242. Futura Publishing Co Inc; 1989:367–393.
3.24 Hypertension and the Kidney
Selected Bibliography
Goldblatt H, Lynch J, Hanzal RF, Summerville WW: Studies on experimental Mailloux LU, Napolitano B, Bellucci AG, et al.: Renal vascular disease
hypertension. I. The production of persistent elevation of systolic blood causing end-stage renal disease, incidence, clinical correlates, and
pressure by means of renal ischemia. J Exp Med 1934, 59:347–381. outcomes: a 20-year clinical experience. Am J Kidney Dis 1994,
Morris GC Jr, DeBakey ME, Cooley MJ: Surgical treatment of renal failure 24:622–639.
of renovascular origin. JAMA 1962, 182:113–116. Appel RG, Bleyer AJ, Reavis S, Hansen KJ: Renovascular disease in older
Novick AC, Ziegelbaum M, Vidt DG, et al.: Trends in surgical revascular- patients beginning renal replacement therapy. Kidney Int 1995,
ization for renal artery disease: ten years’ experience. JAMA 1987, 48:171–176.
257:498–501. Hansen KJ, Thomason RB, Craven TE, et al.: Surgical management of dialysis-
Dustan HP, Humphries AW, DeWolfe VG, et al.: Normal arterial pressure dependent ischemic nephropathy. J Vasc Surg 1995, 21:197–209.
in patients with renal arterial stenosis. JAMA 1964, 187:1028–1029. Hallett JW Jr, Fowl R, O’Brien PC, et al.: Renovascular operations in
Holley KE, Hunt JC, Brown ALJ, et al.: Renal artery stenosis: a clinical- patients with chronic renal insufficiency: do the benefits justify the
pathological study in normotensive and hypertensive patients. Am J risks? J Vasc Surg 1987, 5:622–627.
Med 1964, 34:14–22. Conlon PJ, Athirakul K, Kovalik E, et al.: Survival in renal vascular disease.
Page IH: The production of persistent arterial hypertension by cellophane J Am Soc Nephrol 1998, 9:252–256.
perinephritis. JAMA 1939, 113:2046–2048. Textor SC, McKusick MA, Schirger AA, et al.: Atherosclerotic renovascular
McCormack LJ, Poutasse EF, Meaney TF, et al.: A pathologic-arteriographic disease in patients with renal failure. Adv Nephrol Necker Hosp
correlation of renal arterial disease. Am Heart J 1966, 72:188–198. 1997, 27:281–295.
Pohl MA, Novick AC: Natural history of atherosclerotic and fibrous renal Novick AC, Straffon RA, Stewart BH, et al.: Diminished operative morbidity
artery disease: clinical implications. Am J Kidney Dis 1985, 5:A120–A130. and mortality in renal revascularization. JAMA 1981, 246:749–753.
Zierler RE, Bergelin RO, Davidson RC, et al.: A prospective study of disease Khauli RB, Novick AC, Ziegelbaum M: Splenorenal bypass in the treatment
progression in patients with atherosclerotic renal artery stenosis. of renal artery stenosis: experience with sixty-nine cases. J Vasc Surg
Am J Hypertens 1996, 9:1055–1061. 1985, 2:547–551.
Caps MT, Zierler RE, Polissar NL, et al.: Risk of atrophy in kidneys with Chibaro EA, Libertino JA, Novick AC: Use of the hepatic circulation for
atherosclerotic renal artery stenosis. Kidney Int 1998, 53:735–742. renal revascularization. Ann Surg 1984, 199:406–411.
Goncharenko V, Gerlock AJ Jr, Shaff MI, Hollifield JW: Progression of Novick AC, Stewart R: Use of the thoracic aorta for renal revascularization.
renal artery fibromuscular dysplasia in 42 patients as seen on angio- J Urol 1990, 143:77–79.
graphy. Radiology 1981, 139:45–51.
Tarazi RY, Hertzer NR, Beven EG, et al.: Simultaneous aortic reconstruction
Vaughan ED Jr, Carey RM, Ayers CR, et al.: A physiologic definition of and renal revascularization: risk factors and late results in eighty-nine
blood pressure response to renal revascularization in patients with patients. J Vasc Surg 1987, 5:707–714.
renovascular hypertension. Kidney Int 1979, 15:S83–S92.
Hollenberg NK: Medical therapy of renovascular hypertension: efficacy and
Textor SC: Renovascular hypertension. Curr Opin Nephrol Hyperten
safety of captopril in 269 patients. Cardiovasc Rev Rpts 1983, 4:852–879.
1993, 2:775–783.
Pohl MA: Medical management of renovascular hypertension. In Renal
Working Group on Renovascular Hypertension: Detection, evaluation, and
Vascular Disease. Edited by Novick AC, Scoble J, Hamilton G.
treatment of renovascular hypertension. Final report. Arch Intern Med
London: WB Saunders; 1996, 339–349.
1987, 147:820–829.
Palmaz JC, Kopp DT, Hayashi H, et al.: Normal and stenotic renal arteries:
Hughes JS, Dove HG, Gifford RW Jr, Feinstein AR: Duration of blood
Experimental balloon-expandable intraluminal stenting. Radiology
pressure elevation in accurately predicting surgical cure of renovascular
hypertension. Am Heart J 1981, 101:408–413. 1987, 164:705–708.
Svetkey LP, Himmelstein SI, Dunnick NR, et al.: Prospective analysis of Blum U, Krumme B, Flugel P, et al.: Treatment of ostial renal-artery
strategies for diagnosing renovascular hypertension. Hypertension stenoses with vascular endoprostheses after unsuccessful balloon
1989, 14:247–257. angioplasty. N Engl J Med 1997, 336:459–465.
Setaro JF, Saddler MC, Chen CC, et al.: Simplified captopril renography Harden PN, MacLeod MJ, Rodger RSC, et al.: Effect of renal-artery
in diagnosis and treatment of renal artery stenosis. Hypertension stenting on progression of renovascular renal failure. Lancet 1997,
1991, 18:289–298. 349:1133–1136.
Novick AC, Pohl MA, Schreiber M, et al.: Revascularization for preservation Fiala LA, Jackson MR, Gillespie DL, et al.: Primary stenting of atherosclerotic
of renal function in patients with atherosclerotic renovascular disease. renal artery ostial stenosis. Ann Vasc Surg 1998, 12:128–133.
J Urol 1983, 129:907–912. Canzanello VJ, Millan VG, Spiegel JE, et al.: Percutaneous transluminal
Gifford RW Jr, McCormack LJ, Poutasse EF: The atrophic kidney: its role renal angioplasty in management of atherosclerotic renovascular
in hypertension. Mayo Clin Proc 1965, 40:834–852. hypertension: results in 100 patients. Hypertension 1989,
Pickering TG, Herman L, Devereux RB, et al.: Recurrent pulmonary oedema 13:163–172.
in hypertension due to bilateral renal artery stenosis: treatment by Plouin PF, Chatellier G, Darne B, Raynaud A, for the Essai Multicentrique
angioplasty or surgical revascularisation. Lancet 1988, 2:551–552. Medicaments vs. Angioplastie (EMMA) Study Group: Blood pressure
United States Renal Data System Coordinating Center: Incidence and causes outcome of angioplasty in atherosclerotic renal artery stenosis:
of treated ESRD. In The USRDS 1994 Annual Data Report. Edited a randomized trial. Hypertension 1998, 31:823–829.
by Agodoa LYC, Held PJ, Port FK. Bethesda: USRDS Coordinating Textor SC: Revascularization in atherosclerotic renal artery disease
Center; 1994:43–54. [clinical conference]. Kidney Int 1998, 53:799–811.
Adrenal Causes of
Hypertension
Myron H. Weinberger
T
he adrenal gland is involved in the production of a variety of
steroid hormones and catecholamines that influence blood
pressure. Thus, it is not surprising that several adrenal disorders
may result in hypertension. Many of these disorders are potentially
curable or responsive to specific therapies. Therefore, identifying
adrenal disorders is an important consideration when elevated blood
pressure occurs suddenly or in a young person, is severe or difficult to
treat, or is associated with manifestations suggestive of a secondary
form of hypertension. Because these occurrences are relatively rare, it
is necessary to have a high index of suspicion and understand the
pathophysiology on which the diagnosis and treatment of these problems
is based.
Three general forms of hypertension that result from excessive produc-
tion of mineralocorticoids, glucocorticoids, or catecholamines are reviewed
in the context of their normal production, metabolism, and feedback
systems. The organization of this chapter provides the background for
understanding the normal physiology and pathophysiologic changes
on which effective screening and diagnosis of adrenal abnormalities are
based. Therapeutic options also are briefly considered. Primary aldos-
teronism, Cushing’s syndrome, and pheochromocytoma are discussed.
CHAPTER
4
4.2 Hypertension and the Kidney
Adrenal Hypertension
FIGURE 4-1
PHYSIOLOGIC MECHANISMS IN ADRENAL HYPERTENSION The causes and pathophysiologies of the
three major forms of adrenal hypertension
and the proposed mechanisms by which
Disorder Cause Pathophysiology Pressure mechanism blood pressure elevation results.
Primary aldosteronism Autonomous hypersecretion Increased renal sodium and Extracellular fluid volume
of aldosterone (hyperminer- water reabsorption, expansion, hypokalemia
alocorticoidism) increased urinary (?), alkalosis
excretion of potassium
and hydrogen ions
Cushing’s syndrome Hypersecretion of cortisol Increased activation of Extracellular fluid volume
(hyperglucocorticoidism) mineralocorticoid expansion (?), increased
receptor (?), increased angiotensin II (vasocon-
angiotensinogen (renin striction and increased
substrate) concentration peripheral resistance)
Pheochromocytoma Hypersecretion of Vasoconstriction, increased Increased peripheral
catecholamines heart rate resistance, increased
cardiac output
Medulla
CH3 CH3
C=O C=O O
–OH
O O O
Pregnenolone 17-Hydroxypregnenolone ∆4 Androstene 3,17-dione
21-Hydroxylase
OH2OH CH2OH
C=O C=O
OH
O O
11-Deoxycorticosterone 11-Deoxycortisol
11β-Hydroxylase
CH2OH CH2OH
C=O C=O
HO HO OH
O O
Corticosterone Cortisol
18-Hydroxylase
18-OH-Dehrydrogenase
CH2OH
O
HO
OHC C=O
Aldosterone
} Zona
glomerulosa
only
4.4 Hypertension and the Kidney
FIGURE 4-4
Circadian rhythmicity of steroid production and major stimulatory
factors. Aldosterone and cortisol and their respective major stimulatory
ACTH factors, plasma renin activity (PRA) and adrenocorticotropic hormone
(ACTH), demonstrate circadian rhythms. The lowest values for all of
these components are normally seen during the sleep period when the
PRA need for active steroid production is minimal. ACTH levels increase
early before awakening, stimulating cortisol production in prepara-
Aldosterone tion for the physiologic changes associated with arousal. PRA increas-
es abruptly with the assumption of the upright posture, followed by
an increase in aldosterone production and release. Both steroids
Cortisol demonstrate their highest values through the morning and early after-
noon. Cortisol levels parallel those of ACTH, with a marked decline
Morning 6 AM Noon 6 PM Morning in the afternoon and evening hours. Aldosterone demonstrates a
broader peak, reflecting the postural stimulus of PRA.
Aldosteronism
FIGURE 4-6
Types of primary aldosteronism. (Data from Weinberger and
FIGURE 4-7
coworkers [3].)
Screening tests for primary aldosteronism. Serum potassium levels
range from 3.5 to normal levels of patients with primary aldostero-
nism. Most hypertensive patients with hypokalemia have secondary
rather than primary aldosteronism. The plasma aldosterone-to-plas-
ma renin activity (PRA) ratio (disregarding units of measure) is the
most sensitive and specific single screening test for primary aldos-
teronism. However, because of laboratory variability, normal ranges
must be developed for individual laboratory values. A random
peripheral blood sample can be used to obtain this ratio even while
the patient is receiving antihypertensive medications, when the
effects of the medications on PRA and aldosterone are considered.
(Data from Weinberger and coworkers [3,4].)
FIGURE 4-8 A
Localizing tests for primary aldosteronism. Adrenal venous blood
sampling with determination of both aldosterone and cortisol FIGURE 4-9
concentrations during adrenocorticotropic hormone stimulation Normal and abnormal adrenal isotopic scans. A, Normal scan.
provides the most accurate way to identify unilateral hyperaldos- Increased bilateral uptake of I131-labeled iodo-cholesterol of nor-
teronism. This approach minimizes artefact owing to episodic mal adrenal tissue is shown above the indicated renal outlines.
steroid secretion and to permit correction for dilution of adrenal
(Continued on next page)
venous blood with comparison of values to those in the inferior
vena cava. (see Fig. 4-12). (Data from Weinberger and coworkers [3].)
4.6 Hypertension and the Kidney
FIGURE 4-10
Adrenal venography in primary aldostero-
nism. A, Typical leaflike pattern of the nor-
mal right adrenal venous drainage. B, In
contrast, marked distortion of the normal
venous anatomy by a relatively large (3-cm-
diameter) adenoma of the left adrenal.
Most solitary adenomas responsible for pri-
mary aldosteronism are smaller than 1 cm
in diameter and thus usually cannot be seen
using anatomic visualizing techniques.
A B
TH
TH
AC
AC
AC
AC
TH
TH
A A
C C
A A
C C
A A
C C
FIGURE 4-12
Adrenal venous blood sampling during infusion of adrenocortico- venous blood compared with that of the left adrenal and the inferior
tropic hormone (ACTH) [3]. A, Bilateral aldosteronism. A schematic vena cava. Even if the venous effluent cannot be accurately sampled
representation of the findings in primary aldosteronism owing to from one side (as judged by the levels of cortisol during ACTH
bilateral adrenal hyperplasia is shown on the left. When blood is infusion), when the contralateral adrenal venous effluent has an
sampled from both adrenal veins and the inferior vena cava during aldosterone-to-cortisol ratio lower than that in the inferior vena
ACTH infusion, the aldosterone-to-cortisol ratio is similar in both cava, it can be inferred that the unsampled side is the source of
adrenal effluents and higher than that in the inferior vena cava. In excessive aldosterone production (unless there is an ectopic source).
such cases, medical therapy (potassium-sparing diuretic combinations In such cases, surgical removal of the solitary adrenal lesion usually
such as hydrochlorothiazide plus triamterene, amiloride, or spiro- results in normalization of blood pressure and the attendant metabolic
lactone and calcium channel entry blockers) usually is effective. B, abnormalities. Medical therapy also is effective but often requires
Unilateral aldosteronism. On the right is depicted the findings in a high doses of Aldactone® (GD Searle & Co., Chicago) (200 to 800
patient with a unilateral right adrenal lesion. This lesion can be mg/d), which may be intolerable for some patients because of side
diagnosed by an elevated aldosterone-to-cortisol ratio in right adrenal effects. A—aldosterone; C—cortisol.
4.8 Hypertension and the Kidney
FIGURE 4-14
180
Father Glucocorticoid-remediable aldosteronism. A–C, Seen are the effects
160
of dexamethasone and spironolactone on blood pressure in a father
140 (panel A) and two sons, one aged 6 years (panel B) and the other
120 aged 8 years (panel C). Blood pressure levels are shown before and
after treatment with dexamethasone (left) or spironolactone (right) [5].
100
Note that the maximum blood pressure reduction with dexamethasone
80 required more than 2 weeks of treatment. Similarly, the maximum
mg response to spironolactone was both time- and dose-dependent.
60 200
100
A
160 Son 1
Dexamethasone Spironolactone
140
Blood pressure
120
100
80
60
200
100
B 40
160 Son 2
140
120
100
80
60 200
100
40
C 0 1 2 3 4 5 6 0 2 4 6 8
Weeks Months
Adrenal Causes of Hypertension 4.9
demonstrating that
Urinary aldosterone,
20 20
the plasma aldosterone
concentration failed to
µg/ 24 h
15 15
suppress normally after
10 10 intravenous saline infu-
Dexamethasone
sion (2 L/4 h) [6]. After
5 5 dexamethasone adminis-
tration, both plasma and
urinary aldosterone levels
A 0 1 2 3 4 5 B 0 1 2 3 4 5
decreased markedly
(except for one occasion
Plasma renin activity, ng AI/mL- 3hr
0.8 40 6
ply with dexamethasone
ng/100 mL
FIGURE 4-16
Glomerulosa Glomerulosa
Normal and chimeric aldosterone synthase
AII AII in glucocorticoid-remedial aldosteronism
Aldosterone Aldosterone Aldosterone Aldosterone (GRA). A, Normal relationship between the
stimuli and site of adrenal cortical steroid
production. Aldosterone synthase normally
Cortisol responds to angiotensin II (AII) in the zona
ACTH ACTH + glomerulosa, resulting in aldosterone synthe-
Cortisol Aldosterone
sis and release (see Figs. 4-2 and 4-3). B, In
+
18–OH cortisol
GRA, a chimeric aldosterone synthase gene
Chimeric
Aldos + results from a mutation, which stimulates
18–OXO cortisol production of aldosterone and other steroids
from the zona glomerulosa under the control
of adrenocorticotropic hormone (ACTH)
Fasciculata Fasciculata (Fig. 4-17). Thus, when ACTH production is
A B suppressed by steroid administration, aldos-
terone production is reduced.
4.10 Hypertension and the Kidney
FIGURE 4-17
11–OHase Mutation of the (11-OHase) chimeric aldosterone synthase gene
[8]. The unequal crossing over between aldosterone synthase and
11-hydroxylase genes resulting in the mutated gene responsible for
5' 3' 5' 3' glucocorticoid-remedial aldosteronism is described.
Cushing’s Syndrome
B
FIGURE 4-18 (see Color Plate)
Physical characteristics of Cushing’s syndrome. A, Side profile of a patient with Cushing’s
syndrome demonstrating an increased cervical fat pad (so-called buffalo hump), abdominal
obesity, and thin extremities and petechiae (on the wrist). The round (so-called moon)
facial appearance, plethora, and acne cannot be seen readily here. B, Violescent abdominal
striae in a patient with Cushing’s syndrome. Such striae also can be observed on the inner
A parts of the legs in some patients.
Adrenal Causes of Hypertension 4.11
Pituitary Pituitary
Pituitary CRF
(–)
(–) (–)
ACTH Cortisol
Adrenal cortex
(zona fasciculata
zona reticularis)
Adrenal cortex Adrenal cortex
(zona fasciculata (zona fasciculata
FIGURE 4-19 zona reticularis) zona reticularis)
Normal pituitary-adrenal axis. Corticotropin-
releasing factor (CRF) acts to stimulate the FIGURE 4-20 FIGURE 4-21
release of adrenocorticotropic hormone
Pituitary Cushing’s disease. Pituitary Cushing’s Adrenal Cushing’s syndrome. Adrenal
(ACTH) from the anterior pituitary. ACTH
disease results from excessive production of Cushing’s syndrome typically is caused by
then stimulates the adrenal zona fasciculata
adrenocorticotropic hormone (ACTH), typ- a solitary adrenal adenoma (rarely by carci-
and zona reticularis to synthesize and release
ically owing to a benign adenoma. Excess noma) producing excessive amounts of
cortisol (see Figs. 4-2 and 4-3). The increased
ACTH stimulates both adrenals to produce cortisol autonomously. The increased levels
levels of cortisol feed back to suppress addi-
excessive amounts of cortisol and results in of cortisol feed back to suppress release of
tional release of ACTH. As shown in Figure
bilateral adrenal hyperplasia. The increased adrenocorticotropic hormone (ACTH) and
4-4, ACTH and cortisol have circadian
cortisol production does not suppress ACTH corticotropin-releasing factor. The finding
patterns.
release, however, because the pituitary tumor of very low ACTH levels in the face of
is unresponsive to the normal feedback sup- elevated cortisol values and a loss of the
pression of increased cortisol levels. The circadian pattern of cortisol confirm the
diagnosis usually is made by demonstration diagnosis (see Fig. 4-4). Additional anatomic
of elevated levels of ACTH in the face of studies of the adrenal (computed tomographic
elevated cortisol levels, particularly in the scan and magnetic resonance imaging) usually
afternoon or evening, representing loss of disclose the source of excessive cortisol pro-
the normal circadian rhythm (see Fig. 4-4). duction. Surgical removal usually is effective.
Radiographic studies of the pituitary (com-
puted tomographic scan and magnetic reso-
nance imaging) will likely demonstrate the
source of increased ACTH production. When
the pituitary is the source, surgery and irra-
diation are therapeutic options.
4.12 Hypertension and the Kidney
(–)
FIGURE 4-23
Screening tests for Cushing’s syndrome. Whereas elevated evening
plasma cortisol levels typically indicate abnormal circadian rhythm,
other factors such as stress also can cause increased levels late in
ACTH Cortisol
the day. Urinary levels of 17-hydroxy corticosteroids may be
increased in association with obesity. In such cases, repeat measure-
ACTH ment after a period of dexamethasone suppression may be required
to distinguish this form of increased glucocorticoid excretion from
Cushing’s syndrome. The measurement of urinary-free cortisol is
the most sensitive and specific screening test.
Adrenal cortex
(zona fasciculata
zona reticularis)
FIGURE 4-22
Ectopic etiology of Cushing’s syndrome. Rarely, Cushing’s syn-
drome may be due to ectopic production of adrenocorticotropic
hormone (ACTH) from a malignant tumor, often in the lung. In
such cases, hypercortisolism is associated with increased levels of
ACTH-like peptide; however, no pituitary lesions are found.
Patients with ectopic Cushing’s syndrome often are wasted and
have other manifestations of malignancy.
Catecholamines
FIGURE 4-25
Synthesis, actions, and metabolism of catecholamines. Depicted catecholamines and their metabolites, as noted here. The kidney
is the synthesis of catecholamines in the adrenal medulla [9]. also can contribute catecholamines to the urine. The relative
Epinephrine is only produced in the adrenal and the organ of contributions of norepinephrine and epinephrine to biologic
Zuckerkandl at the aortic bifurcation. Norepinephrine and dopamine events is noted by the plus signs. BMR—basal metabolic rate;
can be produced and released at all other parts of the sympathetic CNS—central nervous system; NEFA—nonesterified fatty acids;
nervous system. The kidney is the primary site of excretion of VMA—vanillylmandelic acid.
4.14 Hypertension and the Kidney
Pheochromocytoma
240
230
220
210
200
190
180
Blood pressure, mm Hg
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
0
FIGURE 4-26
Paroxysmal blood pressure pattern in pheochromocytoma. range, episodic increases to levels of 200/140 mm Hg were
Note the extreme variability of blood pressure in this patient observed. Such paroxysms can be spontaneous or associated
with pheochromocytoma during ambulatory blood pressure with activity of many sorts. (Adapted from Manger and Gifford
monitoring [9]. Whereas most levels were within the normal [9]; with permission.)
FIGURE 4-28
Café au lait lesions
in a patient with
pheochromocytoma.
These light-brown-
colored (coffee-
with-cream-colored)
lesions, sometimes
seen in patients with
pheochromocytoma,
usually are larger
than 3 cm in the
largest dimension.
In this particular
patient, neurofibro-
mas also are present
FIGURE 4-27 (see Color Plate) and can be seen in
Neurofibroma associated with pheochromocytoma. Neurofibromas profile.
are sometimes found in patients with pheochromocytoma. These
lesions are soft, fluctuant, and nontender and can appear anywhere
on the surface of the skin. These lesions can be seen in profile in
Figure 4-28.
Adrenal Causes of Hypertension 4.15
FIGURE 4-29
DISORDERS ASSOCIATED WITH Disorders associated with pheochromocytoma. In addition to the neurofibromas and
PHEOCHROMOCYTOMA café au lait lesions depicted in Figures 4-27 and 4-28, several other associated abnormal-
ities have been reported in patients with pheochromocytoma. (From Ganguly et al. [9];
with permission.)
Cholelithiasis
Renal artery stenosis
Neurofibromas
Café au lait lesions
Multiple endocrine neoplasia, types II and III
Von Hippel-Lindau syndrome
(hemangioblastoma and angioma)
Mucosal neuromas
Medullary thyroid carcinoma
FIGURE 4-30
COMMON SYMPTOMS Common symptoms SCREENING AND DIAGNOSTIC TESTS
AND FINDINGS IN and findings in pheo- IN PHEOCHROMOCYTOMA
PHEOCHROMOCYTOMA chromocytoma. Note
that severe hyperten-
sive retinopathy, Test Sensitivity, % Specificity, %
Patients, % indicative of intense
vasoconstriction, Elevated 24-h urinary catecholamines, ≈85 ≈80
Symptoms frequently is vanillylmandelic acid, homovanillic
Severe headache 82 acid, metanephrines
observed. (Adapted
Perspiration 67 Abnormal clonidine suppression test ≈75 ≈85
from Ganguly
Palpitations, tachycardia 60 Elevated urinary “sleep” norepinephrine >99 >99
et al. [10].)
Anxiety 45
Tremulousness 38
Chest, abdominal pain 38
Nausea, vomiting 35 FIGURE 4-31
Weakness, fatigue 26 Screening and diagnostic tests in pheochromocytoma. Drugs, incom-
Weight loss 15 plete urine collection, and episodic secretion of catecholamines can
Dyspnea 15 influence the tests based on 24-hour urine collections in a patient
Warmth, heat intolerance 15 with a pheochromocytoma. The clonidine suppression test is fraught
Visual disturbances 12
with false-negative and false-positive results that are unacceptably
high for the exclusion of this potentially fatal tumor. The “sleep”
Dizziness, faintness 7
norepinephrine test eliminates the problems of incomplete 24-hour
Constipation 7
urine collection because the patient discards all urine before retiring;
Finding
saves all urine voided through the sleep period, including the first
Hypertension:
specimen on arising; and notes the elapsed (sleep) time [10]. The sleep
Sustained 61
period is typically a time of basal activity of the sympathetic nervous
Paroxysmal 24 system, except in patients with pheochromocytoma (see Fig. 4-32).
Pallor 44
Retinopathy:
Grades I and II 40
Grades III and IV 53
Abdominal mass 9
Associated multiple endocrine 6
adenomatosis
4.16 Hypertension and the Kidney
FIGURE 4-32
Nocturnal (sleep) urinary norepinephrine. The values for urinary
excretion of norepinephrine are shown for normal persons and
1000
patients with essential hypertension as mean plus or minus SD
[10]. Values for patients with pheochromocytoma are indicated by
symbols. Note that the scale is logarithmic and the highest value
for patients with normal or essential hypertension was less than 30
Patient I µg, whereas the lowest value for a patient with pheochromocytoma
Patient II
was about 75 µg. Most patients with pheochromocytomas had val-
Patient III
ues an order of magnitude higher than the highest value for
Sleep urinary norepinephrine excretion, µg
Patient IV
Patient V
patients with essential hypertension.
100 Patient VI
10 Hypertensive
Normal mean + SD
mean + SD
FIGURE 4-34
LOCALIZATION OF PHEOCHROMOCYTOMA Intravenous pyelo-
gram in pheochro-
mocytoma. Note the
Test Sensitivity, % Specificity, % displacement of the
left kidney (right) by
Abdominal plain radiograph ≈40 ≈50 a suprarenal mass.
Intravenous pyelogram ≈60 ≈75
Adrenal isotopic scan ≈85 ≈85
(meta-iodobenzoylguanidine)
Adrenal computed tomographic scan >95 >95
FIGURE 4-33
Localization of pheochromocytoma. Once the diagnosis of
pheochromocytoma has been made it is very important to localize
the tumor preoperatively so that the surgeon may remove it with a
minimum of physical manipulation. Computed tomographic scan
or MRI appears to be the most effective and safest techniques for
this purpose [10]. The patient should be treated with -adrenergic
blocking agents for 7 to 10 days before surgery so that the contracted
extracellular fluid volume can be expanded by vasodilation.
Adrenal Causes of Hypertension 4.17
A B
C D
FIGURE 4-35
A–D, Computed tomographic scans in four patients with pheochro- these four patients. Three patients have left adrenal tumors, and in
mocytoma [10]. The black arrows identify the adrenal tumor in one patient (panel B) the tumor is on the right adrenal.
A B
FIGURE 4-36 (see Color Plates)
A and B, Pathologic appearance of pheochromocytoma before tumor had gross areas of hemorrhage noted by the dark areas
(panel A) and after (panel B) sectioning. This 3.5-cm-diameter visible in the photographs.
4.18 Hypertension and the Kidney
References
1. Netter FH: Endocrine system and selected metabolic diseases. In Ciba 7: Lifton RP, Dluhy RG, Powers M: Hereditary hypertension caused by
Collection of Medical Illustrations, vol. 4; 1981:Section III, Plates 5, 26. chimeric gene duplications and ectopic expression of aldosterone syn-
2. DeGroot LJ, et al.: Endocrinology, edn 2. Philadelphia: WB Saunders; thase. Nat Genet 1992, 2:66–74.
1989:1544. 8. Lifton RP, Dluhy RG, Powers M: A glucocorticoid-remediable aldos-
3. Weinberger MH, Grim CE, Hollifield JW, et al.: Primary aldostero- terone synthase gene causes glucocorticoid-remediable aldosteronism
nism: diagnosis, localization and treatment. Ann Intern Med 1979, and human hypertension. Nature 1992, 355:262–265.
90:386–395. 9. Manger WM, Gifford RW Jr: Pheochromocytoma. New York:
4. Weinberger MH, Fineberg NS: The diagnosis of primary aldosteronism Springer-Verlag; 1977:97.
and separation of subtypes. Arch Intern Med 1993, 153:2125–2129. 10. Ganguly A, Henry DP, Yune HY, et al.: Diagnosis and localization of
5. Grim CE, Weinberger MH: Familial, dexamethasone-suppressible pheochromocytoma: detection by measurement of urinary norepineph-
normokalemic hyperaldosteronism. Pediatrics 1980, 65:597–604. rine during sleep, plasma norepinephrine concentration and computed
axial tomography (CT scan). Am J Med 1979, 67:21–26.
6. Kem DC, Weinberger MH, Mayes D, Nugent CA: Saline suppression
of plasma aldosterone and plasma renin activity in hypertension. Arch
Intern Med 1971, 128:380–386.
Insulin Resistance
and Hypertension
Theodore A. Kotchen
R
esistance to insulin-stimulated glucose uptake is associated with
increased risk for cardiovascular disease [1]. Risk factors for
cardiovascular disease tend to cluster within individuals, and
insulin resistance may be the link between hypertension and dyslipidemia.
Depending on the populations studied and methodologies used for
defining insulin resistance, approximately 25% to 40% of nonobese
nondiabetic patients with hypertension are insulin-resistant [2]. Insulin
resistance also has been observed in genetic and acquired animal models
of hypertension. A constellation of insulin resistance, reactive hyperin-
sulinemia, increased triglycerides, decreased high-density lipoprotein
cholesterol, and hypertension was designated as syndrome X by
Reaven in 1988 [3].
Although a number of putative mechanisms have been proposed, it
is unclear whether insulin resistance or reactive hyperinsulinemia, or
both, actually cause hypertension. The recent observations that insulin-
sensitizing agents attenuate the development of hypertension lend
credence to this hypothesis [4]. As discussed subsequently, however,
these agents may lower blood pressure by different mechanisms.
Whatever mechanism may be involved, the observation that a single
agent may have the capacity to both increase insulin sensitivity and
lower blood pressure is potentially of considerable clinical significance.
Non–insulin-dependent diabetes mellitus represents an extreme of
insulin resistance. Among diabetics, a two- to threefold increased
prevalence of hypertension exists. Hypertension is associated with a
fourfold increase in mortality among patients with non–insulin-depen-
dent diabetes, and antihypertensive drug therapy has a beneficial
impact on both macrovascular and microvascular disease [5]. Despite CHAPTER
the potential concern that diuretics may augment insulin resistance,
diabetic patients benefit from antihypertensive therapy with diuretics.
5
The renal protective effect of antihypertensive drugs varies among
different classes of agents. Angiotensin-converting enzyme inhibitors
decrease proteinuria and retard the progression of renal insufficiency
in diabetic patients with normal blood pressure and hypertension.
5.2 Hypertension and the Kidney
This benefit is independent of an effect on blood pressure dihydropyridine calcium antagonists accelerate the progres-
and may be related specifically to the capacity of these agents sion of diabetic nephropathy, particularly in the short term.
to dilate the efferent renal arteriole. Results of studies evalu- Additional studies are required to evaluate the antihyperten-
ating the effects of calcium antagonists on the progression of sive potential of insulin-sensitizing agents in patients with
diabetic nephropathy are varied. Some studies suggest that non–insulin-dependent diabetes.
Men Women
7.0
50–54 y
Total cholesterol, mmol/L
6.5 40–49 y
40–49 y B. NATIONAL HEALTH AND NUTRITION
EXAMINATION SURVEY II
6.0 30–39 y
30–39 y
5.5 1. Persons with blood pressure >140/90 mm Hg or taking medication for hypertension:
20–29 y 20–29 y
40% have cholesterol >240 mg/dL
5.0 2. Persons with blood cholesterol >240 mg/dL:
46% have blood pressure >140/90 mm Hg
70 80 90 100 70 80 90 100
A Diastolic blood pressure, mm Hg
FIGURE 5-1
Hyperlipidemia and hypertension. A, Epidemiologic studies docu- and Nutrition Examination Survey II, persons with hypertension
ment an association between serum cholesterol and blood pressure have a high prevalence of hyperlipidemia and vice versa [6].
in men and women. B, Based on data from the National Health (Panel A from Bonna and Thelle [7]; with permission.)
FIGURE 5-2
Epidemiologic + clinical association B. HYPERTENSION AND Insulin resistance and hypertension.
Hereditary + acquired mechanisms
INSULIN RESISTANCE A, Genetic and nutritional factors con-
tribute to insulin resistance and resultant
hyperinsulinemia. In addition to obesity
and type II diabetes, hyperlipidemia and
Glucose tolerance ↓ Type II diabetes mellitus
Insulin-resistance Obesity hypertension also may be associated with
Obesity Diabetes type II
Hyperinsulinemia insulin resistance. Insulin resistance may
Essential hypertension
Salt sensitive (?) account for the association of hyperlipi-
Experimental hypertension demia with hypertension. B, Insulin resis-
Dahl-salt-sensitive rats tance is associated with hypertension in a
Spontaneously hypertensive rats number of clinical and experimental set-
Dyslipidemia, hypertension tings. (Panel A from Ferrari and
Weidmann [8]; with permission.)
Insulin Resistance and Hypertension 5.3
Glucose, mmol/L
Plasma glucose, mg/100 mL
Insulin, pmol/L
Plasma insulin, µU/mL
FIGURE 5-5
16
Insulin sensitivity. Insulin sensitivity also
Hypertensive subjects
14 may be assessed using the euglycemic insulin
Control subjects
clamp technique. The frequency distribution
12 for insulin-mediated glucose disposal during
euglycemic insulin clamping (M value) differs
10 in persons with normal blood pressure and
those with hypertension. The percentage of
Count
FIGURE 5-6
SYNDROME X AND As originally defined, syndrome X includes hypertension, hyperinsulinemia, increased
ASSOCIATED CONDITIONS plasma triglycerides, and decreased HDL cholesterol. The syndrome also may be
associated with clustering of additional cardiovascular disease risk factors.
Hypertension
Hyperinsulinemia
Increased triglycerides
Decreased high-density lipoprotein cholesterol
Increased low-density lipoprotein cholesterol
Decreased plasminogen activator
Increased plasminogen activator inhibitor
Increased blood viscosity
Increased uric acid
Increased fibrinogen (?)
5.4 Hypertension and the Kidney
FIGURE 5-7
Obesity Nutrition Genetic predisposition Hypertension associated with insulin resis-
tance. It is unclear whether hyperinsuline-
mia associated with insulin resistance caus-
Resistance to es hypertension, although a number of
Compensatory insulin-stimulated Hyperglycemia
hyperinsulinemia Hyperlipidemia potential mechanisms have been proposed.
glucose uptake
FIGURE 5-10
Sulfonylureas Biguanides Thiazolidinediones Effects of chemically
distinct oral hypo-
R1 glycemic agents on
R1 SO2 NH C NH R2 N C NH C NH2 R1 O CH2 S O blood pressure.
R2
NH NH Sulfonylureas stimulate
O NH
endogenous insulin
C1 O secretion and do not
H 3C N
C NH CH2CH2 SO2 NH C NH N C NH C NH2 CH3CH2 CH2CH2 O CH2 S lower blood pressure.
H 3C O
O NH NH In contrast, biguanides
O NH and thiazolidinediones
increase insulin sensitivity
Glyburide Metformin Pioglitazone
without stimulating
endogenous insulin
secretion, and drugs in
these classes lower
blood pressure.
FIGURE 5-11
160
Control Pioglitazone in the treatment of hypertension in rats. A, Systolic
Pioglitazone blood pressures in Dahl-salt-sensitive rats treated with either vehicle or
Systolic blood pressure,
80
0 2 4 6 8 10 12 14 16 18 20 22
A Day
Insulin Resistance and Hypertension 5.5
FIGURE 5-13
AGENTS THAT INCREASE INSULIN SENSITIVITY, DECREASE PLASMA LIPID Agents that increase insulin sensitivity,
CONCENTRATIONS, AND LOWER BLOOD PRESSURE IN ANIMAL MODELS decrease plasma lipid concentrations, and
AND PRELIMINARY STUDIES IN HUMANS lower blood pressure in animal models and
preliminary studies in humans.
200
EFFECT OF CHOLESTEROL REDUCTION ON BLOOD PRESSURE RESPONSE
Mean arterial pressure, mm Hg
140
FIGURE 5-16
ANTIHYPERTENSIVE MECHANISMS OF Insulin-sensitizing and lipid-lowering agents may lower blood
INSULIN-SENSITIZING AGENTS pressure by a number of different mechanisms. Different agents
may act through different mechanisms.
Block agonist-induced calcium ion entry into vascular smooth muscle cells
Inhibit agonist-mediated vasoconstriction
Inhibit growth of vascular smooth muscle cells
Augment endothelium-dependent vasodilation
Direct effect
Metabolic effect
Natriuresis
Increase 20-hydroxy-eicosatetraenoic acid production
Increase renal medullary blood flow
Intracellular [Ca2+]i
* * P<0.05
0.90 250 (59)
[Ca2+]i(nM)
0.80
0.85 200
0.75
0.80 150 (286) (290)
0.70 0.65 50
0.65 0.60 0
0 100 200 300 400 500 600 700 800 0 100 200 300 400 500 600 700 800 Basal Peak Delta
A Time, s B Time, s 450
Thrombin
400 (213)
* P<0.05
350 *
FIGURE 5-17 (231)
Use of ciglitazone to abolish calcium concentration elevation. Ciglitazone, a thiazolidinedione, 300
[Ca2+]i(nM)
FIGURE 5-18
Use of metformin to attenuate intracellular
calcium concentration elevation. Metformin
is a biguanide that attenuates agonist-stimu-
lated increases of intracellular calcium con-
centrations in vascular smooth muscle. (From
Bhalla and coworkers [15]; with permission.)
Insulin Resistance and Hypertension 5.7
FIGURE 5-19
28
Effect of pioglitazone on insulin-induced proliferation of arterial
24 Insulin smooth muscle cells. Inhibition of insulin-stimulated vascular
hyperplasia and hypertrophy is one potential mechanism by which
Cell number (x104)
20 Insulin + pioglitazone
(days 0–6) insulin-sensitizing and lipid-lowering agents may decrease peripheral
16
resistance. Two kinds of evidence suggest that thiazolidinediones
12 inhibit the growth of vascular smooth muscle cells in vitro. Shown
8 Insulin + pioglitazone here, pioglitazone inhibits insulin-stimulated proliferation of vascular
smooth muscle cells. Pioglitazone also inhibits 3H-thymidine incor-
4 0.4% FCS
poration in vascular smooth muscle cells (Fig. 5-19). FCS—fetal
0 calf serum. (From Dubey and coworkers [11]; with permission.)
0 2 4 6 8 10 12 14
Days in culture
FIGURE 5-20
120
Effect of pioglitazone on 3H-thymidine incorporation in vascular smooth muscle cells.
H-Thymidine incorporation,
100 3H-thymidine incorporation is stimulated by insulin, fetal calf serum (FCS), and epidermal
of these mitogens. Similar observations have been made with pravastatin and lovastatin.
60 (From Dubey and coworkers [11]; with permission.)
40 Insulin = 1 mU/mL
20 EGF = 100 mg/mL
5% FCS
3
0
0.001 0.01 0.1 1 10 100
Pioglitazone concentration, uM
FIGURE 5-21
50 Control 50 Control Decreases in mean arterial pressure in rats treated with pioglita-
Pioglitazone Pioglitazone zone and control Dahl-salt-sensitive rats in response to graded
40 40 infusions of norepinephrine and angiotensin II. In vivo, pressor
Percent of change
Percent of change
10 10
0 0
0 100 200 300 400 500 0 100 200 300 400 500
Norepinephrine, Angiotensin II,
ng/kg/min ng/kg/min
FIGURE 5-22
3 * Half-maximal values for norepinephrine-induced contraction in aortic strips preincubated
Norepinephrine x 10–8 (log M)
with insulin, pioglitazone, or both. In vitro, pressor responsiveness of aortic strips to norep-
inephrine-induced contraction is inhibited by preincubation with insulin plus pioglitazone
2
[16]. The half-maximal value is increased for strips incubated with insulin plus pioglitazone
(ie, higher concentrations of norepinephrine are required to achieve half-maximal contraction)
1 but not in strips incubated with insulin alone or pioglitazone alone.
0
Control Insulin Pioglitazone Insulin
+
pioglitazone
5.8 Hypertension and the Kidney
FIGURE 5-23
Substance P
Acetylcholine Bradykinin Impaired endothelium-dependent vascular
Sodium P B relaxation and insulin resistance. Insulin
nitroprusside M Gq protein resistance is associated with impaired
Endothelium
Gi protein endothelium-dependent vascular relaxation,
Nitric oxide
which is a defect that may be corrected by
L-arginine synthase Nitric oxide
insulin-sensitizing agents. One approach to
EDRF-nitric oxide evaluating vascular endothelial function is
Smooth muscle
to measure vascular relaxation in response
to acetylcholine. EDRF—endothelium
derived relaxing factor.
5 20-Hydroxy-eicosotetraenoic acid
(+)
Acetylcholine x 10–7 (log M)
Control, n = 9 * P<0.05
60 + + + +
4 Clofibrate, n = 12 * Na K Ca2 Mg2
All
50
Protein, pmol/min/mg
* 2 Cl– AA bradykinin
3 R
40 Na
+ PLA vasopressin
+ +
2 * K PLC Ca2
30 20-HETE
1 20 + + 3 Na
+
K K
+
0 10 2K
* –
Control Insulin Pioglitazone Insulin Cl
+ 0
pioglitazone Cortex Outer medulla Liver
FIGURE 5-27
BENEFITS OF CONTROL OF Benefits of hypertension control and blood glucose controls are well established in diabetic
HYPERTENSION AND DIABETES patients. Noninsulin-dependent diabetes mellitus represents an extreme of insulin
resistance, and hypertension is a major contributor to the cardiovascular complications
of diabetes. Despite the potential concern that diuretics increase insulin resistance, overall
Hypertension cardiovascular disease morbidity and mortality are reduced in diabetic patients with
Decreased nephropathy hypertension by antihypertensive therapy with regimens that include diuretics.
Decreased retinopathy
Decreased stroke, myocardial infarction
Drug specific (?)
Diabetes (type I)
Decreased nephropathy
Decreased retinopathy
Decreased neuropathy
Insulin Resistance and Hypertension 5.9
FIGURE 5-28
Start of antihypertensive treatment Course of diabetic
Mean arterial blood
50 0.5
Percent doubling of baseline creatinine
FIGURE 5-30
Cumulative incidence of events in patients with diabetic nephropathy decreases proteinuria and retards the rate of progression of renal
in captopril and placebo groups. A, Time to doubling of serum cre- insufficiency. The cumulative incidence of doubling of serum creati-
atinine. B, Time to end-stage renal disease or death. In type I diabetic nine concentrations over time and development of end-stage renal
patients with nephropathy and either normal blood pressure or hyper- disease are less in patients treated with captopril than in those treat-
tension, treatment with angiotensin-converting enzyme inhibitors ed with placebo. (From Lewis and coworkers [18]; with permission.)
5.10 Hypertension and the Kidney
CHANGES OF MEAN BLOOD PRESSURE, PROTEINURIA, AND GLOMERULAR FILTRATION RATE IN TREATMENT WITH
DIFFERENT ANTIHYPERTENSIVE AGENTS IN PATIENTS WITH INSULIN-DEPENDENT DIABETES MELLITUS AND
NON–INSULIN-DEPENDENT DIABETES MELLITUS WHO HAVE MICROALBUMINURIA OR MACROALBUMINURIA
FIGURE 5-31
Despite similar control of hypertension, different classes of antihyper- diabetic nephropathy. GFR—glomerular filtration rate; MBP—mean
tensive agents have different effects on renal function in patients with blood pressure; Uprot—urine protein. (From Bretzel [19]; with permission.)
References
1. Kotchen TA, Kotchen JM, O’Shaughnessy IM: Insulin and hyperten- 11. Dubey RK, Zhang HY, Reddy SR, et al.: Pioglitazone attenuates
sive cardiovascular disease. Curr Opin Cardiol 1996, 11:483–489. hypertension and inhibits growth in renal arteriolar smooth muscle in
2. Lind L, Berne C, Lithell H: Prevalence of insulin resistance in essential rats. Am J Physiol 1993, 265:R726–R732.
hypertension. J Hypertens 1995, 17:1457–1462. 12. Roman RJ, Ma Y-H, Frohlich B, et al.: Clofibrate prevents the devel-
3. Reaven GM: Role of insulin resistance in human disease. Diabetes opment of hypertension in Dahl salt-sensitive rats. Hypertension
1993, 21:985–988.
1988, 37:1595–1607.
13. Sung BH, Izzo JL, Wilson MF: Effects of cholesterol reduction on BP
4. Kotchen TA: Attenuation of hypertension by insulin-sensitizing
response to mental stress in patients with high cholesterol. Am J
agents. Hypertension 1996, 28:219–223.
Hypertens 1997, 10:592–599.
5. Nadig V, Kotchen TA: Insulin sensitivity, blood pressure and cardio-
14. Pershadsingh H, Szollosi J, Benson S, et al.: Effects of ciglitazone on
vascular disease. Cardiol Rev 1997, 5:213–219.
blood pressure and intracellular calcium metabolism. Hypertension
6. National High Blood Pressure Education Program and National 1993, 21:1020–1023.
Cholesterol Education Program: Working Group Report on 15. Bhalla RC, Toth KF, Tan EQ, et al.: Vascular effects of metformin:
Management of Patients with Hypertension and High Blood possible mechanisms for its antihypertensive action in the sponta-
Cholesterol. National Institutes of Health Publication No. 90-2361. neously hypertensive rat. Am J Hypertens 1996, 9:570–576.
National Institutes of Health, 1990.
16. Kotchen TA, Zhang HY, Reddy S, et al.: Effect of pioglitazone on
7. Bonna KH, Thelle DJ: Association between blood pressure and serum vascular reactivity in vivo and in vitro. Am J Physiol 1996,
lipids in a population: the Tromso study. Circulation 1991, 260:R660–R666.
83:1305–1324.
17. Parving H-H, Andersen AR, Smidt UM, et al.: Effect of antihypertensive
8. Ferrari P, Weidmann P: Insulin, insulin sensitivity and hypertension. treatment on kidney function in diabetic nephropathy. Br Med J 1987,
J Hypertens 1990, 8:491–500. 294:1443–1447.
9. Ferrannini E, Buzzigoli E, Bonadonna R, et al.: Insulin resistance in 18. Lewis EJ, Hunsicker LG, Bain RP, et al.: The effect of angiotensin-
essential hypertension. N Engl J Med 1987, 317:350–357. converting-enzyme inhibition on diabetic nephropathy. N Engl J Med
10. Bigazzi R, Bianchi S, Baldari G, et al.: Clustering of cardiovascular 1993, 329:1456–1462.
risk factors in salt-sensitive patients with essential hypertension: role 19. Bretzel RG: Effects of antihypertensive drugs on renal function in patients
of insulin. Am J Hypertens 1996, 9:24–32. with diabetic nephropathy. Am J Hypertens 1997, 10:208S–217S.
The Role of Hypertension
in Progression of
Chronic Renal Disease
Lance D. Dworkin
Douglas G. Shemin
H
ypertension is a cause and consequence of chronic renal dis-
ease. Data from the United States Renal Data System
(USRDS) identifies systemic hypertension as the second most
common cause of end-stage renal disease, with diabetes mellitus being
the first. Renal failure in patients with hypertension has many causes,
including functional impairment secondary to vascular disease and
hypertensive nephrosclerosis. Even in those in whom hypertension is
not the primary process damaging the kidney, elevations in systemic
blood pressure may accelerate the rate at which kidney function is
lost. This accelerated loss of kidney function occurs particularly in
patients with glomerular diseases and clinically evident proteinuria.
Hypertension may damage the kidney by several mechanisms. Because
autoregulation of glomerular pressure is impaired in chronic renal dis-
ease, elevations in systemic blood pressure also are associated with
increased glomerular capillary pressure. Glomerular hypertension results
in increased protein filtration and endothelial damage, causing increased
release of cytokines and other soluble mediators that promote replace-
ment of normal kidney tissue by fibrosis. An important factor contribut-
ing to progressive renal disease is activation of the renin-angiotensin sys-
tem, which not only tends to increase blood pressure but also promotes
cell proliferation, inflammation, and matrix accumulation.
Numerous studies in experimental animals suggest that antihyper-
CHAPTER
tensive drugs can slow the progression of chronic renal disease. Drugs
that inhibit the renin-angiotensin system may be more effective than
6
are other agents in retarding renal disease progression.
For many reasons, the effects of angiotensin II receptor antago-
nists and angiotensin-converting enzyme (ACE) inhibitors may not
6.2 Hypertension and the Kidney
be identical. Calcium channel blockers also are beneficial in classes of calcium channel blockers have equivalent renal pro-
some settings; however, this effect is critically dependent on tective effects is uncertain.
the degree of blood pressure reduction. Patients with hypertension and chronic renal disease should
The relationship between hypertension and progression of be treated aggressively. A 24-hour urine collection determines
chronic renal disease has been examined in a number of clinical the extent of proteinuria. The patient who excretes more than
trials. Individuals with systemic hypertension are at increased 1 g/24 h of protein or who has diabetes mellitus should receive
risk for developing end-stage renal disease. The rate at which an ACE inhibitor. The target in this group of patients is to
kidney function is lost increases in patients with poorly con- reduce the blood pressure to lower than 120/80 mm Hg. Most
trolled systemic hypertension. Antihypertensive therapy can often, reaching this goal requires the use of combinations of
slow the rate of loss of kidney function in patients with diabet- antihypertensive agents, diuretics, or calcium channel blockers.
ic and nondiabetic renal disease. Studies suggest that ACE Patients who excrete less than 1 g/24 h of protein may be treated
inhibitors are particularly useful in patients with hypertension according to standard recommendations with diuretics, beta
and proteinuria of over 1g/24 h. Calcium channel blockers also blockers, ACE inhibitors, or other agents. The target blood
may slow the progression of renal disease; however, whether all pressure for this group of patients is lower than 130/85 mm Hg.
FIGURE 6-2
Typical autoregulatory response in Imaginary autoregulation curves in normal and diseased kidneys.
normal kidneys Plotted on the y-axis are renal plasma flow (RPF), glomerular
RPF, GRF, and PGC vary with filtration rate (GFR), and glomerular capillary hydraulic pressure
perfusion pressure in chronic (PGC) with undefined units. Ordinarily, RPF, GFR, and PGC remain
renal failure relatively constant over a wide range of perfusion pressures within
PGC, RPF, or GFR
FIGURE 6-3
Mechanism of autoregulation of glomerular capillary pressure in a
single glomerulus from a normal kidney. A, Baseline. B, Increased
perfusion pressure. Glomerular pressure is determined by three fac-
tors: mean arterial pressure (MAP) or perfusion pressure, and the
PGC = PGC relative resistance of both the afferent and efferent arterioles. The
initial response to an increase in MAP is an increase in afferent
arteriolar resistance (RA), preventing transmission of the elevated
systemic pressure to the glomerular capillaries. Efferent arteriolar
RE ↓RE resistance (RE) also may decline. This decrease decompresses the
MAP ↑MAP glomerulus, helping to limit the increase in glomerular capillary
RA ↑RA
hydraulic pressure (PGC), and maintains constant renal plasma flow.
Baseline Increased perfusion pressure
A B
FIGURE 6-4
Mechanism of failure of autoregulation in a glomerulus from a
damaged kidney. A, Baseline. B, Increased perfusion pressure.
To compensate for a partial loss of function, surviving glomeruli
undergo adaptive changes to increase the filtration rate. These
PGC < PGC include a reduction in afferent (RA) and efferent (RE) arteriolar
resistances, tending to increase renal plasma flow and the glomeru-
lar filtration rate. In this setting, an increase in mean arterial pres-
sure (MAP) is transmitted directly to the glomerular capillaries,
↓RE →RE resulting in glomerular capillary hypertension, increased protein
MAP ↑MAP
filtration, and hemodynamically mediated capillary injury. PGC—
↓RA ↓RA
glomerular capillary hydraulic pressure.
Baseline Increased perfusion pressure
A B
6.4 Hypertension and the Kidney
FIGURE 6-6
400 Correlation between systolic blood pressure and glomerular injury
No treatment in rats with remnant kidneys. In these rats, blood pressure was con-
350 Enalapril tinuously monitored by implanting a blood pressure sensor in the
Low dose triple therapy abdominal aorta connected telemetrically to a receiver. The time-
Glomerular injury score
FIGURE 6-7
Tension=pressure x radius The wall tension hypothesis. A, Normal. B, Chronic renal failure.
After a partial loss of kidney function, compensatory adaptations
within surviving nephrons include renal vasodilation. Vasodilation
leads to an increase in glomerular capillary pressure and compen-
satory renal growth associated with an increase in the radius of the
RGC
RGC glomerular capillaries. According to the LaPlace equation, wall ten-
PGC PGC sion in a blood vessel is equal to the product of the transmural pres-
sure and the radius of the vessel. In a surviving glomerular capillary
T of a damaged kidney, therefore, wall tension increases not only
because of the increase in glomerular pressure but also because of
T
an increase in capillary radius. Elevations in wall tension contribute
A B to progressive renal disease by damaging the endothelial and epithe-
lial cells lining the glomerular capillaries. By reducing wall tension,
maneuvers that decrease either glomerular pressure or glomerular
capillary radius are predicted to be beneficial. PGC—glomerular
capillary hydraulic pressure; RGC—glomerular capillary radius;
T—tension. (From Dworkin and Benstein [8]; with permission.)
FIGURE 6-8
Scanning electron micrographs of vascular
casts of glomeruli from normal or uni-
nephrectomized rats. A, A glomerulus from
a rat having had a sham operation, showing
a uniform capillary pattern. (Panels B–D
display casts from uninephrectomized rats.)
B, A uniform pattern with most capillaries
being approximately the same size. C and
D, Nonuniform patterns in which individual
capillary loops (indicated by asterisks) are
markedly dilated. In dilated capillary loops,
wall tension is elevated and capillary wall
A B damage is most likely to occur. The segmen-
tal nature of the capillary dilation may
explain why glomerular sclerosis that even-
tually develops in remnant kidneys is also
focal in early stages of the disease process.
(Panels A–D ≈320.) (From Nagata and
coworkers [9]; with permission.)
C D
6.6 Hypertension and the Kidney
FIGURE 6-10
120 80 Angiotensin-converting enzyme (ACE)
Mean arterial pressure, mm Hg
Glomerular injury, %
Small selective
Small selective
pores
1 pores 1
at CA=0
Fractional volume flux at CA=0
0.1 0.1
volume flux
0.01 0.01
Large nonselective
Large nonselective pores
Fractional
0.001 pores 0.001
0.0001 0.0001
0.0005 0.0005
30 40 50 60 30 40 50 60
A Effective pore radius, A B Effective pore radius, A
FIGURE 6-11
Effect of renal vein constriction on glomerular protein filtration. The constriction (open bars). Renal vein constriction causes an increase
role of angiotensin II (AII) in modulating macromolecular clearance in filtration through large nonselective pores, which accounts for
across the glomerular capillary wall has been examined by Yoshioka increased protein filtration. B, Effects of renal vein constriction
and coworkers [11]. These authors used a model of renal vein were again examined, alone (open bars) and during administration
constriction to increase glomerular pressure and markedly increase of the AII receptor antagonist saralasin (hatched bars). Saralasin
protein filtration. They calculated the volume flux through the small reduced volume flux through the large pores, indicating that
selective pores (effective pore radius, 40–50 Å) within the glomerular increased endogenous AII action was largely responsible for
capillary wall and through the large nonselective pores. A, Volume proteinuria during renal vein constriction. (From Yoshioka and
fluxes under control conditions (hatched bars) and during renal vein coworkers [11]; with permission.)
100
** * P< 0.05 vs cells treated * P<0.05 vs control medium
with A II alone ** P<0.05 vs A II medium without *
90
** P< 0.01 vs unstimulated 15 antibody
Migrated monocytes
80 controls *
**
70
fg RANTES/ 104 cells
10
60
**
50 *
* 5
40
30
20 0
m m b Ab G A II
ediu me
diu ES A TE S t Ig
m
A II
NT N goa -6 M
10 trol i- R A i-R A m a l + 1 0
Con ant ant nor EM
0 i u m+ i u m+ m +m DM
d d di u
me me me
Control A II CGP CGP+ PD PD + los los + trol A II A II
A A II A II A II B Con
FIGURE 6-13
Angiotensin II (AII) may be a proinflammatory molecule. The effect was assessed using a modified Boyden chamber. Migration of monocytes
of AII on production of the chemokine RANTES was examined in was stimulated by conditioned medium from glomerular endothelial cells
cultured glomerular endothelial cells. A, Effects of AII on secretion that were exposed to AII. This effect was blocked by incubation of the
of RANTES by cultured glomerular endothelial cells. AII markedly medium with an anti-RANTES antibody but not by control serum.
stimulated RANTES secretion. Of note is that AII-induced RANTES The anti-RANTES antibody alone was also without effect, as was AII
secretion was prevented by incubation with the AT2 receptor antag- in the absence of conditioned media. The findings are consistent with
onists SCP-42112A (CGP) or PD 1231777 (PD) but not by the AT1 the hypothesis that AII promotes glomerular inflammation by binding
receptor antagonist losartan (los). These finding suggest AT2 recep- to AT2 receptors, promoting RANTES secretion and infiltration of
tors mediate the increase in secretion of RANTES. B, Results of a inflammatory monocytes and macrophages. fg—femtograms. (From
chemotactic assay for human monocytes. Migration of monocytes Wolf and coworkers [13]; with permission.)
FIGURE 6-14
Renin-angiotensin systems
Renin-angiotensin systems. For many reasons the effects of
Angiotensinogen angiotensin-converting enzyme (ACE) inhibitors and angiotensin
II (AII) type 1 AT1 receptor antagonists on the progression of
Bradykinin chronic renal disease may not be identical. In the classic path-
Substance P Renin
Enkephalin way, renin cleaves angiotensinogen to form AI, which is further
Angiotensin I tPA cleaved by ACE to form biologically active AII. ACE inhibitors
Cathepsin G inhibit the renin-angiotensin system by reducing the activity of
CAGE
Tonin ACE and decreasing AII formation. ACE also catalyzes other
ACE Cathepsin G important pathways, however, including the breakdown of
Tonin vasodilator substances such as bradykinin, substance P, and
enkephalin. Increased levels of these substances might account
for some of the biologic effects of ACE inhibition. Levels of
Inactive Angiotensin II
fragments these substances would not increase after administration of an
AT1 receptor antagonist. In contrast, inhibition of the renin-
Other
proteases angiotensin system by ACE inhibitors may be incomplete
because other proteases may catalyze to conversion of angio-
tensinogen to AII (on the right). CAGE— chymostatin-sensitive
Angiotensin III and IV
angiotensin II–generating enzyme; t-PA—tissue plasminogen
activator. (Adapted from Dzau and coworkers [14].)
The Role of Hypertension in Progression of Chronic Renal Disease 6.9
FIGURE 6-15
Subclasses of angiotensin receptors. Another theoretic reason the
Vasoconstriction
Aldosterone AT 1 actions of angiotensin-converting enzyme (ACE) inhibitors and
Growth angiotensin II (AII) receptor antagonists may differ. All of the AII
receptor antagonists currently available for clinical use selectively block
Angiotensin II
the AT1 receptor. This receptor appears to transduce most of the well-
known effects of AII, including vasoconstriction, stimulation of cell
Clearance growth, and secretion of aldosterone. Increasingly, however, potentially
Proteases AT 2
Apoptosis important actions of other angiotensin receptors are being discovered.
For example, AT2 receptors may be involved in regulation of apoptosis
and modulation of inflammation by way of secretion of RANTES (see
Angiotensin III and IV Vasodilation AT 4 Fig. 6-13) [13,15]. AT4 receptors bind other angiotensins preferentially
and may promote endothelially mediated vasodilatation [16]. Activity
of all pathways is reduced after administration of ACE inhibitors,
whereas only AT1 receptor–mediated events are blocked by drugs cur-
rently available. Whether these differences will have important conse-
quences for progression of renal disease is currently unknown.
FIGURE 6-16
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS VERSUS Shown are results of studies comparing the
ANGIOTENSIN II ANTAGONISTS IN EXPERIMENTAL RENAL DISEASE effects of angiotensin II (AII) receptor antago-
nists and angiotensin-converting enzyme
(ACE) inhibitors on experimental renal injury.
Angiotensin II antagonists equivalent to Angiotensin II antagonists inferior to AII receptor antagonists were as effective as
angiotensin-converting enzyme inhibitors angiotensin-converting enzyme inhibitors were ACE inhibitors in the remnant kidney
model; streptozotocin-induced diabetic rats;
Remnant kidney Uninephrectomized spontaneously hypertensive rats the puromycin aminonucleoside model of
Passive Heymann nephritis Obese Zucker rats progressive glomerular sclerosis, preventing
Chronic rejection Passive Heymann nephritis interstitial fibrosis associated with obstructive
Two-kidney, one-clip hypertension uropathy; and an inherited model of glomeru-
Streptozocin-induced diabetes lar sclerosis, the Munich-Wistar Furth/Ztm
Puromycin aminonucleoside rat [17–21]. In contrast, AII receptor antago-
Obstructive uropathy nists were somewhat less effective than were
Munich-Wistar Furth/Ztm rat ACE inhibitors in several other animal mod-
els of chronic renal disease, including
uninephrectomized spontaneously hyperten-
sive rats, obese Zucker rats, and the passive
Heymann nephritis model of membranous
glomerulonephritis [22–24]. Clinical trials are
necessary to determine whether these classes
of drugs will be equally effective in preventing
progressive renal disease in humans.
FIGURE 6-17
Three calcium channel blockers and their effects in experimental ani-
MAP PGC PROT SCLER mals. The results of several studies examining the effects of three dif-
0 ferent dihydropyridine calcium channel blockers on hemodynamics
and injury in the uninephrectomized spontaneously hypertensive rat
model of progressive glomerular sclerosis are summarized. The three
Reduction, %
-20
drugs produced graded declines in mean arterial pressure (MAP),
with nifedipine causing the greatest and amlodipine the least reduc-
-40 tion in systemic pressure. Micropuncture determinations of glomeru-
lar capillary hydraulic pressure (PGC) revealed that only nifedipine
Nifedipine
Felodipine and felodipine caused glomerular pressure to decline significantly.
-60
Amlodipine These drugs reduced both the protein excretion rate (PROT) and
morphologic evidence of glomerular injury (SCLER). The data are
-80 consistent with the hypothesis that antihypertensive agents ameliorate
renal damage by reducing glomerular pressure and that, for calcium
channel blockers, significant reductions in PGC occur only when drug
administration causes a marked decline in systemic pressure. (From
Dworkin [25,26]; with permission.)
6.10 Hypertension and the Kidney
Hypertensive persons, %
Hypertensive nephrosclerosis Tubulointerstitial disease (?) 60
Adult-onset polycystic kidney disease (?)
50
40
FIGURE 6-18 30
The impact of hypertension on the incidence of end-stage renal
disease (ESRD) is vastly underestimated if one considers only 20
those patients in whom systemic hypertension is the primary
process resulting in loss of kidney function. The group of 10
patients in whom ESRD is attributed to hypertension undoubt-
edly includes persons with renal disease of several causes. Some 0
of these causes are occlusive disease of the main renal arteries as 0 10 20 30 40 50 60 70 80 90
a result of atherosclerotic disease, atheroembolic disease of the Mean GFR, mL/min/1.73m 2
FIGURE 6-20
Multifactorial mechanisms for hypertension in clinical renal disease. An increased
intravascular volume, owing to decreased renal excretion of sodium and water as the
glomerular filtration rate declines, is probably the primary cause. Activation of sympa-
thetic tone and involvement of the renin-angiotensin system, which is inappropriately
stimulated in the setting of volume expansion, have been demonstrated in renal failure.
Volume/ total body sodium Decreased activity of nitric oxide and other vasorelaxants and increased activity of
excess endothelin and other endogenous vasoconstrictors also are probably contributory.
Stimulation of Augmented
renin-angiotensin sympathetic
system tone
The Role of Hypertension in Progression of Chronic Renal Disease 6.11
100 1.0
(53)
80 (30)
Free of renal failure, %
(18)
0.8
60 (17)
Probability of survival
40 (7) 0.6 HBP before age 35 NBP after age 35
(2)
20 Normotensive (n=79)
Hypertensive (n=69)
0.4
0
0 5 10 15
Time since biopsy, y
0.2
FIGURE 6-21
Consistent relationship between hypertension and progressive 0
renal disease. Analysis of the Modification of Diet in Renal 0 10 20 30 40 50 60 70 80 90
Disease study, which involved patients with a heterogeneous mis- Age, y
cellany of renal diagnoses, showed that the degree of elevation
of the mean arterial blood pressure correlated with the decline in
the glomerular filtration rate [30]. This finding has been con- FIGURE 6-22
firmed in cohorts of patients with the same renal disease. In Relationship between hypertension and renal failure. Johnson and
immunoglobulin A (IgA) nephropathy, eg, the presence of high Gabow [32] studied over one thousand patients with autosomal domi-
blood pressure at diagnosis is a strong predictor for development nant polycystic kidney disease. These authors demonstrated that the time
of end-stage renal disease. In this study by Radford and cowork- of renal survival was much shorter for patients with hypertension com-
ers [31] of 148 patients with IgA nephropathy, 69 patients with pared with patients whose blood pressure was normal (see Fig. 6-21).
hypertension had a much higher risk of proceeding to renal fail- Renal survival was defined as the time period before the need for dialy-
ure than did the 79 patients who were normotensive. sis. HBP–high blood pressure; NBP–normal blood pressure.
FIGURE 6-23
Systolic blood pressure
Hypertension accelerates progression of renal failure in children and adults. For 2 years,
100
Wingen and coworkers [33] followed almost 200 children and adolescents with renal dis-
ease, aged 2 to 18 years. Here, renal survival is defined as stability of the creatinine clear-
ance rate. Compared with patients with systolic blood pressures lower than 120 mm Hg,
those with systolic blood pressures higher than 120 mm Hg had more rapid development
80 of renal death. Renal death was defined as a decrease in the creatinine clearance rate by
10 mL/min/1.73 m2.
Free of renal endpoints, %
P<0.001
60
40
<120 mm Hg
>120 mm Hg
0
0 1 2
Time, y
6.12 Hypertension and the Kidney
3.0 Stage 2 hypertension stage renal disease (ESRD) later in life. Even men with high-nor-
2.5
Stage 3 hypertension mal blood pressures (defined as a systolic pressure of 130 to 139
Stege 4 hypertension
mm Hg or a diastolic blood pressure of 85 to 89 mm Hg) were at
2.0 a statistically significant greater risk for ESRD than were men
1.5 with blood pressures under 120/80 mm Hg. This risk increases
sequentially with the higher stage of hypertension. This study
1.0 used definitions of hypertension discussed in the Fifth Report of
0.5 the Joint National Committee on Detection, Evaluation and
Treatment of High Blood Pressure (JNC-5). Stage I hypertension
0 is defined as a systolic pressure of 140 to 159 mm Hg and a dias-
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 tolic pressure of 90 to 99 mm Hg. Stage II hypertension is
Years since screening defined as a systolic pressure of 160 to 179 mm Hg and a dias-
tolic pressure of 100 to 109 mm Hg. Stage III hypertension is a
systolic pressure of 180 to 209 mm Hg and a diastolic pressure of
FIGURE 6-24 110 to 119 mm Hg. Stage IV hypertension is a systolic pressure
There long has been controversy over whether hypertension of 210 mm Hg or higher and a diastolic blood pressure of 120
alone, without renal disease, can cause renal failure, especially in mm Hg or greater. The highest relative risk for renal failure was
whites. Recent convincing epidemiologic evidence, however, links among persons with stage III or IV hypertension.
FIGURE 6-25
Deteriorating Deteriorating Hypertension and impact on progression of renal disease caused by
renal renal
hypertension. In a study of 94 patients with essential hypertension
function function
and an initially normal serum creatinine concentration, Rostand
Stable Stable and coworkers [35] showed that hypertension control apparently
renal 16% renal 12%
had little impact on progression of renal disease. When patients
function function
were divided into those with diastolic blood pressures higher and
lower than 90 mm Hg, the percentage whose renal function deteri-
orated was equivalent in both groups. Blacks were at especially
high risk; 23% of black patients with diastolic blood pressures
Controlled Uncontrolled below 90 mm Hg had worsened renal function over time, com-
diastolic blood pressure diastolic blood pressure pared with 11% of white patients with diastolic blood pressures
<90 min Hg <90 min Hg lower than 90 mm Hg.
FIGURE 6-26
Blood pressure
0 Lower-than-usual blood pressure (BP) target. The Modification of
Low BP group Diet in Renal Disease study [36] also prospectively examined the
Decline in GFR mL/min
Usual BP group
3 effect of a lower-than-usual BP target in a larger cohort of patients
with renal insufficiency. Patients were randomized to two target
6 BPs: a usual mean arterial pressure (MAP) target of 107 mm Hg,
corresponding to a BP of 140/90 mm Hg; or a low MAP target of
9 92 mm Hg, corresponding to a BP of 125/75 mm Hg. The changes
in the glomerular filtration rate (GFR) in the two groups over a 3-
12 year follow-up period are depicted. (The y-axis depicts the changes
in GFR, and the x-axis represents months. For example, F36 means
15 36 months after initiation of the study.) Patients in the two groups
B3 F4 F12 F20 F28 F36 had statistically equivalent declines in GFR. Over the last 6 months
Time, mo of the study, however, a trend toward greater stabilization in renal
function occurred in the group randomized to the lower target.
The Role of Hypertension in Progression of Chronic Renal Disease 6.13
FIGURE 6-27
Patients randomized to low BP target Two patient groups in the study of diet in
Patients randomized to the usual BP target renal disease. The Modification of Diet in
Renal Disease (MDRD) study involved two
Study 1 Study 2
0 0 patient groups. The group in which patients
had moderate renal dysfunction (glomerular
filtration rate [GFR] between 25 and 55
Mean rate of GFR decline, mL/min/y
Renal survival
100
1.00
90
0.95 80
Creatinine clearance, mL/min
0.90 70
0.85 60
Proteinuria: <1g/24h 50
0.80
mean BP: <107 mm Hg
40
0.75 Proteinuria: <1g/24h
mean BP: >107 mm Hg 30
0.70 Proteinuria: <1–3g/24h
20
mean BP: <107 mm Hg
0.65 Proteinuria: <1–3g/24h 10
mean BP: >107 mm Hg -12 -6 0 6 12 18 24 30 36
0.60 Group A Group B
0 6 12 18 24 30
Evolution of creatinine clearance
Time, mo
50
45
40 1.6
Percentage with doubling
Ramipril
of baseline creatinine
35
Placebo 1.4 Placebo
30
0.4
FIGURE 6-30
Large study of patients with diabetes mellitus and renal disease 0.2
randomly assigned to captopril or placebo. Lewis and coworkers
[40] have studied the use of the angiotensin-converting enzyme
0
inhibitor captopril in patients with type I diabetes mellitus who n=61 n=36 n=20
have diabetic nephropathy and proteinuria. Captopril provides
strong protection against progression of renal disease. Those Baseline urinary protein excretion, 1g/24h
patients treated with captopril had a significant decrease in pro-
teinuria and a slower rate of disease progression, as defined by
FIGURE 6-31
the time to doubling of the serum creatinine, as compared with
patients randomized to placebo. Study of patients with renal disease not associated with diabetes
randomly assigned to ramipril or placebo. A study structured simi-
larly to that in Figure 6-30 examined the use of the angiotensin-
converting enzyme inhibitor ramipril in over 150 patients with
nondiabetic renal disease [41]. The primary conclusion of the study
is summarized. Blood pressure and proteinuria decreased more sig-
nificantly in the patients treated with ramipril. This group had sig-
nificantly lower rates of decline in glomerular filtration rate (GFR)
over time. This effect was increasingly striking as the baseline level
of proteinuria increased and was most pronounced in patients with
a urinary protein excretion of over 7 g per 24 hours.
FIGURE 6-32
Favors ACE inhibitors Favors other drugs
Meta-analysis of over 1500 patients with
Reference Country Year Patients, n
renal insufficiency. A recent meta-analysis
Zucchelli et al. [43] IT 1992 121 examined randomized studies comparing
Kamper et al. [44] DEN 1992 70 an angiotensin-converting enzyme inhibitor
Brenner (Unpublished data) USA 1993 112 (ACE) to other antihypertensive agents
Toto (Unpublished data) USA 1993 124 [42]. None of the individual studies
van Essen et al. [45] HOL 1994 103 showed that the relative risk for develop-
Hannedouche et al. [46] FR 1994 100 ment of end-stage renal disease (ESRD)
Bannister et al. [47] AUS 1994 51 was statistically lower in patients treated
Himmelmann et al. [48] SW 1995 260 with ACE inhibitors. The pooled relative
Becker et al. and AUS 1996 70 risk, incorporating data from all the stud-
Ihle et al. [49,50]
ies, however, was lower in the cohort
Maschio et al. [51] EUR 1996 583
groups treated with ACE inhibitors.
Overall
Podocytes 100
Glomerular 80
Renal survival, %
basement
membrane
60
40
Dihydropyridine Non-dihydropyridine
calcium channel blockers calcium channel blockers
FIGURE 6-34
Nifedipine Diltiazem The effect of calcium channel blockers on preservation of renal func-
Amlodipine Verapamil tion. Most studies of angiotensin-converting enzyme (ACE) inhibitors
Felodipine versus other agents did not examine calcium channel blockers. In a
Isradipine
Nisolodipine paper by Zucchelli and coworkers [43], patients with nondiabetic
renal diseases and hypertension initially were treated with adrenergic
antagonists, diuretics, and vasodilators. These patients were then ran-
domized to treatment with the dihydropyridine calcium entry antago-
FIGURE 6-33 nist nifedipine or to the ACE inhibitor enalapril. The rate of decline
Calcium channel blockers. Calcium channel blockers are prescribed in renal function was most rapid in the pre-randomization phase in
widely to patients with normal renal function and affect renal pro- patients treated with conventional antihypertensive agents, mostly
tein excretion variably. The general consensus is that the nondihy- adrenergic antagonists. The rate of decline then slowed after random-
dropyridine calcium channel blockers diltiazem and verapamil ization. No significant difference in rates of decline was seen in
decrease proteinuria, whereas the dihydropyridine agents have min- patients treated with nifedipine compared with those treated with
imal or minor effects on proteinuria. captopril. (From Zucchelli and coworkers [43]; with permission.)
FIGURE 6-35
The effect of angiotensin-converting
enzyme inhibitors and other antihyperten-
sive agents on stabilization of renal func-
tion in non–insulin-dependent diabetes.
60
Bakris and coworkers [52] studied patients
Creatinine clearance, mL/min/1.73 m2
FIGURE 6-36
120
Race and ethnicity in choice of antihypertensive agents. Racial and
ethnic differences also may be important in determining the choice
115
of antihypertensive agent to delay progression of chronic renal dis-
110 ease. Blacks are at much higher risk than are whites for progres-
sion of renal disease. In addition, a more aggressive antihyperten-
Mean BP, mm Hg
If hyperkalemia or acute renal failure Treatment with ACE inhibitor Treatment with diuretic,
develops, evaluate possible causes Target blood pressure: ACE inhibitor, or
125/75 mm Hg or lower calcium channel
If no other precipitant, decrease ACE inhibitor dose
blocker
Add diuretic, calcium channel blocker
A B
FIGURE 6-37
Treatment of patients with renal disease and high-normal or elevated B, When protein excretion is less than 1 g/24 h, the blood pres-
blood pressure (BP). A, All patients should have a measurement of sure should be lowered to at least 130/85 mm Hg. No conclusive
24-hour protein excretion. If the protein excretion is over 1 g/24 h, an evidence exists to support the use of one antihypertensive agent
angiotensin-converting enzyme (ACE) inhibitor should be started. The or class of agents over another. However, in patients at risk for
goal of hypertension control in patients with azotemia who have mas- progressive proteinuria (eg, diabetic patients with microalbumin-
sive proteinuria should be a blood pressure of 125/75 mm Hg or lower. uria), ACE inhibitors should be used. Given the importance of
It is unlikely that an ACE inhibitor alone will be able to decrease the sodium retention in the hypertension in renal disease, a loop
blood pressure to this level before hyperkalemia or hemodynamically or thiazide diuretic is a reasonable initial treatment. An ACE
mediated acute renal failure intervenes. A diuretic and medications from inhibitor or calcium channel blocker should be added as a
other classes, such as a calcium channel blocker, should then be added. second-line agent.
The Role of Hypertension in Progression of Chronic Renal Disease 6.17
References
1. Dworkin LD, Grosser M, Feiner HD, et al.: Renal vascular effects of 21. Remuzzi A, Malanchini B, Battaglia C, et al.: Comparison of the
antihypertensive therapy in uninephrectomized spontaneously hyper- effects of angiotensin-converting enzyme inhibition and angiotensin II
tensive rats. Kidney Int 1989, 35:790–798. receptor blockade on the evolution of spontaneous glomerular injury
2. Anderson S, Meyer T, Rennke HG, Brenner BM: Control of glomeru- in male MWF/Ztm rats. Experimental Nephrol 1996, 4:19–25.
lar hypertension limits glomerular injury in rats with reduced renal 22. Anderson AE, Tolbert EM, Esparza AR, Dworkin LD: Effects of an
mass. J Clin Invest 1985, 76:612–619. ACE inhibitor vs. an AII antagonist on hemodynamics, growth and
3. Kakinuma Y, Kawamura T, Bills T, et al.: Blood pressure indepen- injury in spontaneously hypertensive rats. J Am Soc Nephrol 1996,
dent effect of angiotensin inhibition on the glomerular and non- 7:A3014.
glomerular vascular lesions of chronic renal failure. Kidney Int 23. Crary GS, Swan SK, O’Donnell MP, et al.: The angiotensin II receptor
1996, 42: 46–55. antagonist losartan reduces blood pressure but not renal injury in
4. Dworkin LD, Feiner HD, Randazzo J: Glomerular hypertension and obese Zucker rats. J Am Soc Nephrol 1995, 6:1295–1299.
injury in desoxycorticosterone-salt rats on antihypertensive therapy. 24. Hutchinson FN, Webster SK: Effect of ANGII receptor antagonist on
Kidney Int 1987, 31:718–724. albuminuria and renal function in passive Heymann nephritis. Am J
5. Neugarten J, Kaminetsky B, Feiner H, et al.: Nephrotoxic serum Physiol 1992, 263:F311–F318.
nephritis with hypertension: amelioration by antihypertensive therapy. 25. Dworkin LD, Feiner HD, Parker M, Tolbert E: Effects of nifedipine
Kidney Int 1985, 28:135–139. and enalapril on glomerular structure and function in uninephrec-
6. Weir MR, Dworkin LD: Antihypertensive drugs, dietary salt and renal tomized spontaneously hypertensive rats. Kidney Int 1991,
protection: How low should you go and with which therapy. Am J 39:1112–1117.
Kidney Dis 1998, 32:1–22. 26. Dworkin LD, Tolbert E, Recht PA, et al.: Effects of amlodipine on
7. Griffen KA, Picken M, Bidani AK: Radiotelemetric BP monitoring, glomerular filtration, growth, and injury in experimental hyperten-
antihypertensives and glomeruloprotection in remnant kidney model. sion. Hypertension 1996, 27:245–250.
Kidney Int 1994, 46:1010–1018. 27. Breyer JA, Bain RP, Evans JK, et al.: Predictors of the progression
8. Dworkin LD, Benstein JA: Antihypertensive agents, glomerular hemo- of renal insufficiency in patients with insulin-dependent diabetes and
dynamics and glomerular injury. In Calcium Antagonists and the overt diabetic nephropathy. Kidney Int 1996, 50:1651–1658.
Kidney. Edited by Epstein M, Loutzenhiser R. Philadelphia, Hanley & 28. Gisen Group: Randomized placebo-controlled trial of effect of
Belfus; 1990:155–176. ramipril on decline in glomerular filtration rate and risk of terminal
9. Nagata M, Scharer K, Kriz W: Glomerular damage after uninephrec- renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997,
tomy in young rats. I. Hypertrophy and distortion of the capillary 349:1857–1863.
architecture. Kidney Int 1992, 42:136–147. 29. Klahr S, Levey AS, Beck GJ, et al.: The effects of dietary protein
10. Anderson S, Rennke HG, Brenner BM: Therapeutic advantage of con- restriction and blood-pressure control on the progression of chronic
verting enzyme inhibitors in arresting progressive renal disease associ- renal disease. Modification of Diet in Renal Disease Study Group.
ated with systemic hypertension. J Clin Invest 1986, 77:1993–2000. N Engl J Med 1994, 330:877–884.
11. Yoshioka T, Mitarai T, Kon V, et al.: Role for angiotensin II in an 30. Modification of Diet in Renal Disease Study Group: Predictors of the
overt functional proteinuria. Kidney Int 1986, 30:538–545. progression of renal disease in the modification of diet in renal disease
study. Kidney Int 1997, 51:1908–1919.
12. Lee LK, Meyer TM, Pollock AS, Lovett DH: Endothelial cell injury
initiates glomerular sclerosis in the rat remnant kidney. J Clin Invest 31. Radford MG, Donadio JV, Bergstralh EJ, Grande JP: Predicting renal
1995, 96:953–964. outcome in IgA nephropathy. J Am Soc Nephrol 1997, 8199–207.
13. Wolf G, Ziyadeh FN, Thaiss F, et al.: Angiotensin II stimulates expres- 32. Johnson AM, Gabow PA: Identification of patients with autosomal
sion of the chemokine RANTES in rat glomerular endothelial cells. dominant polycystic kidney disease at highest risk for end-stage kid-
J Clin Invest 1997, 100:1047–1058. ney disease. J Am Soc Nephrol 1997, 8:1560–1567.
14. Dzau VJ, Sasamura H, Hein L: Heterogeneity of angiotensin synthetic 33. Wingen A-M, Fabian-Bach C, Shaefer F, Mehls O for the European
pathways and receptor subtypes: physiological and pharmacological Study Group for Nutritional Treatment of Chronic Renal Failure in
implications. J Hypertension 1993, 11(suppl 3):S13–S18. Childhood. Lancet 1997, 349:1117–1123.
15. Yamada T, Horiuchi M, Dzau VJ: Angiotensin II type 2 receptor 34. Klag MJ, Whelton PK, Randall BL, et al.: Blood pressure and end-
mediates programmed cell death. Proc Natl Acad Sci U S A 1996, stage renal disease in men. N Engl J Med 1996, 334:13–18.
93:156–160. 35. Rostand SG, Brown G, Kirk KA, et al.: Renal insufficiency in treated
16. Pörsti I, Bara AT, Busse R, Hecker M: Release of nitric oxide by essential hypertension. N Engl J Med 1989, 320:684–688.
angiotensin (1-7) from porcine coronary endothelium: implications for 36. Klahr S, Levey A, Beck GJ, et al. for the Modification of Diet in Renal
a novel angiotensin receptor. Br J Pharmacol 1994, 111:652–654. Disease Study Group. N Engl J Med 1994, 330:877–884.
17. Lafayette RA, Mayer G, Park SK, Meyer TM: Angiotensin II receptor 37. Peterson JC, Adler S, Burkart JM, et al. for the Modification of Diet
blockade limits glomerular injury in rats with reduced renal mass. in Renal Disease Study Group. Ann Intern Med 1995, 123:754–762.
J Clin Invest 1992, 90:766–771. 38. Locatelli F, Marcelli D, Comelli M, et al. for the Northern Italian
18. Remuzzi A, Perico N, Amuchastegui CS, et al.: Short- and long-term Cooperative Study Group: proteinuria and blood pressure as causal
effect of angiotensin II receptor blockade in rats with experimental components of progression to end-stage renal failure. Nephrol Dial
diabetes. J Am Soc Nephrol 1993, 4:40–49. Transplant 1996, 11:461–467.
19. Tanaka R, Kon V, Yoshioka T, et al.: Angiotensin converting enzyme 39. Praga M, Hernandez E, Montoyo C, et al.: Long-term beneficial
inhibitor modulates glomerular function and structure by distinct effects of angiotensin-converting enzyme inhibition in patients with
mechanisms. Kidney Int 1994, 45:537–543. nephrotic proteinuria. Am J Kidney Dis 1992, 20:240–248.
20. Ishidoya S, Morrissey J, McCracken R, et al.: Angiotensin receptor 40. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD for the Collaborative
antagonist ameliorates renal tubulointerstitial fibrosis caused by uni- Study Group: The effect of angiotensin-converting enzyme inhibition
lateral ureteral obstruction. Kidney Int 1995, 47:1285–1294. on diabetic nephropathy. N Engl J Med 1993, 329:1456–1462.
6.18 Hypertension and the Kidney
41. Gruppo Italiano di Studi Epidemiologici in Nefrologia: Randomised 48. Himmelmann A, Hansson L, Hannson BG, et al.: ACE inhibition
placebo-controlled trial of effect of ramipril on decline in glomerular preserves renal function better than beta-blockers in the treatment
filtration rate and risk of renal failure in proteinuric, non-diabetic of essential hypertension. Blood Pressure 1995, 4:85–90.
nephropathy. Lancet 1997, 349:1857–1863. 49. Becker GJ, Whitworth JA, Ihle BU, et al.: Prevention of progression
42. Giatras I, Lau J, Levey AS for the Angiotensin-Converting Enzyme in non-diabetic chronic renal failure. Kidney Int Suppl 1994,
Inhibition and Progressive Renal Disease Study Group: Effect of 45:S167–S170.
angiotensin-converting enzyme inhibitors on the progression of nondi- 50. Ihle BU, Whitworth JA, Shahinfar S, et al.: Angiotensin-converting
abetic renal disease: a meta-analysis of randomized trials. Ann Intern enzyme inhibition in nondiabetic progressive renal insufficiency: a
Med 1997, 127:337–345. controlled double-blind trial. Am J Kidney Dis 1996, 27:489–495.
43. Zucchelli P, Zuccala A, Borghi M, et al.: Long-term comparison 51. Maschio G, Aliberti D, Janin G, et al.: Effect of the angiotensin-
between captopril and nifedipine in the progression of renal insuffi- converting enzyme inhibitor benazepril on the progression of renal
ciency. Kidney Int 1992, 42:452–458. insufficiency. N Engl J Med 1996, 334:939–945.
44. Kamper AI, Strandgaard S, Leyssac PP: Effect of enalapril on the 52. Bakris GL, Copley JB, Vicknair N, et al.: Calcium channel blockers
progression of chronic renal failure: a randomized controlled trial. versus other antihypertensive therapies on progression of NIDDM
Am J Hypertens 1992, 5:423–430. associated nephropathy. Kidney Int 1996, 50:1641–1650.
45. van Essen GG, Apperloo AJ, Sluiter WJ, et al.: Is ACE inhibition 53. Materson BJ, Reda DJ, Cushman WC, et al.: Single-drug therapy for
superior to conventional antihypertensive therapy in retarding progres- hypertensive men: a comparison of six antihypertensive agents with
sion in non-diabetic renal disease? J Am Soc Nephrol 1996, 7:1400. placebo. N Engl J Med 1993, 328:914–921.
46. Hannedouche T, Landais P, Goldfarb B, et al.: Randomized controlled 54. Hall WD, Kusek JW, Kirk KA, et al. for the African-American Study
trial of enalapril and beta-blockers in non-diabetic chronic renal of Kidney Disease and Hypertension Pilot Study Investigators. Am J
failure. BMJ 1994, 309:833–837. Kidney Dis 1997, 29:720–728.
47. Bannister KM, Weaver A, Clarkson AR, Woodroffe AJ: Effect of
angiotensin-converting enzyme and calcium channel inhibition on
progression of IgA nephropathy. Contrib Nephrol 1995, 111:184–193.
Pharmacologic Treatment
of Hypertension
Garry P. Reams
John H. Bauer
T
his chapter reviews the currently available classes of drugs used
in the treatment of hypertension. To best appreciate the com-
plexity of selecting an antihypertensive agent, an understanding
of the pathophysiology of hypertension and the pharmacology of the
various drug classes used to treat it is required. A thorough under-
standing of these mechanisms is necessary to appreciate more fully the
workings of specific antihypertensive agents. Among the factors that
modulate high blood pressure, there is considerable overlap. The drug
treatment of hypertension takes advantage of these integrated mecha-
nisms to alter favorably the hemodynamic pattern associated with
high blood pressure.
CHAPTER
7
7.2 Hypertension and the Kidney
Pathogenesis of Hypertension
Pathogenesis of hypertension
Autoregulation
FIGURE 7-1
Pathogenesis of hypertension. Mean arterial pressure (MAP) is the (PVR). There are a large number of control mechanisms involved
product of cardiac output (CO) and peripheral vascular resistance in every type of hypertension. (From Kaplan [1]; with permission.)
FIGURE 7-2
Blood pressure changes and diet. Many hypertensive patients appear to be sodium sensitive,
as first suggested by studies in 19 hypertensive subjects who were observed after “normal”
(109 mmol/d), “low” (9 mmol/d), and “high” (249 mmol/d) sodium intake [2]. This figure
shows the percent increase in mean blood pressure in salt-sensitive (SS) and non–salt-sensi-
20 tive (NSS) patients with hypertension when their diet was changed from low sodium to
high sodium. Vertical lines indicate mean ± standard deviation. (From Kawasaki et al. [2];
Increase, %
with permission.)
10
0
SS NSS
Mean arterial pressure
Pharmacologic Treatment of Hypertension 7.3
FIGURE 7-3
Cardiac output. An increase in cardiac output has been suggested
Extracellular fluid
20 33 %
as a mechanism for hypertension, particularly in its early border-
volume, L
19
18 line phase [3,4]. Sodium and water retention have been theorized
17 to be the initiating events. Sequential changes following salt load-
16 4%
ing are depicted [3]. The resultant high cardiac output perfuses the
15
peripheral tissues in excess of their metabolic requirements, result-
ing in a normal autoregulatory (vasoconstrictor) pressure. The
Blood volume,
20 %
6.0 early phase of high cardiac output and normal peripheral vascular
resistance gradually changes to the characteristic feature of the
L
5.5 5%
sustained hypertensive state: normal cardiac output and high
5.0 peripheral vascular resistance. Shown here are segmental changes
in the important cardiovascular hemodynamic variables in the first
Pressure gradient Mean circulatory
filling pressure,
60 %
16 few weeks following the onset of short-term salt-loading hyperten-
mm Hg
14
20 %
sion. Note especially that the arterial pressure increases ahead of
12 the increase in total peripheral resistance. (From Guyton and
10 coworkers [3]; with permission.)
35 %
return, mm Hg
13
for venous
12
11 44 %
10
70 40 %
Cardiac output,
65
L/min
60
55 5%
50
40
Total peripheral
mm Hg/L/min
35 38 %
resistance,
30
25
20
–11 %
15
140 45 %
130
mm Hg
120 22.5 %
110
100
0 4 8 12 16
Days
7.4 Hypertension and the Kidney
4000
200
HR beats min–1
3000
180
100 2000
160
BP, mm Hg
60 1000
140 MAP
70 10
SI mL stroke–1 m–2
120
CI L min–1 m–2
DAP 50
5
100
30
FIGURE 7-4
Peripheral vascular resistance. Most established cases of hypertension dashed line indicates results after 10 years; dotted line indicates results
are associated with an increase in peripheral vascular resistance [5]. after 20 years. BP—blood pressure; CI—cardiac index; DAP—diastolic
These alterations may be related to a functional constriction, the arterial blood pressure; HR—heart rate; MAP—mean arterial pressure;
type observed under the influence of circulating or tissue-generated SAP—systolic arterial blood pressure; SI—stroke index; TPRI—total
vasoconstrictors, or may be a result of structural alterations in the peripheral resistance index; VO2—oxygen consumption. (From Lund-
blood vessel. Solid line indicates values at start of the study [9]; Johansen [5]; with permission.)
Pharmacologic Treatment of Hypertension 7.5
FIGURE 7-6
Hemodynamic response to diuretics. Diuretics reduce mean arterial
BP pressure by their initial natriuretic effect [6]. Acutely, this is achieved
by a reduction in cardiac output mediated by a reduction in plasma
and extracellular fluid volumes [7]. Initially, peripheral vascular
resistance is increased, mediated in part by stimulation of the renin-
PV
angiotensin system. During sustained diuretic therapy, cardiac output
returns to pretreatment levels, probably reflecting restoration of
ISF plasma volume. Chronic blood pressure control now correlates with
a reduction in peripheral vascular resistance. BP—blood pressure;
CO CO—cardiac output; ISF—interstitial fluid; PRA—plasma renin
CO activity; PV—plasma volume; Rx—treatment; TPR—total peripheral
TPR TPR resistance. (Adapted from Tarazi [7].)
Rx No Rx
PRA
Time
7.6 Hypertension and the Kidney
Generic (trade) name First dose, mg Usual dose Maximum dose Duration of action, h
Hydrochlorothiazide (G) 12.5 12.5–50 mg QD 100 6–12
(Hydrodiuril, Microzide)
Chlorthalidone (G) 12.5 12.5–50 mg QD 100 48–72
(Hygroton)
Indapamide 1.25 2.5–5.0 mg 5 15–18
(Lozol)
Metolazone
(Mykrox)*; 0.5 0.5–1.0 1 12–24
(Zaroxolyn) 2.5 2.5–10 mg QD 20 12–24
B. DIURETICS: LOOP
Generic (trade) name First dose, mg Usual dose Maximum dose Duration of action, h
Bumetanide (G) 0.5 0.5–2 mg bid 10 4–6
(Bumex)
Ethacrynic Acid 25 25–50 mg bid 200 6–8
(Edecrin)
Furosemide (G) 20 20–120 mg bid 600 6–8
(Lasix)
Torsemide 5 5–50 mg bid 100 6–8
(Demadex)
(G)—generic available.
Generic (trade) name First dose, mg Usual dose Maximum dose Duration of action, h
Spironolactone (G) 25 50–1 00 mg QD 400 48–72
(Aldactone)
Amiloride (G) 5 5–10 mg QD 20 24
(Midamor)
Triamterene (G) 50 50-100 mg bid 300 7–9
(Dyrenium)
(G)—generic available.
FIGURE 7-7
A–C. Diuretics: benzothiadiazides and related agents, loop diuretics, diuretics. Because of their steep dose-response curves and natri-
and potassium-sparing agents. A partial list of benzothiadiazides uretic potency, they are especially useful when the glomerular
and their related agents is given [6]. With the exception of inda- filtration rate is less than 30 mL/min/1.73 m2. The third group
pamide and metolazone, their dose-response curves are shallow; is the potassium-sparing diuretics. The major therapeutic use of
they should not be used when the glomerular filtration rate is these drugs is to attenuate the loss of potassium induced by the
less than 30 mL/min/1.73 m2. The second group listed is loop other diuretics.
Pharmacologic Treatment of Hypertension 7.7
DCT PC
PT
DT
Lumen Blood
HCO3 Na 3Na
~ Lumen Blood
H 2K
HCO3
H2CO3
H2CO3
CAI CA Loop Na 3Na
CA CAI diuretics K ~
H2O + CO2 2Cl 2K
H2O + CO2
CD
PT
TAL
LH
FIGURE 7-8
Mechanisms of action of diuretics. This figure depicts the The diuretic/natriuretic action of potassium-sparing diuretics is
major sites and mechanisms of action of diuretic drugs [8]. predicated on their gaining access to the luminal side of the principal
The diuretic/natriuretic action of benzothiadiazide-type diuretics cells located in the late distal tubule and cortical collecting duct and
is predicated on their gaining access to the luminal side of the blocking luminal sodium channels. Because Na+ uptake is blocked,
distal convoluted tubule and inhibiting Na+ - Cl- cotransport the lumen negative voltage is reduced, inhibiting K+ secretion. The
by competing for the chloride site. potassium-sparing diuretic spironolactone does this indirectly by
The diuretic/natriuretic action of loop diuretics is competing with aldosterone for its cytosolic receptor. CA—carbonic
predicated on their gaining access to the luminal side of anhydrase; CAI—carbonic anhydrase inhibitor; CD—collecting duct;
the thick ascending limb of the loop of Henle and inhibiting DCT—distal convoluted tubule; DT—distal tubule; LH—loop of
Na+ - K+ -2Cl- electroneutral cotransport by competing for Henle; PC—principal cell; PT—proximal tubule; TAL—thick ascend-
the chloride site. ing limb. (From Ellison [8]; with permission.)
7.8 Hypertension and the Kidney
FIGURE 7-9
THE SIDE EFFECT PROFILE OF DIURETIC THERAPY The side effect profile of diuretic therapy.
The complications of diuretic therapy are
typically related to dose and duration of
Side effects Mechanisms therapy, and they decrease with lower
dosages. This table lists the most common
Thiazide-type diuretic side effects of diuretics and their proposed
Azotemia Enhanced proximal fluid and urea reabsorption secondary mechanism of action [6].
to volume depletion
Hypochloremia, hypokalemia, metabolic alkalosis Increased delivery of sodium to distal tubule facilitating Na+-
K+ and Na+-H+ exchange; increased net acid excretion;
increased urinary flow rate; secondary aldosteronism
Hypomagnesemia Increase fractional Mg2+ excretion by inhibiting reabsorp-
tion in ascending limb of loop of Henle
Hyponatremia Impaired free water clearance
(distal cortical diluting segment)
Hypercalcemia May reflect an increased protein-bound fraction secondary
to volume depletion
Hyperuricemia Impair enhanced proximal fluid and urate reabsorption
secondary to volume depletion
Carbohydrate intolerance Hypokalemia impairing insulin secretion; decreased
insulin sensitivity
Hyperlipidemia
Increased total triglyceride May be due to extracellular fluid depletion
Increased total cholesterol
Loop-type diuretics
Ototoxicity High plasma concentration of furosemide or
ethacrynic acid
Hypocalcemia Increase fractional excretion of calcium by interfering with
reabsorption in loop of Henle
Potassium-sparing diuretics
Hyperkalemia Blocks potassium excretion
Decreased sexual function, gynecomastia, menstrual Spironolactone only; lower circulatory testosterone levels
irregularity, hirsutism by increasing metabolic clearance and/or preventing
compensatory rise in testicular androgen production
Renal stone Triamterene only
Pharmacologic Treatment of Hypertension 7.9
FIGURE 7-10
Adrenal gland
-adrenergic antagonists. -adrenergic antagonists attenuate sym-
pathetic activity through competitive antagonism of catecholamines
at both 1- and 2-adrenergic receptors [6,9]. In the absence of
partial agonist activity (PAA), the acute systemic hemodynamic
effects are a decrease in heart rate and cardiac output and an increase
Heart ↓ CO in peripheral vascular resistance proportional to the degree of cardio-
β1 depression; blood pressure is unchanged. Chronically, there is a gradual
Kidney decrease in blood pressure proportional to the fall in peripheral
β-blockers
Effector cell
E vascular resistance, which is dependent on the degree of cardiac
BP sympathetic drive. -adrenergic antagonists with sufficient partial
NE
agonist activity to maintain heart rate and cardiac output may not
β2 evoke acute reflex vasoconstriction: Blood pressure falls propor-
Blood
vessels ↑ TPR
tional to the decrease in peripheral resistance (see Fig. 7-11) [10].
+ BP—blood pressure; CO—cardiac output; E—epinephrine; NE—
NE
norepinephrine; TPR—total peripheral resistance.
Sympathetic
neuron
FIGURE 7-11
100 Hemodynamic changes associated with -adrenergic blockade. Time course of hemody-
MAP, %
namic changes after treatment with a -adrenergic blocker devoid of partial agonist activ-
90
ity (PAA) (solid line) as compared with hemodynamic changes after administration of a
80 -adrenergic blocker with sufficient PAA to replace basal sympathetic tone (eg, pindolol)
(broken line). MAP—mean arterial pressure. (From Man in’t Veld and Schalekamp [10];
Cardiac output, %
80
130
120
Vascular resistance, %
110
100
90
80
Generic (trade) name First dose, mg Usual daily dose, mg Maximum daily dose, mg Duration of action, h
Nadolol (G) 40 40–240 QD 320 >24
(Corgard)
Propranolol (G)
(Inderal) 40 40–120 bid 480 >12
(Inderal LA) 80 80–240 QD 480 >12
Timolol (G)
(Blockadren) 10 10–30 bid 60 >12
G—generic available.
Generic (trade) name First dose, mg Usual daily dose, mg Maximum daily dose, mg Duration of action, h
Pindolol (G) 5 10–30 bid 60 12
(Visken)
Carteolol 2.5 2.5–10 QD 10 24
(Cartrol)
Penbutolol 10 10–20 QD 40 24
(Levatol)
G—generic available.
Generic (trade) name First dose, mg Usual daily dose, mg Maximum daily dose, mg Duration of action, h
Atenolol (G) 50 50–100 QD 200 24
(Tenormin)
Metoprolol Tartrate (G) 50 50–150 bid 400 12
(Lopressor)
Metoprolol Succinate 50 100–300 QD 400 12
(Toprol-XL)
Betaxolol 5 10–20 QD 40 >24
(Kerlone)
Bisoprolol 5 5–20 QD 40 12
(Zebeta)
G—generic available.
FIGURE 7-12
Dosing schedules for -adrenergic antagonists. A, Nonselective - -adrenergic antagonists with partial agonist activity. C, 1-selective
adrenergic antagonists that lack partial agonist activity. B, Nonselective adrenergic antagonists that lack partial agonist activity.
(Continued on next page)
Pharmacologic Treatment of Hypertension 7.11
Generic (trade) name First dose, mg Usual daily dose, mg Maximum daily dose, mg Duration of action, h
Acebutolol 200 400–800 QD 1200 24
(Sectrol)
Generic (trade) name First dose, mg Usual daily dose, mg Maximum daily dose, mg Duration of action, h
Labetalol (G) 100 100-600 bid 2400 12
(Normodyne)
(Trandate)
Carvedilol 6.25 6.25-25 bid 50 6
(Coreg)
G—generic available.
FIGURE 7-13
Pharmacokinetics of -adrenergic antagonists.
FIGURE 7-14
THE SIDE EFFECT PROFILE OF -ADRENERGIC ANTAGONISTS The side effect profile of -adrenergic
antagonists. The side effect profile of beta-
blockers is related to the specific blockade
Side effects Mechanisms of 1 or 2 receptors. This table lists the
more common side effects and their pro-
Bronchospasm Blockade of 2-adrenergic receptors; increased airway resistance posed mechanism(s) of action [6,9].
Bradycardia Blockade of atrial 1/2-adrenergic receptors; decrease in heart rate
Congestive heart failure; decrease in Blockade of ventricular 1-adrenergic receptors
exercise tolerance
Claudication Blockade of peripheral vascular 2-adrenergic receptors
Constipation, dyspepsia Blockade of gastrointestinal 1/2-adrenergic receptors; decreased motili-
ty and relaxation of sphincter tone
Central nervous system manifestations Blockade of CNS 1/2-adrenergic receptors
(sleep disturbances, depression)
Sexual dysfunction (impotence, Unknown
decrease libido)
Impaired glucose tolerance Impaired 2-adrenergic–mediated islet cell insulin secretion; increase
hepatic glucose, and/or decrease insulin-stimulated glucose disposal
Prolonged insulin-induced Block epinephrine-mediated counterregulatory mechanisms
hypoglycemia
Hepatocellular necrosis Labetalol only, idiosyncratic reaction
Withdrawal syndrome Acute overshoot in heart rate with increased myocardial oxygen demand
Unstable angina due to increase in number and/or sensitivity of -adrenergic receptors
Myocardial infarction during chronic blockade
Dyslipidemia Increased -adrenergic tone; reduced lipoprotein lipase activity
Increased total triglycerides
Decreased high-density lipoproteins
cholesterol
Pharmacologic Treatment of Hypertension 7.13
FIGURE 7-15
Phsysiologic effect of central
α2-adrenergic agonists Central 2-adrenergic agonists. Central 2-adrenergic agonists cross the blood-brain barrier
and stimulate 2-adrenergic receptors in the vasomotor center of the brain stem [6,9].
α-Methyldopa Stimulation of these receptors decreases sympathetic tone, brain turnover of norepinephrine,
guanfacine Clonidine and central sympathetic outflow and activity of the preganglionic sympathetic nerves. The
guanabenz
net effect is a reduction in norepinephrine release. The central 2-adrenergic agonist clonidine
Stimulates Stimulates also binds to imidazole receptors in the brain; activation of these receptors inhibits central
sympathetic outflow. Central 2-adrenergic agonists may also stimulate the peripheral 2-
Central α2 I1-Imidazoline adrenergic receptors that mediate vasoconstriction; this effect predominates at high plasma
adrenoceptor receptor
drug concentrations and may precipitate an increase in blood pressure. The usual physiologic
effect is a decrease in peripheral resistance and slowing of the heart rate; however, output
is either unchanged or mildly decreased. Preservation of cardiovascular reflexes prevents
postural hypotension.
NTS RVLM
Nucleus Rostral
tractus ventrolateral
solitarii medulla
Inhibition of central
sympathetic activity
Blood pressure
reduction
Generic (trade) name First dose, mg Usual daily dose Maximum daily dose Duration of action
-Methyldopa (G) (Aldomet) 250 250–1000 mg bid 3000 24–48 h
Clonidine (G) (Catapres) 0.1 0.1–0.6 mg bid/tid 2.4 6–8 h
Clonidine TTS (Catapres-TTS) 2.5 mg (TTS-1) 2.5–7.5 mg (TTS–1 to TTS–3) qwk 15 mg (TTS-3x2) 9 wk 7d
Guanabenz (Wytensin) 4 4–16 mg bid 64 12 h
Guanfacine (Tenex) 1 1–3 mg QD 3 36 h
FIGURE 7-16
Central 2-adrenergic agonists. -Methyldopa is a methyl-substituted insufficiency, the plasma half-life (12 to 16 hours) may be extended
amino acid that is active only after decarboxylation and conversion to more than 40 hours; dose reduction is required. When clonidine
to -methyl-norepinephrine. The antihypertensive effect results from is administered transdermally, therapeutic plasma levels are achieved
accumulation of 2-adrenergic receptors, displacing and competing with within 2 to 3 days.
endogenous catecholamines. Methyldopa is absorbed poorly Guanabenz, a guanidine derivative, is highly selective for central
(<50%); peak plasma concentrations occur in 2 to 4 hours. It is 2-adrenergic receptors. It is absorbed well (>75%); peak plasma
metabolized in the liver and excreted in the urine mainly as the inactive levels are reached in 2 to 5 hours. Guanabenz undergoes extensive
O-sulfate conjugate. The plasma half-life of methyldopa (1 to 2 hours) hepatic metabolism; less than 2% is excreted unchanged in the urine.
and its metabolites is prolonged in patients with renal insufficiency; The plasma half-life (approximately 6 hours) is not prolonged in
dose reduction is required. patients with renal insufficiency.
Clonidine, an imidazoline derivative, acts by stimulating either Guanfacine is a phenylacetyl-guanidine derivative with a longer
central 2-adrenergic receptors or imidazole receptors. Clonidine may plasma half-life than guanabenz. It is absorbed well (>90%); peak
be administered orally or by a transdermal delivery system (TTS). plasma concentrations are reached in 1 to 4 hours. The drug is
When given orally, it is absorbed well (>75%); peak plasma con- primarily metabolized in the liver. Guanfacine and its metabolites
centrations occur in 3 to 5 hours. Clonidine is metabolized mainly are excreted primarily by the kidneys; 24% to 37% is excreted as
in the liver; fecal excretion ranges from 15% to 30%, and 40% to unchanged drug in the urine. The plasma half-life (15 to 17 hours)
60% is excreted unchanged in the urine. In patients with renal is not prolonged in patients with renal insufficiency [6,9].
7.14 Hypertension and the Kidney
FIGURE 7-17
THE SIDE EFFECT PROFILE OF CENTRAL The side effect profile of central 2-adrenergic agonists. The side
2-ADRENERGIC AGONISTS effect profile of these agents is diverse [6,9].
NE
NE
NE
β1
α1 α2
Generic (trade) name First dose, mg Usual daily dose, mg Maximum daily dose, mg Duration of action
Reserpine (G) (Serpasil) 0.1 0.1–.25 QD 0.5 2–3 wk
FIGURE 7-19
Central and peripheral adrenergic neuronal blocking agents. Reserpine pressure is maximally lowered 2 to 3 weeks after beginning therapy.
is the most popular rauwolfia product used. It is absorbed poorly Reserpine is metabolized by the liver; 60% of an oral dose is recovered
(approximately 30%); peak plasma concentrations occur in 1 to 2 in the feces. Less than 1% is excreted in the urine as unchanged drug.
hours. Catecholamine depletion begins within 1 hour of drug The plasma half-life (12 to 16 days) is not prolonged in patients
administration and is maximal in 24 hours. Catecholamines are with renal insufficiency.
restored slowly. Chronic doses of reserpine are cumulative. Blood
NE
increased gastric acid secretion NE
Increased appetite/weight gain Unknown
Sexual dysfunction Unknown
Impotence NE
Decreased libido
β1
α2 α1
FIGURE 7-22
Varicosity Vesicle Adrenergic synapse. Nerve activity releases
containing NA the endogenous neurotransmitter noradren-
Postganglionic Nerve impulse aline (NA) and also adrenaline from the
sympathetic neuron induces Sympathetic varicosities. Noradrenaline and adrenaline
exocytotic NA release + – C-fiber reach the postsynaptic -adrenoceptors (or
Presynaptic β Presynaptic -adrenoceptors) on the cell membrane of
α
β-receptor α-receptor
the target organ by diffusion. On receptor
NA Synaptic
stimulation, a physiologic or pharmacologic
cleft
Varicosities effect is initiated. Presynaptic 2-adrenocep-
α
Effector tors on the membrane (enlarged area), when
cell activated by endogenous noradrenaline as
Synaptic Postsynaptic
well as by exogenous agonists, inhibit the
cleft α-receptor Response
amount of transmitter noradrenaline released
per nerve impulse. Conversely, the stimulation
NA of presynaptic 2-receptors enhances nora-
drenaline release from the varicosities. Once
noradrenaline has been released, it travels
Target through the synaptic cleft and reaches both
Postsynaptic
organ - and -adrenoceptors at postsynaptic
α- receptors
sites, causing physiologic effects such as
vasoconstriction or tachycardia. (Adapted
from Van Zwieten [11].)
Generic (trade) name First dose, mg Usual daily dose, mg Maximum daily dose, mg Duration of action
Prazosin (G) (Minipress) 1 2-6 bid/tid 20 6-12 w
Terazosin (Hytrin) 1 2-5 QD/bid 20 12-24 h
Doxazosin (Cardura) 1 2-4 QD 16 24 h
G—generic available.
FIGURE 7-23
Peripheral 1-adrenergic antagonists. Prazosin is a lipophilic metabolized by the liver and predominantly excreted in the
highly selective 1-adrenergic antagonist. It is absorbed well feces. The plasma half-life of terazosin (approximately 12 hours)
(approximately 90%) but undergoes variable first-pass hepatic is not prolonged in patients with renal insufficiency.
metabolism. Peak plasma concentrations occur in 2 to 3 hours. Doxazosin is also a water-soluble quinazoline analogue of
It is extensively metabolized by the liver and predominantly prazosin, with about half its potency. It is absorbed well but
excreted in the feces. The plasma half-life of prazosin (2 to undergoes significant first-pass hepatic metabolism; bioavail-
4 hours) is not prolonged in patients with renal insufficiency. ability is approximately 65%. Peak concentrations occur in
Terazosin is a water-soluble quinazoline analogue of prazosin 2 to 3 hours. It is extensively metabolized by the liver and
with about one third of its potency. It is completely absorbed primarily eliminated in the feces. The plasma half-life of doxa-
and undergoes minimal first-pass hepatic metabolism. Peak zosin (approximately 22 hours) is not prolonged in patients
plasma concentrations occur in 1 to 2 hours. It is extensively with renal insufficiency [6,9].
Pharmacologic Treatment of Hypertension 7.17
FIGURE 7-24
150 Placebo Lying The side effect profile of the peripheral 1-adrenergic antagonists.
Standing
140 1-Adrenergic antagonists are associated with relatively few side
effects [6,9]; the most striking is the “first-dose effect” [12]. It
Mean BP, mm Hg
130 occurs 30 to 90 minutes after the first dose and is dose dependent.
120 It is minimized by initiating therapy in the evening and by careful
dose titration. The “first-dose effect” is exaggerated by fasting,
110 upright posture, volume contraction, concurrent -adrenergic
100 antagonism, or excessive catecholamine activity (eg, pheochromo-
Day 0
cytoma). (From Graham and coworkers [12]; with permission.)
Prazosin, 2 mg
140
130
120
110
Mean BP, mm Hg
100
90
80
70
60
50
Day 1
140
Prazosin, 2 mg
130
120
Mean BP, mm Hg
110
100
90
80 Day 4
β1
α2 α1
Generic (trade) name First dose, mg Usual daily dose, mg Maximum of action, mg Duration of action
Phenoxybenzamine (Dibenzyline) 10 20-40 bid 120 3–4 d
FIGURE 7-26
Moderately selective peripheral 1-adrenergic antagonists. approximately 3 to 4 days. Phenoxybenzamine is primarily used in
Phenoxybenzamine is the only drug in its class. Absorption is variable the management of preoperative or inoperative pheochromocytoma.
and incomplete (20% to 30%). Peak blockade occurs in 3 to 4 Efficacy is dependent on the degree of underlying excessive -adrenergic
hours. Its plasma half-life is 24 hours. The duration of action is vascular tone [6,9].
Pharmacologic Treatment of Hypertension 7.19
FIGURE 7-27
THE SIDE EFFECT PROFILE OF PHENOXYBENZAMINE The side effect profile of phenoxybenzamine. The common side
effects are listed [6,9].
NE
β1
α1 α2
Generic (trade) name First dose, mg Usual daily dose, mg Maximum daily dose, mg Duration of action
Guanethidine (Ismelin) 10 25–75 QD 150 7–21 d
Guanadrel (Hylorel) 5 10–50 bid 150 4–14 h
FIGURE 7-29
Peripheral adrenergic neuronal blocking agents. Guanethidine is 87.5% of a steady-state level. By administering loading doses of
the prototype peripheral adrenergic neuronal blocking agent. guanethidine at 6-hour intervals (the nearly maximal effect from a
Absorption is incomplete and variable; only 3% to 30% is absorbed single oral dose), blood pressure can be lowered in 1 to 3 days. In
over 12 hours. Peak plasma levels are reached in 6 hours. The drug patients with severe renal insufficiency, drug excretion is decreased;
rapidly leaves the plasma for extravascular storage sites, including dose reduction is required.
sympathetic neurons. Guanethidine is eliminated with a plasma Guanadrel is a guanethidine derivative with a short therapeutic
half-life of 4 to 8 days, a time course that corresponds with its anti- half-life. Absorption is greater than 85%; peak plasma concentra-
hypertensive effect. Approximately 24% of the drug is excreted tions are reached in 1 to 2 hours. Guanadrel is metabolized by the
unchanged in the urine; the remainder is metabolized by the liver liver. Elimination occurs through the kidney; approximately 40%
into more polar, less active, metabolites that are excreted in the of the drug is excreted unchanged in the urine. In patients with
urine and feces. When therapy is initiated or the dosage is changed, renal insufficiency, the plasma half-life (10 to 12 hours) is pro-
three half-lives (approximately 15 days) are required to accumulate longed; dose reduction is required [6,9].
FIGURE 7-30
THE SIDE EFFECT PROFILE OF PERIPHERAL The side effect profile of peripheral adren-
ADRENERGIC-NEURONAL BLOCKING AGENTS ergic neuronal blocking agents. The specific
side effects of this class are related to either
excessive sympathetic blockade or a relative
Side effects Mechanisms increase in parasympathetic activity. GFR—
glomerular filtration rate.
Decrease renal function (GFR) Decreased renal perfusion; effect is magnified in the upright position
Fluid retention/weight gain Decreased filtered load and fractional excretion of sodium; diuretic should be
used in combination
Dizziness/weakness Postural hypotension accentuated by hot weather, alcohol ingestion, and/or
Syncope physical exercise
Intestinal cramping/diarrhea Unopposed parasympathetic activity, increasing gastrointestinal motility
Sexual dysfunction Inhibition of bladder neck closure, unknown
Retrograde ejaculation
Impotence
Decreased libido
Sinus bradycardia Interferes with cardiac sympathetic compensating reflexes
Atrioventricular block
Bronchospasm Catecholamine depletion aggravates airway resistance
Congestive heart failure Decreased cardiac output
Pharmacologic Treatment of Hypertension 7.21
FIGURE 7-31
Plasma Direct-acting vasodilators. Direct-acting vasodilators may have an
membrane VGC Leak ROC VGC effect on both arterial resistance and venous capacitance vessels;
however, the currently available oral drugs are highly selective for
resistance vessels [6,9]. Their specific mechanism of vascular relax-
ation and reason for selectivity are unknown. By altering cellular calci-
Ca2+ Ca2+ um metabolism, they interfere with the calcium movements respon-
sible for initiating or maintaining a contractile state. The net physi-
Ca2+
Altered calcium
metabolism (?)
Myofilaments
Contraction of vascular
smooth muscle
Hypertension
DIRECT-ACTING VASODILATORS
Generic (trade) name First dose, mg Usual daily dose, mg Maximum daily dose, mg Duration of action, h
Hydralazine (G) (Apresoline) 10 50–100 bid/tid 300 10–12
Minoxidil (G) (Loniten) 5 10–20 QD/bid 80 75
G—generic available.
FIGURE 7-32
Direct-acting vasodilators. Hydralazine is the prototype of direct- Minoxidil is a substantially more potent direct-acting vasodilator
acting vasodilators. Absorption is more than 90%. Peak plasma than hydralazine. Absorption is greater than 95%. Peak plasma levels
levels occur within 1 hour but may vary widely among individuals. occur within 1 hour. Following a single oral dose, blood pressure
This is because hydralazine is subject to polymorphic acetylation; declines within 15 minutes, reaches a nadir between 2 and 4 hours,
slow acetylators have higher plasma levels and require lower drug and recovers at an arithmetically linear rate of 30% per day.
doses to maintain blood pressure control compared with rapid Approximately 90% is metabolized by conjugation with glucuronic
acetylators. Bioavailability for slow acetylators ranges from 30% acid and by conversion to more polar products. Known metabolites,
to 35%; bioavailability for rapid acetylators ranges from 10% to which are less pharmacologically active than minoxidil, are excreted
16%. Hydralazine undergoes extensive hepatic metabolism; it is in the urine. The plasma half-life of minoxidil is approximately 4
mainly excreted in the urine in the form of metabolites or as hours; dose adjustments are unnecessary in patients with renal insuf-
unchanged drug. The plasma half-life is 3 to 7 hours. Dose reduction ficiency. Minoxidil and its metabolites are removed by hemodialysis
may be required in the slow acetylator with renal insufficiency. and peritoneal dialysis; replacement therapy is required [6,9].
7.22 Hypertension and the Kidney
FIGURE 7-33
Side effects of direct-acting vasodilators
The side effect profile of direct-acting
↑ Heart rate vasodilators. The most common and most
serious effects of hydralazine and minoxidil
↑ Myocardial ↑ Cardiac
contractility output
are related to their direct or reflex-mediated
VASODILATORS
↑ Sympathetic hemodynamic actions, including flushing,
function ↓ Venous headache, palpitations, anginal attacks, and
capacitance electrocardiographic changes of myocardial
↑ Peripheral ischemia [6,9]. These effects may be pre-
↓ Peripheral vascular vented by concurrent administration of a
vascular resistance PROPRANOLOL -adrenergic antagonist. Sodium retention
resistance with expansion of extracellular fluid volume
is a significant problem. Large doses of
potent diuretics may be required to prevent
↓ Arterial ↑ Plasma ↑ Circulating ↑ Aldosterone
fluid retention and the development of
pressure renin angiotensin secretion pseudotolerance [13]. (From Koch-Weser
activity [13]; with permission.)
Repeated administration of hydralazine
DIURETICS can lead to a reversible syndrome that
resembles disseminated lupus erythematosus.
↑ Plasma and The incidence is dose dependent; it rarely
↓ Sodium extracellular
excretion
occurs in patients receiving less than 200
fluid volume mg/day. Hypertrichosis is a common trouble-
some but reversible side effect of minoxidil;
it develops during the first 3 to 6 weeks of
therapy in approximately 80% of patients.
FIGURE 7-34
Calcium antagonists. The calcium antagonists share a common
Plasma antihypertensive mechanism of action: inhibition of calcium ion
membrane VGC ROC VGC movement into smooth muscle cells of resistance arterioles through
L-type (long-lasting) voltage-operated channels [6,9]. The ability of
these drugs to bind to voltage-operated channels, causing closure of
the gate and subsequent inhibition of calcium flux from the extra-
Ca2+ Ca2+ cellular to the intracellular space, inhibits the essential role of calci-
um as an intracellular messenger, uncoupling excitation to contrac-
Ca2+
tion. Calcium ions may also enter cells through receptor-operated
channels. The opening of these channels is induced by binding neu-
rohumoral mediators to specific receptors on the cell membrane.
Ca2+ SR Ca2+ SR
Calcium antagonists inhibit the calcium influx triggered by the
stimulation of either -adrenergic or angiotensin II receptors in a
dose-dependent manner, inhibiting the influence of -adrenergic ago-
nist and angiotensin II on vascular smooth muscle tone. The net
physiologic effect is a decrease in vascular resistance.
Myofilaments Although all the calcium antagonists share a basic mechanism of
action, they are a highly heterogeneous group of compounds that
differ markedly in their chemical structure, pharmacologic effects
on tissue specificity, pharmacologic behavior side-effect profile, and
clinical indications [6,9,14]. Because of this, calcium antagonists
have been subdivided into several distinct classes: phenylalkamines,
dihydropyridines, and benzothiazepines. ROC—receptor-operated
channel; SR—sarcoplasmic reticulum; VGC—voltage-gaited channels.
Pharmacologic Treatment of Hypertension 7.23
Generic (trade) name First dose, mg Usual dose, mg Maximum daily dose, mg Duration of action, h
Verapamil (G) (Isoptin, Calan) 80 80–120 tid 480 8
Verapamil SR (Isoptin SR, Calan SR) 90 90–240 bid 480 12–24
Verapamil SR—pellet (Veralan) 120 240–480 QD 480 24
Verapamil COER-24 (Covera HS) 180 180–480 qhs 480 24
G—generic available.
Generic (trade) name First dose, mg Usual dose, mg Maximum daily dose, mg Duration of action, h
Amlodipine (Norvasc) 5 5–10 QD 10 24
Felodipine (Plendil) 5 5–1 0 QD 20 24
Isradipine (DynaCirc) 2.5 2.5-5 bid 20 12
Isradipine CR (DynaCirc CR) 5 5–20 QD 20 24
Nicardipine SR (Cardine SR) 30 30–60 bid 120 12
Nifedipine Caps (G) (Procardia) 10 10–30 tid/qid 120 4–6
Nifedipine ER (Adalat CC) 30 30–90 QD 120 24
Nifedipine GITS (Procardia XL) 30 30–90 QD 120 24
Nisoldipine (Sular) 20 20–40 QD 60 24
G—generic available.
Generic (trade) name First dose, mg Usual dose, mg Maximum daily dose, mg Duration of action, h
Diltiazem (G) (Cardizem) 60 60–120 tid/qid 480 8
Diltiazem SR (Cardizem SR) 180 120–240 bid 480 12
Diltiazem CD (Cardizem CD) 180 240–480 QD 480 24
Diltiazem XR (Dilacor XR) 180 180–480 QD 480 24
Diltiazem ER (Tiazac) 180 180–480 QD 480 24
G—generic available.
FIGURE 7-35
A–C. Dosing schedules for calcium antagonists: phenylalkamine derivatives,
dihydropyridine derivatives, and benzothiazepine derivatives.
7.24 Hypertension and the Kidney
Absorption, % First-pass hepatic Peak concentration Route of elimination Active metabolite Plasma half-life, h Dose reduction
Verapamil >90 70%–80% 1–2 h (tablet) Liver Yes 4–12 (tablet) No
5 h (SR caplet) 12 (SR pellet)
7–9 h (SR pellet)
11 h (COER)
Amlodipine >90 Minimal 6–12 h Liver No 30–50 No
Felodipine >90 Extensive 2.5–5 h Liver No 11–16 No
Isradipine >90 Extensive 1–2 h (tablet) Liver No 8 No
7–18 h (CR)
Nicardipine >90 Extensive 1–4 h (SR) Liver No 8–9 No
Nifedipine >90 20%–30% <30 min (cap) Liver No 2 No
2.5–5 h (ER) 24
6 h GITS) 24
Nisoldipine >85 Extensive 6–12 h Liver Yes 7–12 No
Diltiazem >80 50% 2–3 h (tablet) Liver Yes 4–6 Yes
6–11 h (SR) 5–7
10–14 h (CD) 5–8
4–6 h (XR) 5–10
7 h (ER) 4–10
FIGURE 7-36
Pharmacokinetics of the calcium antagonists: phenylalkamine derivatives,
dihydropyridine derivatives, and benzothiazepine derivatives.
FIGURE 7-37
THE SIDE EFFECTS PROFILE OF CALCIUM ANTAGONISTS The side effect profile of calcium antagonists
[10,13,18]. AV—atrioventricular.
ACE inhibition and angiotensin II type I receptor antagonists: mechanisms for decrease in peripheral vascular resistance
Functions::
+
– Renal tubular
sodium reabsorption
+
Aldosterone
release
Angiotensinogen Non-renin enzymes + Vasoconstriction, +
AT1 Blood
(renin substrate) vascular smooth
receptor pressure
muscle
1 Non-ACE enzymes +
Renin Remodeling,
3
vascular smooth
muscle
Angiotensin I Angiotensin II +
(decapeptide) (octapeptide) Sympathetic activity
2 (central and peripheral)
–
ACE 4 Baroreceptor
sensitivity
Inactive
AT2 receptor ? Function
fragments
Nitric oxide
+ –
Bradykinin Prostaglandin E2
Prostaglandin I2
–
FIGURE 7-38
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II Mechanisms proposed for the observed decrease in peripheral
type I receptor antagonists. Angiotensin-converting enzyme resistance are shown [15]. Sites of pharmacologic blockade in the
inhibitors and angiotensin II type I receptor antagonists lower renin angiotensin system: 1) renin inhibitors, 2) ACE inhibitors,
blood pressure by decreasing peripheral vascular resistance; there 3) angiotensin II type I receptor antagonists, 4) angiotensin II
is usually little change in heart rate or cardiac output [6,9,15]. type II receptor antagonists.
7.26 Hypertension and the Kidney
Generic (trade) name First dose, mg Usual dose, mg Maximum dose, mg Duration of action, h
Captopril (G) (Capoten) 12.5 12.5–50 bid/tid 150 6–12
Generic (trade) name First dose, mg Usual dose, mg Maximum dose, mg Duration of action, h
Benazepril (Lotensin) 10 10–20 QD 40 24
Enalapril (Vasotec) 5 5–10 QD/bid 40 12–24
Lisinopril (Prinivil,Zestril) 10 20–40 QD 40 24
Moexipril (Univasc) 7.5 7.5–15 QD/bid 30 24
Quinapril (Accupril) 5–10 20–40 QD 40 24
Ramipril (Altace) 2.5 2.5–20 QD/bid 40 24
Trandolapril (Mavik) 1 2–4 QD 8 24
Generic (trade) name First dose, mg Usual dose, mg Maximum dose, mg Duration of action, h
Fosinopril (Monopril) 10 20–40 QD/bid 40 24
G—generic available.
FIGURE 7-39
A–C. Classification of and dosing schedule for angiotensin-converting conformation, and lipophilicity [6,9]. They are generally classified
enzyme (ACE) inhibitors. Angiotensin-converting enzyme inhibitors into one of three main chemical classes according to the ligand of
differ in prodrug status, ACE affinity, potency, molecular weight and the zinc ion of ACE: sulfhydryl, carboxyl, or phosphinic acid.
Pharmacologic Treatment of Hypertension 7.27
FIGURE 7-40
Pharmacokinetics of angiotensin-converting enzyme (ACE) inhibitors: sulfhydryl-
containing, carboxyl-containing, and phosphinic acid–containing.
FIGURE 7-41
THE SIDE EFFECTS PROFILE OF ACE INHIBITORS The side effect profile of angiotensin-con-
verting enzyme (ACE) inhibitors. ACE
inhibitors are well tolerated; there are few
Side effects Mechanisms side effects [6,9].
FIGURE 7-42
230 Renal artery Essential Angiotensin-converting enzyme (ACE) inhibition in acute renal failure.
pressure, mm Hg
stenosis hypertension ACE inhibitors may produce functional renal insufficiency in patients
190 with essential hypertension and hypertensive nephrosclerosis, in
Arterial
440 unilateral renal artery stenosis, a drop in the critical perfusion and
mL/min
100
Although ACE inhibition may invariably decrease the GFR of the
90 stenotic kidney, it is unlikely to cause renal ischemia owing to
preservation of ERPF; GFR usually returns to pretreatment values
80 following cessation of therapy.
Shown is the effect of captopril (50 mg) on total clearances of
1000 131I-sodium iodohippurate (ERPF) and 126I-thalamate (GFR) in 14
patients with unilateral renal artery stenosis and in 17 patients with
Plasma renin, mU/L
10 Captopril 50 mg Captopril 50 mg
–15 0 30 60 –15 0 30 60
Time, min
β1
α1 α2
Generic (trade) name First dose, mg Usual daily dose, mg Maximum dose, mg Duration of action, h
Metyrosine (Demser) 250 25 qid 1000 qid 3–4
FIGURE 7-44
Tyrosine hydroxylase inhibitor. Metyrosine is the only drug in its Following discontinuation of therapy, the clinical and biochemical
class. The initial recommended dose is 1 g/d, given in divided doses. effects may persist 2 to 4 days. Metyrosine is variably absorbed
This may be increased by 250 to 500 mg daily to a maximum of from the gastrointestinal tract; bioavailability ranges from 45%
4 g/d. The usual effective dosage is 2 to 3 g/d. The maximum bio- to 90%. Peak plasma concentrations are reached in 1 to 3 hours.
chemical effect occurs within 2 to 3 days. In hypertensive patients in The plasma half-life is 3 to 4 hours. Metyrosine is not metabolized;
whom there is a response, blood pressure decreases progressively the unchanged drug is recovered in the urine. Drug dosage should
during the first days of therapy. In patients who are usually nor- be reduced in patients with renal insufficiency. Metyrosine is exclu-
motensive, the dose should be titrated to the amount that will sively used in the management of preoperative or inoperative
reduce circulating or urinary catecholamines by 50% or more. pheochromocytoma [6,9].
FIGURE 7-45
THE SIDE EFFECTS PROFILE OF METYROSINE The side effect profile of metyrosine. The adverse reactions observed
with metyrosine are primarily related to the central nervous system
and are typically dose dependent [6,9]. Metyrosine crystalluria
Side effects Mechanisms (needles or rods), which is due to the poor solubility of the drug in
the urine, has been observed in patients receiving doses greater
CNS symptoms Depletion of CNS dopamine than 4 g/d. To minimize this risk, patients should be well hydrated.
Sedation CNS—central nervous system.
Extrapyramidal signs
Drooling
Speech difficulty
Tremor
Trismus
Parkinsonian syndrome
Psychic dysfunction
Anxiety
Depression
Disorientation
Confusion
Crystalluria, uroliathiasis Poor urine solubility
Diarrhea Direct irritant to bowel mucosa
Insomnia (temporary) Following drug withdrawal
7.30 Hypertension and the Kidney
Generic (trade) name First dose, mg Usual dose, mg Maximum dose, mg Duration of action, h
Losartan (Cozaar) 50 50–100 QD/bid 100 12–24
Valsartan (Diovan) 80 80–160 QD 320 24
Irbesaftan (Avapro) 150 150–300 QD 300 24
FIGURE 7-46
Angiotensin II receptor antagonists. These drugs antagonize longer half-life (between 4 and 9 hours). The metabolite is cleared
angiotensin II–induced biologic actions, including proximal sodium equally by the liver and the kidney; there may be enhanced hepatic
reabsorption, aldosterone release, smooth muscle vasoconstriction, clearance in renal insufficiency [15]. Dose reduction is not required
vascular remodeling, and baroreceptor sensitivity. Antihypertensive in patients with renal insufficiency.
efficacy appears dependent on an activated renin-angiotensin system; Valsartan is a nonpeptide, specific angiotensin II antagonist acting
bilateral nephrectomy and volume expansion abolish their activity. on the AT1 subtype receptor. Peak response occurs within 6 hours
Losartan is a nonpeptide, specific angiotensin II receptor antagonist of dosing. Peak plasma concentrations are reached 2 to 4 hours
acting on the antagonist AT1 subtype receptor. Peak response occurs after dosing. The average elimination half-life is about 6 hours.
within 6 hours of dosing. It is readily absorbed; peak plasma concen- Oral bioavailability is approximately 25%. Dose reduction is not
trations are achieved within 1 hour. It has a relatively short terminal required in patients with renal insufficiency [15].
half-life of 1.5 to 2.5 hours. Oral bioavailability is approximately Irebsartan is a nonpeptide, specific angiotensin II antagonist acting
33%. Losartan undergoes extensive first-pass hepatic metabolism on the AT1 subtype receptor. Peak response occurs in 4 to 8 hours.
to the predominant circulatory form of the drug Exp-3174. This There is no active metabolite. Dose reduction is not required in
metabolite is 15 to 30 times more potent than losartan with a patients with renal insufficiency [15].
FIGURE 7-47
THE SIDE EFFECTS PROFILE OF ANGIOTENSIN II The side effect profile of angiotensin II receptor antagonists.
RECEPTOR ANTAGONISTS Angiotensin II receptor antagonists are well tolerated. In contrast
to the angiotensin-converting enzyme (ACE) inhibitors, cough and
angioedema are rarely (if at all) associated with this class of antihy-
Side effects Mechanisms pertensive drug. Similar to ACE inhibitors, however, hyperkalemia
and acute renal failure may occur in patients at risk [15].
Hyperkalemia Blockade of angiotensin II
Reduced aldosterone secretion
Acute renal dysfunction Hypotension with impaired efferent anteriolar
autoregulation
Pharmacologic Treatment of Hypertension 7.31
FIGURE 7-49
JNC VI DECISION ANALYSIS FOR TREATMENT Decision analysis for treatment based on the
Sixth Report of the Joint National Committee
on Detection, Evaluation, and Treatment of
Risk group B Risk Group C High Blood Pressure (JNC VI) [17].
Risk group A (at least 1 risk factor, (TOD/CCD and/or
Blood pressure stages (no risk factors, no not including diabetes; diabetes, with or with-
(mm Hg) TOD/CCD)* no TOD/ CCD) out other risk factors)†
High normal Lifestyle modification Lifestyle modification Drug therapy‡
(130–139/85–89)
Stage 1 Lifestyle modification Lifestyle modification Drug therapy
(140–159/90–99) (up to 12 months) (up to 6 months)
Stages 2 and 3 Drug therapy Drug therapy Drug therapy
(>160/≥100)
Lifestyle modification should be adjunctive therapy for all patients recommended for pharmacologic therapy.
*TOD/CCD indicates target organ disease/clinical cardiovascular disease.
†For patients with multiple risk factors, clinicians should consider drugs as initial therapy plus lifestyle modifications.
‡For those with heart failure, renal insufficiency, or diabetes.
FIGURE 7-50
CRITERIA FOR INITIAL DRUG THERAPY Selection of initial drug therapy. The Sixth Report of the Joint
National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC VI) recommends that
Reduce peripheral vascular resistance either a diuretic or a -blocker be chosen as initial drug therapy,
No sodium retention based on numerous randomized controlled trials that show reduction
No compromise in regional blood flow
in morbidity and mortality with these agents [17]. Not all authorities
agree with this recommendation.
No stimulation of the renin-angiotensin-aldosterone system
In selecting an initial drug therapy to treat a hypertensive patient,
Favorable profile with concomitant diseases
several criteria should be met [6,9]. The drug should decrease
Once a day dosing
peripheral resistance, the pathophysiologic hallmark of all hypertensive
Favorable adverse effect profile
diseases. It should not produce sodium retention with attendant
Cost effective (low direct and indirect cost)
pseudotolerance. The drug should neither stimulate nor suppress
the heart, nor should it compromise regional blood flow to target
organs such as the heart, brain, or the kidney. It should not stimulate
the renin-angiotensin-aldosterone axis. Drug selection should consider
concomitant diseases such as arteriosclerotic cardiovascular and
peripheral vascular disease, chronic obstructive pulmonary disease,
diabetes mellitus, hypertensive cardiovascular disease, congestive
heart failure, and hyperlipidemia. Drug dosing should be infrequent.
The drug’s side effect profile, including its effect on physical state,
emotional well-being, sexual and social function, and cognitive
activity, should be favorable. Drug costs, both direct and indirect,
should be reasonable. It is readily apparent that no current class of
antihypertensive drug fulfills all these criteria.
Pharmacologic Treatment of Hypertension 7.33
FIGURE 7-51
Options for monotherapy. Given the drugs that we have and their 6) thiazide-type diuretics [6,9,15]. All these drugs, given as monotherapy,
pharmacologic profiles, what are the best classes for initial drug therapy? are effective in lowering blood pressure in 50% to 60% of patients
Alphabetically, they include 1) angiotensin-converting enzyme (ACE) with mild to moderate hypertension. 1-adrenergic antagonists, ACE
inhibitors, 2) 1-adrenergic antagonists, 3) angiotensin II type I receptor inhibitors, and angiotensin II receptor antagonists are less efficacious
antagonists, 4) 1-adrenergic antagonists, 5) calcium antagonists, and in blacks than in whites.
7.34 Hypertension and the Kidney
FIGURE 7-52
Options for subsequent antihypertensive therapy
Options for subsequent antihypertensive
therapy. The majority of patients with mild
Not at goal blood pressure (<140/<90 mm Hg); to moderate hypertension can be controlled
lower goal in patients with diabetes mellitus or renal disease with one drug. If, after a 1- to 3-month
interval, the response to the initial choice of
therapy is inadequate, however, three
options for subsequent antihypertensive
No response or troublesome side effects Inadequate response but well tolerated
drug therapy may be considered: 1) increase
the dose of the initial drug, 2) discontinue
the initial drug and substitute a drug from
Add a second agent from a different class
Sustitute another drug from a different class (diuretic if not already used) another class, or 3) add a drug from another
class (combination therapy). Recommendations
from the Sixth Report of the Joint National
Committee on Detection, Evaluation, and
Not a goal blood pressure Treatment of High Blood Pressure (JNC VI)
are provided [17].
FIGURE 7-53
COMBINATION THERAPIES Combination therapies. If a second drug is required, the addition of a low-dose thiazide-
type diuretic to a nondiuretic drug will usually enhance the effectiveness of the first drug
[6,9,17]. Newly developed formulations, using combinations of low doses of two agents
Mild to moderate (stage 1 or 2) hypertension from different classes, are available and effective and may minimize the likelihood of a
dose-dependent adverse effect. The fixed doses used in these formulations were chosen to
Addition of low-dose thiazide-type diuretic to: control mild to moderate (JNC VI stage 1 or 2) hypertension. More severe (JNC VI stage 3)
ACE inhibitor cases of hypertension that are unresponsive to this therapeutic strategy may respond either
1-adrenergic antagonist to a variety of combination therapies given together as separate formulations or to classic
1-adrenergic antagonist triple-drug therapy (ie, diuretic, -adrenergic antagonist, and direct-acting vasodilator) [6,9].
Angiotensin III receptor antagonist ACE—angiotensin-converting enzyme; JNC—Joint National Committee.
Severe (Stage 3) hypertension
Classic triple drug therapy
Diuretic
1-adrenergic antagonist
Direct-acting vasodilator
ACE inhibitor plus calcium antagonist
1-adrenergic antagonist plus 1-adrenergic antagonist
1-adrenergic antagonist plus dihydropyridine
calcium antagonist
Pharmacologic Treatment of Hypertension 7.35
FIGURE 7-54
JNC VI LIFE STYLE MODIFICATIONS Follow-up in antihypertensive therapy. During follow-up visits,
pharmacologic therapy should be reconfirmed or readjusted. As a
rule, antihypertensive therapy should be maintained indefinitely.
Lose weight if overweight Cessation of therapy in patients who were correctly diagnosed as
Limit alcohol intake to no more than 1 oz (30 mL) ethanol (eg, 24 oz [720 mL] beer, hypertensive is usually (but not always) followed by a return of
10 oz [300 mL] wine, or 2 oz [60 mL] 100-proof whiskey) per day or 0.5 oz (15 mL) blood pressure to pretreatment levels. After blood pressure has
ethanol per day for women and lighter weight people been controlled for 1 year and at least four visits, however, attempts
Increase aerobic physical activity (30 to 45 minutes most days of the week) should be made to reduce antihypertensive drug therapy “in a
Reduce sodium intake to no more than 100 mmol/d deliberate, slow, and progressive manner;” such “step-down therapy”
(2.4 g sodium or 6 g sodium chloride) may be successful in patients following lifestyle modification [17].
Maintain adequate intake of dietary potassium (approximately 90 mmol/d) Patients for whom drug therapy has been reduced or discontinued
Maintain adequate intake of dietary calcium and magnesium for general health should have regular follow-up, since blood pressure may increase
Stop smoking and reduce intake of dietary saturated fat and cholesterol for again to hypertensive levels. JNC—Joint National Committee.
overall cardiovascular health
FIGURE 7-55
CAUSES OF RESISTANT HYPERTENSION Resistant hypertension. Causes of failure to achieve or sustain control
of blood pressure with drug therapy are listed [6,9].
FIGURE 7-56
DIURETIC RESISTANCE Diuretic resistance. Diuretic resistance may
result from patient noncompliance, impaired
bioavailability in an edematous syndrome,
Problem Mechanism Solution impaired diuretic secretion by the proximal
tubule, protein binding in the tubule lumen
Limits active transport of diuretics Reduced renal blood flow Use of large doses of a diuretic and (eg, nephrotic syndrome), reduced glomerular
into proximal tubular fluid, reducing appropriate dosing interval to achieve filtration rate, or enhanced sodium chloride
inhibitory effect at a more distal a therapeutic tubular drug concentration
intraluminal membrane site
reabsorption [7,8]. Resultant fluid retention
will attenuate the effectiveness of most anti-
Limits absolute amount of sodium Reduced glomerular filtration rate Use loop diuretics with steep dose
filtered response curve and/or block multiple hypertensive drugs. Renal mechanisms,
sites of sodium reabsorption: loop problems, and solutions are provided in this
diuretic with thiazide-like diuretic table [6,8,9].
Sodium recaptured at late distal Secondary hyperaldosteronism Addition of a potassium-sparing diuretic
tubule and collecting duct to above, to maintain urine
sodium/potassium ratio > 1
References
1. Kaplan NM: Clinical Hypertension, edn 6. Baltimore: Williams & 11. Van Zwieten PA: Antihypertensive drug interacting with -and -adreno-
Wilkins; 1994:50. ceptors: a review of basic pharmacology. Drugs 1988, 35(suppl 6):6–19.
2. Kawasaki T, Delea CS, Bartter FC, Smith H: The effect of high-sodium 12. Graham RM, Thornell IR, Gain JM, et al.: Prazosin: the first dose
and low-sodium intakes on blood pressure and other related variables phenomenon. Br Med J 1976, 2:1293–1294.
in human subjects with idiopathic hypertension. Am J Med 1978, 13. Koch-Weser J: Vasodilation drugs in the treatment of hypertension.
64:193–198. Arch Intern Med 1974, 133:1017–1025.
3. Guyton AC, Coleman TG, Yang DB, et al.: Salt balance and long-term 14. Entel SI, Entel EA, Clozel J-P: T-type Ca2+ channels and pharmacological
blood pressure control. Annu Rev Med 1980, 31:15–27. blockade: potential pathophysiological relevance. Cardiovasc Drugs
4. Julius S, Krause L, Schork NJ: Hyperkinetic borderline hypertension Ther 1997, 11:723—739.
in Tecumseh, Michigan. J Hypertens 1991, 9:77–84. 15. Bauer JH, Ream GP: The angiotensin II type 1 receptor antagonists.
5. Lund-Johansen P: Cetra haemodynamics in essential hypertension at Arch Intern Med 1995, 155:1361–1368.
rest and during exercise: a 20-year follow-up study. J Hypertens 1989, 16. Wenting GJ, Tan-Tjiong HL, Derkx FMH, et al.: Split renal function
7(suppl 6): 552–555. after captopril in unilateral renal artery stenosis. Br Med J 1974,
6. Bauer JH, Reams GP: Mechanisms of action, pharmacology, and use 288:886–890.
of antihypertensive drugs. In The Principles and Practice of Nephrology. 17. JNC VI: The Sixth Report of the Joint National Committee on
Edited by Jacobson HR, Striker GE, Klahr S. St. Louis: Mosby; Detection, Evaluation, and Treatment of High Blood Pressure. Arch
1995:399–415. Intern Med 1993, 153:154–183.
7. Tarazi RC: Diuretic drugs: mechanisms of antihypertensive action. In 18. Peterson JC, Adler S, Burkart JM, et al.: Blood pressure control,
Hypertension: Mechanisms and Management. The 26th Hahnemann proteinuria, and the progression of renal disease. Ann Intern Med
Symposium. Edited by Oneti G, Kim KE, Moer JH. New York: Grune 1995, 123:754–762.
and Stratton; 1973:255.
19. Hebert LA, Kusek JW, Greene T, et al.: Effects of blood pressure con-
8. Ellison DH: The physiologic basis of diuretic synergism: its role in trol on progressive renal disease in blacks and whites. Hypertension
treating diuretic resistance. Ann Intern Med 1991, 114:886–894. 1997, 30 (part 1):428–435.
9. Bauer JH, Reams GP: Antihypertensive drugs. In The Kidney, edn 5.
Edited by Brenner BM. Philadelphia: W.B. Saunders Co.; 1995:
2331–2381.
10. Man in’t Veld AJ, Schalekamp MADH: How intrinsic sympathomimetic
activity modulates the haemodynamic responses to -adrenoceptor
antagonists: a clue to the nature of their antihypertensive mechanism.
Br J Clin Pharmac 1982, 13:2455–2575.
Hypertensive Crises
Charles R. Nolan
M
ost patients with hypertension remain asymptomatic for many
years, until complications from atherosclerosis, cerebrovascular
disease, or congestive heart failure supervene. In some patients,
this so-called benign course is punctuated by a hypertensive crisis.
Hypertensive crisis is defined as the turning point in the course of an
illness at which acute management of the elevated blood pressure
plays a decisive role in the eventual outcome [1]. The haste with which
blood pressure must be controlled varies with the type of hypertensive
crisis. If the patient’s outcome is to be optimal, however, the crucial
role of hypertension in the disease process must be identified and a
plan for management of the blood pressure successfully implemented.
The absolute level of the blood pressure clearly is not the most important
factor in determining the existence of a hypertensive crisis. For example,
in children, pregnant women, and other previously normotensive persons
in whom mild to moderate hypertension develops suddenly, a hyper-
tensive crisis can occur at a level of blood pressure that normally is
well-tolerated by adults with chronic hypertension. Furthermore, a
crisis can occur in adults with mild to moderate hypertension with the
onset of acute end-organ dysfunction involving the heart or brain.
CHAPTER
8
8.2 Hypertension and the Kidney
FIGURE 8-1
HYPERTENSIVE CRISES Malignant hypertension is a clinical syndrome characterized by
marked elevation of blood pressure, with widespread acute arterio-
lar injury (hypertensive vasculopathy). Funduscopy reveals hyper-
Malignant hypertension tensive neuroretinopathy with flame-shaped hemorrhages, cotton-
(Hypertensive neuroretinopathy present) wool spots (soft exudates), and sometimes papilledema. Regardless
Benign (nonmalignant) hypertension with acute complications
of the severity of blood pressure elevation, malignant hypertension
cannot be diagnosed in the absence of hypertensive neuroretinopa-
(Acute organ system dysfunction without hypertensive neuroretinopathy)
thy. Thus, hypertensive neuroretinopathy is an extremely important
Hypertensive encephalopathy (also common in malignant hypertension)
clinical finding, indicating the presence of a hypertension-induced
Acute hypertensive heart failure (also common in malignant hypertension)
arteriolitis that may involve the kidneys, heart, and central nervous
Acute aortic dissection
system. In malignant hypertension, rapid and relentless progression
Central nervous system catastrophe
to end-stage renal disease occurs if effective blood pressure control
Intracerebral hemorrhage is not implemented. Mortality can result from acute hypertensive
Subarachnoid hemorrhage heart failure, intracerebral hemorrhage, hypertensive encephalopa-
Severe head trauma thy, or complications of uremia. Malignant hypertension represents
Acute myocardial infarction or unstable angina a hypertensive crisis given that adequate control of blood pressure
Active bleeding, including postoperative bleeding clearly prevents these morbid complications. Even in patients with
Uncontrolled hypertension in patients requiring surgery so-called benign (nonmalignant) hypertension, in which hyperten-
Severe postoperative hypertension sive neuroretinopathy is absent, a hypertensive crisis may occur based
Post–coronary artery bypass hypertension on the development of concomitant acute end-organ dysfunction.
Post–carotid endarterectomy hypertension Hypertensive crises caused by benign hypertension with acute
Catecholamine excess states complications include hypertension in the setting of hypertensive
Pheochromocytoma encephalopathy, acute hypertensive heart failure, acute aortic
Monoamine oxidase inhibitor–tyramine interactions dissection, intracerebral hemorrhage, subarachnoid hemorrhage,
Miscellaneous hypertensive crises severe head trauma, acute myocardial infarction or unstable angina,
Preeclampsia and eclampsia and active bleeding. Poorly controlled hypertension in patients
Scleroderma renal crisis requiring surgery increases the risk of intraoperative cerebral or
Autonomic hyperreflexia in quadriplegic patients myocardial ischemia and postoperative acute renal failure. Severe
postoperative hypertension, including post–coronary artery bypass
hypertension and post–carotid endarterectomy hypertension, increases
the risk of postoperative bleeding, hypertensive encephalopathy,
pulmonary edema, and myocardial ischemia. The various
catecholamine excess states can cause a hypertensive crisis with
hypertensive encephalopathy or acute hypertensive heart failure.
Preeclampsia and eclampsia represent hypertensive crises unique to
pregnancy. Scleroderma renal crisis is a hypertensive crisis because
failure to adequately control blood pressure with a regimen that
includes a converting enzyme inhibitor results in rapid irreversible
loss of renal function. Hypertensive crises as a result of autonomic
hyperreflexia induced by bowel or bladder distention also can occur
in patients with quadriplegia. The sudden onset of hypertension in
this setting can lead to hypertensive encephalopathy or acute
pulmonary edema. Each hypertensive crisis is discussed in more
detail in the figures that follow.
Hypertensive Crises 8.3
FIGURE 8-2
HYPERTENSIVE SYNDROMES SOMETIMES Hypertensive syndromes sometimes misdiagnosed as hypertensive
MISDIAGNOSED AS HYPERTENSIVE CRISES crises. It should be noted that the finding of severe hypertension
does not always imply the presence of a hypertensive crisis. In
patients with severe uncomplicated hypertension (formally known
Severe uncomplicated hypertension as urgent hypertension) in which severe hypertension is not accom-
(Severe hypertension without hypertensive neuroretinopathy or acute end-organ panied by evidence of malignant hypertension or acute end-organ
dysfunction, formerly known as urgent hypertension) dysfunction, eventual complications due to stroke, myocardial
Benign hypertension with chronic end-organ complications infarction, or congestive heart failure tend to occur over months to
Chronic renal insufficiency from primary renal parenchymal disease years, rather than hours to days. Long-term control of blood pressure
Chronic congestive heart failure from systolic or diastolic dysfunction can prevent these eventual complications. However, a hypertensive
Atherosclerotic coronary vascular disease (previous myocardial infarction, stable angina)
crisis cannot be diagnosed because no evidence exists that acute
reduction of blood pressure results in improvement in short- or
Cerebrovascular disease (history of transient ischemic attack or cerebrovascular accident)
long-term prognosis. Moreover, the presence of chronic hypertensive
end-organ complications in a patient with nonmalignant hypertension
does not imply the existence of a hypertensive crisis requiring rapid
control of blood pressure. The category of benign hypertension
with chronic complications includes hypertensive patients with
chronic renal insufficiency due to underlying primary renal
parenchymal disease, chronic congestive heart failure as a result
of either systolic or diastolic dysfunction, atherosclerotic coronary
vascular disease (stable angina or previous myocardial infarction),
or chronic cerebrovascular disease (previous transient ischemic
attacks or cerebrovascular accident). Long-term inadequate blood
pressure control increases the risk of further deterioration of end-
organ function in each of these conditions. However, no evidence
exists that rapid control of blood pressure is necessary to prevent fur-
ther complications. Therefore, a true hypertensive crisis does not exist.
8.4 Hypertension and the Kidney
FIGURE 8-4
Vascular lesions in malignant hypertension Distribution of vascular lesions in malignant
hypertension. Malignant hypertension is
essentially a systemic vasculopathy induced
Malignant hypertension
by severe hypertension. Fibrinoid necrosis and
proliferative endarteritis occur throughout the
body in numerous vascular beds, leading to
Fibrinoid necrosis Proliferative endarteritis ischemic changes. In the retina, striate hem-
orrhages and cotton-wool spots develop.
The finding of hypertensive neuroretinopathy
Occlusion of vessels is the clinical sine qua non of malignant
hypertension. Vascular lesions in the gastro-
intestinal tract (GI) can lead to hemorrhage
Ischemia or bowel necrosis. Hemorrhagic pancreatitis
also can occur. Cerebrovascular lesions can
lead to cerebral infarction or intracerebral
hemorrhage. Hypertensive encephalopathy
also can develop as a result of failure of
Retinal CNS Cardiac Renal GI Pancreatic autoregulation with cerebral overperfusion
Hemorrhages Intracerebral Left ventricular Glomerulosclerosis Hemorrhage Necrosis
Cotton-wool hemorrhage and edema (Fig. 8-22). Vascular lesions also
dysfunction Tubular atrophy Bowel necrosis Hemorrhage
spots Hypertensive Interstitial fibrosis can develop in the myocardium; however,
Papilledema encephalopathy acute hypertensive heart failure is largely the
result of acute diastolic dysfunction induced
by the marked increase in afterload that
accompanies malignant hypertension (Figs. 8-
24 and 8-25). CNS—central nervous system.
FIGURE 8-6
Tertiary hyperaldosteronism after treatment Tertiary hyperaldosteronism after treatment of malignant hyperten-
of malignant hypertension sion. The diagnosis of primary hyperaldosteronism must be made
with caution in patients with a history of malignant hypertension.
Malignant hypertension After successful treatment of malignant hypertension, plasma renin
Vascular
activity rapidly normalizes, whereas aldosterone secretion may
Antihypertensive
lesions heal treatment with remain elevated for up to a year. This phenomenon has been attrib-
Renal ischemia resolution of malignant uted to persistent adrenal hyperplasia induced by long-standing
hypertension hyperreninemia during the malignant phase [10]. During this phase
Activation
of renin- Renin levels of tertiary hyperaldosteronism, despite suppressed renin activity,
angiotensin decrease rapidly hypokalemia, metabolic alkalosis, and aldosterone levels that are
axis not suppressible, mimic primary hyperaldosteronism. Adrenal
imaging studies reveal bilateral nodular adrenal hyperplasia. With
Resolves slowly over
Bilateral adrenal hyperplasia 1 year after control continued long-term control of blood pressure this hyperaldostero-
of blood pressure nism remits spontaneously.
Nonsuppressible aldosteronism
Renal potassium-wasting
Metabolic alkalosis
with hypokalemia
FIGURE 8-14
1–0 Prognosis in accelerated hypertension versus malignant hypertension.
No papilledema In the original Keith and Wagener [11] classification of hypertensive
Papilledema retinopathy, malignant hypertension (grade IV) was defined by the
presence of papilledema, whereas the term accelerated hypertension
(grade III) was used when hemorrhages and exudates occurred in
0–8 the absence of papilledema. However, more recent studies indicate
that the prognosis is the same in hypertensive patients with striate
hemorrhages and cotton-wool spots whether or not papilledema is
Estimated survival
0
0 2 4 6 8 10
Years
FIGURE 8-17
Malignant hypertension is a progressive systemic vasculopathy in
which renal involvement is a relatively late finding. In this regard,
patients with malignant hypertension can present with a spectrum
of renal involvement ranging from normal renal function with minimal
FIGURE 8-16 (see Color Plate) albuminuria to end-stage renal disease (ESRD) indistinguishable
Micrograph of proliferative endarteritis in malignant hypertension from that seen in primary renal parenchymal disease. In patients
(musculomucoid intimal hyperplasia). In malignant nephrosclerosis, initially exhibiting preserved renal function, in the absence of adequate
the interlobular (cortical radial) arteries reveal characteristic lesions. blood pressure control, it is common to observe subacute deterio-
These lesions are variously referred to as proliferative endarteritis, ration of renal function to ESRD over a period of weeks to months.
endarteritis fibrosa, musculomucoid intimal hyperplasia, or the Transient deterioration of renal function with initial control of
onionskin lesion. The typical finding is marked thickening of the blood pressure is a well-documented entity in patients initially
intima that obstructs the vessel lumen. In severely affected vessels exhibiting mild to moderate renal impairment. Occasionally,
the luminal diameter may be reduced to the caliber of a single ery- patients with malignant hypertension initially exhibit oliguric acute
throcyte. Occasionally, complete obliteration of the lumen by a renal failure, necessitating initiation of dialysis within a few days of
superimposed fibrin thrombus occurs. hospitalization. Because erythrocyte casts sometimes appear in the
Traditionally, three patterns of intimal thickening have been urine sediment, malignant nephrosclerosis initially may be misdiag-
described [15]. (1) The onionskin pattern consists of pale layers of nosed as a rapidly progressive glomerulonephritis or systemic vasculitis
elongated concentrically arranged myointimal cells along with deli- [18]. Careful examination of the fundus for evidence of hypertensive
cate connective tissue fibrils that give rise to a lamellar appearance. neuroretinopathy confirms the diagnosis of malignant hypertension.
The media often appears as an attenuated layer stretched around Patients with malignant hypertension can also present with estab-
the expanded intima. (2) In the mucinous pattern, intimal cells are lished renal failure. Often, it is impossible to determine clinically
sparse. Seen is an abundance of lucent, faintly basophilic-staining whether a patient initially exhibiting hypertensive neuroretinopathy
amorphous material. (3) In fibrous intimal thickening, seen are few and renal failure has primary malignant hypertension or secondary
cells with an abundance of hyaline deposits, reduplicated bands of malignant hypertension with underlying primary renal parenchymal
elastica, and coarse layers of collagen. The renal histology in Blacks disease. The presence of normal-sized kidneys on ultrasonography
with malignant hypertension demonstrates a characteristic finding supports a diagnosis of primary malignant nephrosclerosis that
in the larger arterioles and interlobular arteries known as musculo- potentially is reversible with long-term blood pressure control.
mucoid intimal hyperplasia, with an abundance of cells and a small However, a renal biopsy may be required for definitive diagnosis.
amount of myxoid material (that is light blue in color on hema- All patients with malignant hypertension should receive aggressive
toxylin and eosin staining) between the cells [16, 17]. These various antihypertensive therapy to prevent further renal damage, regardless
intimal findings may represent progression over time from an ini- of the degree of renal impairment. Control of blood pressure in
tially cellular lesion to fibrosis of the intima. Electron microscopy patients with malignant hypertension and renal insufficiency often
demonstrates that in each type of intimal thickening the most abun- causes further deterioration of renal function, especially when the
dant cellular element is a modified smooth muscle cell. This cell is initial glomerular filtration rate (GFR) is less than 20 mL/min.
called a myointimal cell. Proliferative endarteritis is thought to However, a fall in GFR is not a contraindication to intensive blood
occur as a result of phenotypic modulation of medial smooth mus- pressure control aimed at normalization of blood pressure. Control
cle cells that dedifferentiate from the normal contractile phenotype of hypertension protects other vital organs, such as the heart and
to acquire a more embryologic proliferative-secretory phenotype. It brain, whose function cannot be replaced. Moreover, with rigid
has been proposed that the endothelial injury in malignant hyper- blood pressure control, renal function may eventually recover over
tension results in attachment of platelets with release of platelet- the ensuing months, even in patients with apparent ESRD owing to
derived growth factor (PDGF) that may induce the phenotypic primary malignant nephrosclerosis [19,20].
change in smooth muscle cells. PDGF stimulates chemotaxis of
medial smooth muscles to the intima, where they proliferate and
secrete mucopolysaccharide and later collagen and other extracellu-
lar matrix proteins, resulting in proliferative endarteritis, musculo-
mucoid hyperplasia, and ultimately fibrous intimal thickening.
(Hematoxylin and eosin stain, original magnification 100.)
Hypertensive Crises 8.11
FIGURE 8-19
INDICATIONS FOR PARENTERAL THERAPY Malignant hypertension must be treated expeditiously to prevent
IN MALIGNANT HYPERTENSION complications such as hypertensive encephalopathy, acute hypertensive
heart failure, and renal failure. The traditional approach to patients
with malignant hypertension has been the initiation of potent par-
Hypertensive encephalopathy enteral agents. Listed are the settings in which parenteral antihy-
Rapidly failing vision pertensive therapy is mandatory in the initial management of
Pulmonary edema
malignant hypertension. Parenteral therapy generally should be
used in patients with evidence of acute end-organ dysfunction or
Intracerebral hemorrhage
those unable to tolerate oral medications. Nitroprusside is the
Rapid deterioration of renal function
treatment of choice for patients requiring parenteral therapy.
Acute pancreatitis
Diazoxide, employed in minibolus fashion to avoid sustained over-
Gastrointestinal hemorrhage or acute abdomen from mesenteric vasculitis
shoot hypotension, may be advantageous in patients for whom
Patients unable to tolerate oral therapy because of intractable vomiting
monitoring in an intensive care unit is not feasible. It generally is
safe to reduce the mean arterial pressure by 20% or to a level of
160 to 170 mm Hg systolic over 100 to 110 mm Hg diastolic. The
use of a short-acting agent such as nitroprusside has obvious
advantages because blood pressure can be stabilized quickly at a
higher level if complications develop during rapid blood pressure
reduction. When no evidence of vital organ hypoperfusion is seen
during this initial reduction, the diastolic blood pressure can be
lowered gradually to 90 mm Hg over a period of 12 to 36 hours.
Oral antihypertensive agents should be initiated as soon as possible to
minimize the duration of parenteral therapy. The nitroprusside
infusion can be weaned as the oral agents become effective. The
cornerstone of initial oral therapy should be arteriolar vasodilators
such as calcium channel blockers, hydralazine, or minoxidil. Usually,
-blockers are required to control reflex tachycardia, and a diuretic
must be initiated within a few days to prevent salt and water retention,
in response to vasodilator therapy, when the patient’s dietary salt
intake increases. Diuretics may not be necessary as a part of initial
parenteral therapy because patients with malignant hypertension
often present with volume depletion (Fig. 8-20).
Many patients with malignant hypertension definitely require initial
parenteral therapy. However, some patients may not yet have evidence
of cerebral or cardiac dysfunction or rapidly deteriorating renal
function and therefore do not require instantaneous control of blood
pressure. These patients often can be managed with an intensive oral
regimen, often with a -blocker and minoxidil, designed to bring
the blood pressure under control within 12 to 24 hours. After the
immediate crisis has resolved and the patient’s blood pressure has
been controlled with initial parenteral therapy, oral therapy, or
both, lifelong surveillance of blood pressure is mandatory. If blood
pressure control lapses, malignant hypertension can recur even
after years of successful antihypertensive therapy. Triple therapy
with a diuretic, -blocker, and a vasodilator often is required to
maintain satisfactory long-term blood pressure control.
Hypertensive Crises 8.13
FIGURE 8-20
Role of diuretics to treat malignant hypertension Role of diuretics in the treatment of malignant hypertension.
Traditionally, it had been taught that patients with malignant
hypertension require potent parenteral diuretics in conjunction
Malignant hypertension with potent vasodilator therapy during the initial phase of manage-
ment of malignant hypertension. However, evidence now exists to
suggest that parenteral diuretic therapy during the acute management
Abrupt increase in blood pressure phase actually may be deleterious. In experimental animals, sponta-
neous natriuresis appears to be the initiating event in the transition
Pressure-induced natriuresis and diuresis from benign to malignant hypertension, and treatment with volume
expansion leads to resolution of the malignant phase [24]. Rapid
weight loss often occurs in patients with malignant hypertension,
Vicious
Intravascular volume depletion
circle
which is consistent with a pressure-induced natriuresis. In analgesic
nephropathy, profound volume depletion often accompanies malignant
hypertension, perhaps owing to tubular dysfunction with salt-wasting
Activation of the renin-angiotensin axis [5]. In this setting, restoration of normal volume status actually
lowers blood pressure and leads to resolution of the malignant
phase. Thus, some patients with malignant hypertension may benefit
Angiotensin II–mediated vasoconstriction
from a cautious trial of volume expansion. Volume depletion should
be suspected when there is exquisite sensitivity to vasodilator therapy
with a precipitous decrease in blood pressure at relatively low infusion
rates. Even patients with malignant hypertension complicated by
pulmonary edema may not be total-body salt and water overloaded.
Pulmonary congestion in this setting may result from acute hyper-
tensive heart failure caused by an acute decrease in left ventricular
(LV) compliance precipitated by severe hypertension. In this setting,
pulmonary edema occurs owing to a high LV end-diastolic pressure
with normal LV end-diastolic volume (Fig. 8-24). Thus, the need
for diuretic therapy during the initial phases of management of
malignant hypertension depends on a careful assessment of volume
status. Unless obvious fluid overload is present, diuretics should
not be given initially. Overdiuresis may result in deterioration of
renal function owing to superimposed volume depletion. Moreover,
volume depletion may further activate the renin-angiotensin system
and other pressor hormone systems. Although vasodilator therapy
will eventually result in salt and water retention by the kidneys, an
increase in total body sodium content cannot occur unless the
patient is given sodium. Eventually, during long-term treatment
with oral vasodilators, the use of diuretics becomes imperative to
prevent fluid retention and adequately control blood pressure.
8.14 Hypertension and the Kidney
FIGURE 8-21
Pathogenesis and treatment of hypertensive encephalopathy Pathogenesis and treatment of hypertensive encephalopathy.
Hypertensive encephalopathy is a hypertensive crisis in which acute
Malignant hypertension Sudden or severe nonmalignant cerebral dysfunction is attributed to sudden or severe elevation of
(hypertensive neuroretinopathy hypertension blood pressure [25–27]. Hypertensive encephalopathy is one of the
present) (hypertensive neuroretinopathy absent) most serious complications of malignant hypertension. However,
malignant hypertension (hypertensive neuroretinopathy) need not
be present for hypertensive encephalopathy to develop. Hypertensive
Sudden onset or severe hypertension encephalopathy also can occur in the setting of severe or sudden
hypertension of any cause, especially if an acute elevation of blood
pressure occurs in a previously normotensive person, eg, from
Failure of autoregulation of cerebral blood flow
(breakthrough of autoregulation)
postinfectious glomerulonephritis, catecholamine excess states, or
eclampsia. Under normal circumstances, autoregulation of the cerebral
microcirculation occurs, and therefore, cerebral blood flow remains
Forced vasodilation of cerebral arterioles constant over a wide range of perfusion pressures. However, in the
setting of sudden severe hypertension, autoregulatory vasoconstric-
tion fails and there is forced vasodilation of cerebral arterioles with
Endothelial damage Cerebral hyperperfusion endothelial damage, extravasation of plasma proteins, and cerebral
(increased permeability to (increased capillary hyperperfusion with the development of cerebral edema. This
plasma proteins) hydrostatic pressure) breakthrough of cerebral autoregulation underlies the development
of hypertensive encephalopathy. In patients with chronic hypertension,
structural changes occur in the cerebral arterioles that lead to a shift
Cerebral edema in the autoregulation curve such that much higher blood pressures
can be tolerated without breakthrough. This phenomenon may
explain the clinical observation that hypertensive encephalopathy
Hypertensive encephalopathy
occurs at much lower blood pressure in previously normotensive
(headache, vomiting, altered mental status, seizures)
persons than it does in those with chronic hypertension. Clinical
features of hypertensive encephalopathy include severe headache,
Prompt blood pressure reduction with nitroprusside blurred vision or occipital blindness, nausea, vomiting, and altered
mental status. Focal neurologic findings can sometimes occur. If
aggressive blood pressure reduction is not initiated, stupor, convul-
sions, and death can occur within hours. The sine qua non of
New or progressive focal findings Dramatic clincal improvement hypertensive encephalopathy is the prompt and dramatic clinical
(suspect primary central nervous (diagnostic of hypertensive improvement in response to antihypertensive drug therapy. When a
system process) encephalopathy) diagnosis of hypertensive encephalopathy seems likely, antihyper-
tensive therapy should be initiated promptly without waiting for
the results of time-consuming radiographic examinations. The goal
of therapy, especially in previously normotensive patients, should
be reduction of blood pressure to normal or near-normal levels as
quickly as possible. Theoretically, cerebral blood flow could be
jeopardized by rapid reduction of blood pressure in patients with
chronic hypertension in whom the lower limit of cerebral blood
flow autoregulation is shifted to a higher blood pressure. However,
clinical experience has shown that prompt blood pressure reduction
with the avoidance of frank hypotension is beneficial in patients
with hypertensive encephalopathy [25]. Of the conditions in the
differential diagnosis of hypertension with acute cerebral dysfunc-
tion, only cerebral infarction might be adversely affected by the
abrupt reduction of blood pressure. Pharmacologic agents that
have rapid onset and short duration of action such as sodium
nitroprusside should be used so that the blood pressure can be
titrated carefully, with close monitoring of the patient’s neurologic
status. A prompt improvement in mental status with blood pressure
reduction confirms the diagnosis of hypertensive encephalopathy.
Conversely, when blood pressure reduction is associated with new
or progressive focal neurologic deficits, the presence of a primary
central nervous system event, such as cerebral infarction, should be
considered.
Hypertensive Crises 8.15
FIGURE 8-22
CAUSES OF HYPERTENSIVE ENCEPHALOPATHY Hypertensive encephalopathy can complicate malignant hyperten-
sion of any cause. However, not all patients with hypertensive
encephalopathy have hypertensive neuroretinopathy, indicating the
Malignant hypertension of any cause presence of malignant hypertension. In fact, hypertensive
Acute glomerulonephritis, especially postinfectious encephalopathy most commonly occurs in previously normotensive
Eclampsia
persons who experience a sudden onset or worsening of hyperten-
sion. In acute postinfectious glomerulonephritis, the abrupt onset
Catecholamine-induced hypertensive crises
of even moderate hypertension may cause breakthrough of
Pheochromocytoma
autoregulation of cerebral blood flow, resulting in hypertensive
Monoamine oxidase inhibitor–tyramine interactions
encephalopathy. Eclampsia can be viewed as a variant of hyperten-
Abrupt withdrawal of centrally acting 2-agonists
sive encephalopathy that complicates preeclampsia. Moreover,
Phenylpropanolamine overdose
hypertensive encephalopathy is a common complication of cate-
Cocaine-hydrochloride or alkaloid (crack cocaine) intoxication cholamine-induced hypertensive crises such as pheochromocytoma,
Phencyclidine (PCP) poisoning monoamine oxidase inhibitor–tyramine interactions, clonidine
Acute lead poisoning in children withdrawal, phencyclidine (PCP) poisoning, and phenyl-
High-dose cyclosporine for bone marrow transplantation in children propanolamine overdose. Cocaine use also can induce a sudden
Femoral lengthening procedures increase in blood pressure accompanied by hypertensive
Scorpion envenomation in children encephalopathy. In children, acute lead poisoning, high-dose
Acute renal artery occlusion from thrombosis or embolism cyclosporine for bone marrow transplantation, femoral lengthening
Atheroembolic renal disease (cholesterol embolization) procedures, and scorpion envenomation may be accompanied by
Recombinant erythropoietin therapy the sudden onset of hypertension with hypertensive encephalopa-
Transplantation renal artery stenosis thy. Acute renal artery occlusion resulting from thrombosis or renal
Acute renal allograft rejection embolism can induce hypertensive encephalopathy. Likewise,
Paroxysmal hypertension in acute or chronic spinal cord injuries atheroembolic renal disease (cholesterol embolization) can cause a
Post–coronary artery bypass or post–carotid endarterectomy hypertension sudden increase in blood pressure complicated by encephalopathy.
Recombinant erythropoietin therapy occasionally results in
encephalopathy and seizures. This complication is unrelated to the
extent or rate of increase in hematocrit; however, it is associated
with a rapid increase in blood pressure, especially if the patient
was normotensive previously. Transplantation renal artery stenosis
or acute renal allograft rejection may cause sudden severe hyper-
tension with encephalopathy. Hypertensive encephalopathy may
complicate acute or chronic spinal cord injury. Sudden elevation of
blood pressure occurs owing to autonomic stimulation by bowel or
bladder distention or noxious stimulation in a dermatome below
the level of the injury. Hypertensive encephalopathy also may com-
plicate the rebound hypertension that follows coronary artery
bypass procedures or carotid endarterectomy.
8.16 Hypertension and the Kidney
pressure, mm Hg
200 120 5.0
Mean arterial
150 B B
90
100 NP
100 60 2.5 NP
50
30 0
AHHF NF
0 0 0 P<0.005 P<0.005
NS NS NS
Stroke work index, g m/m2 LVEDP, mm Hg LVEDV, mL/m2
LVEDP, mm Hg
9 30
45 NP
6 NP 20
B B NP
75 30 100 10
3 B NP
15 0 0
0 0 0 P<0.005 NS P<0.005 P<0.025
NS P<0.005 NS
Hemodynamic parameters at baseline (B) and during nitroprusside (NP) infusion
A Baseline hemodynamics in acute hypertensive heart failure (AHHF) vs no failure (NF) B
FIGURE 8-24
Treatment of acute hypertensive heart failure. The left ventricular
60
(LV) end-diastolic pressure-volume relationships (compliance
curves) in acute hypertensive heart failure (AHHF) before and after
50 treatment with sodium nitroprusside are represented schematically.
Left ventricular end-diastolic
al
rm pulmonary edema. Treatment with sodium nitroprusside causes
10 No
a reduction in the elevated systemic vascular resistance, with a
concomitant decrease in impedance to LV ejection. As a result, LV
0 compliance improves. Pulmonary edema resolves owing to a reduc-
40 80 120 160 200 240 tion in LVEDP, despite the fact that LVEDV actually increases dur-
Left ventricular end-diastolic volume, mL/m2 ing treatment. Sodium nitroprusside is the preferred drug for treat-
ment of AHHF. There is no absolute blood pressure goal. The infu-
sion should be titrated until signs and symptoms of pulmonary
edema resolve or the blood pressure decreases to hypotensive lev-
els. Rarely is it necessary to lower the blood pressure to this extent,
however, because reduction to levels still within the hypertensive
range is usually associated with dramatic clinical improvement.
Although hemodynamic monitoring is not always required, it is
essential in patients in whom concomitant myocardial ischemia or
compromised cardiac output is suspected. After the hypertensive
crisis has been controlled and pulmonary edema has resolved, oral
antihypertensive therapy can be substituted as the patient is
weaned from the nitroprusside infusion. As in the treatment of
hypertensive patients with chronic congestive heart failure symp-
toms owing to isolated diastolic dysfunction, agents such as -
blockers, angiotension-converting enzyme inhibitors, or calcium
channel blockers may represent logical first-line therapy. These
agents directly improve diastolic function in addition to reducing
systemic blood pressure. In patients with malignant hypertension
or resistant hypertension, however, adequate control of blood pres-
sure may require therapy with more than one drug. Potent direct-
acting vasodilators such as hydralazine or minoxidil may be used
in conjunction with a -blocker to control reflex tachycardia and
a diuretic to prevent reflex salt and water retention.
8.18 Hypertension and the Kidney
FIGURE 8-25
Aortic dissection
Aortic dissection. Classification of aortic dissection is based on the
presence or absence of involvement of the ascending aorta [29].
Transverse
aortic arch Descending The dissection is defined as proximal if there is involvement of the
aorta ascending aorta. The primary intimal tear in proximal dissection
may arise in the ascending aorta, transverse aortic arch, or descending
Ascending aorta. In distal dissections, the process is confined to the descending
aorta
aorta without involvement of the ascending aorta, and the primary
intimal tear occurs most commonly just distal to the origin of the
left subclavian artery. Proximal dissections account for approximately
57% and distal dissections 43% of all acute aortic dissections.
Acute aortic dissection is a hypertensive crisis requiring immediate
antihypertensive treatment aimed at halting the progression of the
dissecting hematoma. The three most frequent complications of
aortic dissection are acute aortic insufficiency, occlusion of major
arterial branches, and rupture of the aorta with fatal hemorrhage
(location of rupture-hemorrhage: ascending aorta–hemopericardium
Proximal Distal with tamponade, aortic arch–mediastinum, descending thoracic
(Type A) (Type B) aorta–left pleural space, abdominal aorta– retroperitoneum).
Patients with acute dissection should be stabilized with intensive
antihypertensive therapy to prevent life-threatening complications
before diagnostic evaluation with angiography. The initial therapeutic
goal is the elimination of pain that correlates with halting of the
dissection, and reduction of the systolic pressure to the 100 to 120
mm Hg range or to the lowest level of blood pressure compatible
with the maintenance of adequate renal, cardiac, and cerebral
perfusion [30]. Even in the absence of systemic hypertension the
blood pressure should be reduced. Antihypertensive therapy should
be designed not only to lower the blood pressure but also to decrease
the steepness of the pulse wave. The most commonly used treatment
regimens consist of initial treatment with intravenous -blockers
such as propranolol, metoprolol, or esmolol followed by treatment
with sodium nitroprusside. After control of the blood pressure,
angiography or transesophageal echocardiography, or both, should
be performed. The need for surgical intervention is determined based
on involvement of the ascending aorta. In proximal dissections, sur-
gical therapy is clearly superior to medical therapy alone (70% vs
26% survival, respectively). In contrast, in patients with distal
dissection, intensive drug therapy alone leads to an 80% survival
rate compared with only 50% in patients treated surgically. The
explanation for the advantage of surgical therapy in proximal
dissection is probably that the risks of complications such as cerebral
ischemia, acute aortic insufficiency, and cardiac tamponade are
higher and managed more effectively with surgery. Because these
complications do not occur in distal dissection, in the absence of
occlusion of a major arterial branch or development of a saccular
aneurysm during long-term follow-up, medical therapy is preferred.
Patients with distal dissection tend to be elderly with more advanced
aortic atherosclerosis and therefore are at higher risk of complications
from operative intervention. (Adapted from Wheat [29];
with permission.)
Hypertensive Crises 8.19
FIGURE 8-28
Hypertensive crises after carotid endarterectomy Hypertensive crisis after carotid endarterectomy. Hypertension in
the immediate postoperative period occurs in up to 60% of patients
Carotid endarterectomy after carotid endarterectomy [38]. A history of chronic hypertension,
especially if the blood pressure is poorly controlled preoperatively,
dramatically increases the risk of postoperative hypertension. The
mechanism of post-endarterectomy hypertension is unknown. The
Postoperative hypertension Repair of high-grade
(mechanism unknown) stenosis incidence of hypertension is the same whether or not the carotid
sinus nerve is preserved. Hypertension after endarterectomy is a
hypertensive crisis because it is associated with increased risk of
Sudden increase in perfusion pressure intracerebral hemorrhage and increases the postoperative mortality
in arteriocapillary bed that was rate [39]. A mechanism for the development of post–carotid
previously protected from hypertension endarterectomy cerebral hemorrhage owing to postoperative hyper-
tension has been proposed. In patients with high-grade carotid
artery stenosis, the distal cerebral circulation has been relatively
Failure of autoregulation of cerebral blood flow
(breakthrough of autoregulation) protected from systemic hypertension. In this regard, the autoregu-
latory curve may be shifted to a lower threshold to compensate for
reduced perfusion pressure. After repair of the obstructing lesion, a
Overperfusion of cerebral circulation relative increase in perfusion pressure occurs in the cerebral arterio-
capillary bed. In the setting of systemic hypertension the increased
blood flow and perfusion pressure may overwhelm the autoregula-
Vessel rupture tory mechanisms. Overperfusion and rupture may then occur,
(hemorrhage and infarction)
resulting in hemorrhagic infarction. Because poor preoperative blood
pressure control increases the risk of postoperative hypertension,
strict blood pressure control is essential before elective carotid
endarterectomy. Furthermore, intra-arterial pressure should be
monitored in the operating room and in the immediate postoperative
period. Ideally, the patient should be awake and extubated before
reaching the recovery room so that serial neurologic examinations
can be performed to assess for the development of focal deficits.
When the systolic blood pressure exceeds 200 mm Hg, an intravenous
infusion of sodium nitroprusside should be initiated to maintain
the systolic blood pressure between 160 and 200 mm Hg. The use
of a short-acting parenteral agent is imperative to avoid overshoot
hypotension and cerebral hypoperfusion.
8.22 Hypertension and the Kidney
Intracerebral hemorrhage
Hypertension may
help maintain
blood flow in
ischemic areas
Cerebral hyperperfusion Impairment of autoregulation of Increased risk of rebleeeding
with cerebral edema blood flow in ischemic area (expansion of hematoma)
surrounding hematoma
(shift of lower limit of
autoregulation)
Sodium nitroprusside
FIGURE 8-30
Hypertensive crises due to intracerebral hemorrhage. Chronic hypertension is the major
risk factor for intracerebral hemorrhage. The most common sites of hemorrhage are the
small-diameter penetrating cerebral end-arteries in the basal ganglia, pons, thalamus, cere-
bellum, and deep hemispheric white matter. Lacunar infarcts arise from the same vessels
and are similarly distributed. Intracerebral hemorrhage characteristically begins abruptly
with headache and vomiting followed by steadily increasing focal neurologic deficits and
alteration of consciousness [44]. More than 90% of hemorrhages rupture through brain
parenchyma into the ventricles, producing bloody cerebrospinal fluid. Patients presenting
with intracerebral hemorrhage are invariably hypertensive. In contrast to cerebral infarction,
the hypertension does not tend to decrease spontaneously during the first week. The patient’s
condition worsens steadily over a period of minutes to days until either the neurologic deficit
stabilizes or the patient dies. When death occurs, most often it is due to herniation caused
by the expanding hematoma and surrounding edema. Treatment of hypertension in the setting
of intracerebral hemorrhage is controversial. An increase in intracranial pressure accompanied
by a reflex increase in systemic blood pressure almost always occurs. Because cerebral perfusion
pressure is a function of the difference between arterial pressure and intracranial pressure,
reduction of blood pressure could compromise cerebral perfusion. Moreover, as in cerebral
infarction, autoregulation is impaired in the area of marginal ischemia surrounding the
hemorrhage. In contrast, cerebral vasogenic edema may be exacerbated by hypertension.
Moreover, hypertension may increase the risk of rebleeding with expansion of the hematoma.
Thus, in deciding to treat hypertension in the setting of intracerebral hemorrhage, a pre-
carious balance must be struck between beneficial reduction in cerebral edema on the one
hand, and deleterious reduction of cerebral blood flow on the other. Studies have shown
that the lower limit of autoregulation after intracerebral hemorrhage is approximately
80% of the initial blood pressure; therefore, a 20% decrease in mean arterial pressure
should be considered the maximal goal of blood pressure reduction during the acute stage
[45]. Antihypertensive therapy should be undertaken only in conjunction with intracranial
and intra-arterial pressure monitoring to allow for assessment of cerebral perfusion pressure.
The short duration of action of nitroprusside makes its use preferable over other agents
with a longer duration of action and the risk of sustained overshoot hypotension, despite
the theoretic concern that nitroprusside treatment could lead to an increase in intracranial
pressure by way of dilation of cerebral veins and arteries.
8.24 Hypertension and the Kidney
Pheochromocytoma
Acute treatment with
Episodic release of nitroprusside or phentolamine
catecholamines followed by β-blockers
Paroxysmal hypertension
FIGURE 8-31
Hypertensive crisis with pheochromocytoma. In most patients, pheochromocytoma causes
sustained hypertension that sometimes becomes malignant as evidenced by the presence of
hypertensive neuroretinopathy. Paroxysmal hypertension is present in approximately 30%
of patients. Spontaneous paroxysms consist of severe hypertension, headache, profuse
diaphoresis, pallor, coldness of hands and feet, palpitations, and abdominal discomfort.
Paroxysmal hypertension in pheochromocytoma represents a hypertensive crisis because it
can lead to intracerebral hemorrhage, hypertensive encephalopathy, or acute hypertensive
heart failure with pulmonary edema. Prompt control of the blood pressure is mandatory to
prevent these life-threatening complications. Although the nonselective -blocker phentolamine
often is cited as the treatment of choice for pheochromocytoma-related hypertensive crises,
sodium nitroprusside is equally effective and easier to administer [46]. Only after blood
pressure has been controlled with nitroprusside or phentolamine can intravenous -blockers,
such as esmolol, labetalol, or propranolol, be used to control tachycardia or arrhythmias.
After resolution of the hypertensive crisis, oral antihypertensive agents should be instituted
as the parenteral agents are weaned. The nonselective -blocker phentolamine usually is
administered orally for 1 to 2 weeks before elective surgery. After adequate -blockade is
achieved, based on the presence of moderate orthostatic hypotension, oral -blocker therapy
can be initiated as needed to control tachycardia. Oral or intravenous -blockers should
never be administered before adequate -blockade. Doing so can precipitate a hypertensive
crisis as the result of intense -adrenergic vasoconstriction that is no longer opposed by
-adrenergic vasodilatory stimuli. Careful attention to volume status also is mandatory in
the preoperative period. Catecholamine-induced hypertension induces a pressure natriure-
sis with volume depletion. Moreover, alleviation of the chronic state of vasoconstriction by
-blockade results in increases in both arterial and venous capacitances. Preoperative volume
expansion, guided by measurement of central venous pressure or wedge pressure often is
advocated to reduce the risk of intraoperative hypotension [47]. During surgery, rapid and
wide fluctuations in blood pressure should be anticipated. Careful intraoperative monitoring
of intra-arterial pressure, cardiac output, wedge pressure, and systemic vascular resistance
is mandatory to manage the rapid swings in blood pressure. Despite adequate preoperative
-blockade with phenoxybenzamine, severe hypertension can occur during intubation or
intraoperatively as a result of catecholamine release during tumor manipulation. Sodium
nitroprusside is the treatment of choice for controlling acute hypertension owing to
pheochromocytoma during surgery. At the opposite end of the spectrum, profound intra-
operative hypotension can occur. Hypotension or even frank shock can supervene after
isolation of tumor venous drainage from the circulation, with resultant abrupt decrease in
circulating catecholamine levels. Volume expansion is the treatment of choice for intraop-
erative and postoperative hypotension [46]. Pressors only should be employed when
hypotension is unresponsive to volume repletion.
Hypertensive Crises 8.25
Accumulation of catecholamines in
Hepatic monamine
nerve terminal storage granules
oxidase inhibition
with decreased
Increased circulating
oxidative metabolism
tyramine level
of tyramine
Massive release of catecholamines Tachyarrhythmias
Vasoconstriction
(increased systemic vascular resistance)
FIGURE 8-32
Hypertensive crises secondary to monoamine oxidase inhibitor–tyramine interactions.
Severe paroxysmal hypertension complicated by intracerebral or subarachnoid hemorrhage,
hypertensive encephalopathy, or acute hypertensive heart failure can occur in patients treated
with monoamine oxidase (MOA) inhibitors after ingestion of certain drugs or tyramine-
containing foods [48,49]. Because MAO is required for degradation of intracellular amines,
including epinephrine, norepinephrine, and dopamine, MAO inhibitors lead to accumulation
of catecholamines within storage granules in nerve terminals. The amino acid tyramine is a
potent inducer of neurotransmitter release from nerve terminals. As a result of inhibition
of hepatic MAO, ingested tyramine escapes oxidative degradation in the liver. In addition,
the high circulating levels of tyramine provoke massive catecholamine release from nerve
terminals, resulting in vasoconstriction and a paroxysm of severe hypertension. A hyper-
adrenergic syndrome resembling pheochromocytoma then ensues. Symptoms include severe
pounding headache, flushing or pallor, profuse diaphoresis, nausea, vomiting, and extreme
prostration. The mean increase in blood pressure is 55 mm Hg systolic and 30 mm Hg
diastolic [49]. The duration of the attacks varies from 10 minutes to 6 hours. Attacks can
be provoked by the ingestion of foods known to be rich in tyramine: natural or aged
cheeses, Chianti wines, certain imported beers, pickled herring, chicken liver, yeast, soy
sauce, fermented sausage, coffee, avocado, banana, chocolate, and canned figs.
Sympathomimetic amines in nonprescription cold remedies also can provoke neurotransmitter
release in patients treated with an MAO inhibitor. Either sodium nitroprusside or phentolamine
can be used to manage this type of hypertensive crisis. Because most patients are normotensive
before onset of the crisis the goal of blood pressure treatment should be normalization of
the blood pressure. After blood pressure control, intravenous -blockers may also be
required to control heart rate and tachyarrhythmias. Because the MAO inhibitor–tyramine
hypertensive crisis is self-limited, parenteral antihypertensive agents can be weaned without
institution of oral antihypertensive agents.
8.26 Hypertension and the Kidney
FIGURE 8-33
Mechanism of action and metabolism of nitroprusside Mechanism of action and metabolism of nitroprusside. Sodium
nitroprusside is the drug of choice for management of virtually all
+
NO hypertensive crises, including malignant hypertension, hypertensive
encephalopathy, acute hypertensive heart failure, intracerebral
CN- CN- hemorrhage, perioperative hypertension, catecholamine-related
t1/2=3–4 min
Fe++ Free cyanide hypertensive crises, and acute aortic dissection (in combination
CN- CN- Metabolized by (CN-) with a -blocker) [1,50]. Sodium nitroprusside is a potent intravenous
direct combination hypotensive agent with immediate onset and brief duration of action.
CN- with -SH groups The site of action is the vascular smooth muscle. Nitroprusside has
in erythrocytes
and tissues Thiocyanate no direct action on the myocardium, although it may affect cardiac
Nitroprusside performance indirectly through alterations in systemic hemodynamics.
t1/2=1 wk
Combination of nitroso Nitroprusside is an iron (Fe) coordination complex with five cyanide
group with cysteine moieties and a nitroso (NO) group. The nitroso group combines with
Renal excretion
cysteine to form nitrosocysteine and other short-acting S-nitrosothiols.
Nitrosocysteine
Nitrosocysteine is a potent activator of guanylate cyclase, thereby
causing cyclic guanosine monophosphate (cGMP) accumulation
Activation of
and relaxation of vascular smooth muscle [51,52]. Nitroprusside
guanylate cyclase causes vasodilation of both arteriolar resistance vessels and venous
capacitance vessels. Its hypotensive action is a result of a decrease
t1/2=2–3min
in systemic vascular resistance. The combined decrease in preload
Metabolized by
cGMP accumulation in and afterload reduces myocardial wall tension and myocardial oxygen
cGMP-specific
vascular smooth muscle
phosphodiesterases demand. The net effect of nitroprusside on cardiac output and
heart rate depends on the intrinsic state of the myocardium. In
patients with left ventricular (LV) systolic dysfunction and elevated
LV end-diastolic pressure, nitroprusside causes an increase in stroke
Venodilation Dilation of arteriolar resistance vessels volume and cardiac output as a result of afterload reduction and
(increased venous capacitance) (decreased systemic vascular resistance)
heart rate may actually decrease in response to improved cardiac
performance. In contrast, in the absence of LV dysfunction, venodi-
lation and preload reduction can result in a reflex increase in sym-
Decreased blood pressure
pathetic tone and heart rate. For this reason, nitroprusside must be
Afterload reduction
used in conjunction with a -blocker in acute aortic dissection. The
hypotensive action of nitroprusside appears within seconds and is
immediately reversible when the infusion is stopped. The cGMP in
vascular smooth muscle is rapidly degraded by cGMP-specific phos-
phodiesterases. Nitroprusside is rapidly metabolized with a half-life
(t1/2) of 3 to 4 minutes. Cyanide is formed as a short-lived intermediate
product by direct combination with sulfhydryl (SH) groups in ery-
throcytes and tissues. The cyanide groups are rapidly converted to
thiocyanate by the liver in a reaction in which thiosulfate acts as a
sulfur donor. Thiocyanate is excreted by the kidneys, with a half-life
of 1 week in patients with normal renal function. Thiocyanate
accumulation and toxicity can occur when a high-dose or prolonged
infusion is required, especially in patients with renal insufficiency.
When these risk factors are present, thiocyanate levels should be
monitored and the infusion stopped if the level is over 10 mg/dL.
Thiocyanate toxicity is rare in patients with normal renal function
requiring less than 3 µg/kg/min for less than 72 hours [50]. Cyanide
poisoning is a very rare complication, unless hepatic clearance of
cyanide is impaired by severe liver disease or massive doses of
nitroprusside (over 10 µg/kg/min) are used to induce deliberate
hypotension during surgery [50].
VARIOUS ANTIHYPERTENSIVE DRUGS FOR PARENTERAL USE IN THE MANAGEMENT OF MALIGNANT HYPERTENSION AND OTHER HYPERTENSIVE CRISES
FIGURE 8-34
Mechanism of Method of
Drug action Onset of action Peak effect Duration of action administration Advantages Disadvantages Side effects Comments
Sodium Direct arteriolar Instantaneous Immediate 2–3 min after infusion Continuous infusion: Precise titration of Monitoring in ICU Nausea, vomiting, Discontinue if
nitroprusside vasodilation and stopped Initial, 0.5 µg/kg/min BP. Consistently required apprehension. thiocyanate level
venodilation Average, 3 µg/kg/min effective when Thiocyanate toxic- >10 mg/dL
Maximum, 10 µg/kg/min other drugs fail. ity with prolonged
Parenteral agent infusion, renal
of choice for insufficiency
hypertensive crises
Diazoxide Direct arteriolar 1–2 min 10–15 min 4–24 h IV minibolus: 50–100 mg Long duration of Sustained Nausea, vomiting, Contraindicated in
vasodilation IV given rapidly over action. Constant hypotension with hyperglycemia, aortic dissection,
5–10 min. Total dose, monitoring not CNS and myocar- myocardial cerebrovascular
150–600 mg required after ini- dial ischemic can ischemia, uterine disease, myocardial
tial titration occur. Reflex sym- atony ischemia
pathetic cardiac
stimulation
Trimethaphan Ganglionic blockage Minutes Minutes 5–10 min after infu- Continuous infusion: Blocks barorecep- Parasympathetic Dry mouth, blurred Tilt-bed enhances
camsylate with venodilation and sion stopped Initial, 0.5 mg/min tor-mediated blockade vision, urinary effect; tachyphylaxis
arteriolar vasodilation Maximum, 5.0 mg/min sympathetic retention, paralyt- after 24–48 h;
cardiac stimulation ic ileus, respirato- contraindicated
ry arrest in respiratory
insufficiency and
glaucoma;
potentiates
succinylcholine
Nitroglycerin Direct venodilation at Minutes Minutes 1–5 min after infusion Continuous infusion: Theoretic advan- Fails to control BP Headache, nausea, Dilates intracoronary
vascular resistance
Reserpine Sympathetic dysfunc- 2–4 h 2–4 h 2–8 h Intramuscular: None—not Delayed onset Nasal congestion, Contraindicated in
tion owing to central Initial, 0.5–1.0 mg recommended for of action, CNS sedation, hypertensive
and peripheral cate- 2–4 mg over 3 h use in hyperten- unpredictable bradycardia, encephalopathy,
cholamine dysfunc- 2–4 mg over 3–12 h sive crises hypotensive effect exacerbates pep- CNS catastrophe,
tion; decreased SVR, tic ulcer disease, cumulative hypoten-
decreased CO depression sive response
Normotensives (n=10) considerable safety margin exists for blood pressure reduction
150 before cerebral autoregulation of blood flow fails, even in patients
with severe untreated hypertension. Moreover, symptoms of cerebral
ischemia did not develop until the blood pressure was reduced
100 substantially below the autoregulatory threshold because even in
the face of reduced blood flow, cerebral metabolism can be main-
79
72 tained and ischemia prevented by an increase in oxygen extraction
50 ± 45
10% ±
74 by the tissues. The lowest tolerated MAP, defined as the level at
±
29% ± 46 45
12% 6% ± ±
which mild symptoms of brain hypoperfusion developed (ie, yawning,
16% 12% nausea, and hyperventilation), was 65 ±10 mm Hg in patients with
0
uncontrolled hypertension, 53 ±18 mm Hg in persons with treated
Baseline mean Lower limit of Lowest tolerated mean hypertension, and 43 ±8 mm Hg in normotensive persons. The
arterial pressure autoregulation arterial pressure
numbers on the bars illustrate that these MAP values were approx-
imately 45% of the baseline blood pressure level in each group.
FIGURE 8-35 Thus, symptoms of cerebral hypoperfusion did not occur until the
Risks of rapid blood pressure reduction in hypertensive crises. It MAP was reduced by an average of 55% from the presenting level.
has been argued over the years that rapid reduction of blood pressure In the reported cases of neurologic sequelae sustained during rapid
in the setting of hypertensive crises may have a detrimental effect reduction of blood pressure in patients with hypertensive crises, the
on cerebral perfusion because the autoregulatory curve of cerebral MAP was reduced by more than 55% of the presenting blood pres-
blood flow is shifted upward in patients with chronic hypertension. sure. This frank hypotension was sustained for a period of hours to
Conversely, this upward shift protects the brain from hypertensive days, mostly as a result of treatment with bolus diazoxide, which
encephalopathy in the face of severe hypertension. However, this has long duration of action [54]. The general guideline for acute
autoregulatory shift could be deleterious when the blood pressure blood pressure reduction in the treatment of hypertensive crises is
is reduced acutely because the lower limit of autoregulation is shifted reduction of systolic blood pressure to 160 to 170 mm Hg and
to a higher level of blood pressure. Theoretically, aggressive reduction diastolic pressure to 100 to 110 mm Hg, which equates to MAPs
of the blood pressure in chronically hypertensive patients could of 120 to 130 mm Hg. Alternatively, the initial goal of antihyper-
induce cerebral ischemia. Nonetheless, in clinical practice, moderately tensive therapy can be a 20% reduction of the MAP from the
controlled reduction of blood pressure in patients with hypertensive patient’s initial level at presentation. This level should be above the
crises rarely causes cerebral ischemia. This clinical observation may predicted autoregulatory threshold. Once this goal is obtained the
be explained by the fact that even though the cerebral autoregulatory patient should be evaluated carefully for evidence of cerebral
curve is shifted in patients with chronic hypertension, a considerable hypoperfusion. Further reduction of blood pressure can then be
difference still exists between the initial blood pressure at presentation undertaken in a controlled fashion based on the overall clinical
and the lower limit of autoregulation. Illustrated are the differences status of the patient. Of course, in previously normotensive persons
in the lower autoregulatory threshold during blood pressure reduction in whom hypertensive crises develop, such as patients with acute
with trimethaphan in patients with uncontrolled hypertension and glomerulonephritis complicated by hypertensive encephalopathy,
treated hypertension, and those in the control group [53]. At least the autoregulatory curve should not yet be shifted. Therefore, the
eight of the 13 patients with uncontrolled hypertension had hyper- initial goal of therapy should be normalization of blood pressure.
tensive neuroretinopathy consistent with malignant hypertension. In terms of avoiding sustained overshoot hypotension in the treat-
The control groups included nine patients with a history of severe ment of hypertensive crises, the use of potent parenteral agents
hypertension in the past whose blood pressure was effectively with short duration of action, such as sodium nitroprusside or
controlled at the time of study and a group of 10 normotensive intravenous nitroglycerin, has obvious advantages. If neurologic
persons. Baseline mean arterial pressures (MAPs) in the three sequelae develop during blood pressure reduction with these agents,
groups were 145 ±17 mm Hg, 116 ±18 mm Hg, and 96 ±17 mm these sequelae can be reversed quickly by tapering the infusion and
Hg, respectively. The lower limit of blood pressure at which autoreg- allowing the blood pressure to stabilize at a higher level. Agents
ulation failed was 113 ±17 mm Hg in persons with uncontrolled with a long duration of action have an inherent disadvantage in
hypertension, 96 ±17mm Hg in persons with treated hypertension, that excessive reduction of blood pressure cannot be reversed
and 73 ±9 mm Hg in normotensive persons. Although the absolute easily. Thus, bolus diazoxide, labetalol, minoxidil, hydralazine,
level at which autoregulation failed was substantially higher in converting enzyme inhibitors, calcium channel blockers, and
patients with uncontrolled hypertension, the percentage reduction central 2-agonists should be used with extreme caution in patients
in blood pressure from the baseline level required to reach the requiring rapid but controlled blood pressure reduction in the
autoregulatory threshold was similar in each group. The numbers setting of hypertensive crises. (Adapted from Strandgaard [53];
on the bars indicate the percentage reduction from the baseline with permission.)
Hypertensive Crises 8.29
References
1. Nolan CR, Linas SL: Malignant hypertension and other hypertensive 31. Goldman L, Caldera DL: Risks of general anesthesia and elective
crises. In Diseases of the Kidney, edn 6. Edited by Schrier RW, operation in the hypertensive patient. Anesthesiology 1979, 50:285.
Gottschalk CW. Boston: Little, Brown; 1997:1475–1554. 32. Breslin DR, et al.: Elective surgery in hypertensive patients: preoperative
2. Derow HA, et al.: The nature of malignant hypertension. Ann Intern considerations. Surg Clin North Am 1970, 50:585.
Med 1941, 14:1768. 33. Prys-Roberts C: Hypertension and anesthesia: fifty years on.
3. Perez-Fontan M, et al.: Idiopathic IgA nephropathy presenting as Anesthesiology 1979, 50:281.
malignant hypertension. Am J Nephrol 1986, 6:482. 34. Reichgott MJ: Hypertension in the perioperative patient. In Medical Care
4. Holland NH, et al.: Hypertension in children with chronic of the Surgical Patient: A Problem-Oriented Approach to Management.
pyelonephritis. Kidney Int 1975, 8(suppl):S234. Edited by Goldman DR, Brown FH, Levy KW et al. Philadelphia:
5. Nanra RS, et al.: Analgesic nephropathy: etiology, clinical syndrome, Lippincott; 1982:78–86.
and clinicopathologic correlations in Australia. Kidney Int 1978, 13:79. 35. Estafanous RG, Tarazi RC: Systemic arterial hypertension associated
6. Davis BA, et al.: Prevalence of renovascular hypertension in patients with cardiac surgery. Am J Cardiol 1980, 46:685.
with grade III or grade IV hypertensive neuroretinopathy. N Engl J 36. Fouad FM, et al.: Hemodynamics of postmyocardial revascularization
Med 1979, 301:1273. hypertension. Am J Cardiol 1978, 41:564.
7. Lim K, et al.: Malignant hypertension in women of childbearing age 37. Cohn JN: Paroxysmal hypertension and hypovolemia. N Engl J Med
and its relation to the contraceptive pill. Br Med J 1987, 294:1057. 1966, 275:643.
8. Traub YM, et al.: Hypertension and renal failure (scleroderma renal 38. Skydell JL, et al.: Incidence and mechanism of post-carotid
crisis) in progressive systemic sclerosis. Medicine 1983, 62:335. endarterectomy hypertension. Arch Surg 1987, 122:1153.
9. Cacoub P, et al.: Malignant hypertension with antiphospholipid syndrome 39. Towne JB, Bernhard VM: The relationship of postoperative hypertension
without overt lupus nephritis. Clin Exp Rheumatol 1993, 11:479–485. to complications after carotid endarterectomy. Surgery 1980, 88:575.
10. McAllister RG, et al.: Malignant hypertension: effect of therapy on 40. Wallace JD, et al.: Blood pressure after stroke. JAMA 1981, 246:2177.
renin and aldosterone. Circ Res 1971, 28(suppl II):II–160.
41. Britton M, et al.: Hazards of therapy for excessive hypertension in
11. Keith NM, Wagener HP, Barker NW: Some different types of essential acute stroke. Acta Med Scand 1980, 207:253.
hypertension: their course and prognosis. Am J Med Sci 1939, 197:332.
42. Lavin P: Management of hypertension in patients with acute stroke.
12. Kirkendall WM: Retinal changes of hypertension. In The Eye in Systemic Arch Intern Med 1986, 146:66.
Disease. Edited by Mausolf FA. St Louis: Mosby; 1975:212–222.
43. Meyer JS, et al.: Impaired neurogenic cerebrovascular control and
13. Dollery CT: Hypertensive retinopathy. In Hypertension: Pathophysiology dysautoregulation after stroke. Stroke 1973, 4:169.
and Treatment. Edited by Genest O, Kuchel O, Hamet P. New York:
McGraw-Hill; 1983:723–732. 44. Cuneo RA, et al.: The neurologic complications of hypertension. Med
Clin North Am 1977, 61:565.
14. McGregor E, Isles CG, Jay JL, et al.: Retinal changes in malignant
hypertension. Br Med J 1986, 292:233–234. 45. Kaneko T, et al.: Lower limit of blood pressure in treatment of acute
hypertensive intracranial hemorrhage. J Cerebral Blood Flow Metab
15. Sinclair RA, Antonovych TT, Mostofi FL: Renal proliferative arteri- 1983, 3(suppl 1):S51.
opathies and associated glomerular changes: a light and electron
microscopy study. Hum Pathol 1976, 7:565. 46. Shapiro B, Rig LM: Management of pheochromocytoma. Endocrinol
Metab Clin North Am 1989, 18:443.
16. Pitcock JA, et al.: Malignant hypertension in blacks: malignant intrarenal
arterial disease as observed by light and electron microscopy. Hum 47. Pinaud M, et al.: Preoperative acute volume loading in patients with
Pathol 1976, 7:33. pheochromocytoma. Care Med 1985, 13:460.
17. Jones DB: Arterial and glomerular lesions associated with severe 48. Glazener RS, et al.: Pargyline, cheese, and acute hypertension. JAMA
hypertension. Lab Invest 1974, 31:303. 1964, 188:754.
18. Mattern WD, Sommers SC, Kassiere JP: Oliguric acute renal failure in 49. Blackwell B, et al.: Hypertensive interactions between monoamine
malignant hypertension. Am J Med 1972, 52:187. oxidase inhibitors and foodstuffs. Br J Psychiatry 1967, 113:349.
19. Isles CG, McLay A, Boulton-Jones JM: Recovery in malignant hyper- 50. Palmer RF, Lasseter KC: Sodium nitroprusside. N Engl J Med 1975,
tension presenting as acute renal failure. Q J Med 1984, 53:439. 292:294.
20. Bacon BR, Ricanatie ES: Severe and prolonged renal insufficiency. 51. Gruetter CA, et al.: Relationship between cyclic guanosine 3’:5’
Reversal in a patient wit malignant hypertension. JAMA 1978, 239:1159. monophosphate formation and relaxation of coronary arterial smooth
muscle by glyceryl trinitrate, nitroprusside, nitrite and nitric oxide.
21. Shirley D, et al.: Clinical documentation of end-stage renal disease due J Pharmacol Exp Ther 1981, 219:181.
to hypertension . Am J Kidney Dis 1994, 23:655.
52. Ignarro IJ, et al.: Mechanism of vascular smooth muscle relaxation by
22. Freedman BI, Iskander SS, Appel RG: The link between hypertension organic nitrates, nitrites, nitroprusside, and nitric oxide. J Pharmacol
and nephrosclerosis. Am J Kidney Dis 1995, 25:207. Exp Ther 1981, 218:739.
23. Rerneger TV, et al.: Diagnosis of hypertensive end-stage renal disease: 53. Strandgaard S: Autoregulation of cerebral blood flow in hypertensive
effect of patient’s race. Am J Epidemiol 1995, 141:10. patients. Circulation 1976, 53:720.
24. Möhring J, et al.: Effects of saline drinking on the malignant course of 54. Franklin SS: Hypertensive emergencies: the case for more rapid lowering
renal hypertension in rats. Am J Physiol 1976, 230:849. of blood pressure. In Controversies in Nephrology and Hypertension.
25. Gifford RW Jr, et al.: Hypertensive encephalopathy: mechanisms, clin- Edited by Narins RG. New York: Grune & Stratton; 1973:191–197.
ical features, and treatment. Progr Cardiovasc Dis 1974, 17:115. 55. Fagan TC: Acute reduction of blood pressure in asymptomatic
26. Dinsdale HB: Hypertensive encephalopathy. Neurol Clin 1983, 1:83. patients with severe hypertension. An idea whose time has come–and
27. Ziegler DK, et al.: Hypertensive encephalopathy. Arch Neurol 1965, gone. Arch Intern Med 1989, 149:2169.
12:472. 56. Ferguson RK, Vlasses PH: Hypertensive emergencies and urgencies.
28. Cohn JN, Rodriguera E, Guiha NH: Left ventricular function in JAMA 1986, 255:1607.
hypertensive heart disease. In Hypertension Mechanisms and 57. Veterans Administration Cooperative Study Group on
Management. Edited by Onesti O, Kim KE, Moyer JH. New York: Antihypertensive Agents. Effects of treatment on morbidity in hyper-
Grune & Stratton; 1973:191–197. tension. Result in patients with diastolic blood pressure averaging 115
29. Wheat MW Jr: Acute dissecting aneurysms of the aorta: diagnosis and through 129 mm Hg. JAMA 1967, 202:1028.
treatment, 1979. Am Heart J 1980, 99:373. 58. Zeller KR, et al.: Rapid reduction of severe asymptomatic hyperten-
30. DeSanctis RW, et al.: Aortic dissection. N Engl J Med 1987, 317:1060. sion. Arch Intern Med 1989, 149:2186.
Diabetic Nephropathy:
Impact of Comorbidity
Eli A. Friedman
T
hroughout the industrialized world, diabetes mellitus is the
leading cause of end-stage renal disease (ESRD), surpassing
glomerulonephritis and hypertension. Both the incidence and
the prevalence of ESRD caused by diabetes have risen each year over
the past decade, according to reports from European, Japanese, and
North American registries of patients with renal failure. Illustrating
the dominance of diabetes in ESRD is the 1997 report of the United
States Renal Data System (USRDS), which noted that of 257,266
patients receiving either dialytic therapy or a kidney transplant in
1995 in the United States, 80,667 had diabetes [1], a prevalence rate
of 31.4%. Also, during 1995 (the most recent year for which summa-
tive data are available), of 71,875 new (incident) cases of ESRD,
28,740 (40%) patients were listed as having diabetes.
In America, Europe, and Japan, the form of diabetes is predomi-
nantly type II; fewer than 8% of diabetic Americans are insulinopenic,
C-peptide-negative persons with type I disease. It follows that ESRD
in diabetic persons reflects the demographics of diabetes per se [2]: 1)
The incidence is higher in women [3], blacks [4], Hispanics [5], and
native Americans [6]. 2) The peak incidence of ESRD occurs from the
fifth to the seventh decade. Consistent with these attack rates is the
fact that blacks older than the age of 65 face a seven times greater risk
of diabetes-related renal failure than do whites. Within our Brooklyn
and New York state hospital ambulatory hemodialysis units in
October 1997, 97% of patients had type II diabetes. Despite wide-
spread thinking to the contrary, vasculopathic complications of dia-
betes, including hypertension, are at least as severe in type II as in type
I diabetes [7,8]. When carefully followed over a decade or longer,
cohorts of type I and type II diabetic individuals have equivalent rates
CHAPTER
of proteinuria, azotemia, and ultimately ESRD. Both types of diabetes
1
show strong similarities in their rate of renal functional deterioration
[9] and onset of comorbid complications. Initial nephromegaly as well
as both glomerular hyperfiltration and microalbuminuria (previously
thought to be limited to type I) is now recognized as equally in type II [10].
1.2 Systemic Diseases and the Kidney
FIGURE 1-2
Maintenance hemodialysis. In the United States, the large majority (more than 80%) of
diabetic persons who develop end-stage renal disease (ESRD) will be treated with mainte-
nance hemodialysis. Approximately 12% of diabetic persons with ESRD will be treated
with peritoneal dialysis, while the remaining 8% will receive a kidney transplant. A typical
hemodialysis regimen requires three weekly treatments lasting 4 to 5 hours each, during
which extracorporeal blood flow must be maintained at 300 to 500 mL/min. Motivated
patients trained to perform self-hemodialysis at home gain the longest survival and best
rehabilitation afforded by any dialytic therapy for diabetic ESRD. When given hemodialy-
sis at a facility, however, diabetic patients fare less well, receiving significantly less dialysis
than nondiabetic patients, owing in part to hypotension and reduced blood flow [11].
Maintenance hemodialysis does not restore vigor to diabetic patients, as documented by
Lowder and colleagues [12]. In 1986, they reported that of 232 diabetics on maintenance
hemodialysis, only seven were employed, while 64.9% were unable to conduct routine
daily activities without assistance [12]. Approximately 50% of diabetic patients begun on
maintenance hemodialysis die within 2 years of their first dialysis session. Diabetic
hemodialysis patients sustained more total, cardiac, septic, and cerebrovascular deaths
than did nondiabetic patients.
When initially applied to diabetic patients with ESRD in the 1970s, maintenance
hemodialysis was associated with a first-year mortality in excess of 75%, with inexorable
loss of vision in survivors. Until the at-first-unappreciated major contribution of type II
diabetes to ESRD became evident, kidney failure was incorrectly viewed as predominantly
limited to the last stages of type I (juvenile, insulin-dependent) diabetes. Illustrated here is
a blind 30-year-old man undergoing maintenance hemodialysis after experiencing 20 years
of type I diabetes. A diabetic renal-retinal syndrome of blindness and renal failure was
thought to be inevitable until the salutary effect of reducing hypertensive blood pressure
became evident. Without question, reduction of hypertensive blood pressure levels was the
key step that permitted improvement in survival and reduction in morbidity.
Diabetic Nephropathy: Impact of Cormorbidity 1.3
FIGURE 1-3
Statistical increase in diabetes. In the past 20 years, since the diabetic patient with end-
Diabetes stage renal disease (ESRD) is no longer excluded from dialytic therapy or kidney trans-
28,740 40% plantation, there has been a steady increase in the proportion of all patients with ESRD
who have diabetes. In the United States, according to the 1997 report of the United States
Renal Data System (USRDS) for the year 1995, more than 40% of all newly treated
(incident) patients with ESRD have diabetes. For perspective, the USRDS does not list
43,135 the actual incidence of a renal disease but rather tabulates those individuals who have
been enrolled in federally reimbursed renal programs. The distinction may be important
All other in that a relaxation in policy for referral of diabetic kidney patients would be indistin-
60% guishable from a true increase in incidence.
20 19
18 18
15 15 16 Country Percentage
15 14
Japan 99
10 Germany 90
10 9
7 8
United States Pima Indians 95
5
5 4
0
FIGURE 1-5
Black Mexican Puerto Japanese Filipinos Chinese Koreans
Rican Percent of diabetic ESRD. Noted first in United States inner-city
dialysis programs, type II diabetes is the predominant variety noted
in those individuals undergoing maintenance hemodialysis. Our
FIGURE 1-4 recent survey of hemodialysis units in Brooklyn, New York, found
Prevalence of diabetes mellitus in minority populations. Attack that 97% of the mainly African-American patients had type II dia-
rates (incidence) for diabetes are higher in nonwhite populations betes. Thus, there has been a reversal of the previously held
than in whites. Type II diabetes accounts for more than 90% of all impression that uremia was primarily a late manifestation of type I
patients with end-stage renal disease (ESRD) with diabetes. As diabetes. (From Ritz and Stefanski [14] and Nelson and coworkers
studied by Carter and colleagues [13], the effect of improved nutri- [15]; with permission.)
tion on expression of diabetes is remarkable. The American diet
not only induces an increase in body mass but also may more than
double the expressed rate of diabetes, especially in Asians. (From
Carter and coworkers [13]; with permission.)
C-PEPTIDE CRITERIA
IGT Type II Type I 70
60
60
Proportion on insulin, %
Type I (90% concordence between clinical criteria
50 and C-peptide testing)
Insulin requiring 40 Basal C-peptide <0.17 pmol/mL
33
Type II Type I Increment above basal at 6 min <0.07 pmol/mL
30
decreased insulin β-cell destruction
secretion/sensitvity 20
13
10
FIGURE 1-9
0
FIGURE 1-7 C-peptide criteria. Multiple strategies have
0–5 5–10 10–15
Type I and type II compared. Differentiating been proposed to distinguish type I from
Years of NIDDM
type I from type II diabetes may be difficult, type II diabetes. Each has limitations. Service
especially in young nonobese adults with and colleagues [20] employed baseline and
minimal insulin secretion. Furthermore, FIGURE 1-8 stimulated C-peptide levels to differentiate
with increasing duration of type II diabetes, Increasing insulin treatment in non–insulin- between the two. They found satisfactory
beta cells may decrease their insulin secre- dependent diabetes mellitus (NIDDM). A differentiation of type I from type II diabetes
tion, sometimes to the range diagnostic of decision to treat diabetes with insulin does with minimal overlap using the screening
type I diabetes. Shown here is a modifica- not necessarily equate with establishing a levels shown. (From Service and coworkers
tion of the schema devised by Kuzuya and diagnosis of type I diabetes. Terms such as [20]; with permission.)
Matsuda [18] that suggests a continuum of “insulin-requiring” do not help because the
diabetes classification based on amount of need for insulin is physician-determined and
insulin secreted. Lacking in this construction will vary from clinician to clinician. After
is the realization of the genetic determina- 10 to 15 years of metabolic regulation of
tion of type I diabetes (all?) and the clear type II diabetes, treatment with insulin has
hereditary predisposition (despite inconstant been initiated in more than half of individu-
genetic analyses) of many individuals with als with this disorder. Even in patients with
type II diabetes. At present, classification of type II diabetes treated with insulin, mea-
diabetes is pragmatic and will likely change sured secretion of insulin may fall in the
with larger-population screening studies. normal range. (From Clauson and cowork-
IGT—impaired glucose tolerance. (From ers [19]; with permission.)
Kuzuya and Matsuda [18]; with permission.)
FIGURE 1-10
TERMINOLOGY IN DIABETIC NEPHROPATHY Terminology. Clarification of the course of both types of diabetes
was made possible by recognizing two functional perturbations:
microalbuminuria and glomerular hyperfiltration. Additionally,
Hyperfiltration early glomerular mesangial expansion was noted to be a constant
A supernormal glomerular filtration rate associated with hyperglycemia during the finding in diabetic nephropathy.
early years of diabetes
Microalbuminuria
Urinary albumin excretion of 30 to 300 mg/day or 20 to 200 g/min—a predictor of
nephropathy
Mesangial expansion
An increase in mesangial matrix often but not always associated with basement
membrane thickening
Diabetic Nephropathy: Impact of Cormorbidity 1.5
A B
FIGURE 1-12
Mesangial expansion. Expansion of the mesangium is depicted in
light and electron microscopic views of a kidney biopsy specimen
from a patient with type I diabetes with a urinary albumin concen-
tration of 500 mg/dL. A, Electron microscopic view of a greatly
expanded mesangium in a glomerulus is shown. B, Less advanced
changes are seen on a silver stain. C, Progression to nodular inter-
capillary glomerulosclerosis is shown.
C
1.6 Systemic Diseases and the Kidney
A B
C D
FIGURE 1-13
Glomerular basement membrane thickening. B and D, Glomerular panel B. In panel D, a mesangial nodule (MN) is present. A and C,
basement membrane thickening is a constant abnormality in diabetic Electron photomicrographs from a normal kidney. BM—basement
nephropathy, as seen in these photomicrographs from a biopsy speci- membrane; C—capillary; E—epithelial cell; MN—mesangial nodule;
men in type I diabetes. Note the loss of epithelial foot processes in M—mesangial cell.
FIGURE 1-15
Key pathologic findings. Nondiabetic renal disorders (eg, amyloido-
sis, cryoglobulinemia, nephrosclerosis) may simulate the nodular and
diffuse intercapillary glomerulosclerosis of diabetes (both type I and
FIGURE 1-14 type II). When associated with afferent and efferent arteriolosclero-
Diabetic nephropathy is a microvasculopathy. Microaneurysms are sis, nodular and diffuse intercapillary glomerulosclerosis is pathogno-
visible in the retina and occasionally in glomerular capillaries. A monic for diabetic nephropathy. A—afferent artery arteriosclerosis;
microaneurysm in a biopsy specimen from a 42-year-old woman D—diffuse intercapillary glomerulosclerosis; E—efferent artery arte-
with type I diabetes is shown. riosclerosis; N—nodular intercapillary glomerulosclerosis.
Diabetic Nephropathy: Impact of Cormorbidity 1.7
>4
4.0
3.5
3.0
Urinary albumin, g/d
2.5
2.0
1.5
Clinical
1.0 nephropathy
0.5
0
0 3 6 9 12 15 18 21 24 27
A Hyperglycemia, y
B
FIGURE 1-18
A and B, Progression of nephropathy. Microalbuminuria, the excretion Typically, proteinuria increases to the nephrotic range, leading to
of minute quantities of albumin in the urine (more than 20 mg/day), is edema of the extremities and subsequent anasarca, which are often
a marker of subsequent renal deterioration in diabetic nephropathy. the presenting complaints in diabetic nephropathy.
1.8 Systemic Diseases and the Kidney
140 (13)
Clinical
Cumulative incidence
120 (69)
GFR, mL/min
100
5 (205)
80
60
(447)
40
(812) (30)
(1,377)
20 (1,832)
0
0 (136) (112) (75) (49)
0 3 6 9 12 15 18 21 24 27 0 5 10 15 20 25 30 35
Hyperglycemia, y Years from diagnosis of diabetes
130 130
Creatinine clearance, mL/min
120 120
Creatinine clearance, mL/min
0 1 2 3 4 5 6 7 8 9 10 11 0 1 2 3 4 5 6 7 8 9 10 11
A Time, y B Time, y
FIGURE 1-21
Creatinine clearance. Further evidence of the similarity in course of in creatinine clearance over the course of a decade in subjects with
diabetic nephropathy in type I (A) and type II (B) diabetes was pre- either type of diabetes in Heidelberg, Germany. (From Ritz and
sented in Ritz and Stefansky’s study [22] of equivalent deterioration Stefanski [22]; with permission.)
Diabetic Nephropathy: Impact of Cormorbidity 1.9
14
Hyperfiltration >4
>4 12
4.0
FIGURE 1-23
Clinical recognition of diabetic nephropathy. The timing of reno-
FIGURE 1-22 protective therapy in diabetes is a subject of current inquiry.
Diabetic nephropathy in types I and II. Whereas microalbuminuria Certainly, hypertension, poor metabolic regulation, and hyperlipi-
and glomerular hyperfiltration are subtle pathophysiologic manifes- demia should be addressed in every diabetic individual at discovery.
tations of early diabetic nephropathy, transformation to overt clini- Discovery of microalbuminuria is by consensus reason to start
cal diabetic nephropathy takes place over months to many years. In treatment with an angiotensin-converting enzyme inhibitor in
this figure, the curve for loss of glomerular filtration rate is plotted either type of diabetes, regardless of blood pressure elevation. As is
together with the curve for transition from microalbuminuria to true for other kidney disorders, however, nearly the entire course of
gross proteinuria, affording a perspective of the course of diabetic renal injury in diabetes is clinically silent. Medical intervention
nephropathy in both types of diabetes. While not all microalbumin- during this “silent phase,” however (comprising blood pressure
uric individuals progress to proteinuria and azotemia, the majority regulation, metabolic control, dietary protein restriction, and
are at risk for end-stage renal disease due to diabetic nephropathy. administration of angiotensin-converting enzyme inhibitors), is
GFR—glomerular filtration rate. renoprotective, as judged by slowed loss of glomerular filtration.
FIGURE 1-24
50 Renoprotection with enzyme inhibitors. Streptozotocin-induced dia-
betic rats manifest slower progression to proteinuria and azotemia
Doubling of base-line creatinine, %
45
when treated with angiotensin-converting enzyme inhibitors than
40
with other antihypertensive drugs. The consensus supports the view
35
that angiotensin-converting enzyme inhibitors afford a greater level of
30 Placebo
renoprotection in diabetes than do other classes of antihypertensive
25 P=0.007 drugs. Large long-term direct comparisons of antihypertensive drug
20 regimens in type II diabetes are now in progress. In the study shown
15 here by Lewis and colleagues [23], treatment with captopril delayed
10 Captopril the doubling of serum creatinine concentration in proteinuric type I
5 diabetic patients. Trials of different angiotensin-converting enzyme
inhibitors in both types of diabetes confirm their effectiveness but not
0 their unique renoprotective properties in humans. For patients who
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 cannot tolerate angiotensin-converting enzyme inhibitors because of
Follow-up, y
cough, hyperkalemia, azotemia, or other side effects, substitution of
Placebo 202 184 173 161 142 99 75 45 22 an angiotensin-converting enzyme receptor blocker (losartan) may be
Captopril 207 199 190 180 167 120 82 50 24 renoprotective, although clinical trials of its use in diabetes are
uncompleted. (From Lewis and coworkers [23]; with permission.)
1.10 Systemic Diseases and the Kidney
FIGURE 1-25
Normoalbuminuric Microalbuminuric Albumin excretion rate. In the recently completed Italian Euclid mul-
10 70
ticenter study, both microalbuminuric and normalbuminuric type I
60 diabetic patients showed benefit from treatment with lisinopril, an
8
angiotensin-converting enzyme inhibitor. Although microalbumin-
50
uria, with or without hypertension, is now sufficient reason to start
AER, µg/min
AER, µg/min
6 40 treatment with an angiotensin-converting enzyme inhibitor, the ques-
tion of whether normalbuminuric, normotensive diabetic individuals
4 30
should be started on drug therapy is unanswered. AER—albumin
20 excretion rate. (From Euclid study [24]; with permission.)
2
Lisinopril 10
Placebo
0 0
0 6 12 18 24 0 6 12 18 24
Time from randomization, m
n 227 202 201 179 193 34 33 29 25 32
n 213 196 179 170 191 45 37 34 32 37
FIGURE 1-26
120
Normal diet Restricting protein. Dietary protein restriction in limited trials in
small patient cohorts has slowed renal functional decline in type I
100 diabetes. Because long-term compliance is difficult to attain, the
Glomerular filtration rate,
line indicates trend line slope. (From Zeller and colleagues [25];
60 with permission.)
40
20
0
0 10 20 30 40 50
A Time, mo
120
Protein-restricted diet
100
Glomerular filtration rate,
80
mL/min/1.73 m2
60
40
20
0
0 10 20 30 40 50
B Time, mo
Diabetic Nephropathy: Impact of Cormorbidity 1.11
125 80
100
60
Rate of change in AER, % /year
50
20
25
0 0
0 10 12 14 6 8 10 12 14
A Mean Hb A1, % B Mean Hb A1, %
FIGURE 1-27
Metabolic regulation studies. Multiple studies of the strict metabolic hyperglycemia, as indicated by hemoglobin A1 (Hb A1) levels in
regulation of type I and type II diabetes all indicate that reduction of both type I (A) and type II (B) diabetes. As for other studies using
hyperglycemic levels to near normal slows the rate of renal function- different markers, the courses of both types of diabetes over time
al deterioration. In this study, the albumin excretion rate (AER)— were found to be equivalent. (From Gilbert and coworkers [26];
another way of expressing albuminuria—correlates directly with with permission.)
FIGURE 1-28
Function Pathology Stages of nephropathy. The interrelationships between functional
and morphologic markers of the stages of diabetic nephropathy are
Hyperfiltration shown. Additional pathologic studies are needed to time with pre-
Mesangial expansion
cision exactly when glomerular basement membrane (GBM) thick-
ening and glomerular mesangial expansion take place. ESRD—end-
Microalbuminuria stage renal disease.
GBM thickening
Proteinuria Glomerulosclerosis
ESRD
FIGURE 1-35
RETINOPATHY Retinopathy. Blindness due to the hemorrhagic and fibrotic changes of diabetic retinopathy
is the most dreaded extrarenal complication feared by diabetic kidney patients. The patho-
genesis of proliferative retinopathy reflects release by retinal and choroidal cells of growth
Hyperglycemia (angiogenic) factors triggered by hypoxemia, which is caused by diminished blood flow. The
Hypertension interrelationship among hyperglycemia, hypertension, hypoxemia, and angiogenic factors is
Volume overload
now being defined. There is reason to hope that specifically designed interdictive measures
may halt progression of loss of sight.
Photocoagulation
Erythropoietin
FIGURE 1-36
Retinopathic changes. Proliferative retinopathy, microcapillary
aneurysms, and dot plus blot hemorrhages are present in this fun-
duscopic photograph taken at the time of initial renal evaluation of
a nephrotic 37-year-old woman with type I diabetes. After pre-
scription of a diuretic regimen, immediate consultation with a
laser-skilled ophthalmologist was arranged.
A B
FIGURE 1-37
Panretinal photocoagulation (PRP). A, PRP is the therapeutic of proliferative retinopathy were attained with PRP, as shown in
technique performed for proliferative retinopathy using an argon this fundus, photographed 6 weeks after the one shown in panel
laser to deliver approximately 1500 discrete retinal burns, avoid- A. Vision stabilized, and sight has been retained through the past
ing the fovea and disk (IA<I). By reducing the amount of retina 6 years of observation. If applied before retinal traction and
to be perfused by 35%, PRP somehow lessens the stimulus to detachment supervene, PRP is effective in preserving sight in
release angiogenic factors, and proliferative retinopathy regresses. more than 90% of diabetic patients undergoing dialytic therapy
B, Disappearance of hemorrhages and nearly complete regression or kidney transplantation.
1.14 Systemic Diseases and the Kidney
FIGURE 1-38
AMPUTATION Amputation. After blindness, no comorbid complication limits rehabilitation in diabetic
kidney patients more than lower limb amputation. A combination of macrovascular and
microvascular disease in the limb, loss of pain perception due to sensory nephropathy, and
Inspection impaired resistance to infection converts any minor insult to the foot into a major threat
Shoes to the limb and life. Previously regarded as unavoidable in as many as 30% of patients
Socks
with end-stage renal disease treated with dialysis or kidney transplantation, programs that
emphasize prophylactic foot care as a component of preventive medicine have reduced the
Nails
incidence of limb amputation to about 5% after 3 years.
Prompt treatment
B
FIGURE 1-39
Genesis of foot problems. The genesis of diabetic foot problems
includes peripheral neuropathy, peripheral vascular disease, impaired
vision (nail cutting), edema (heart and kidney), and slow wound
healing. A, Note the demarcated hair line indicative of peripheral
vascular insufficiency. B, The foot radiograph shows a Charcot’s
A joint. (From Shaw and Boulton [29]; with permission.)
FIGURE 1-45
NEPHROTIC SYNDROME Nephrotic syndrome. Proteinuria in diabetic nephropathy typically progresses more than
3.5 g/day (nephrotic range), leading to hypoproteinemia, hyperlipidemia, and extracellular
fluid accumulation (nephrotic syndrome). Management of a nephrotic diabetic patient
Precedes renal failure includes minimizing protein loss using an angiotensin-converting enzyme inhibitor (ACEi)
May arrest or revert (15±%) and promoting diuresis with a combination of loop diuretics (furosemide) and thiazide
Confused with cardiac failure
diuretics (metolazone). Distinction between congestive heart failure and nephrotic edema
requires assessment of cardiac function. (From Herbert et at. [33] and Gault and
Intensifies risk to feet
Fernandez [34]; with permission.)
Management: ACEi + metolazone + furosemide
FIGURE 1-46
ANASARCA Anasarca. Anasarca is a long-term management problem in diabetic nephropathy. As renal
reserve decreases, the balance between volume overload and excessive diuresis may be dif-
ficult to maintain. Having the patient measure and record weight daily as a guide for each
Hypoproteinemia (renal loss, liver disease) day’s dose of diuretics (metolazone plus furosemide) is a workable strategy. Once the crea-
Glycated albumin (more permeable) tinine clearance falls below 10 mL/min, ambulatory dialysis may be the only means of
Heart failure (coronary disease)
continuing life outside the hospital.
Management includes
Daily weight
Metolazone + furosemide
Cardiac compensation
1.16 Systemic Diseases and the Kidney
peritoneal dialysis (CAPD) affords the advantages of freedom from a machine, ability to be
performed at home, rapid training, minimal cardiovascular stress, and avoidance of heparin
5 0
[35]. Some enthusiasts believe CAPD to be “a first choice treatment” for diabetic patients
D ia
with ESRD [36]. Consistent with the author’s view, however, is the report of Rubin and col-
be
10
15
5
tic
leagues [37]. They found that in a largely black diabetic population, only 34% of patients
s
continued CAPD after 2 years, and at 3 years, only 18% remained on CAPD.
In fairness, comparisons of either mortality or comorbidity in patients receiving
hemodialysis versus peritoneal dialysis suffer from the limitations of starting with unequal
30
90
cohorts reflecting selection bias. Data subsets from the United States Renal Data System
Creatinine
(USRDS) report for 1997 [1] show that in diabetic patients, all cohorts have a higher risk
clearance,
mL/min
of death with CAPD than with hemodialysis. Furthermore, patients receiving peritoneal
dialysis in the United States have a 14% greater risk of hospitalization than do patients
45
75
FIGURE 1-48
PLANNING FOR ESRD Treatment for end-stage renal disease (ESRD). Ideally, treatment for ESRD should be select-
ed without stress or urgency on the basis of prior thought and planning. Discussions with
representatives of patient self-help groups, such as the American Association of Kidney
Expose patient to treatment options Patients, and institutional transplant coordinators aid in communicating the information
Establish vascular or peritoneal access required by patients to enable them to select from available options for uremia therapy.
Encourage intrafamilial kidney donation
Schedule visit with transplant surgeon
Monitor creatinine, general well being
Err on side of early dialysis start
FIGURE 1-49
Nondiabetic Diabetic Management with dialysis. As tabulated in the 1997 report of the
United States Renal Data System [1], diabetic patients with end-stage
40–64 y
renal disease (ESRD) are less likely than nondiabetic patients with
51.5% 71.5% ESRD to receive a kidney transplant and are most often managed
Center hemo Center hemo
with maintenance hemodialysis (center hemo). A greater proportion
of diabetic patients with ESRD are managed with continuous ambu-
Transplant latory peritoneal dialysis (CAPD) or machine-based continuous cyclic
13.0% peritoneal dialysis (CCPD) than are nondiabetic patients with ESRD.
Transplant
36.3%
Center hemo
Home hemo
CAPD
CCPD
Transplant
Diabetic Nephropathy: Impact of Cormorbidity 1.17
Surviving, %
60 57.9
205.4
40 36.9
279.9 26.5
20 20.1
3.9
0 50 100 150 200 250 300 0
Deaths per 1000 Patient Years 0 1 2 5 10
Time after initiatling treatment, y
FIGURE 1-50
Survival rates of diabetics and nondiabetics. As tabulated in the FIGURE 1-51
1997 report of the United States Renal Data System [1], there are Survival rates of diabetic ESRD patients. After a decade of treatment,
sharp differences in survival between diabetic and nondiabetic the remarkable superiority of renal transplantation over dialysis
patients with end-stage renal disease (ESRD) as well as between (combined peritoneal dialysis and hemodialysis, lower curve) is
treatment by dialysis versus kidney transplantation. The highest starkly evident in these survival curves drawn from the 1997 report
death rate is suffered by diabetic dialysis patients (combined peri- of the United States Renal Data System [1]. Fewer than 1 in 20
toneal dialysis and hemodialysis), while the best survival is experi- diabetic patients with end-stage renal disease (ESRD) treated with
enced by nondiabetic renal transplant recipients. Selection bias in any form of dialysis will live a decade. In contrast, kidney trans-
choosing more fit ESRD patients for kidney transplantation while plantation from a living donor (upper curve) or a cadaver donor
leaving a residual pool of sicker patients for dialysis accounts for (middle curve) permits substantive cohorts to survive.
some of the difference in mortality. Other variables, especially
extrarenal comorbidity, are probably more important in defining
the less favorable course in diabetes.
42.4
40 Transplant USRDS 1996
Hemodialysis Ages 45–64
Peritoneal dialysis
Deaths per 1000 Patient Years
30.9
30
21.5
20 19
15.1 14.5
10 8.7
7.5 7.5 6.8
6.3 4.5 4.0
2.4 3.7 3.0
2.0 1.8 1.6
1.4 0.4 0.1 1.6 0.1
0
+] [K+] Diab
MI Nondiab MI Diab CVA Nondiab CVA Diab Cancer Nondiab Cancer Diab [K Nondiab
FIGURE 1-52
Comorbidity in ESRD. Death of diabetic patients with end-stage cause of death, rates are higher in patients receiving peritoneal dialy-
renal disease (ESRD) relates to comorbidity, as shown in this table sis than in those receiving hemodialysis and are lowest in renal trans-
abstracted from the 1997 report of the United States Renal Data plant recipients. For undetermined reasons, deaths due to cancer are
System (USRDS) [1]. Representative subsets of patients with ESRD less frequent in diabetic than in nondiabetic patients with ESRD.
with and without diabetes treated by peritoneal dialysis, hemodialy- CVA—cerebrovascular accident; Diab—diabetes; K+—potassium;
sis, or renal transplantation are shown. Note that for each comorbid MI—myocardial infarction.
1.18 Systemic Diseases and the Kidney
Rehabilitation
OPTIONS IN DIABETES WITH ESRD 100
Karnofsky score
Diabetic complications Progress Progress Slow progression Hemodialysis
Rehabilitation Poor Poor Fair to excellent 50 Peritoneal dialysis
Patient acceptance Fair Fair Good to excellent
FIGURE 1-56
Options in diabetes with ESRD. Comparing outcomes of various options for uremia thera- Withdrawal
py in diabetic patients with end-stage renal disease (ESRD) is flawed by the differing crite-
0
ria for selection for each treatment. Thus, if younger, healthier subjects are offered kidney Death
transplantation, then subsequent relative survival analysis will be adversely affected for the
residual pool treated by peritoneal dialysis or hemodialysis. Allowing for this caveat, the
table depicts usual outcomes and relative rehabilitation results for continuous ambulatory FIGURE 1-57
peritoneal dialysis (CAPD), continuous cyclic peritoneal dialysis (CCPD), hemodialysis, Karnofsky scores in rehabilitation. Graphic
and transplantation. depiction of rehabilitation in diabetic
patients with end-stage renal disease (ESRD)
as judged by Karnofsky scores. Few diabetic
patients receiving hemodialysis or peritoneal
dialysis muster the strength to resume full-
time employment or other gainful activities.
Originally devised for use by oncologists,
the Karnofsky score is a reproducible, sim-
ple means of evaluating chronic illness from
any cause. A score below 60 indicates mar-
ginal function and failed rehabilitation.
Diabetic Nephropathy: Impact of Cormorbidity 1.19
FIGURE 1-58
Complications of the hemodialysis regimen
are more frequent in diabetic than in nondia-
betic patients. A, Axillary vein occlusion
proximal to an arteriovenous graft used for
dialysis access is shown. B, Balloon angio-
plasty proffers only temporary respite owing
to a high rate (70% in 6 months) of resteno-
sis in diabetic patients. The value of an intra-
luminal stent prosthesis is being studied.
A B
76.2
USRDS 1996
LIFE PLAN FOR DIABETIC
75 PD + Hemo NEPHROPATHY
74.4
74
73.1
72.6 Explore and endorse treatment goals
Enlist patient as key team member
Surviving, %
References
1. United States Renal Data System: USRDS 1997 Annual Data Report. 21. Humphrey LL, et al.: Chronic renal failure in non-insulin-dependent
Bethesda, MD: The National Institutes of Health, National Institute diabetes mellitus: a population-based study in Rochester, Minnesota.
of Diabetes and Digestive and Kidney Diseases; April, 1997. Ann Intern Med 1989, 111:788–796.
2. Zimmet PZ: Challenges in diabetes epidemiology—from West to the 22. Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes. Am J
rest (Kelly West Lecture 1991). Diabetes Care 1992, 15:232–252. Kidney Dis 1996, 27:167–194.
3. Harris M, Hadden WC, Knowles WC, and colleagues: Prevalence of 23. Lewis EJ, et al.: The effect of angiotensin-converting-enzyme inhibition
diabetes and impaired glucose tolerance and plasma glucose levels in on diabetic nephropathy: the Collaborative Study Group. N Engl J
U.S. population aged 20-74 yr. Diabetes 1987, 36:523–534. Med 1993, 329:1456–1462.
4. Stephens GW, Gillaspy JA, Clyne D, and colleagues: Racial differences 24. The Euclid Study Group: Randomised placebo-controlled trial of lisino-
in the incidence of end-stage renal disease in types I and II diabetes pril in normotensive patients with insulin-dependent diabetes and nor-
mellitus. Am J Kidney Dis 1990, 15:562–567. moalbuminuria or microalbuminuria. Lancet 1997, 349:1787–1792.
5. Haffner SM, Hazuda HP, Stern MP, and colleagues: Effects of socioe- 25. Zeller K, et al.: Effect of restricting dietary protein on the progression
conomic status on hyperglycemia and retinopathy levels in Mexican of renal failure in patients with insulin-dependent diabetes mellitus.
Americans with NIDDM. Diabetes Care 1989, 12:128–134. N Engl J Med 1991, 324:78–84.
6. National Diabetes Data Group: Diabetes in America. Bethesda, MD: 26. Gilbert RE, Tsalamandris C, Bach LA, et al.: Long-term glycemic control
NIH Publication No. 85-1468; August, 1985. and the rate of progression of early diabetic kidney disease. Kidney Int
1993, 44:855–859.
7. Mauer SM, Chavers BM: A comparison of kidney disease in type I
and type II diabetes. Adv Exp Med Biol 1985, 189:299–303. 27. Biesenbach G, Zazgornik J: High mortality and poor quality of life
during predialysis period in type II diabetic patients with diabetic
8. Melton LJ, Palumbo PJ, Chu CP: Incidence of diabetes mellitus by
nephropathy. Ren Fail 1994, 16:263–272.
clinical type. Diabetes Care 1983, 6:75–86.
28. Shaffer D, Simpson MA, Madras PN, et al.: Kidney transplantation in
9. Biesenback G, Janko O, Zazgornik J: Similar rate of progression in
diabetic patients using cyclosporine. Five-year follow-up. Arch Surg
the predialysis phase in type I and type II diabetes mellitus. Nephrol
1995, 130:287–288.
Dial Transplant 1994, 9:1097–1102.
29. Shaw JE, Boulton AJ: The pathogenesis of diabetic foot problems: an
10. Wirta O, Pasternack A, Laippala P, Turjanmaa V: Glomerular filtra-
overview. Diabetes 1997, 46 (suppl 2): S58–S61.
tion rate and kidney size after six years disease duration in non-
insulin-dependent diabetic subjects. Clin Nephrol 1996, 45:10–17. 30 Spallone V, Menzinger G: Diagnosis of cardiovascular autonomic
neuropathy in diabetes. Diabetes 1997, 46 (suppl 2):S67–S76.
11. Cheigh J, Raghavan J, Sullivan J, and colleagues: Is insufficient dialysis
a cause for high morbidity in diabetic patients [abstract]? J Am Soc 31. Enck P, Frieling T: Pathophysiology of diabetic gastroparesis. Diabetes
Nephrol 1991, 317. 1997, 46 (suppl 2):S77–S81.
12. Lowder GM, Perri NA, Friedman EA: Demographics, diabetes type, 32. Soykan I, et al.: The effect of chronic oral domperidone therapy on
and degree of rehabilitation in diabetic patients on maintenance gastrointestinal symptoms, gastric emptying, and quality of life in
hemodialysis in Brooklyn. J Diabet Complications 1988, 2:218–226. patients with gastroparesis. Am J Gastroenterol 1997, 92:976–980.
13. Carter JS, et al.: Non-insulin-dependent diabetes mellitus in minorities 33. Hebert LA, Bain RP, Verme D, Cattran Det al.: Remission of nephrotic
in the United States. Ann Intern Med 1996, 125:221–232. range proteinuria in type I diabetes: Collaborative Study Group.
Kidney Int 1994, 46:1688–1693.
14. Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes. Am J
Kidney Dis 1996, 27:167–194. 34. Gault MH, Fernandez D: Stable renal function in insulin-dependent
diabetes mellitus 10 years after nephrotic range proteinuria. Nephron
15. Nelson RG, Pettitt DJ, Carraher MJ, et al.: Effect of proteinuria on 1996, 72:86–92.
mortality in NIDDM. Diabetes 1988, 37:1499–1504.
35. Lindblad AS, Nolph KD, Novak JW, Friedman EA: A survey of the
16. Shafrir E: Development and consequences of insulin resistance: lessons NIH CAPD Registry population with end-stage renal disease attributed
from animals with hyperinsulinemia. Diabetes Metab 1996, 22:122–131. to diabetic nephropathy. J Diabet Complications 1988, 2:227-232.
17. Schalin-Jantii C, et al.: Polymorphism of the glycogen synthase gene in 36. Legrain M, Rottembourg J, Bentchikou A, et al.: Dialysis treatment of
hypertensive and normotensive subjects. Hypertension 1996, 27:67–71. insulin dependent diabetic patients: ten years experience. Clin Nephrol
18. Kuzuya T, Matsuda A: Classification of diabetes on the basis of etiologies 1984, 21:72-81
versus degree of insulin deficiency. Diabetes Care 1997, 20:219–220. 37. Rubin J, Hsu H: Continuous anbulatory peritoneal dialysis: ten years
19. Clausson P, Linnarsson R, Gottsater A, et al.: Relationships between at one facility. Am J Kidney Dis 1991, 17: 165-169.
diabetes duration, metabolic control and beta-cell function in a repre- 38. Habach G, Bloembergen WE, Mauger EA, et al.: Hospitalization
sentative population of type 2 diabetic patients in Sweden. Diabet among United States dialysis patients: hemodialysis versus peritoneal
Med 1994, 11:794–801. dialysis. J Am Soc Nephrol 1995, 11:1940-1948.
20. Service FJ, Rizza RA, Zimmerman BR, et al.: The classification of
diabetes by clinical and C-peptide criteria: a prospective population-
based study. Diabetes Care 1997, 20:198–201.
Vasculitis (Polyarteritis
Nodosa, Microscopic
Polyangiitis, Wegener’s
Granulomatosis, Henoch-
Schönlein Purpura)
J. Charles Jennette
Ronald J. Falk
T
he kidneys are affected by a variety of systemic vasculitides
[1,2]. This is not surprising given the numerous and varied types
of vessels in the kidneys. The clinical manifestations and even the
pathologic expressions of vasculitis often are not specific for a particular
diagnostic category of vasculitis. An accurate precise diagnosis usually
requires the integration of many different types of data, including clinical
signs and symptoms, associated diseases (eg, asthma, systemic lupus
erythematosus, rheumatoid arthritis, hepatitis virus, polymyalgia
rheumatica), vascular distribution (ie, types and locations of involved
vessels), histologic pattern of inflammation (eg, granulomatous versus
necrotizing), immunopathologic features (eg, presence and composition
of vascular immunoglobulin deposits), and serologic findings (eg,
cryoglobulins, hypocomplementemia, hepatitis B antibodies, hepatitis C
antibodies, antineutrophil cytoplasmic autoantibodies, anti–glomerular
basement membrane [GBM] antibodies, antinuclear antibodies). Specific
CHAPTER
diagnosis of a vasculitis is very important because the prognosis and
appropriate therapy vary substantially among different types of vasculitis.
2
A general overview of the major categories of vasculitis that affect
the kidneys is presented. The focus is primarily on polyarteritis
nodosa, Henoch-Schönlein purpura, Wegener’s granulomatosis, and
microscopic polyangiitis.
2.2 Systemic Diseases and the Kidney
Overview
FIGURE 2-1
SELECTED CATEGORIES OF VASCULITIS Many different approaches to categorizing vasculitis exist. We use
the approach adopted by the Chapel Hill International Consensus
Conference on the Nomenclature of Systemic Vasculitis [3]. The
Large vessel vasculitis Chapel Hill System divides vasculitides into those that have a
Giant cell arteritis predilection for large arteries (ie, the aorta and its major branches),
Takayasu arteritis
medium-sized vessels (ie, main visceral arteries), and small vessels
(predominantly capillaries, venules, and arterioles, and occasional-
Medium-sized vessel vasculitis
ly, small arteries). However, there is so much overlap in the size of
Polyarteritis nodosa
the vessel involved by different vasculitides that other criteria are
Kawasaki disease
very important for precise diagnosis, especially when distinguishing
Small vessel vasculitis
among the different types of small vessel vasculitis. ANCA—anti-
ANCA small vessel vasculitis
neutrophil cytoplasmic antibody.
Microscopic polyangiitis
Wegener’s granulomatosis
Churg-Strauss syndrome
Immune complex small vessel vasculitis
Henoch-Schönlein purpura
Cryoglobulinemic vasculitis
Lupus vasculitis
Serum sickness vasculitis
Infection-induced immune complex vasculitis
Anti–GBM small vessel vasculitis
Goodpasture’s syndrome
FIGURE 2-2
Distribution of renal vascular involvement
Predominant distributions of renal vascular involvement. This diagram
depicts the predominant distributions of renal vascular involvement
Small vessel vasculitis by large, medium-sized, and small vessel vasculitides [2]. Note that
all three categories may affect arteries, although arteries are least
often affected by the small vessel vasculitides and often are not
involved at all by this category of vasculitis. By the Chapel Hill
Large vessel vasculitis
definitions, glomerular involvement (ie, glomerulonephritis) is
confined to the small vessel vasculitides, which provides a concrete
criterion for separating the diseases in this category from those in
Medium-sized vessel vasculitis the other two categories [3].
Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura) 2.3
FIGURE 2-3
RENAL INJURY CAUSED BY DIFFERENT The type of renal vessel involved by a vasculitis determines the
CATEGORIES OF VASCULITIS resultant renal dysfunction. Large vessel vasculitides cause renal
dysfunction by injuring the renal arteries and the aorta adjacent to
the renal artery ostia. These injuries result in reduced renal blood
Large vessel vasculitis flow and resultant renovascular hypertension. Medium-sized vessel
Ischemia causing renovascular hypertension (uncommon) vasculitis most often affects lobar, arcuate, and interlobular arter-
Medium-sized vessel vasculitis
ies, resulting in infarction and hemorrhage. Small vessel vasculi-
tides most often affect the glomerular capillaries (ie, cause
Renal infarcts (frequent)
glomerulonephritis), but some types (especially the antineutrophil
Hemorrhage (uncommon)
cytoplasmic antibody vasculitides) may also affect extraglomerular
and rupture (rare)
parenchymal arterioles, venules, and capillaries. Anti-GBM disease
ANCA small vessel vasculitis
is a form of vasculitis that involves only capillaries in glomeruli or
Pauci-immune crescentic glomerulonephritis (common)
pulmonary alveoli, or both. This category of vasculitis is consid-
Arcuate and interlobular arteritis (occasional) ered in detail seperately in this Atlas.
Medullary angiitis (uncommon)
Interstitial granulomatous inflammation (rare)
Immune complex small vessel vasculitis
Immune complex proliferative or membranoproliferative glomerulonephritis with or
without crescents (common)
Arteriolitis and interlobular arteritis (rare)
Anti–GBM small vessel vasculitis
Crescentic glomerulonephritis (common)
Extraglomerular vasculitis (only with concurrent ANCA disease)
FIGURE 2-6
Photograph of kidneys showing gross features of polyarteritis nodosa.
The patient died from uncontrollable hemorrhage of a ruptured
aneurysm that bled into the retroperitoneum and peritoneum. The
cut surface of the left kidney and external surface of the right kid-
ney are shown. The upper pole of the left kidney has three large
aneurysms filled with dark thrombus. These aneurysms are actually
pseudoaneurysms because they are not true dilations of the artery
wall but rather are foci of necrotizing erosion through the artery
wall into the perivascular tissue. These necrotic foci predispose to
thrombosis with distal infarction, and if they erode to the surface
of a viscera they can rupture and cause massive hemorrhage. The
kidneys also have multiple pale areas of infarction with hemor-
rhagic rims, which are seen best on the surface of the right kidney.
A B C
FIGURE 2-7
Antemortem abdominal CAT scans showing polyarteritis nodosa aneurysms (pseudoaneurysms), and a perirenal hematoma adjacent
(A–E). These are the same kidneys shown in Figure 2-6. Demonstrated to the right kidney (left sides of panels) that resulted from rupture
are echogenic oval defects in both kidneys corresponding to the of one of the aneurysms.
(Continued on next page)
Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura) 2.5
D E
FIGURE 2-11
Algorithm for differentiating among the major categories of small vessel vasculitis that affect the kidneys. In a patient
with signs and symptoms of small vessel vasculitis, the type of glomerulonephritis is useful for categorization.
Identification of IgA nephropathy is indicative of Henoch-Schönlein purpura. Type I membranoproliferative glomeru-
lonephritis (MPGN) suggests cryoglobulinemia and/or hepatitis C infection, and pauci-immune necrotizing and crescen-
tic glomerulonephritis suggest some form of ANCA-associated vasculitis [1,2]. The different forms of ANCA vasculitis
are distinguished by the presence or absence of certain features in addition to the necrotizing vasculitis, ie, granuloma-
tous inflammation in Wegener’s granulomatosis, asthma and blood eosinophilia in Churg-Strauss syndrome, and neither
granulomatous inflammation nor asthma in microscopic polyangiitis. Approximately 80% of patients with active
untreated Wegener’s granulomatosis or microscopic polyangiitis have ANCA, but it is important to realize that a small
proportion of patients with typical clinical and pathologic features of these diseases do not have detectable ANCA.
Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura) 2.7
FIGURE 2-12
All of the small vessel vasculitides share signs and symptoms of small ally manifests as purpura caused by venulitis, but occasionally is more
vessel injury in multiple different tissues; however, the frequency of nodular or necrotizing secondary to arteritis or granulomatous inflam-
involvement varies among the different diseases [1]. Combined renal mation. Nodular cutaneous lesions, as well as neuropathies, abdomi-
and pulmonary involvement (pulmonary-renal syndrome) is most com- nal pain, and musculoskeletal symptoms also can be caused by medi-
mon in ANCA vasculitis, whereas combined renal and dermal involve- um sized vessel vasculitis (eg, polyarteritis nodosa), and thus these clin-
ment (dermal-renal syndrome) is most common in immune complex ical manifestations are not specific for a small vessel vasculitis; whereas
vasculitis. The cutaneous involvement in small vessel vasculitides usu- glomerulonephritis, purpura, or alveolar capillaritis are.
Henoch-Schönlein Purpura
FIGURE 2-19
Fibrinoid necrosis obliterating the wall of an arteriole in a renal
biopsy specimen from a patient with Henoch-Schönlein purpura
(hematoxylin and eosin). Involvement of renal vessels other than
glomeruli is rare in Henoch-Schönlein purpura.
Pauci-immune crescentic
glomerulonephritis
Microscopic
polyangiitis
Wegener's
granulomatosis
P-ANCA/MPO-ANCA C-ANCA/PR3-ANCA
FIGURE 2-22
Approximate relative frequency of P-ANCA/MPO-ANCA versus C-
ANCA/PR3-ANCA in patients with pauci-immune necrotizing and
crescent glomerulonephritis without systemic vasculitis (“renal-limit-
ed vasculitis”), microscopic polyangiitis, and Wegener’s granulo- FIGURE 2-23(see Color Plate)
matosis. Note that most patients with renal-limited disease have P- Early segmental fibrinoid necrosis and infiltration by neutrophils in
ANCA/MPO-ANCA, most patients with Wegener’s granulomatosis an ANCA-positive patient with Wegener’s granulomatosis (Masson
have C-ANCA/PR3-ANCA, and patients with microscopic polyangi- trichrome stain). There also is fibrin (red/fuchsinophilic material) in
itis do not have a major preponderance of either ANCA specificity. Bowman’s space, which is a precursor event to crescent formation.
Glomerulonephritis
P-ANCA alone
(MPO-ANCA)
disease
Systemic small
vessel vasculitis
(eg, MPA)
Pulmonary–
renal Wegener's
vasculitic granulomatosis
syndrome
C-ANCA
Anti-GBM (PR3-ANCA)
FIGURE 2-32 disease
disease
Hemorrhagic alveolar capillaritis in a wedge biopsy from the lung
of a patient with microscopic polyangiitis (hematoxylin and eosin).
Note the neutrophils within alveolar capillaries and the massive
hemorrhage into the air spaces. This pattern of injury can be seen
in both microscopic polyangiitis and Wegener’s granulomatosis. FIGURE 2-33
The pulmonary hemorrhage of anti-GBM disease usually does not Categorization of patients with crescentic glomerulonephritis with
have conspicuous neutrophils in alveolar capillaries. respect to both the immunopathologic category of disease (immune
complex versus anti-GBM versus ANCA) and the clinicopathologic
expression (glomerulonephritis alone versus Wegener’s granulomato-
sis versus Goodpasture’s syndrome versus other small vessel vasculi-
tis) [11]. Note that most patients with ANCA have some expression
of systemic vasculitis rather than glomerulonephritis alone. Most
patients with Wegener’s granulomatosis have C-ANCA/PR3-ANCA
but some have P-ANCA/MPO-ANCA. Also note that some patients
with anti-GBM and some patients with immune complex disease
also are ANCA positive. (Adapted from Jennette [11]).
Vasculitis (Polyarteritis Nodosa, Microscopic Polyangiitis, Wegener’s Granulomatosis, Henoch-Schönlein Purpura) 2.13
References
1. Jennette JC, Falk RJ: Small vessel vasculitis. N Engl J Med 1997, 7. Dillon MJ, Ansell BM: Vasculitis in children and adolescents. Rheum
337:1512–1523. Dis Clin North Am 1995, 21:1115–1136.
2. Jennette JC, Falk RJ: The pathology of vasculitis involving the kidney. 8. Gross WL, Schmitt WH, Csernok E: ANCA and associated diseases:
Am J Kidney Dis 1994, 24:130–141. immunodiagnostic and pathogenetic aspects. Clin Exp Immunol
3. Jennette JC, Falk RJ, Andrassy K, et al.: Nomenclature of systemic 1993, 91:1–12.
vasculitides: the proposal of an international consensus conference. 9. Kallenberg CGM, Brouwer E, Weening JJ, Cohen Tervaert JW:
Arthritis Rheum 1994, 37:187–192. Anti-neutrophil cytoplasmic antibodies: current diagnostic and
4. Klein RG, Hunder GG, Stanson AW, et al.: Larger artery involvement pathophysiologic potential. Kidney Int 1994, 46:1–15.
in giant cell (temporal) arteritis. Ann Intern Med 1975, 83:806–812. 10. Jennette JC, Falk RJ: Anti-neutrophil cytoplasmic autoantibodies:
5. Arend WP, Michel BA, Bloch DA, et al.: The American College of discovery, specificity, disease associations and pathogenic potential.
Rheumatology 1990 criteria for the classification of Takayasu arteritis. Adv Pathol Lab Med 1995, 8:363–377.
Arthritis Rheum 1990, 33:1129–1134. 11. Jennette JC: Anti-neutrophil cytoplasmic autoantibody-associated
6. Lhote F, Guillevin L: Polyarteritis nodosa, microscopic polyangiitis, and disease: a pathologist’s perspective. Am J Kidney Dis 1991,
Churg-Strauss syndrome. Rheum Dis Clin North Am 1995, 21:911–947. 18:164–170.
Amyloidosis
Robert A. Kyle
Morie A. Gertz
T
he word amyloid was first coined in 1838 by Schleiden, a German
botanist, to describe a normal constituent of plants. Virchow [1]
observed the similarity of the staining properties of the amyloid to
those of starch and named it amyloid.
All forms of amyloid appear homogeneous when viewed under a light
microscope and are pale pink when stained with hematoxylin-eosin. Under
polarized light, amyloid stained with Congo red dye produces the charac-
teristic apple-green birefringence. The modification of alkaline Congo red
dye by Puchtler and Sweat [2] is used most often. The amorphous hyaline-
like appearance of amyloid is misleading because it is a fibrous protein. On
electron microscopy, amyloid deposits are composed of rigid, linear, non-
branching fibrils 7.5- to 10-nm wide and of indefinite length. The fibrils
aggregate into bundles. The deposits occur extracellularly and ultimately
lead to damage of normal tissue.
In primary amyloidosis (AL) the fibrils consist of the variable portions of
monoclonal () or () immunoglobulin light chains or, very rarely, heavy
chains. In secondary amyloidosis (AA) the fibrils consist of protein A, a non-
immunoglobulin. In familial amyloidosis (AF) the fibrils are composed of
mutant transthyretin (prealbumin) or, rarely, fibrinogen or apolipoprotein.
In senile systemic amyloidosis the fibrils consist of normal transthyretin. The
amyloid fibrils associated with long-term dialysis (A 2M dialysis arthropa-
thy) consist of 2-microglobulin.
Amyloid P component is a glycoprotein composed of 10 identical gly-
cosylated polypeptide subunits, each with a molecular weight of 23,500
and arranged as two pentamers. The liver produces human serum amyloid
P (SAP) component. SAP is present in healthy persons and shows 50% to
60% homology with C-reactive protein. SAP is bound to the amyloid fib-
rils; it is not an integral part of the fibrillar structure. It is found in all types
of amyloid, including the vessel walls in patients with Alzheimer’s disease. CHAPTER
The physiologic function of SAP and its pathologic role in amyloidosis are
unknown. Glycosaminoglycans are present in amyloid deposits. Their role
3
also is unknown. Catabolism or breakdown of the fibrils is an important
factor in pathogenesis; however, little is known of the process [3].
No obvious predisposing condition is associated with primary amyloidosis.
Secondary amyloidosis is associated with an inflammatory process, malignancy,
and many other conditions. No monoclonal protein exits in the serum or urine.
3.2 Systemic Diseases and the Kidney
SYSTEMIC AMYLOIDOSIS
FIGURE 3-4
Systemic amyloidosis. Types of proteins constituting the amyloid of 2-microglobulin. The amyloid fibrils consist of mutated transthyretin
fibrils. In primary amyloidosis the fibrils consist of monoclonal or or, rarely, fibrinogen or lysozyme in familial amyloidosis. Senile
light chains. In secondary amyloidosis the fibrils consist of protein A. systemic amyloidosis is characterized by the deposition of normal
Systemic amyloidosis associated with long-term hemodialysis consists transthyretin in the heart. (From Kyle and Gertz [5]; with permission.)
FIGURE 3-5
Familial, 3.5% (5) Secondary (AA), 3.5% Distribution of forms of amyloidosis seen in patients at the Mayo Clinic in 1996. Of the
Senile, 2% (2) (5) 135 patients with amyloidosis, 83% had the primary form. Familial, secondary, and senile
Localized, 8% (11) amyloidosis accounted for less than 10% of patients. Localized amyloid is limited to the
involved organ and never becomes systemic. In localized amyloidosis, the fibrils consist of
an immunoglobulin light chain; however, the patients do not have a monoclonal protein in
Primary (AL), 83% their serum or urine. Most localized amyloidosis occurs in the respiratory tract, genitouri-
(112) nary tract, or skin.
n=135
30
with permission.)
23
22
20
10
10
7
1
0
<40 40–49 50–59 60–69 70–79 ≥80
Age, y
3.4 Systemic Diseases and the Kidney
FIGURE 3-7
70 Symptoms of primary systemic amyloidosis in patients during an
62 Range: 4–200 lb
60 Median: 23 lb 11-year study at the Mayo Clinic. Weakness or fatigue and weight
52 loss were the most frequent initial symptoms seen within 30 days
of diagnosis. Weight loss occurred in more than half of patients.
With symptoms, %
50
The median weight loss was 23 lb; five patients lost more than
40 100 lb each. Purpura, particularly in the periorbital and facial
areas, was noted in about one sixth of patients. Gross bleeding was
30
reported initially in only 3%. Skeletal pain was a major symptom
20 in only 5% and usually was related to lytic lesions or fractures
15 associated with multiple myeloma. Dyspnea, pedal edema, pares-
10 thesias, light-headedness, and syncope were noted. (From Kyle and
5
Gertz [5]; with permission.)
0
Fatigue Weight loss Purpura Bone pain
Symptoms
FIGURE 3-9
Nodules causing
occlusion of the
auditory canal in a
patient with primary
systemic amyloidosis.
The external audito-
ry canal may be
occluded completely
by nodules of amy-
loid. This condition
frequently produces
deafness, which
may be the initial
symptom. (From
Gertz and Kyle [6];
FIGURE 3-8 with permission.)
Macroglossia in a man with primary systemic amyloidosis.
Macroglossia occurs initially in about 10% of patients. Note the
imprint of the teeth on the dorsum of the tongue. This patient
was unable to close his mouth and complained of drooling.
Macroglossia may cause obstruction of the airway, sometimes
necessitating a tracheostomy. (From Kyle [4]; with permission.)
FIGURE 3-10
Shoulder pad sign in a woman with primary systemic amyloidosis.
Infiltration of the periarticular tissues with amyloid may produce this
sign. The shoulder pad sign causes pain and limitation of motion and
is very difficult to treat. (From Kyle [4]; with permission.)
Amyloidosis 3.5
FIGURE 3-11
Hypertrophic form of primary systemic amyloidosis in a 39-year-old man with prominent
and firm muscles. Despite the muscular appearance, results of a biopsy revealed displace-
ment of muscle fibers with amyloid. Patients often exhibit stiffness or limitation of move-
ment. (From Kyle and Greipp [7]; with permission.)
FIGURE 3-12
30
Signs of primary systemic amyloidosis in patients during an 11-year
25 24
study at the Mayo Clinic. The liver was palpable in about one fourth
of patients seen within 30 days of diagnosis. Hepatomegaly is due to
20
infiltration of amyloid or congestion from heart failure. The spleen is
palpable in only 5% of patients and rarely extends more than 5 cm
Patients, %
15
below the left costal margin. Lymphadenopathy occurs infrequently.
(Adapted from Kyle and Gertz [5]; with permission.)
10 9
5
5
3
0
Liver palpable Spleen palpable Lymphadenopathy Macroglossia
Signs of primary amyloidosis
FIGURE 3-14
Serum creatinine (mg/dL) in patients at
FIGURE 3-13
diagnosis of primary systemic amyloidosis.
Hemoglobin and platelet values within 30 days of diagnosis of primary systemic amyloidosis. Renal insufficiency was present in almost
Anemia was not a prominent feature. When present, it usually is due to multiple myeloma, renal half of patients. Proteinuria was present in
insufficiency, or gastrointestinal bleeding. Thrombocytosis was relatively common; in 9% of about 75% of patients.
patients the platelet count was over 500 109/L. Functional hyposplenism from amyloid
replacement of the spleen may occur [8]. Hyposplenism is manifested by the presence of Howell-
Jolly bodies and occurs in about one fourth of patients. (Adapted from Kyle and Gertz [5].)
3.6 Systemic Diseases and the Kidney
S+, U–
κ
16%
23%
S–, U–
λ 11% S+, U+
50% 56%
Negative S–, U+
27% n=429 17%
n=408
100
80
Survival, %
60
40
20
0
0 1 2 3
Years after dialysis
ALKALINE PHOSPHATASE, ASPARTATE AMINOTRANS- PROTHROMBIN TIME, CAROTENE, AND B12 VALUES
FERASE, AND BILIRUBIN VALUES WITHIN 30 DAYS OF WITHIN 30 DAYS OF DIAGNOSIS OF PRIMARY
DIAGNOSIS OF PRIMARY SYSTEMIC AMYLOIDOSIS, SYSTEMIC AMYLOIDOSIS, MAYO CLINIC, 1981–1992
MAYO CLINIC, 1981–1992
Factor Patients, %
Factor Normal value Values above normal, n (%) Prothrombin time >13 s 16
Alkaline phosphatase ≤250 U/L >250 (26) Carotene <48 µg/dL 6
≥500 (11) Serum B12 <150 pg/mL 3
Aspartate aminotransferase ≤30 U/L >30 (34)
≥100 (3)
Total bilirubin ≤1.1 mg/dL >1.1 (11)
≥5 (1) FIGURE 3-26
Prothrombin time, carotene, and vitamin B12 values within 30 days
of diagnosis of primary systemic amyloidosis. The prothrombin
time was increased in one sixth of patients at the time of diagnosis.
FIGURE 3-25 It has been shown that prolongation of thrombin time occurs in
Alkaline phosphatase, aspartate aminotransferase, and bilirubin 40% of patients [10]. A deficiency in factor X occurs in 15% but
values within 30 days of diagnosis of primary systemic amyloido- is not associated with bleeding. Malabsorption as manifested by a
sis. The serum alkaline phosphatase level was increased in one low carotene or serum B12 level occurs infrequently. (Adapted from
fourth of 474 patients at the time of diagnosis. The aspartate Kyle and Gertz [5].)
aminotransferase value was increased in one third of patients but
rarely reached 100 U/L. Hyperbilirubinemia was an infrequent
finding but when present was associated with short survival [5].
(Adapted from Kyle and Gertz [5].)
FIGURE 3-29
Radiograph showing
marked cardiac
enlargement in a
patient with primary
systemic amyloidosis.
Overt congestive heart
failure is present in
about one sixth of
patients at the time
of diagnosis. Pleural
effusion is common.
FIGURE 3-30
Electrocardiogram in a patient with primary systemic amyloidosis,
showing low voltage in the limb leads or loss of anterior septal
forces that mimics the findings in myocardial infarction. However,
ischemic heart disease is not present. Arrhythmias may include atrial
fibrillation, junctional tachycardia, premature ventricular complexes,
or heart block.
≥20 mm 100
11% P=0.0003
75
Survival, %
15–19 mm < 15 mm (n=64)
≤11 mm 36% 50
24%
25
≥ 15 mm (n=57)
12–14 mm 0
29% 0 1 2 3 4 5
n=121 Time, y
FIGURE 3-34
Cross section of the heart showing marked thickening of the left
ventricular wall and septum in primary systemic amyloidosis. The
ventricular cavity is greatly reduced in volume. (From Gertz and
Kyle [3]; with permission.)
FIGURE 3-35
40 At diagnosis Analysis of previously unexplained syndromes in patients with pri-
During follow-up mary systemic amyloidosis at the time of diagnosis in an 11-year
2 n=474 study at the Mayo Clinic. Nephrotic syndrome or renal failure was
30 present in 28% of patients, congestive heart failure (CHF) in 17%,
and carpal tunnel syndrome in 21%. Peripheral neuropathy and
Patients, %
5 0.5
20 orthostatic hypotension also were common features. The possibility
0.5
of primary systemic amyloidosis must be considered in every
1.5 patient who has monoclonal protein in the serum or urine and who
10 has unexplained nephrotic syndrome, CHF, sensorimotor peripher-
al neuropathy, carpal tunnel syndrome, hepatomegaly, or malab-
28 17 21 17 11 sorption. (Adapted from Kyle and Gertz [5]; with permission.)
0
Nephrotic/ CHF Carpal Peripheral Orthostatic
renal failure tunnel neuropathy hypotension
(142) (104) (102) (81) (58)
Symptoms (number of patients)
FIGURE 3-36
100 97 100 Diagnosis of primary systemic amyloidosis
94
90 86 based on the presence of amyloid in tissue
80 82 83 in an 11-year study at the Mayo Clinic.
80 75
The initial diagnostic procedure should be
an abdominal fat aspirate [11]. The diagno-
Positive, %
60 56
sis will be confirmed in 80% of patients.
Experience in the staining technique and
40
interpretation of the fat aspirate is important
before routine use. A bone marrow aspirate
20
and bone marrow biopsy specimen should
be obtained to determine the degree of plas-
0
Abdominal Bone Rectum Kidney Carpal Liver Small Skin Sural Heart macytosis, and results of amyloid stains are
fat marrow ligament intestine nerve positive in more than half of patients. Either
(212) (394) (194) (81) (20) (32) (23) (19) (21) (16) the abdominal fat aspirate or bone marrow
Presence of amyloid in tissue (number of patients) biopsy specimen is positive in 90% of
patients. When amyloid is still suspected and
the test results of these tissues are negative,
one should proceed to performing a rectal
biopsy, which is positive in approximately
80% of patients. The specimen must include
the submucosa. When the test results for
these sites are negative, tissue should be
obtained from an organ with suspected
involvement. (From Kyle and Gertz [5];
with permission.)
Amyloidosis 3.11
Survival, %
50
25
0
0 1 2 3 4 5 6 7 8
Time, y
FIGURE 3-37 (see Color Plate)
Aspirate of subcutaneous abdominal fat from a patient with prima-
FIGURE 3-38
ry systemic amyloidosis. The specimen shows the characteristic
apple-green birefringence when stained with Congo red dye and Analysis of median survival in patients with primary systemic amy-
viewed with a polarizing light source. loidosis in an 11-year study at the Mayo Clinic. The median sur-
vival of 474 patients seen within 1 month of diagnosis was 13.2
months. The median duration of survival was 4 months for the
80 patients who exhibited congestive heart failure on presentation.
(From Kyle and Gertz [5]; with permission.)
FIGURE 3-39
Infection
8%
Causes of death in patients with primary systemic amyloidosis in an 11-year study at the
Renal Mayo Clinic. Of the 285 patients who died, death was attributed to cardiac involvement
6%
from congestive heart failure or arrhythmias in 48%. The actual percentage of cardiac-
related deaths was probably higher because some patients whose death was attributed to
Other primary amyloidosis almost certainly had terminal cardiac arrhythmia. (Adapted from
8% Kyle and Gertz [5]; with permission.)
Cardiac
Unknown 48%
13%
"Primary
amyloidosis"
17%
n=285
FIGURE 3-40
100
Arm Months Survival curves in patients with primary systemic amyloidosis. Because
MP 18 amyloid fibrils consist of monoclonal immunoglobulin light chains,
80
MPC 17 treatment with alkylating agents that are effective against plasma cell
C 8.5 neoplasms is warranted. We treated 220 patients who had positive
60 results on biopsy. The patients were randomized to receive colchicine
Patients, %
FIGURE 3-41
OTHER THERAPY FOR PRIMARY AMYLOIDOSIS Other therapy for primary amyloidosis. High-dose dexamethasone
has been reported to be beneficial in treating patients with primary
systemic amyloidosis [13]. More intensive therapy consisting of
High-dose dexamethasone high-dose chemotherapy followed by rescue with peripheral stem
Stem cell transplantation cells shows promise [14]. The introduction of 4-iodo-4-deoxy-
4’-iodo-4’-deoxydoxorubicin
doxorubicin, which has an affinity for amyloid fibrils, may be an
important treatment option [15].
Secondary Amyloidosis
Cause Patients, n
Rheumatic disease
Feature Patients, %
Rheumatoid arthritis 31 Proteinuria or renal insufficiency 91
Ankylosing spondylitis 5 Diarrhea, obstipation, or malabsorption 22
Other 6 Goiter 9
Total 42 Hepatomegaly 5
Infection Neuropathy or carpal tunnel syndrome 3
Inflammatory bowel disease 6 Lymphadenopathy 2
Bronchiectasis 5 Hematuria 2
Osteomyelitis 5 Cardiac amyloidosis 0
Other 3
Total 19
Malignancy 2
None 1 FIGURE 3-43
Presenting features of secondary amyloidosis. Proteinuria is the
most frequent laboratory finding in patients with secondary amy-
loidosis. Involvement of the gastrointestinal tract as manifested by
FIGURE 3-42 diarrhea, obstipation, or malabsorption occurred in one fifth of
Causes of secondary amyloidosis. Rheumatoid arthritis is the most our patients. Treatment of secondary amyloidosis depends on the
frequent cause of secondary amyloidosis. In our study of 64 underlying disease. Familial Mediterranean fever frequently is asso-
patients, rheumatoid arthritis was present for a median of 18 years ciated with secondary amyloidosis unless the patient is treated with
before the diagnosis was made [16]. Inflammatory bowel disease, colchicine. (From Gertz and Kyle [16]; with permission.)
bronchiectasis, and osteomyelitis are not uncommon causes of sec-
ondary amyloidosis. (From Gertz and Kyle [16]; with permission.)
25 FIGURE 3-44
Proteinuria and renal insufficiency in patients with secondary
20 19 amyloidosis. The clinical target organ was the kidney in 91% of
17 17 17 patients. (From Gertz and Kyle [16]; with permission.)
15 14 14 14
Patients, n
10
7
0
0 1–3 3–8 >8 ≤1 1.1–2 2.1–4 >4
24-h urinary protein, g/d Serum creatinine, mg/dL
n=55 n=64
Amyloidosis 3.13
FIGURE 3-45
100
Creatinine <2.0 mg/dL, n=32
Association between serum creatinine levels and survival in patients
Creatinine ≥2.0 mg/dL, n=32
with secondary amyloidosis. A serum creatinine value of 2 mg/dL or
80 P=0.003
more was associated with a shorter survival than was a value of less
than 2 mg/dL. (From Gertz and Kyle [16]; with permission.)
Survival, %
60
40
20
0
0 24 48 72 96 120
Time, mo
Familial Amyloidosis
FIGURE 3-46
Wide geographic distribution of familial amyloidosis. Familial or
2 1 hereditary amyloidosis has an autosomal dominant pattern of
inheritance. It accounts for 3.5% of our cases of amyloidosis. In
2
1
1 1 our practice, the geographic distribution is wide and not associated
2
1 1
6 1 5 with clustering. Frequently, a family history of amyloidosis was not
1 1 1 2
1 1 3 4
obtained until after amyloidosis was diagnosed [17]. More than 50
2
3 transthyretin mutations have been recognized [18]. (Adapted from
6 7 6 2
Gertz et al. [17]; with permission.)
2
3
2
2 3
Dialysis-Associated Amyloidosis
References
1. Virchow R: Cited by Schwartz P: Amyloidosis: Cause and Manifestation 15. Gianni L, Bellotti V, Gianni AM, et al.: New drug therapy of amyloi-
of Senile Deterioration. Springfield, IL: Charles C Thomas; 1970. doses: resorption of AL-type deposits with 4-iodo-4-deoxydoxoru-
2. Puchtler H, Sweat F: Cited by Elghetany MT, Saleem A: Methods for bicin. Blood 1995, 86:855–861.
staining amyloid in tissues: a review. Stain Technol 1988, 63:201–212. 16. Gertz MA, Kyle RA: Secondary systemic amyloidosis: response and
3. Gertz MA, Kyle RA: Amyloidosis. In Neoplastic Diseases of the survival in 64 patients. Medicine 1991, 70:246–256.
Blood, edn 3. Edited by Wiernik PH, Canellos GP, Dutcher JP, et al. 17. Gertz MA, Kyle RA, Thibodeau SN: Familial amyloidosis: a study of
New York: Churchill Livingstone; 1996:635–677. 52 North American-born patients examined during a 30-year period.
4. Kyle RA: Amyloidosis. In Hematology: Basic Principles and Practice. Mayo Clin Proc 1992, 67:428–440.
Edited by Hoffman R, Benz EJ Jr, Shattil SJ, et al. New York: 18. Saraiva MJM: Molecular genetics of familial amyloidotic polyneu-
Churchill Livingstone; 1991:1038–1047. ropathy. J Peripheral Nerv Syst 1996, 1:179–188.
5. Kyle RA, Gertz MA: Primary systemic amyloidosis: clinical and labo- 19. Ostertag B: Demonstration einer eigenartigen familiaren “paraamyloi-
ratory features in 474 cases. Semin Hematol 1995, 32:45–59. dose” [abstract]. Zentralbl Allg Pathol 1932, 56:253–254.
6. Gertz MA, Kyle RA: Primary systemic amyloidosis: a diagnostic 20. Weiss SW, Page DL: Amyloid nephropathy of Ostertag with special
primer. Mayo Clin Proc 1989, 64:1505–1519. reference to renal glomerular giant cells. Am J Pathol 1973,
7. Kyle RA, Greipp PR: Amyloidosis (AL): clinical and laboratory fea- 72:447–460.
tures in 229 cases. Mayo Clin Proc 1983, 58:665–683. 21. Lanham JG, Meltzer ML, De Beer FC, et al.: Familial amyloidosis of
8. Gertz MA, Kyle RA, Greipp PR: Hyposplenism in primary systemic Ostertag. Q J Med 1982, 51:25–32.
amyloidosis. Ann Intern Med 1983, 98:475–477. 22. Mornaghi R, Rubinstein P, Franklin EC: Familial renal amyloidosis:
case reports and genetic studies. Am J Med 1982, 73:609–614.
9. Gertz MA, Kyle RA, O’Fallon WM: Dialysis support of patients with
primary systemic amyloidosis: a study of 211 patients. Arch Intern 23. Benson MD, Liepnieks J, Uemichi T, et al.: Hereditary renal amyloi-
Med 1992, 152:2245–2250. dosis associated with a mutant fibrinogen alpha-chain. Nat Genet
1993, 3:252–255.
10. Gastineau DA, Gertz MA, Daniels TM, et al.: Inhibitor of the throm-
bin time in systemic amyloidosis: a common coagulation abnormality. 24. Uemichi T, Liepnieks JJ, Benson MD: Hereditary renal amyloidosis
Blood 1991, 77:2637–2640. with a novel variant fibrinogen. J Clin Invest 1994, 93:731–736.
11. Gertz MA, Li C-Y, Shirahama T, Kyle RA: Utility of subcutaneous fat 25. Muckle TJ: The “Muckle-Wells” syndrome. Br J Dermatol 1979,
aspiration for the diagnosis of systemic amyloidosis (immunoglobulin 100:87–92.
light chain). Arch Intern Med 1988, 148:929–933. 26. Kyle RA, Gertz MA: Amyloidosis of the liver. In Schiff’s Diseases of
12. Kyle RA, Gertz MA, Greipp PR, et al.: A trial of three regimens for pri- the Liver, edn 8. Edited by Schiff ER, Sorrell MF, Maddrey WC.
mary amyloidosis: colchicine alone, melphalan and prednisone, and mel- Philadelphia: Lippincott-Raven; in press.
phalan, prednisone, and colchicine. N Engl J Med 1997, 336:1202–1207. 27. Gejyo F, Arakawa M: 2-microglobulin-associated amyloidoses. J Intern
13. Dhodapkar M, Jagannath S, Vesole D, et al.: Efficacy of pulse dexam- Med 1992, 232:531–532.
ethasone (DEX) plus maintenance alpha interferon (IFN) in primary 28. Kay J: 2-Microglobulin amyloidosis. Int J Exp Clin Invest 1997,
systemic amyloidosis (AL) [abstract]. Blood 1995, 86(suppl 1):442A. 4:187–211.
14. Comenzo RL, Vosburgh E, Sarnacki DL, et al.: High-dose melphalan 29. Gejyo F, Homma N, Hasegawa S, et al.: A new therapeutic approach
with blood stem-cell support for AL amyloidosis [abstract]. Blood to dialysis amyloidosis: intensive removal of 2-microglobulin with
1995, 86 (suppl 1):206A. adsorbent column. Artif Organs 1993, 17:240–243.
Sickle Cell Disease
L.W. Statius van Eps
H
errick [1] was the first to discover sickle cell hemoglobin (2
S2) with sickle-shaped erythrocytes. In 1910, he described
the case of a young black student from the West Indies with
severe anemia characterized by “peculiar elongated and sickle-shaped
red blood corpuscles.” Herrick also noted a slightly increased volume
of urine of low specific gravity and thus observed the most frequent
feature of sickle cell nephropathy: inability of the kidney to concen-
trate urine normally.
CHAPTER
4
4.2 Systemic Diseases and the Kidney
EF EF1
FIGURE 4-3
Schematic representation of the interactions
β α α β of sickle red cells. Sickle red cells (dark circles)
traverse the microcirculation, releasing oxy-
β α α β gen from oxyhemoglobin, and change into
O2 deoxyhemoglobin (light circles).
Deoxygenation of hemoglobin S induces a
change in conformation in which the sub-
units move away from each other. The
β hydrophobic patch at the site of the 6
α
β where the valine replacement has occurred
β α (shown as a projection) can bind to a com-
α
β plementary hydrophobic site of the 6 valine
α β replacement (shown as an indentation). This
α mechanism is important for the formation of
β
β α a polymer (see Fig. 4-4). The diagram to the
α
right shows the assembly of deoxyhemoglo-
β
α β bin S into a helical 14-strand fiber: a poly-
α mer is formed (see Fig. 4-5). As the deoxyhe-
β
β α moglobin S polymerizes and fibers align, the
α erythrocyte is transformed into a “sickle”
β shape, observed at the bottom by scanning
α
electron micrography. (Adapted from Bunn
[4]; with permission).
Cell
Polymer
FIGURE 4-4
Nucleation Polymerization of sickle cell hemoglobin. This polymerization occurs in three stages: 1)
nucleation, 2) fiber growth, and 3) fiber alignment. The end stage is a complicated structure
for a helical fiber: four inner fibers surrounded by 10 outer filaments. Sickling, the process of
polymerization, occurs under three different circumstances: 1) deoxygenation, 2) acidosis,
and 3) extracellular hyperosmolality. These circumstances produce shrinking of the erythro-
cytes that causes elevation of the intracellular hemoglobin concentration. This mechanism
Alignment Growth occurs in the inner medulla of the kidney and renal papillae as a result of countercurrent
multiplication. Extracellular osmolality increases with the results previously mentioned [8].
Sickle Cell Disease 4.5
A B C D
Polymerization of Hemoglobin S
A B
FIGURE 4-6
Polymerization of hemoglobin S. Polymerization of deoxygenated on the localization of the polymers in the cell. A collection of electron
hemoglobin S is the primary event in the molecular pathogenesis of microscopy scans of sickle cells undergoing intracellular polymeriza-
sickle cell disease, resulting in a distortion of the shape of the erythro- tion is shown here. The slides were created in different laboratories.
cyte and a marked decrease in its deformability. These rigid cells are A, Characteristic peripheral blood smear from a patient with sickle cell
responsible for the vaso-occlusive phenomena that are the hallmark of anemia. Extreme sickled forms and target cells are seen. B, Electron
the disease [4]. Interesting shapes of variable forms result depending microscopy scan of normal erythrocytes.
(Continued on next page)
4.6 Systemic Diseases and the Kidney
C D E
F G
H I J
FIGURE 4-6 (Continued)
C, Electron microscopy scan of a normal
erythrocyte and a sickle cell. D–L, This
series of sickle cells show many possible
formations of sickled erythrocytes. The
variety of shapes results from the intracellu-
lar localization of the polymers. In banana-
or sickle-shaped cells the polymers have
formed bundles of fibers oriented along the
long axis of the cell. In cells with a holly-
leaf shape (panel E), the hemoglobin fibers
point in different directions.
K L
Sickle Cell Disease 4.7
A B
C D
FIGURE 4-7
Types of sickle cells and released membrane structures. Franck and
coworkers [10] reported that the normal membrane phospholipid
organization is altered in sickled erythrocytes. These authors present-
ed evidence of enhanced trans-bilayer movement of phosphatidyl-
choline in deoxygenated reversibly sickled cells and put forward the
hypothesis that these abnormalities in phospholipid organization are
confined to the characteristic protrusions of these cells. Scanning
electron micrographs of various types of sickle cells and released
membrane structures are shown. A, Deoxygenated despicular red
sickle cells (RSC). B, Deoxygenated native RSC. C, Oxygenated irre-
versibly sickled cell. D, Spicules. E, Purified microvesicles. The free
spicules released from RSC by repeated sickling and unsickling as
well as the remnant despicular cells were studied by following the
fate of 14C-labeled phosphatidylcholine. The results are shown in
Figure 4-8. The free spicules have the same lipid composition as do
the native cell but are deficient in spectrin. These spicules markedly
enhance the rate of thrombin and prothrombin formation, explain-
E ing the prethrombotic state of the patient with sickle cell disease and
the tendency toward the occurrence of crises. The prethrombotic
state, also present in the renal circulation, stimulates sickle cell for-
mation occurring in the inner renal medulla and papillae where
hyperosmosis also contributes to sickling and microthrombi formation
in the vasa recta. (From Franck and coworkers. [10]; with permission.)
4.8 Systemic Diseases and the Kidney
FIGURE 4-8
Penetration and destruction of the erythrocyte membrane. A, The
membrane is penetrated and destroyed by the intracellular forma-
tion of polymers, resulting in spicule formation. B, Interruption
of the binding between the membrane and protein skeleton
results in a massive exchange of lipids between the inside and
outside of the cell. This process is called flip-flop. An abnormal
membrane skeleton causes an increased flip-flop. The result in the
spicule is a change of the chemical structure, increasing the ten-
dency toward coagulation of sickle cell blood (prethrombotic
Band 3 Actin Band 4.1 Spectrin Ankyrin
state). C, The relationship between the protein skeleton of the
C erythrocyte and lipid membrane is shown. (Adapted from Franck
[11]; with permission.)
Sickle Cell Disease 4.9
C E
FIGURE 4-9
Macroscopy and microradioangiographs of sickle cell kidneys. The kidneys of patients with sickle cell disease usually
are of near normal size, and most kidneys show no significant gross alterations. Abnormalities can be expected in the
renal medulla as erythrocytes form sickles more readily in the relatively hypoxic and hyperosmotic renal medulla than in
other capillary circulations. Formation of microthrombi causes further impairment of the vasa recta circulation. A and
B, Injection microradioangiographs of the kidney in a person without hemoglobinopathy are shown: the entire kidney
(panel A) and a detailed view (panel B). C and D, Injection microradioangiographs of the kidney in a patient with sickle
cell disease are shown: the entire kidney (panel C) and a detailed view (panel D). E, Injection microradioangiograph of a
kidney in a patient with sickle cell hemoglobin C disease . In the normal kidney (panel A), vasa recta are visible radiat-
ing into the renal papilla. In sickle cell anemia (panel D), vasa recta are virtually absent. Those vessels that are present
show abnormalities: they are dilated, form spirals, end bluntly, and many appear to be obliterated. In the patient with
hemoglobin SC (panel E) changes are seen intermediately between patients with hemoglobin SC and normal persons.
(From van Eps et al. [5]; with permission.)
4.10 Systemic Diseases and the Kidney
1200
Urine osmolality, mosmol/kg
600
Cortex
400
0
1 5 10 50 100 500
A Urine arginine vasopressin, pg min–1 C –1osm
FIGURE 4-10
A–H, Models to demonstrate the principle of countercurrent multi-
Thin
plier in creating high urine concentration. The first panel illustrates
segment
Medulla
1 2 3 4
Loop of Henle
Urine
5 6
D
4.12 Systemic Diseases and the Kidney
Urine concentration and dilution: countercurrent diffusion (exchange) FIGURE 4-10 (Continued)
285 100
285 315 300
Na+Cl– Na+Cl–
300 300 Urea 100 300 Urea
H 2O H 2O Na+Cl–
300 Urea
H 2O
Na+Cl– Na+Cl–
Urea 750 750
750 750 Urea 550 750
H 2O H 2O
Na+Cl–
Urea
H 2O
750
Na+Cl–
Na+ Cl–
Urea 975 975
975 975 Urea 775 975 H 2O
H 2O
Na+Cl–
Na+Cl– Urea
975 H 2O
Urea
H 2O Na+Cl–
1200 Urea
1200 1200 1000 H 2O 1200 1200
1200
1 2
F
Sickle Cell Disease 4.13
280 280
% of fil
0
28
Na+Cl–H O Urea 20
trat
Na+Cl–
Cortex
2 100
e
H 2O
Urea
280 280
Na+Cl–
10
H 2O
0% of
Urea
280 280 lt r a 100 280
i f
te
280
2 5 % of filtrate
3 0 % of filtrate
300
280
100
280 280
Na+Cl– Na+Cl–
Na+Cl–
H 2O
300
325
H 2O
Na+Cl– H 2O
H 2O Na+Cl–
300 300 100 100 300
Na+Cl– Na+Cl– H 2O
H 2O H 2O Na+Cl– Na+Cl–
Na+Cl–
Medulla
325
350
375
H 2O
Na+ Cl –
H 2O Na+Cl– H 2O
H 2O Na+Cl– 100
Na+Cl–
te 400
H 2O
400 400 tra 400
2 0 % o f f il 100
10% of
filtrate
G
4.14 Systemic Diseases and the Kidney
285 285
% of fil
5
28
Na+Cl–H O Urea 20
trat
Na+Cl–
Cortex
2 100
e
H 2O
Urea H 2O
285 285
Na+Cl–
10
H 2O 200
0% of
Urea H 2O ADH
285 285 lt r a 100 285
i f
te
285
2 5 % of filtrate
3 0 % of filtrate
375
225
285
Urea Na+Cl–
H 2O Na+ Cl –
H 2O
Urea Urea
H 2O Na+Cl–
525 525 325 Urea 525
525
H 2O
525
Na+Cl–
Urea Na+Cl– Na+Cl– ADH
Medulla
H 2O
750
H 2O
Na+Cl– Urea
750 750 Urea 550 Na+Cl– 750
H 2O Urea
H 2O 750
750
Na+Cl–
Urea Na+Cl– ADH Na+Cl–
H 2O
Na+ –
975
Cl
Urea H 2O
975 975 H 2O 775 Na+Cl– Urea 975
Urea
H 2O 975
Na+Cl–
Urea Na+Cl–
H 2O ADH
Na+Cl–
975
+ –
120 Na Cl 0 H 2O
1200 0 100 120
0
Urea 1200
25% of f iltrate 1200
1% of
filtrate
H
Sickle Cell Disease 4.15
900
700
500
200
50
200
50
1500
mL/min
CPAH ,
1000
500
fraction, %
Filtration
15
5
A
Sickle Cell Disease 4.17
content,
15
g%
CCreatinine , Urine osmolality, Hemoglobin, Hb
content,
15
g%
Hemoglobin, Hb
5
5
100
%
100
%
0
0 A S F
A S F
mosm/kg H2O
CInuline , CCreatinine , Urine osmolality,
800
mL/min mL/min mosm/kg H2O
1100 600
900 400
700
mL/min
200 200
50 50
200 200
mL/min
CInuline ,
50 50
1500 2000
mL/min
mL/min
CPAH ,
CPAH ,
1000 1500
500 1000
fraction, %
Filtration
fraction, %
Filtration
20 15
10 10
5
B C
15
g%
Urine osmolality, Hemoglobin, Hb
100 A
S
%
F
0
mosm/kg H2O
800
600
400
CCreatinine ,
200
mL/min
50
200
mL/min
CInuline ,
50
1500
mL/min
CPAH ,
1000
500
Filtration
fraction,
20
%
10
15
g%
CInuline , CCreatinine , Urine osmolality, Hemoglobin, Hb
5
100 A
%
S
F
0
mL/min mosm/kg H2O
800
600
400
200
50
200
mL/min
50
1500
mL/min
CPAH ,
1000
500
Filtration
fraction,
20
%
10
E
Sickle Cell Disease 4.19
200
A
100
Increase in maximal urinary osmolality, %
80
60
40
20
0
0 10 20 30 40 50
B Time, y
Inner
zone
Urinary Acidification
FIGURE 4-16
SS Anemia
A, Urinary acidification. Patients with
75 70
Ammonium chloride Ammonium chloride hemoglobin SS or SC demonstrate an
incomplete form of renal tubular acidosis.
T.A., µ-equiv/min/1.73 m2
70
nary pH during acid loading. Investigators
from several centers have found no evi-
Urinary pH
6.0
dence of metabolic acidosis in the absence
50
of a sickle cell crisis; however, they have
found changes consistent with mild chronic
respiratory alkalosis [15].
5.0 30
(Continued on next page)
10
4.0
2 4 6 8 10 2 4 6 8 10
A Time, h Time, h
Sickle Cell Disease 4.21
1000
800
600
400
0 1.00
0 1 2 3 4 5 6 7 8
Phosphate, mg/100 mL
4.22 Systemic Diseases and the Kidney
Systolic
140
120
mm Hg
100
80 Diastolic
60
<0.01 <0.01 ns ns <0.02 <0.05 <0.05 P
References
1. Herrick JB: Peculiar elongated and sickle shaped red blood corpuscles 11. Frank PFH: Studies on the phospolid organization in membranes of
in a case of severe anemia. Arch Intern Med 1910, 6:517. abnormal erythrocytes [PhD thesis]. Utrecht: State University of
2. Pauling L, et al.: Sickling cell anemia, molecular disease. Science 1949, Utrecht; 1984.
110:543. 12. Statius van Eps LW, Schouten H, Ter Haar Romeny Wachter CCh, la
Porte-Wijsman LW: The relation between age and renal concentrating
3. Ingram VM: Gene mutations in human hemoglobin: the chemical
capacity in sickle cell disease and hemoglobin C disease. Clin Chim
difference between normal and sickle cell hemoglobin. Nature 1959,
Acta 1970, 27:501.
180:326.
13. Statius van Eps LW, Schouten H, la Porte-Wijsman LW, Struyker
4. Bunn HF: Mechanisms of disease: pathogenesis and treatment of sick- Boudier AM: The influence of red blood cell transfusions on the
le cell disease. N Engl J Med 1997, 337:762–769. hyposthenuria and renal hemodynamics of sickle cell anemia. Clin
5. Statius van Eps LW, Pinedo Veels C, De Vries H, De Koning J: Nature Chim Acta 1967, 17:449.
of concentrating defect in sickle cell nephropathy, microradioangio- 14. Schmidt-Nielsen B, O’Dell R: Structure and concentrating mechanism
graphic studies. Lancet 1970, 1:450. in the mammalian kidney. Am J Physiol 1961, 200:1119.
6. Hostetter TH, et al.: Hyperfiltration in remnant nephrons: a potential- 15. Keitel HG, et al.: Hyposthenuria in sickle cell anemia: a reversible
ly adverse response to renal ablation. Am J Physiol 1981, 241:F85. renal defect. J Clin Invest 1956, 35:998.
7. Dickerson RE, Geis I: The Structure and Action of Proteins. New 16. Statius van Eps LW, De Jong PE: Sickle cell disease. In Diseases of the
York: Harper and Row, 1969, 1971. Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little,
8. Perillie PE, Epstein, FH: Sickling phenomenon produced by hyperton- Brown; 1997:2201.
ic solutions: a possible explanation for the hyposthenuria of sicklemia. 17. Goossens JP, Statius van Eps LW, Schouten H, Gieterson AL:
J Clin Invest 1963, 42:570. Incomplete renal tubular acidosis in sickle cell disease. Clin Chim
9. Edelstein SJ: Structure of the fibers of hemoglobin S: human hemoglo- Acta 1972, 41:149.
bins and hemoglobinopathies: a review to 1981. Galveston: University 18. De Jong PE, et al.: The tubular reabsorption of phosphate in sickle
of Texas; 1981. cell nephropathy. Clin Sci 1978, 55:429.
10. Franck PF, Bevers EM, Lubin BH, et al.: Uncoupling of the membrane 19. De Jong PE, Landman H, Statius van Eps LW: Blood pressure in sickle
skeleton from the lipid bilayer: the cause of accelerated phospholipid cell disease. Arch Intern Med 1982, 142:1239.
flip-flop leading to an enhanced procoagulant activity of sickled cells. 20. De Jong PE, Statius van Eps LW: Sickle cell nephropathy: new insights
J Clin Invest 1985, 75:183–190. into its pathophysiology. Editorial review. Kidney Int 1985, 27:711.
Renal Involvement
in Malignancy
Richard E. Rieselbach
A. Vishnu Moorthy
Marc B. Garnick
P
atients with malignancy are particularly vulnerable to development
of renal abnormalities [1]. Additionally, patients with renal abnor-
malities who have undergone kidney transplantation are at
increased risk for malignancy, which may involve the kidney [2].
Malignancy may directly involve the urinary tract. More commonly, how-
ever, the many systemic manifestations of cancer and the toxicity of its
treatment are involved in the pathogenesis of diverse clinical syndromes
involving the kidney [3].
Malignant neoplasms directly involving the renal parenchyma, renal
pelvis, or ureter may be primary or secondary in origin. Metastatic neo-
plasms are the cause of renal malignancy more frequently than primary
tumors. These secondary lesions are usually asymptomatic, however, and
most often are discovered incidentally only at postmortem examination
[4]. Additionally, extrarenal malignancy may involve the kidney by pro-
ducing obstruction of urine flow via extrinsic compression of the urinary
tract. This occurs most often with gynecologic and other pelvic neo-
plasms in women and with prostatic cancer in men.
Systemic manifestations of cancer may involve the kidney via forma-
tion of immune complexes, which may produce glomerulonephritis [5].
Also, paraproteins generated by multiple myeloma and other lymphoid
neoplasms may produce renal dysfunction [6]. In addition to tumor
products, malignancy-induced metabolic abnormalities, such as hyper-
calcemia and hyperuricemia, may impair renal function.
Finally, a high percentage of cancer patients are candidates for aggres-
CHAPTER
sive chemotherapy or radiation therapy, or both. Nephrotoxicity due to
5
chemotherapy may manifest as acute renal failure, chronic renal failure,
or specific tubular dysfunction causing fluid and electrolyte imbalance
[7]. The nephrotoxicity of radiation therapy may be synergistic with that
of chemotherapy in some settings, or radiation therapy may by itself pro-
duce significant renal damage.
5.2 Systemic Diseases and the Kidney
FIGURE 5-1
CLINICAL SYNDROMES OF RENAL Clinical syndromes of renal involvement in malignancy. Renal
INVOLVEMENT IN MALIGNANCY involvement in malignancy may present as one or more of four
clinical syndromes. Additionally, the incidence of a broad spectrum
of malignancies is increased in the renal transplant patient, and the
Acute renal failure malignancy may directly involve the transplanted kidney.
Prerenal
Intrinsic
Postrenal
Hematuria and/or nephrotic syndrome
Chronic renal failure
Specific tubular dysfunction and associated fluid and electrolyte disorders
Malignancy in the renal transplant patient
60
ic-uremic syndrome (HUS) can be observed. As noted, the greatest
risk for development of ARF occurs 10 to 21 days after BMT, with
50 the usual cause at this time being prerenal acute renal failure due to
Azotemia hepatic veno-occlusive disease. This causes a syndrome very similar to
40 the hepatorenal syndrome (HRS). There are five clinical similarities
Patients, %
A B
FIGURE 5-5 (see Color Plate)
Hemolytic-uremic syndrome (HUS). A 46-year-old woman with agents. The risk of developing mitomycin C–induced HUS is 2% to
metastatic carcinoma of the lung and congestive heart failure devel- 10%, and cumulative doses larger than 60 mg are often associated
oped renal insufficiency over a 12-week period. A percutaneous with the disease [19]. The patients with cancer are often in remis-
renal biopsy revealed that several glomeruli had the acute changes sion at the time of diagnosis. The mortality rate has been as high
of swelling and detachment of endothelial cells and luminal occlu- as 70%, usually in the first 2 months, and is related to renal failure
sion (panel A, periodic acid–Schiff stain). The arterioles and arter- and sepsis.
ies showed intimal cellular swelling and hyperplasia and fibrin The diagnosis of HUS should be considered in the clinical setting
deposition. Immunofluorescence microscopy revealed glomerular of acute renal failure associated with thrombocytopenia and
fibrin deposition (panel B). microangiopathic hemolytic anemia with schistocytes (seen on a
Hemolytic-uremic syndrome is a thrombotic microangiopathy peripheral blood smear). The renal biopsy results show a variety of
presenting as an acute illness characterized by renal failure, throm- glomerular and vascular changes, such as endothelial cell swelling,
bocytopenia, and microangiopathic hemolytic anemia. Vascular detachment of thrombi, and thrombotic occlusion of the lumen.
and endothelial cell injury leads to microvascular thrombosis and Fibrin is noted in the walls of blood vessels of glomeruli on
ischemic organ damage. HUS can occur in diverse clinical settings, immunofluorescence microscopy. On electron microscopy, endothe-
including metastatic carcinoma, particularly of the stomach, breast, lial cell swelling and detachment from the basement membrane,
or lung [17]. The initiating factor is presumably tumor emboli. subendothelial granular material, and luminal thrombi may be seen
These patients have an extremely poor prognosis and often die in the glomeruli. Treatment is generally supportive, including dialy-
within a few weeks of diagnosis [18]. HUS also has been reported sis. Hemolytic-uremic syndrome with vascular endothelial injury
after chemotherapy for cancer. This form of chemotherapy-related both in the glomeruli and in the intrarenal blood vessels may occur
HUS is mainly associated with mitomycin C but has also been in patients with disseminated malignancy or after chemotherapy
noted after therapy with bleomycin and platinum-containing for malignancy.
FIGURE 5-9
Light-chain cast nephropathy. The kidney at autopsy of a 68-year-
old man with multiple myeloma who died 2 years after diagnosis
owing to sepsis and renal failure. Note the dense, lamellated, and
fractured casts in the renal tubules surrounded by multinucleated
giant cells. There is also interstitial fibrosis.
FIGURE 5-10
Nephrocalcinosis in a patient with multiple myeloma. Irregular fractured hema-
toxylinophilic deposits of calcium are seen in this fibrotic renal tissue. Hypercalcemia may
produce serious structural changes in the kidney, resulting in acute or chronic renal failure.
Hypercalcemia is a relatively common complication of malignancy. Increased bone reab-
sorption is most often responsible owing to bone metastases or to the release of humoral
substances such as parathyroid hormone–like peptide or cytokines such as transforming
growth factor- [32]. Secretion of calcitriol, the active form of vitamin D, also may occur in
some lymphomas [33]. Renal dysfunction in the setting of hypercalcemia results from both
calcium-induced constriction of the afferent arteriole and the deposition of calcium in the
tubules and interstitium, leading to intratubular obstruction and secondary tubular atrophy
and interstitial fibrosis [34]. Prompt treatment generally restores renal function, but irre-
versible damage can occur with long-standing hypercalcemia [35]. Recovery of the glomeru-
lar filtration rate varies inversely with the extent of nephrocalcinosis, interstitial scarring,
associated obstructive uropathy, infection, and hypertension. All the foregoing reflect the
duration and severity of hypercalcemia. (From Skarin [31]; with permission.)
FIGURE 5-11
Acute uric acid nephropathy (AUAN). Intrarenal obstruction caused by uric acid precipita-
tion in collecting ducts produces severe tubular dilatation (DeGalantha stain). This patient,
who received chemotherapy for acute lymphocytic leukemia before allopurinol was avail-
able, had a plasma urate concentration of 44 mg/dL at the time of death.
Acute uric acid nephropathy is most frequently encountered in patients with a large
tumor burden (often due to rapidly proliferating lymphoma or leukemia) in whom aggres-
sive radiation or chemotherapy has been recently initiated. If rapid lysis of tumor cells
occurs, massive quantities of uric acid precursors (and often other tumor products) are
released. This induces a marked increase in synthesis of uric acid and thus acute hyper-
uricemia. The subsequent renal uricosuric response may be of sufficient magnitude to
exceed solubility limits for uric acid in the distal nephron, particularly in the presence of
dehydration or metabolic acidosis. The resultant intrarenal obstruction produces a charac-
teristic pattern of acute renal failure [36]. In the setting of particularly extensive disease
with rapid cell lysis, profound hyperkalemia, hyperphosphatemia, and hypocalcemia (due
to precipitation of calcium phosphate) may be observed. This is termed acute tumor lysis
syndrome [37]. This syndrome usually occurs after treatment of poorly differentiated lym-
phoma or leukemia; if it arises spontaneously, hyperphosphatemia is not prominent
because phosphate is incorporated into rapidly proliferating tumor cells.
Rarely, xanthine nephropathy can occur during tumor lysis when allopurinol is used to
prevent the production of uric acid. The resultant xanthine oxidase inhibition can produce
a marked increase in blood and urine xanthine and hypoxanthine concentrations.
Xanthine, like uric acid, is poorly soluble in an acidic urine; xanthine crystalluria occurs
when its concentration exceeds its solubility, thereby causing obstructive nephropathy [38].
Renal Involvement in Malignancy 5.7
FIGURE 5-12
PROPHYLAXIS AND TREATMENT OF ACUTE URIC ACID Prevention and management of acute uric
NEPHROPATHY AND ACUTE TUMOR LYSIS SYNDROME acid nephropathy (AUAN) and the acute
tumor lysis syndrome (ATLS). The metabol-
ic consequences of rapid malignant cell lysis
Prophylaxis are many, ranging from moderate hyper-
A. Patients presenting (before chemotherapy) with evidence of large, rapidly proliferating tumor burden and uricemia to death from hyperkalemia. The
hyperuricemia measures employed for prevention and
1. Correct initial electrolyte and fluid imbalance, and azotemia, if possible; dialysis as indicated for established renal management vary according to the type and
failure or unresponsive electrolyte or metabolic abnormalities extent of the tumor and whether cytolytic
2. Maintain adequate hydration and urine output (>3 L/d). May require 4 to 5 L/24 h of intravenous hypotonic therapy has been initiated.
saline or bicarbonate; diuretics as indicated In recent years, with appropriate prophy-
3. Give Allopurinol* (300 mg/m2) at least 3 days before therapy if possible laxis and dialytic therapy, AUAN and ATLS
4. Alkalinize urine to pH >7.0 (hypotonic NaHCO3 infusion; Diamox if necessary) rarely represent life-threatening problems.
5. Postpone chemotherapy (if possible) until uric acid and electrolytes are reasonably normalized When acute renal failure (ARF) does occur,
6. Continuous-flow leukapheresis might be indicated for patients with a high circulating blast count (white cell prognosis is excellent. The approach to
count >100,000/mm3) AUAN and ATLS is divided into two
B. Patients presenting (before chemotherapy) with normouricemia, but still at risk stages. The first is to prevent or minimize
1. Allopurinol* 300 mg/m2; at least 2 days before therapy if possible the metabolic consequences, and the second
2. 4 to 5 L/d of intravenous fluid as described above involves treatment if prophylaxis has not
3. Urinary alkalinization as described above been successful. The approach to both pro-
Treatment phylaxis and treatment includes inhibition
C. Patients presenting (usually after chemotherapy) with renal failure of xanthine oxidase, forced diuresis, and
1. Same as for patients with tumor and hyperuricemia if sufficient renal function remains. If dialysis is necessary,
urinary alkalinization. If treatment is not
continuous hemodialysis or hemofiltration may be preferable if severe hyperuricemia or hyperkalemia is present successful and ARF develops, these patients
2. Discontinue urine alkalinization when uric acid homeostasis is achieved (to avoid Ca3[PO412]precipitation) respond very well to hemodialysis, with
3. Treat symptomatic hypocalcemia after correction of hyperphosphatemia morbidity and mortality usually related to
the underlying disease process [39].
B
tration or occasionally by the presence of a large solitary tumor.
A Renal failure due to parenchymal infiltration by lymphoma cells is
extremely rare. In one large series, uremia resulting from lym-
FIGURE 5-15 phomatous replacement of kidney tissue was the cause of death in
Renal involvement in lymphoma. A, Renal involvement in a patient only 0.7% of patients [42]. As with leukemia, when lymphoma has
with diffuse large cell lymphoma. There is little remaining parenchy- caused renal failure, chemotherapy and radiation therapy have led
ma in this specimen, which exhibits many large, gray-white nodules to improvement in kidney function.
of tumor. Although primary renal lymphoma is rare, 5% to 10% of B, Lymphoma with renal infiltration. A 65-year-old-man present-
patients with disseminated lymphoma exhibit clinically detectable ed with left flank pain and microscopic hematuria of 6 weeks’
renal involvement. At autopsy, the incidence of renal involvement duration. He had a left renal mass demonstrable on abdominal
by lymphoma has been estimated by several series to be more than ultrasound. Left renal perihilar and retroperitoneal lymph node
30% [41]. The incidence was higher in patients with lymphosarco- enlargement was noted on a CT scan. He was normotensive and
ma or histiocytic lymphoma than in those having Hodgkin’s disease, had a serum creatinine level of 1.2 mg/dL. A needle biopsy of the
with its occurrence in mycosis fungoides being intermediate in fre- renal mass, under CT guidance, revealed renal parenchymal infil-
quency. The majority of patients had involvement of both kidneys. tration with lymphoid cells with neoplastic characteristics. (Panel A
Lymphoma may involve the kidney by multinodular or diffuse infil- from Skarin [31]; with permission.)
Renal Involvement in Malignancy 5.9
FIGURE 5-17
Urinary tract obstruction. Obstruction is a prominent feature of
Uterus urinary tract involvement in gynecologic cancers [45]. The ureters
Nodal
obstruction may be invaded by tumor or compressed by the tumor mass or
tumor-filled lymph nodes. Ureteral stricture may be the cause of
obstruction following radiation therapy or surgery. Also, the blad-
der may be subject to direct extension of tumor with occlusion of
ureteral orifices. In this figure, the anterior wall of the bladder is
Bladder
ulceration cut away to illustrate these as well as other forms of urinary tract
Stricture involvement by gynecologic cancers. In this setting, obstruction
Uretovaginal may produce either acute or chronic renal failure depending on the
fistula
location of the obstruction and the rapidity of tumor growth.
(Adapted from Rieselbach and Garnick [1].)
Bladder
Vesicovaginal
fistula
Vagina
5.10 Systemic Diseases and the Kidney
A B
FIGURE 5-20
Membranous glomerulonephritis and the nephrotic syndrome in a chest mass. He died 10 months later. Membranous glomeru-
patient with bronchogenic carcinoma. A 76-year-old veteran pre- lonephritis and bronchogenic carcinoma were diagnosed at autopsy.
sented with ankle edema and weight gain of 8 weeks’ duration. He A, Light microscopic study of the kidney of this patient. Note the
was noted to have the nephrotic syndrome with 5 grams of protein- thickening of capillary walls and spikes (PAM stain). B, Immuno-
uria per day. A chest radiograph revealed a perihilar mass. A bron- fluorescence microscopy of renal tissue showing peripheral
choscopic biopsy of the mass was diagnostic of malignancy. He was glomerular capillary deposition of IgG in a granular pattern indica-
managed conservatively with diuretics and radiotherapy for the tive of immune-complex-mediated glomerulonephritis.
(Continued on next page)
5.12 Systemic Diseases and the Kidney
C D
FIGURE 5-20 (Continued)
C, Electron microscopy of the glomerulus showing subepithelial of cases [5]. Although a variety of malignancies have been observed
electron-dense deposits along the capillary walls. There is efface- to be associated with membranous glomerulonephritis, the most
ment of the epithelial cell foot processes, which is a common find- common sites are the breast, the lung, and the colon. In some
ing in patients with nephrotic syndrome. D, Bronchogenic carcino- instances, the tumor antigen or antitumor antibodies have been
ma noted at autopsy in this patient (hematoxylin and eosin stain). detected in the glomeruli. Development of the nephrotic syndrome
Membranous glomerulonephritis is an immune-complex–mediat- has been temporally related to the malignancy in several instances,
ed glomerular disease, often resulting in nephrotic syndrome as a and successful cure of the malignancy has led to a remission in the
clinical manifestation. In adults older than the age of 50, a coexist- nephrotic syndrome. Relapses have been associated with reappear-
ing malignancy, usually a carcinoma, may be present in up to 10% ance of proteinuria [46].
A B
FIGURE 5-21
Minimal change nephrotic syndrome in Hodgkin’s disease. A, Light occurrence of glomerular diseases has been noted [5,46]. Several his-
microscopic study of a renal biopsy specimen from a 57-year-old tologic types of glomerular diseases have been documented in these
man with nephrotic syndrome of 3 months’ duration. Urine protein instances; the most common type has been minimal change nephrotic
excretion was 7.1 g/d. The serum creatinine concentration was 1.3 syndrome [47]. The glomeruli of these patients are normal on light
mg/dL. The patient also had cervical lymphadenopathy, biopsy of microscopic study and are devoid of hypercellularity or capillary
which revealed Hodgkin’s disease of the mixed cellularity type. He wall thickening. No immunoglobulins are noted in the glomeruli on
was treated with irradiation to the upper mantle region with reso- immunofluorescence microscopy. On electron microscopy, efface-
lution of the lymphadenopathy. Proteinuria also declined to 2 g/d ment of the epithelial cell foot processes is the only abnormality pre-
in 2 weeks and was absent in 8 weeks. The glomerulus was normo- sent. Proteinuria has been noted to remit with cure of lymphoma
cellular with delicate capillary walls diagnostic of minimal change (with use of surgery, radiotherapy, or chemotherapy) in some cases;
nephrotic syndrome (PAM stain). relapses in nephrotic syndrome occur with recurrence of the tumor.
B, Electron microscopy of a glomerulus from the same patient This has been documented to occur several times in some patients
showing glomerular capillaries with extensive effacement of the [47]. The pathogenesis of minimal change nephrotic syndrome in
epithelial foot processes but without electron-dense deposits. patients with malignancy remains unknown. It is possible that a
In patients with Hodgkin’s disease and other malignancies arising cytokine or tumor cell product may be responsible for the increase in
from lymph nodes as well as different types of chronic leukemias, the glomerular permeability with resultant proteinuria [48].
Renal Involvement in Malignancy 5.13
A. COMPARISON OF PARAPROTEINEMIAS
FIGURE 5-24
PRESENTING SIGNS AND SYMPTOMS Presenting signs and symptoms of renal cell carcinoma. Patients
OF RENAL CELL CARCINOMA with renal cell cancer present with symptoms produced by the
local neoplasm, with signs and symptoms of paraneoplastic phe-
nomena, or with other aspects of systemic disease. Alternatively,
Feature Frequency, % the patient may be totally asymptomatic and may be diagnosed
from a radiologic abnormality detected on ultrasound or abdomi-
Hematuria 40–65 nal CT scanning. Fewer than 10% of patients present with the
Pain 20–50 classic triad of hematuria, abdominal mass, and flank pain. The
Flank or abdominal mass 20–40 most common features include hematuria (70%), flank pain
Weight loss 30 (50%), palpable mass (20%), fever (15%), and erythrocytosis
Symptoms from distant metastatic spread 10 (infrequent). Other features may include acute onset of lower
Fever 15–20 extremity edema, or, in males, the presence of a left-sided varico-
Classic triad (pain, hematuria, mass) 10 cele, indicating obstruction of the left gonadal vein at its point
Polycythemia <5 of entry into the left renal vein by a tumor thrombus [53,54].
Acute varicocele <5
Renal Involvement in Malignancy 5.15
FIGURE 5-25
FREQUENCY OF SYSTEMIC EFFECTS IN PATIENTS Frequency of systemic effects. The most frequent systemic manifes-
WITH RENAL CELL CARCINOMA tations of renal cell cancer are noted [55]. Other paraneoplastic
and systemic manifestations include liver function abnormalities,
high-output congestive heart failure, and manifestations of the
Symptom Incidence, % secretion of substances such as prostaglandins, renin, glucocorti-
coids, and cytokines (eg, interleukin-6). At presentation, a small
Elevated ESR 362/6.51 (55.6) percentage of tumors are bilateral, while nearly a third of patients
Anemia 409/991 (41.3) have demonstrable metastatic disease, which may occur in virtually
Hypertension 89/237 (37.6) any organ. Most common sites of metastases include lung, bone,
Cachexia 338/979 (34.5) liver, and brain. ESR—erythrocyte sedimentation rate. (From
Pyrexia 164/954 (17.2) Chisholm and Roy [55]; with permission.)
Abnormal liver function 60/400 (15.0)
Elevated alkaline phosphatase 64/434 (14.7)
Hypercalcemia 33/577 (5.7)
Polycythemia 33/903 (3.7)
Neuromyopathy 13/400 (3.3)
Amyloidosis 12/573 (2.1)
FIGURE 5-26
Stage I Stage III The staging of renal adenocarcinoma. Renal cell cancer can be
staged using one of two systems in common use. The TNM (tumor,
node, metastasis) system has the advantage of being more specific
but the disadvantage of being cumbersome; a modification of the
Robson staging system (as illustrated here) is more practical and
more widely used in the United States. In this system, stage I repre-
Vena cava Aorta sents cancer that is confined to the kidney capsule; stage II indi-
cates invasion through the renal capsule, but not beyond Gerota’s
Stage II Stage IV
fascia; stage III reflects involvement of regional lymph nodes and
the ipsilateral renal vein or the vena cava; and stage IV indicates
the presence of distant metastases [57].
With regard to pathologic assessment, previously renal carcino-
mas were classified according to cell type and growth pattern. The
former included clear cell, spindle cell, and oncocytic carcinoma,
Stage I: Confined to kidney while the latter included acinar, papillary, and sarcomatoid vari-
Stage II: Including renal vein involvement eties. Recently, this classification has undergone a transformation
Stage III: Lymph node and caval involvement to reflect more accurately the morphologic, histochemical, and
Stage IV: Adjacent organ metastases molecular basis of differing types of adenocarcinoma [58]. Based
on these studies, five distinct types of carcinoma have been identi-
fied: clear cell, chromophilic, chromophobic, oncocytic, and col-
lecting duct. Each of these types has a unique growth pattern, cell
of origin, and cytogenetic characteristics [59,60]. (From Brenner
and Rector [56].)
5.16 Systemic Diseases and the Kidney
360 Dialysate
Serum
Osmolality, mOsm/L
340
Osmotic
320 equilibrium
300
0 1 2 3 4
C Dwell time, h
FIGURE 5-27
Diagnostic evaluation of and therapeutic approach to primary renal If the sonographic criteria for a simple cyst are not met or the
cancer—an algorithm for diagnosis and management of a renal intravenous pyelogram suggests a solid or complex mass, a CT scan
mass. The discovery of evidence during the history or physical should be performed. If a renal neoplasm is demonstrated on CT
examination that suggests a renal abnormality should be followed scanning, renal vein or vena caval involvement should be assessed
by either an intravenous pyelogram or an abdominal ultrasound. with CT scanning or magnetic resonance imaging. Although used
With increasing frequency, however, evidence of a space-occupying frequently in the past, selective renal arteriography has assumed a
lesion in the kidney is found incidentally during radiographic testing more limited use, mainly in further evaluating the renal vasculature
for other unrelated conditions. Renal ultrasonography may help dis- in patients who are to undergo partial nephrectomy (nephron-spar-
tinguish simple cysts from more complex abnormalities. A simple ing surgery). CT scanning is also very helpful in determining the
cyst is defined sonographically by the lack of internal echoes, the presence of lymphadenopathy.
presence of smooth borders, and the transmission of the ultrasound The differential diagnosis of a renal mass detected on CT scanning
wave. If these three features are present, the cyst is most likely includes primary renal cancers, metastatic lesions of the kidney, and
benign. At one time, cyst puncture was used, but it seems to be benign lesions. The latter include angiomyolipomas (renal hamar-
unnecessary today in the asymptomatic patient without hematuria. tomas), oncocytomas, and other rare or unusual growths. If a renal
Periodic repetition of the ultrasound is suggested for follow-up. If a cancer is considered based on the radiographic studies of the kidney,
change in the lesion occurs, cyst puncture, needle aspiration, or CT the patient should undergo a preoperative staging evaluation to
scanning should be considered to evaluate the lesion further. assess the presence of metastases in the lung, bone, or brain.
(Continued on next page)
Renal Involvement in Malignancy 5.17
(Continued) The operative and diagnostic approach is dictated considered for nephrectomy following the response, however.
according to the preoperative stage of the patient. For example, the Finally, since many renal tumors can become quite large, considera-
patient who presents with stage IV disease by virtue of a positive tion should be given to palliative nephrectomy (in the setting of
bone scan may need only a needle biopsy of either the kidney lesion metastatic disease), especially if the patient experiences uncontrol-
or the bone lesion to establish the tissue diagnosis and thus avoid lable hematuria or pain or is catabolic secondary to the sheer mass
more extensive surgery on the kidney. In contrast, a patient with an of the tumor.
isolated pulmonary lesion may be considered for both nephrectomy The medical management of patients with either locally advanced
and pulmonary nodulectomy at one operative intervention. renal cancer or metastatic disease provides a great challenge to physi-
The standard therapy for localized renal cell carcinoma is radical cians and clinical investigators. Although chemotherapy and hor-
nephrectomy, which includes removal of the kidney, Gerota’s fascia, monal treatments have been studied extensively in patients with
the ipsilateral adrenal gland, and regional hilar lymph nodes. The metastatic renal cancer, no single treatment protocol or program has
value of an extended hilar lymphadenectomy seems to be its ability been uniformly effective. Therefore, most physicians treating the dis-
to provide prognostic information, since there is rarely a therapeutic ease usually rely on novel modalities of treatment, including biologic
reason for performing this portion of the operation. In the past, the response modifiers, investigational anticancer agents, differentiation
removal of the ipsilateral adrenal gland was done routinely; today, agents (such as retinoic acid), vaccines, and gene therapy. Interferon
most data suggest that it is involved less than 5% of the time, more therapy with interferon-, -, or - has led to responses in approxi-
frequently with large upper-pole lesions. Thus, today, ipsilateral mately 15% to 20% of treated patients [64]. Interferons demonstrate
adrenalectomy is reserved for those patients with abnormal-appear- antiproliferative activity against renal cell cancers in vitro, stimulate
ing glands or enlarged glands on CT scan or those with large upper- immune cell function, and can modulate the expression of major his-
pole lesions, in which the probability of direct extension of the tocompatibility complex molecules. Although responses have been
tumor to the adrenal gland is more likely [61]. seen in cancers involving many different anatomic areas, patients
Partial nephrectomy (nephron-sparing surgery) has become more who have had a prior nephrectomy with isolated pulmonary metas-
popular, especially for patients with small tumors, for those at risk for tases and who are otherwise well may enjoy a higher response rate
developing bilateral tumors, or for patients in whom the contralateral [65]. Duration of response is usually less than 2 years; longer lasting
kidney is at risk for other systemic diseases, such as diabetes or hyper- remissions have been noted in a few selected patients. Interferons
tension [62]. The main concern associated with partial nephrectomy have been combined with other immune modifiers as well as with
is the likelihood of tumor recurrence in the operated kidney, since chemotherapy agents with no real improvement in patient outcome
many renal cancers may be multicentric. Local recurrence rates of 4% in larger-scale trials. Several smaller trials have combined interferon
to 10% have been reported; lower rates have been reported when with interleukin-2 or chemotherapy agents (eg, 5-fluorouracil) with
partial nephrectomy was performed for smaller lesions (< 3 cm) with some encouraging preliminary results.
a normal contralateral kidney. Lesions that are centrally located, how- Interleukin 2 (Il-2) has received a great deal of attention as a
ever, still require radical nephrectomy. Frequent follow-up, usually potential advance in the treatment of renal cell cancer. This agent
with CT scanning or ultrasonography, will be necessary in those enhances both proliferation and functioning of lymphocytes involved
patients who undergo partial nephrectomy. Inferior vena caval in antigen recognition and tumor elimination. Initial studies used
involvement with renal cancer occurs more frequently with right- very high doses of Il-2 in association with ex vivo populations of
sided tumors and is usually associated with metastases in nearly 50% lymphoid cells grown and matured under the influence of Il-2 [66].
of patients. Vena caval obstruction may lead to the diagnosis; it may These programs resulted in substantial toxicity, including patient
present with abdominal distention from ascites, hepatic dysfunction, deaths, but nevertheless had early and encouraging therapeutic
nephrotic syndrome, abdominal wall venous collaterals, varicocele, results. Unfortunately, the initial encouraging results were not consis-
malabsorption, or pulmonary embolus. The anatomic location of the tently observed in larger-scale trials. Efforts are now directed at
caval thrombus is important prognostically; supradiaphragmatic selectively manipulating the immune-enhancing features of the treat-
lesions, which may involve the heart, can be resected, but the progno- ment, with modification of the toxic effects. In several recent studies,
sis is poor. Subdiaphragmatic lesions enjoy a better 5-year survival, the use of lower doses of Il-2 without the cellular components has
but the survival rate is usually less than 50% [63]. In the surgical resulted in comparable results with less toxicity.
management of these patients, a team of specialists is required, espe- The toxicity of Il-2 is related to alterations in vascular permeabil-
cially if a cardiac tumor thrombectomy is contemplated. ity, leading to a capillary leak type of syndrome. Although the drug
The role of surgery in the management of metastatic disease either is approved by the Food and Drug Administration for the manage-
at initial presentation or later remains controversial. Although most ment of patients with metastatic renal cell cancer, its use should be
data that support nephrectomy plus metastatectomy are anecdotal, restricted to those patients who can tolerate the side effect profile
many patients with synchronous renal cell cancer and an isolated and those patients with acceptable cardiac, renal, pulmonary, and
pulmonary nodule may be considered for surgical resection of both hepatic function.
lesions. Likewise, patients who develop an isolated lesion in the liver Investigational therapies continue to be studied for renal cell cancer.
or lung some time following the removal of the kidney also may be These include novel cytokines such as interleukin-12, combinations of
considered for surgical removal of the metastasis. Nevertheless, even biologics with or without chemotherapeutic agents, circadian timing of
when such vigorous surgery is carried out, most patients do poorly. chemotherapy administration, vaccine therapy, various forms of cellular
Additional controversy surrounds the practice of performing therapy, and gene therapy [67]. Although all these approaches have a
nephrectomy in patients with widespread metastatic disease as a solid scientific preclinical rationale, none, unfortunately, can be consid-
means of potentially improving their response to systemic therapy. ered standard treatment. The sobering fact still remains that nearly
Many investigative programs require such resection, but at this writ- 50% of all patients diagnosed with renal cell cancer die of their disease
ing, the practice should be considered investigational. A patient who within 5 years of diagnosis, and a substantial proportion have advanced
does experience an excellent response to systemic therapy should be stages of cancer spread at initial presentation.
5.18 Systemic Diseases and the Kidney
FIGURE 5-28
Metastatic malignant melanoma involving the kidney. The urinary
tract is a common site of melanoma metastases. If not amelanotic,
the metastatic nodules are brownish black. Metastatic infiltration
of the kidneys is often an incidental finding at autopsy but is a rare
cause of functional impairment [68]. Most renal metastases are
multiple and bilateral. Glomeruli tend to be spared, possibly
because of their lack of lymphatic channels. Pulmonary carcinoma
is the most commonly reported form of metastatic solid tumor
involving the kidneys, followed by metastatic stomach and breast
carcinoma [69].
Metastatic melanoma is an example of a tumor that may be
transplanted at the time of cadaver kidney transplantation, with
subsequent rapid proliferation in the immunosuppressed recipient;
tumor rejection may occur with cessation of immunosuppressive
therapy [70] (see Fig. 5-37). The presence of renal metastases is
often overlooked during life due to the absence of any specific
physical or laboratory findings. The laboratory finding most likely
to occur is hematuria due to tumor erosion of intrarenal vessels.
(From Skarin [31]; with permission.)
C
5.20 Systemic Diseases and the Kidney
FIGURE 5-31
Toxic therapeutic agents. Nephrotoxicity due to antineoplastic may induce nephrotoxicity soon after initiation of therapy or
agents may result in chronic renal failure but also may manifest only after long-term administration. The risk of nephrotoxicity
as acute renal failure, specific tubular dysfunction, or the varies with each agent. This table summarizes the risk of
nephrotic syndrome. Nephrotoxicity has been observed with use nephrotoxicity, time of onset, and type of functional impairment
of alkylating agents, antimetabolites, antitumor antibiotics, and produced by each agent. (From Massry and Glassock [73];
biologic agents, as outlined in the table. These neoplastic agents with permission.)
FIGURE 5-32
Semustine nephropathy. A, Photomicrograph of the late stages of
semustine nephrotoxicity in a specimen obtained at autopsy.
(Continued on next page)
A
Renal Involvement in Malignancy 5.21
A B
FIGURE 5-33
Radiation nephritis is the basis for the atrophy of the superior portion of the left kidney
shown in this intravenous pyelogram. The right kidney shows straightening of its medial bor-
der due to irradiation atrophy. A, Preirradiation pyelogram; B, film showing radiation field.
Radiation nephropathy refers to damage to the kidney parenchyma and vasculature as a
result of ionizing radiation [14]. Fortunately, this disease is relatively uncommon. It was
more prevalent before meticulous detail to abdominal organ shielding was widely prac-
ticed or understood. Historically, patients receiving whole abdominal radiation therapy for
lymphoma, seminoma, or other retroperitoneal tumors were the most likely to suffer the
consequences of this disorder. Doses greater than 30 to 35 gray and single large fractions
were likely to cause damage.
Pathologically, the disease is characterized by damage to the microvasculature, prolifera-
tion of fibrous tissue, and disruption of the renal capillaries and arterioles. FIGURE 5-34
Clinically, the disease manifests predominantly with renal dysfunction and hypertension. Bilateral ureteral obstruction by diffuse
Hematuria, oliguria, fatigue, and gradually developing renal atrophy are common manifes- large-cell lymphoma. Extensive retroperi-
tations. The chronic form of radiation nephropathy may occur 10 to 15 years after the toneal involvement is evident. Confluent
radiation treatments. (From Rieselbach and Garnick [1]; with permission.) adenopathy of retroperitoneal lymph nodes
has led to bilateral encasement and com-
pression of the ureters by pink-tan, fleshy
tumor. This may produce chronic renal fail-
ure if tumor involvement is slowly progres-
sive or involves predominantly one ureter.
(From Skarin [31]; with permission.)
5.22 Systemic Diseases and the Kidney
FIGURE 5-37
Malignant lymphoma in the transplanted kidney. A 55-year-old
man with end-stage renal disease due to diabetic nephropathy
received a cadaveric renal transplant. He was managed with pred-
nisone, azathioprine, and antilymphocyte globulin (ALG). The allo-
graft functioned poorly despite therapy a week later with OKT3.
Results of a percutaneous renal biopsy were suspicious for a lym-
phoproliferative disorder in the renal allograft. He had a transplant
nephrectomy 5 weeks after the original surgery. Pathologic study of
the allograft showed extensive infiltration of the interstitium, renal
pelvis, and blood vessels with large round and ovoid lymphocytes
with many nucleoli and scant cytoplasm, diagnostic of a malignant
lymphoma. Special studies revealed the lymphoid cells to be poly-
clonal in nature, and the patient’s serologic testing was positive for
Epstein-Barr virus. Immunosuppression was stopped, and therapy
with ganciclovir was started.
5.24 Systemic Diseases and the Kidney
References
1. Rieselbach RE, Garnick MB (eds): Cancer and the Kidney. 23. Garnick MB, Mayer RJ: Management of acute renal failure associated
Philadelphia: Lea & Febiger, 1982. with neoplastic disease. Oncologic Emergencies. Edited by Yarbo J,
2. Marple JT, MacDougall M: Development of malignancy in the end- Bornstein R. New York: Grune and Stratton; 1981:247.
stage renal disease patient. Semin Nephrol 1993, 13:306–314. 24. Von Hoff DD, Penta JS, Helman LJ, Slavik M: Incidence of drug-
3. Flombaum C: Electrolyte and renal abnormalities. In Critical Care of related deaths secondary to high-dose methotrexate and citrovorum
the Cancer Patient, edn 2. Edited by Groeger JS. St. Louis: Mosby factor administration. Cancer Treat Rep 1977, 61:745.
Year Book; 1991:140–164. 25. Hande KR, Donehower RC, Chabner BA: Pharmacology and pharmo-
4. Garnick MB, Richie JP: Primary neoplasms of the kidney and renal kinetics of high dose methotrexate in man. In Clinical Pharmacology
pelvis. In Diseases of the Kidney, edn 6. Edited by Schrier RW, of Antineoplastic Drugs. Edited by Pinedo HM. New York:
Gottschalk CW. Boston: Little, Brown; 1997:779–802. Elsevier/North Holland; 1978.
5. Norris SH: Paraneoplastic glomerulopathies. Semin Nephrol 1993, 26. Jacobs SA, Stoller RG, Chabner BA, Johns DG: 7-Hydroxy
13:258–272. methotrexate as a urinary metabolite in human subjects and rhesus
monkeys receiving high dose methotrexate. J Clin Invest 1976,
6. Sanders PW, Herrera GA: Monoclonal immunoglobulin light chain-
57:534.
related renal disorders. Semin Nephrol 1993, 13:324–341.
27. Johnson WJ, Kyle RA, Pineda AA, et al.: Treatment of renal failure
7. Safirstein RL: Renal diseases induced by antineoplastic agents. In
associated with multiple myeloma. Arch Intern Med 1990,
Diseases of the Kidney, edn 6. Edited by Schrier RW, Gottschalk CW.
50:863–869.
Boston: Little, Brown; 1996:1153–1165.
28. Solomon A, Weiss DT, Kattine AA: Nephrotoxic potential of Bence-
8. Guleria AS, Yang JC, Topalian SL, et al.: Renal dysfunction associated
Jones proteins. N Engl J Med 1991, 324:1845–1851.
with the administration of high-dose interleukin-2 in 199 consecutive
patients with metastatic melanoma or renal cell carcinoma. J Clin 29. Kyle RA, Gertz MA: Systemic amyloidosis. Crit Rev Oncol Hematol
Oncol 1994, 12:2714–2722. 1990, 10:49–87.
9. Zager RA: Acute renal failure in the setting of bone marrow trans- 30. Preud’homme JL, Aucouturier P, Striker L: Monoclonal immunoglob-
plantation. Kidney Int 1994, 46:1443–1458. ulin deposition disease (Randall type): relationship with structural
abnormalities of immunoglobulin chains. Kidney Int 1994,
10. Merouani A, Shpall EJ, Jones RB, et al.: Renal function in high dose
46:965–972.
chemotherapy and autologous hematopoietic cell support treatment
for breast cancer. Kidney lnt 1996, 50:1026–1031. 31. Skarin AT: Atlas of Diagnostic Oncology. New York: Gower Medical
Publishing; 1991.
11. Zimmerman SW, Moorthy AV, Burkholder PM, Jenkins PG:
Glomerulopathies associated with neoplastic disease. In Cancer and 32. Rosol TJ, Capen CC: Mechanisms of cancer-induced hypercalcemia.
the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea Lab Invest 1992, 67:680–702.
& Febiger; 1982. 33. Seymour JF, Gagel RF: Calcitriol: the major humoral mediator of
12. Jenkins PG, Rieselbach RE: Acute renal failure: diagnosis, clinical hypercalcemia in Hodgkin’s disease and non-Hodgkin’s lymphomas.
spectrum, and management. In Cancer and the Kidney. Edited by Blood 1993, 82:1383–1394.
Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982. 34. Benabe JE, Martinez-Maldonado M: Hypercalcemic nephropathy.
13. Baker LRJ, Cattell WR, Fry IK, Mallison WJ: Acute renal failure due Arch Intern Med 1978, 138:777–779.
to bacterial pyelonephritis. Q J Med 1979, 48:603. 35. Coe FL, Favus MJ, Kathpalia SC, et al.: Calcium and phosphorus
14. Mayer RJ: Infiltrative and metastatic disease of the kidney. In Cancer metabolism in cancer: hypercalcemic nephropathy. In Cancer and the
and the Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea &
Lea & Febiger; 1982. Febiger; 1982.
15. Greenberger JS, Weichselbaum RR, Cassady JR: Radiation nephropa- 36. Rieselbach RE, Sorensen LB: Uric acid metabolism in cancer: hyper-
thy. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick MB. uricemic nephropathy. In Cancer and the Kidney. Edited by
Philadelphia: Lea & Febiger; 1982. Rieselbach RE, Garnick MB. Philadelphia: Lea & Febiger; 1982.
16. Lodish JR, Boxer RJ: Urinary tract hemorrhage. In Cancer and the 37. Bishop MR, Coccia PF: Tumor lysis syndrome. In Clinical Oncology.
Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea & Edited by Abeloff MD, Armitage JO, Lichter AS, Niederhuber JR.
Febiger; 1982. New York: Churchill Livingstone; 1995:557–561.
17. Murgo AJ: Thrombotic microangiopathy in the cancer patient includ- 38. Band PR, Silverberg DS, Henderson JF, et al.: Xanthine nephropathy
ing those induced by chemotherapeutic agents. Semin Hematol 1987, in a patient with lymphosarcoma treated with allopurinol. N Engl J
24:161–174. Med 1970, 2283:354.
18. D’Elia JA, Aslani M, Schermer S, et al.: Hemolytic-uremic syndrome 39. Pichette V, Leblanc M, Bonnardeaux A, et al.: High dialysate flow
and acute renal failure in metastatic adenocarcinoma treated with mit- rate continuous arteriovenous hemodialysis: a new approach for the
omycin: case report and literature review. Renal Failure 1987, treatment of acute renal failure and tumor lysis syndrome. Am J
170:107–113. Kidney Dis 1994, 23:591.
19. Remuzzi G, Ruggenenti P: The hemolytic-uremic syndrome. Kidney 40. Hande KR, Noone RM, Stone WJ: Severe allopurinol toxicity:
Int 1995, 47:2–19. Description and guidelines for prevention in patients with renal insuf-
20. Gonzalez-Vitale JC, et al.: The renal pathology in clinical trials of cis- ficiency. Am J Med 1984, 76:47–56.
platinum (II) diamminedichloride. Cancer 1977, 39:1362.21. 41. Obrador GT, Price B, O’Meara Y, Salant DJ: Acute renal failure due
Bhuchar VK, Lanzotti VJ: High-dose cisplatin for lung cancer. Cancer to lymphomatous infiltration of the kidneys. J Am Soc Nephrol 1997,
Treat Rep 1982, 66:375. 8:1348–1354.
21. Bhuchar VK, Lanzotti VJ: High-dose cisplatin for lung cancer. Cancer 42. Richmond J, Sherman RS, Diamond HD, Craver LF: Renal lesions
Treat Rep 1982, 66:375. associated with malignant lymphomas. Am J Med 1962, 32:184–207.
22. Schilsky RL, Anderson T: Hypomagnesemia and renal magnesium
wasting in patients receiving cisplatin. Ann Intern Med 1979, 90:929.
Renal Involvement in Malignancy 5.25
43. Gutmann FD, Boxer RJ: Pathophysiology and management of urinary 64. Nanus DM, Pfeffer LM, Bander NH, et al.: Antiproliferative and anti-
tract obstruction. In Cancer and the Kidney. Edited by Rieselbach RE, tumor effects of alpha-interferon in renal cell carcinomas: correlation
Garnick MB. Philadelphia: Lea & Febiger; 1982. with the expression of a kidney-associated differentiation glycopro-
44. Boxer RJ, Garnick MB, Anderson T: Extrarenal cancer of the geni- tein. Cancer Res 1990, 50:4190–4194.
tourinary tract. In Cancer and the Kidney. Edited by Rieselbach RE, 65. Minasian LM, Motzer RJ, Gluck L, et al.: Interferon alfa-2a in
Garnick MB. Philadelphia: Lea & Febiger; 1982. advanced renal cell carcinoma: treatment results and survival in 159
45. Kearney GP, Knapp RC: Genitourinary complications of gynecologic patients with long-term follow-up. J Clin Oncol 1993, 11:1368–1375.
cancers. In Cancer and the Kidney. Edited by Rieselbach RE, Garnick 66. Law TM, Motzer RJ, Mazumdar M, et al.: Phase III randomized trial
MB. Philadelphia: Lea & Febiger; 1982. of interleukin-2 with or without lymphokine activated killer cells in
46. Eagen JW, Lewis EJ: Glomerulopathies of neoplasia. Kidney Int 1977, the treatment of patients with advanced renal cell carcinoma. Cancer
11:297–306. 1995, 76:824–832.
47. Moorthy AV, Zimmerman SW, Burkholder PM: Nephrotic syndrome 67. Wigginton JM, Komschlies KL, Back TC, et al.: Administration of
in Hodgkin’s disease: evidence for pathogenesis alternative to immune interleukin-12 with pulse interleukin-2 and the rapid and complete
complex deposition. Am J Med 1976, 61:471–477. eradication of murine renal carcinoma. J Natl Cancer Inst 1996,
88:38–43.
48. Shalhoub RJ: Pathogenesis of lipoid nephrosis: a disorder of T-cell
function. Lancet 1974, 2:556–560. 68. Manning EC, Belenko MI, Frauenhoffer EE, Ahsan N: Acute renal
failure secondary to solid tumor renal metastases: case report and
49. Tsuji M, Ochiai S, Taka T, et al.: Nonamyloidotic nephrotic syndrome
review of the literature. Am J Kidney Dis 1996, 27:284–291.
in Waldenstrom’s macroglobulinemia. Nephron 1990, 54:176–178.
69. Wagle DG, Moore RH, Murphy GP: Secondary carcinomas of the
50. Kyle RA: “Benign” monoclonal gammopathy—after 20-35 years of
kidney. J Urol 1975, l 14:30–32.
follow-up. Mayo Clin Proc 1993, 68:26–36.
70. Wilson RE, Hager EB, Hampers CL, et al.: Immunologic rejection of
51. Garnick MB: Bladder, renal and testicular cancer. Scientif Am Med
human cancer transplanted with a renal allograft. N Engl J Med
1995: 12:ixB 1–5.
1968, 278:479–483.
52. Shapiro CL, Garnick MB, Kantoff PW: Tumors of the kidney, ureter,
71. Sharland A, Snowdon L, Joshua DE, et al.: Hemodialysis: an appro-
and bladder. In Cecil Textbook of Medicine, edn 20. Edited by
priate therapy in myeloma-induced renal failure. Am J Kidney Dis
Bennett JC. Philadelphia: WB Saunders; 1996:867.
1997, 30:786–792.
53. McDougal WS, Garnick MB: Clinical signs and symptoms of kidney
cancer. In Comprehensive Textbook of Genitourinary Oncology. 72. Gertz MA, Kyle RA, Greipp PR: Response rates and survival in pri-
Edited by Vogeizang NJ, Scardino PT, Shipley WU, et al. Baltimore: mary systemic amyloidosis. Blood 1991, 77:257–262.
Williams & Wilkins; 1996:P546. 73. Massry, Glassock: Textbook of Nephrology, edn 3. Baltimore:
54. Motzer RJ, Bander NH, Nanus DM: Renal-cell carcinoma. N Engl J Williams & Wilkins; 1995.
Med 1996, 335:8665–8875. 74. Harmon WC, Cohen HJ, Schneeberger E, et al.: Chronic renal failure
55. Chisholm GD, Roy RR: The systemic effects of malignant renal in children treated with methyl CCNU. N Engl J Med 1979,
tumors. Br J Urol 1971, 43:687–700. 300:1200–1203.
56. Brenner B, Rector F: The Kidney, edn 5. Philadelphia: WB Saunders 75. Daniels RA, Weisenfeld I: Tumorous phosphaturic osteomalacia:
Co.; 1996. report of a case associated with multiple hemangiomas of bone. Am J
Med 1979, 67:155–159.
57. Beahrs OH, Henson DE, Hutter RVP, et al.: Handbook for the
Staging of Cancer: From the Manual for Staging Cancer, edn 4. 1993, 76. Simpson DP, Wen SF, Chesney RW: Fluid and electrolyte abnormalities
Philadelphia: J.B. Lippincott; 1993. due to tumors, their products, or metabolites. In Cancer and the
Kidney. Edited by Rieselbach RE, Garnick MB. Philadelphia: Lea &
58. Storkel S, van den Berg E: Morphologic classification of renal cancer. Febiger; 1982.
World J Urol 1995, 13:153–158.
77. Hauck WA, Olson KB, Horton J: Clinical features of tumor metastasis
59. Latif F, Tory K, Gnarra J, et al.: Identification of the von Hippel- to the pituitary. Cancer 1970, 26:656.
Lindau tumor suppressor gene. Science 1993, 260:1317–1320.
78. Pickering TG, Catovsky D: Hypokalemia and raised lysozyme level in
60. Storkel S, Stearata PV, Drenckhain D, Thoenes W: The human chro- acute myeloid leukemia: Q J Med 1973, 42:677–682.
mophobe cell renal carcinoma: its probable relation to intercalated
cells of the collecting duct. Virchows Arch B Cell Pathol 1989, 79. Bennett JS, et al.: Hypouricemia in Hodgkin’s disease. Ann Intern
56:237–245. Med 1972, 76:751–756.
61. Shalev M, Cipolia B, Guille F, et al.: Is ipsilateral adrenalectomy a 80. Chan L, Kam I, Spees EK: Outcome and complications of renal trans-
necessary component of radical nephrectomy? J Urol 1995, plantation. In Diseases of the Kidney, edn 6. Edited by Schrier RW,
153:1415–1417. Gottschalk CW. Boston: Little, Brown; 1997:2713–2769.
62. Licht MR, Novick AC, Goormastic M: Nephron sparing surgery in 81. Stone RM, Mark EJ, Ferry JA: Case records of the Massachusetts
incidental versus suspected renal cell carcinoma. J Urol 1994, General Hospital: Weekly clinicopathological exercises. A 67-year-old
152:39–42. renal-transplant recipient with anemia, leukopenia, and pulmorary
lesions. N Engl J Med 1997, 337:1065–1074.
63. Thrasher JB, Paulson DF: Prognostic factors in renal cancer. Urol Clin
North Am 1993, 20:247–262.
Renal Involvement in
Tropical Diseases
Rashad S. Barsoum
Magdi R. Francis
Visith Sitprija
T
ropical nephrology is no longer a regional issue. With the enor-
mous expansion of travel and immigration, the world has become
a global village. Today, a health problem in a particular region has
worldwide repercussions. Typical examples are the acquisition of malaria
in European airports, renal disease associated with herbal medications,
and increasing encounters of parasitic infections in immunocompromised
persons [1–3].
Lessons learned from the study of tropical diseases have considerably
enriched worldwide medical knowledge of the basic and clinical aspects
of nontropical diseases. Examples include better understanding of
macrophage function in vitro, the role of cytokines in acute renal failure,
and the importance of immunoglobulin A deposits in the progression of
glomerular disease [4–7].
The so-called typical tropical nephropathies are broadly classified as
infective or toxic. Infective nephropathies include renal diseases associat-
ed with endemic bacterial, viral, fungal, and parasitic infections. Toxic
tropical nephropathies include exposure to poisons of animal origin, such
as snake bites, scorpion stings, and intake of raw carp bile, and plant ori-
gin, such as certain mushrooms and the djenkol bean [3].
Tropical bacterial infections often are associated with renal complica-
tions that vary according to the causative organism, severity of infection,
and individual susceptibility. The principal acute infections reported to
affect the kidneys are salmonellosis, shigellosis, leptospirosis, melioidosis, CHAPTER
cholera, tetanus, scrub typhus, and diphtheria [8–16]. Renal involvement
in mycobacterial infections such as tuberculosis and leprosy usually pur-
6
sues a subacute or chronic course [17–19].
6.2 Systemic Diseases and the Kidney
The clinical spectrum of renal involvement extends all the way Mycotic infections are described in detail elsewhere.
from asymptomatic proteinuria or urinary sediment abnormalities Discussed here is a fairly common mycotic infection, mucormy-
to fatal acute renal failure. The respective renal pathologies include cosis, which occurs in underdeveloped tropical regions, partic-
glomerular, microvascular, and tubulointerstitial lesions. ularly among immunocompromised patients. Also described is
The pathogenesis of renal complications in tropical bacterial ochratoxin, a fungal toxin often incriminated in the pathogen-
infections is multifactorial. The principal factors are direct tis- esis of Balkan nephropathy. Ochratoxin also contributes to pro-
sue invasion by the causative organisms and remote cellular and gressive interstitial nephropathy in Africa [20].
humoral effects of bacterial antigens and endotoxins. The rela- Three ways exist by which parasitic infections cause renal
tive significance of the different pathogenetic mechanisms disease: 1) direct physical invasion of the kidneys or urinary
varies with the causative organism. tract, as in schistosomiasis, echinococcosis, and filariasis; 2)
In tropical zones many viral nephropathies are endemic, such renal injury as a consequence of the acute systemic effects of
as those associated with human immunodeficiency virus and parasitic infection, eg, falciparum malaria; and 3) immune-
hepatitis A, B, and C viruses. These are addressed in Chapter 7. mediated renal injury resulting from the concomitant host-par-
Here the focus is on an important viral disease endemic in asite interaction, eg, schistosomiasis, malaria, filariasis, leish-
Southeast Asia that often causes minor epidemics in Africa and maniasis, trichinosis, echinococcosis, toxoplasmosis, and try-
other tropical countries, dengue hemorrhagic fever. panosomiasis [21–32].
Disease Abnormal sediment Proteinuria ARF CRF HUS Hemolysis DIC Jaundice Commonly associated features
Salmonellosis +++ ++++ + - + + + + Gastrointestinal
Shigellosis + - ++* + + + Neurologic†
Leptospirosis ++++ ++++ ++++ - + + + ++++ Hemorrhagic tendency
Polyuria‡
Melioidosis +++++ + ++ - Hyponatremia§
Cholera + - Hypokalemia, acidosis
Tetanus + ++++ +++ - Sympathetic overflow
Scrub typhus + ++ + - + +
Diphtheria + + + - Myocarditis, polyneuritis
Tuberculosis ++ +/+++ + Retroperitoneal nodes
Leprosy ++ +++ + + Lepromas
ARF—acute renal failure; CRF—chronic renal failure; DIC—disseminated intravascular coagulation; HUS—hemolytic uremic syndrome; +—<10%; ++—10%–24%;
+++—25%–49%; ++++—50%–80%; +++++—>80%.
Dash indicates not reported.
FIGURE 6-1
Clinical manifestations of tropical bacterial nephropathies. Note the wide spectrum of
clinical manifestations that may ultimately reflect on the kidneys [33–35].
Renal Involvement in Tropical Diseases 6.3
Other tubular
Disease Glomerulonephritis Vasculitis AIN ATN changes
Deposits of
immunoglobulins,
complement,
MPGN EXGN MCGN MN NG CGN Amyloid and antigen
Salmonellosis ++ ++* G,M,A,C3,Ag† ++ + Cloudy swelling
Shigellosis + + + Cloudy swelling
Leptospirosis + + M,C3 + ++ +++
Melioidosis + +++ + Cloudy swelling
Cholera ++ Vacuolation‡
Tetanus ++
Scrub typhus + + + Cloudy swelling
Diphtheria ++ +/++ Degeneration§
Tuberculosis + +
Leprosy +/+++ + + +¶ + G,M,A,C3 + +/+++** Functional defects
FIGURE 6-2
Spectrum of renal pathology in tropical bacterial infections [36–38].
A B
FIGURE 6-3
Glomerular lesions associated with tropical bacterial patient with shigellosis. B, Exudative glomerulonephritis in a
infections. A, Simple proliferative glomerulonephritis in a patient with salmonellosis.
(Continued on next page)
6.4 Systemic Diseases and the Kidney
C D
FIGURE 6-3 (Continued)
C, Necrotizing vasculitis in a patient with leptospirosis. D, Membranous nephropathy
associated with leprosy. (Hematoxylin-eosin stain 150.)
FIGURE 6-4
Glomerular amyloid deposits in a patient with leprosy.
(Hematoxylin-eosin stain 200.)
FIGURE 6-5
Acute tubular pathology associated with
bacterial infections. A, Acute tubular
necrosis with erythrocyte aggregates in the
tubular lumina in a patient with leptospiro-
sis. (Hematoxylin-eosin stain 250.)
B, Cortical necrosis in a child with severe
shigellosis and hemolytic uremic syndrome.
(Hematoxylin-eosin stain 200.)
A B
Renal Involvement in Tropical Diseases 6.5
FIGURE 6-6
Extensive vacuolation of the proximal tubules (hypokalemic
nephropathy) in a patient with cholera. (Hematoxylin-eosin stain
300.) (From Sinniah and coworkers [39]; with permission.)
A B
C D
FIGURE 6-7
Interstitial lesions associated with bacterial infections. stain 100.) C, Renal abscess in a patient with septicemic
A, Acute interstitial nephritis in a patient with diphtheria. melioidosis. (Hematoxylin-eosin stain 75.) D, Micro-
(Hematoxylin-eosin stain 100.) B, Perivenular monocytic abscesses in a patient with typhoid fever [40]. (Hematoxylin-
infiltration in a patient with scrub typhus. (Hematoxylin-eosin eosin stain 75.)
6.6 Systemic Diseases and the Kidney
Bacterial infection
FIGURE 6-10
Common pathogenetic mechanisms of renal injury in tropical bacterial infections. Depending on the bacterial
species and strain, as well as on the host’s resistance and genetic background, bacteria may directly invade the
renal parenchyma, induce an immune reaction, injure the capillary endothelium or provoke a nonspecific
humoral or hematologic response. The subsequent evolution of these pathways may lead to different forms of
renal injury. The asterisk indicates that the role of hemolysis is augmented in patients with glucose-6-phosphate
dehydrogenase (G6PD) deficiency. ATN—acute tubular necrosis; DIC—disseminated intravascular coagulation;
IL—interleukin; NO—nitric oxide; ROM—reactive oxygen molecules; TNF-—tumor necrosis factor-.
Renal Involvement in Tropical Diseases 6.7
Disease Monokines Hypovolemia Hemolysis Rhabdomyolysis Disseminated intravascular coagulation Complement activation
Salmonellosis + + + + + ++
Shigellosis + ++ + + +
Leptospirosis ++ + + + +
Melioidosis + + + +
Cholera + +++ ++*
Tetanus ++ +
Scrub typhus + + +
Diphtheria + +
Leprosy + -
FIGURE 6-11
Pathogenetic mechanisms in acute tubular necrosis associated with bacterial infections.
Note the multiplicity of factors depending on the bacterial species and their host targets.
Viral Infections
FIGURE 6-12
90
Clinical manifestations of renal involvement in dengue hemorrhag-
80 ic fever. Note that proteinuria and abnormal urinary sediment are
70 the most common manifestations. Also note the high incidence of
60 hyponatremia, like with many other tropical infections [40,41].
Incidence, %
50
40
30
20
10
0
Urinary Proteinuria Hyponatremia Lactic Acute renal
sediment acidosis failure
abnormalities
Selected important features
6.8 Systemic Diseases and the Kidney
FIGURE 6-13
Renal lesions in a patient with dengue hem-
orrhagic fever. A, Mesangial proliferative
glomerulonephritis, which usually is associ-
ated with deposits of immunoglobulins G
and M and complement 3. (Hematoxylin-
eosin stain 200.) B, Acute tubular necro-
sis, which is associated with interstitial
edema and mononuclear cell infiltration.
(Hematoxylin-eosin stain 175.)
A B
Mycotic Infections
Parasitic Infections
FIGURE 6-16
Schistosoma hemalobium Global distribution of important parasitic
Schistosoma mansoni
nephropathies. Note the high prevalence of
schistosomal, malarial, filarial, and
echinococcal renal complications in Africa;
Echinococcosis S. mansoni and hydatid in South America;
Plasmodium falciparum malaria and filariasis in South
Quartan falciparum East Asia and filariasis in India [3].
malaria
Schistosoma mansoni
Filariasis
FIGURE 6-17
Urinary schistosomiasis. A, A sheet of
Schistosoma haematobium ova in tissues.
(Silver stain 350.) B, S. haematobium
granuloma. Shown is a delayed hypersensi-
tivity reaction of the host to soluble oval
antigens released from the ova through
micropores in their shells. The granuloma
is composed of mononuclear cells, a few
neutrophils, eosinophils, and fibroblasts,
surrounding a distorted egg. (Hematoxylin-
eosin stain 300.)
A B
6.10 Systemic Diseases and the Kidney
A B C
FIGURE 6-18
Cystoscopic appearances of different bladder lesions associated with Schistosoma haema-
tobium infection. A, Bilharzial (schistosomal) pseudotubercles. B, Bilharzial submucous
mass covered by pseudotubercles. C, Bilharzial ulcer surrounded by pseudotubercles.
D, Bilharzial ulcer surrounded by sandy patches. (Courtesy of N. Makar, MD.)
Antigens
Merozoites
Erythrocyte
Monocyte
Hemolysis
Cell membrane
changes TH1 TH2
TNF-α CIC
Platalet
CD8+ B Immunoglobulins
Endothelial activation
B
FIGURE 6-23
Renal lesions in a patient with falciparum malaria. A, Proliferative
and exudative glomerulonephritis, an immune-complex–mediated
lesion that may lead to an acute nephritic syndrome, which usually
is reversible by antimalarial treatment. (Hematoxylin-eosin stain
A 175.) B, Acute tubular necrosis (ATN) associated with interstitial
mononuclear cell infiltration. ATN is seen in 1% to 4% of patients
with falciparum malaria and in up to 60% of those with malignant
malaria. (Hematoxylin-eosin stain 200.)
(Continued on next page)
6.12 Systemic Diseases and the Kidney
FIGURE 6-24
The broad lines of the immune response to
+
CDCT parasitic infections. Note the pivotal role of
ACDC the monocyte, activated by exposure to para-
ADCC
– sitic antigens, in stimulating both T-helper 1
Parasite (TH1) and T-helper 2 (TH2) cells. The differ-
Eosinophil –
+ ent cytokine mediators and parasite elimina-
+ + + + Neutrophil tion mechanisms are shown. B—B-lympho-
cyte; -IFN—-interferon; CIC—circulating
Complement
Antigen immune complexes; GM-CSF—granulocyte-
CIC + macrophage colony-stimulating factor;
IL-5,13 IL-2 IgM,E,G,A Ig—immunoglobulin; IL—interleukin.
IL-1,6,12
GM-CSF
+
B
TH2 TH1 + +
γ-IFN
IL-2
IL-4,5,10
FIGURE 6-25
The T-helper1–T-helper 2 (TH1-TH2) cell balance that determines
the clinical expression of different parasitic nephropathies. TH1
predominance leads to either reversible acute proliferative glomeru-
lonephritis or acute interstitial nephritis. TH2 predominance tends
to lessen the severity of the lesions and may lead to chronic
Active monocytes Inactive monocytes
TH2, CD8 cells TH2 ,CD8 cells glomerulonephritis in the presence of copathogenic factors such as
IgG1,2,3 IgM,IgG4,IgA concomitant infection (malaria, schistosomiasis), autoimmunity
IL-1,6;+γIFN IL-4,5,10 (malaria, filariasis, schistosomiasis), or immunoglobulin A (IgA)
switching (Schistosoma mansoni) [7, 9, 49–52]. CD4—T-helper
cells; CD8—cytotoxic cells; -INF—-interferon; IL—interleukin.
FIGURE 6-26
Leishmaniasis. A, Amastigotes in peripheral
blood monocytes. Amastigotes downregu-
late the host cells that show no attempt at
eradicating the parasite. (Hematoxylin-
eosin stain 450.) B, Interstitial nephritis
representing a TH1 predominant state,
which is self-limited owing to the parasite-
induced monocyte inhibition [53].
(Hematoxylin-eosin stain 175.)
A B
FIGURE 6-27
Trichinosis. A, Here Trichinella spiralis is
encysted in the muscle tissue of a patient.
(Hematoxylin-eosin stain 75.) B, Asso-
ciated proliferative glomerulopathy in a
patient. This lesion usually is subclinical
but may be manifested as an acute nephritic
syndrome that can be resolved with anti-
parasitic treatment. This lesion represents a
TH1 predominant state. (Hematoxylin-
eosin stain 150.)
A B
6.14 Systemic Diseases and the Kidney
A
FIGURE 6-28
Echinococcosis. A, Mesangiocapillary type
III glomerulonephritis. (Hematoxylin-eosin
stain 200.) B, Electron micrograph
showing subepithelial deposits. (Hema-
toxylin-eosin stain 25,000.) C, Peri-
pheral part of a hydatid cyst showing the
daughter cysts in a patient. (Hematoxylin-
eosin stain 75.) C
FIGURE 6-29
Onchocercosis. A, The parasite Onchocerca
volvulus deposits lesions in tissues. (Hema-
toxylin-eosin stain 150.) B, Associated
mesangial proliferative lesion. This lesion rep-
resents a TH1 predominant state. Some
patients, however, develop an autoimmune
reaction that leads to progressive glomeru-
lonephritis. (Hematoxylin-eosin stain 175.)
A B
Renal Involvement in Tropical Diseases 6.15
FIGURE 6-30
Quartan malarial nephropathy. A, Prolifer-
ative glomerulonephritis with capillary wall
thickening. (Hematoxylin-eosin stain
200.) B, Subendothelial deposits with split-
ting of the basement membrane. (Silver
stain 500.) This lesion occurs under TH2
predominance and usually is encountered in
genetically predisposed persons. This lesion
also is associated with autoimmunity or
concomitant viral infection.
A B
A B
FIGURE 6-31 FIGURE 6-32
Intestinal schistosomiasis. A, Pair of adult Schistosoma mansoni worms in colonic mucosa. Patient with hepatosplenic schistosomiasis,
(Hematoxylin-eosin stain 75.) B, Colonic granuloma around a viable ovum. (Hema- complicating intestinal mansoniasis. Note
toxylin-eosin stain 150.) the shrunken liver and very large spleen,
surface marked on the abdominal wall by
black ink. Of these patients, 15% develop
clinically overt glomerular lesions. Half of
the 15% become hypertensive, most become
nephrotic at some stage, and almost all
progress to end-stage disease [54].
6.16 Systemic Diseases and the Kidney
FIGURE 6-33
Early glomerular lesion in a patient with
schistosomiasis. A, Mesangial proliferation.
(Hematoxylin-eosin stain 200.) B, Sch-
istosomal gut antigen deposits in the
mesangium. Other immunofluorescent
deposits at this stage include immunoglobu-
lins M and G and complement C. This
lesion may be encountered in infection by
Schistosoma mansoni, S. haematobium, or
S. japonicum. The lesion does not necessari-
ly progress any further. (Hematoxylin-eosin
stain 300.)
A B
A B
C D
FIGURE 6-34
Histologic lesions in a patient with progressive Schistosoma segmental glomerulosclerosis. (Masson trichrome stain 150.)
mansoni glomerulopathy. A, Mesangial proliferative glomeru- The two lesions in panels C and D are associated with advanced
lonephritis. (Hematoxylin-eosin stain 150.) B, Exudative hepatic fibrosis, impaired macrophage function, and predomi-
glomerulonephritis, often encountered with concomitant nant immunoglobulin A mesangial deposits [7,55]. The lesions
Salmonella paratyphi A infection [9]. (Hematoxylin-eosin stain shown are categorized, respectively, as classes I to IV schistoso-
150.) C, Mesangial proliferation with areas of mesangiocapil- mal glomerulopathy according to the classification system of the
lary changes. (Hematoxylin-eosin stain 150.) D, Focal and African Association of Nephrology [54].
Renal Involvement in Tropical Diseases 6.17
Glomerular deposits
A C
FIGURE 6-36 (see Color Plate)
Renal amyloidosis in schistosomiasis. A, Schistosomal granuloma (top), three glomeruli with extensive amyloid
deposits (bottom), and dense interstitial infiltration and fibrosis in a patient with massive Schistosoma haematobi-
um infection. (Hematoxylin-eosin stain 75.) B, Amyloid deposition in the mesangium associated with mild
mesangial cellular proliferation in a patient with S. mansoni glomerulopathy (African Association of Nephrology
class V). (Hematoxylin-eosin stain 175.) C, Early amyloid deposits seen as green (birefringent) deposits in a
glomerulus with considerable mesangial proliferation in a patient with hepatosplenic schistosomiasis. (Congo red
stain 200, examined under polarized light.)
6.18 Systemic Diseases and the Kidney
FIGURE 6-37
Pathogenesis of schistoma-associated amyloidosis
Pathogenesis of schistosoma-associated amyloidosis. The monocyte
Interleukin-1,6 Hepatocyte continues to release interleukin-1 and interleukin-6 under the influ-
+
Antigen ence of schistosomal antigens. These antigens stimulate the hepato-
cytes to release AA protein, which has a distinct chemoattractant
function. The monocyte is the normal scavenger of serum AA pro-
Uptake
tein, a function that is impaired in hepatosplenic schistosomiasis.
AA protein Serum AA protein accumulates and tends to deposit in tissue.
Matrix adhesion
FIGURE 6-39
Pathogenetic mechanisms in snake venom nephrotoxicity
Pathogenetic mechanisms in snake venom
nephrotoxicity. The immediate effect of
Snake venom
exposure is attributed to direct hematologic
toxicity involving the coagulation system
Direct toxicity Immunologic
reaction and red cell membranes. The massive
release of cytokines and rhabdomyolysis
also contribute. Late effects may be encoun-
Disseminated Hemolysis Cytokines tered as a consequence of the immune
intravascular Rhabdomyolysis Mediators Mesangiolysis response to the injected antigens.
coagulation
Hemodynamic
Vasculitis
changes
Renal ischemia
Acknowledgment
The authors acknowledge the help of Professor Amani Amin University, for providing very valuable material included in
Soliman, Chairperson of the Parasitology Department, Cairo this work.
References
1. Giacomini T, Toledano D, Baledent F: The severity of airport malaria. 4. Prina E, Lang T, Glaichenhaus N, et al.: Presentation of the protective
Bull Soc Pathol Exot Faliales 1988, 81:345–350. parasite antigen LACK by Leishmania-infected macrophages. J
2. Vanherweghem JL: A new form of nephropathy secondary to the Immunol 1996, 156: 4318–4327.
absorption of Chinese herbs. Bull Mem Acad R Med Belg 1994, 5. Persat F, Vincent C, Schmitt D, et al.: Inhibition of human peripheral
149:128–135. blood mononuclear cell proliferative response by glycosphingolipids
3. Barsoum R, Sitprija V: Tropical nephrology. In Diseases of the from metacestodes of Echinococcus multilocularis. Infect Immun
Kidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little, 1996, 64:3682–3687.
Brown and Company; 1997:2221–2268.
6.20 Systemic Diseases and the Kidney
6. Clark IA: Suggested importance of monokines in pathophysiology 31. Ginsburg BE, Wasserman J, Huldt G, et al.: A case of glomeru-
of endotoxin shock and malaria. Klin Wochenschr 1982, lonephritis associated with acute toxoplasmosis. Br Med J 1974,
60:756–758. 3:664–665.
7. Barsoum RS, Nabil M, Saady G, et al.: Immunoglobulin A and the 32. Lindsley HB, Nagle RB, Werner PA, et al.: Variable severity of
pathogenesis of schistosomal glomerulopathy. Kidney Int 1996, glomerulonephritis in inbred rats infected with Trypanosoma rhode-
50:920–928. siense: correlation with immunoglobulin class-specific antibody
8. Khajehdehi P, Tastegar A, Karazmi A: Immunological and clinical responses to trypanosomal antigens and total IgM levels. Am J Trop
aspects of kidney disease in typhoid fever in Iran. Q J Med 1984, Med Hyg 1980, 29:348–357.
209:101–107. 33. Srivastava RN, Mocedgil A, Bagga A, et al.: Hemolytic uremic syn-
9. Bassily S, Farid Z, Barsoum RS, et al.: Renal biopsy in schistosoma- drome in children in northern India. Pediatr Nephrol 1991,
salmonella associated nephrotic syndrome. J Trop Med Hyg 1976, 5:284–288.
79:256–258. 34. O’Riordan T, Kavanagh P, Mellotte G, et al.: Haemolytic uraemic syn-
10. Benish ML, Harris JR, Wojtyniak BJ , et al.: Death in shigellosis: inci- drome in shigella. Irish Med J 1990, 83:72–73.
dence and risk factors in hospitalized patients. J Infect Dis 1990, 35. Magaldi AJ, Yasuda PN, Kudo LH, et al.: Renal involvement in lep-
161:500–506. tospirosis: a pathophysiologic study. Nephron 1992, 62:332–339.
11. Sitprija V: Leptospirosis. Med Int 1992, 106:4476–4479. 36. Sinniah R, Churg J, Sobin LH (eds.): Renal Disease: Classification and
12. Susaengrat W, Dhiensiri T, Sinavatana P, et al.: Renal failure in melioi- Atlas of Infectious and Tropical Diseases. Chicago: ASCP Press; 1988.
dosis. Nephron 1987, 46:167–169. 37. Melby EI, Jacobsen J, Olsnes S, et al.: Entry of protein toxins in
13. World Health Organization: Cholera in Africa. WHO Weekly polarized epithelial cells. Cancer Res 1993, 53:1753–1760.
Epidemiol Rec 1997, 72:89–92. 38. Nigam P, Pant KC, Kapoor KK, et al.: Histo-functional status of kid-
ney in leprosy. Indian J Lepr 1986, 58:567–575.
14. Martinelli R, Matos CM, Rocha H: Tetanus as a cause of acute renal
failure: possible role of rhabdomyolysis. Rev Soc Bras Med Trop 39. American Society of Clinical Pathologists: Renal Disease:
1993, 26:1–4. Classification and Atlas of Infection and Tropical Diseases. Edited by
Sinniah R, Chugh J, Sobin LH. Chicago: ASCP Press; 1988:137.
15. Hsu GJ, Young T, Peng MY, et al.: Acute renal failure associated with
scrub typhus, report of a case. J Formosan Med Assoc 1993, 40. Baker NM, Mills AE, Rachman I, et al.: Hemolytic uremic syndrome
92:475–477. in typhoid fever. Br Med J 1974, 2:84–87.
16. Singh M, Saidali A, Bakhtiar A: et al.: Diphtheria in Afghanistan: 41. Sitprija V, Boonpucknavig W: The kidney in dengue. Proceedings of
review of 155 cases. J Trop Med Hyg 1985, 88:373–376. the 11th Asian Colloquium of Nephrology. Singapore; 1996:260–265.
17. Latimer JK: Renal tuberculosis. N Engl J Med 1975, 273:208–214. 42. Boonpucknavig V, Bhamarapravati N, Boonpucknavig E, et al.:
Glomerular changes in dengue hemorrhagic fever. Arch Pathol Lab
18. Chugh KS, Damle PB, Kaur S: Renal lesions in leprosy amongst North
Med 1976, 100:206–212.
Indian patients. Postgrad Med J 1983, 59:707–711.
43. Kilejian A, Abati A, Trager W: Plasmodium falciparum and
19. Madiwale CV, Mittal BV, Dixit M , et al.: Acute renal failure due to
Plasmodium coatney: immunogenicity of knoblike protrusions on
crescentic glomerulonephritis complicating leprosy. Nephrol Dial
infected erythrocyte membrane. Exp Parasitol 1977, 42:157.
Transplant 1994, 9:178–179.
44. Kojima S: Molecular biology of malaria. XIV International Congress
20. Saadi MG, Abdulla E, Fadel F, et al.: Prevalence of ochratoxin-A (OT-
on Nephrology, Sydney; 1997:S5.
A) among Egyptian children and adults with different renal diseases
[abstract]. Second International Congress on Geographic Nephrology, 45. Leech JH, Barnwell JW, Aikawa M, et al.: Plasmodium falciparum
Hurghada, Egypt; 1993:22. malaria: association of knobs on the surface of infected erythrocytes
with a histidine-rich protein and the erythrocyte skeleton. J Cell Biol
21. Barsoum RS: Schistosomiasis. In Oxford Textbook of Clinical
1984, 98:1256.
Nephrology. Oxford: Oxford University Press; Edited by Cameron S,
Davidson A, Grunfeld JP, et al. 1992:1729–1741. 46. Parra ME, Evans CB, Taylor DW: Identification of Plasmodium falci-
parum histidine-rich protein 2 in the plasma of humans with malaria.
22. Beyribey S, Cetinkaya M, Adsan O, et al.: Treatment of renal hydatid J Clin Microbiol 1991, 29:1629–1634.
disease by pedicled omentoplasty. J Urol 1995, 154:25–27.
47. Butthep P, Bunyaratvej A: An unusual adhesion between red cells and
23. Addiss DG, Dimock KA, Eberhard ML, et al.: Clinical, parasitologic platelets in falciparum malaria. J Med Assoc Thai 1992, 75(suppl
and immunologic observations of patients with hydrocele and ele- 1):195–202.
phantiasis in an area with endemic lymphatic filariasis. J Infect Dis
1995, 171:755–758. 48. Udeinya IJ, Schmidt JA, Aikawa M, et al.: Falciparum malaria infect-
ed erythrocytes specifically bind to cultured human endothelial cells.
24. Sitprija V: Nephrology forum: nephropathy in falciparum malaria. Science 1981, 213:555.
Kidney Int 1988, 34:867–877.
49. Wedderburn N, Ochs HD, Clark EA, et al.: Glomerulonephritis in
25. Sobh M, Moustafa F, El-Arbagy A, et al.: Nephropathy in asympto- common marmosets infected with Plasmodium brazilianum and
matic patients with active Schistosoma mansoni infection. Int Urol Epstein-Barr virus. J Infect Dis 1988, 148:289.
Nephrol 1990, 22:37–43.
50. Yahya TM, Benedict S, Shalabi A, et al.: Antineutrophil cytoplasmic
26. Hendrickse RG, Adeniyi A: Quartan malarial nephrotic syndrome in antibody (ANCA) in malaria is directed against cathepsin G. Clin Exp
children. Kidney Int 1979, 16:64–74. Immunol 1997, 110:41–44.
27. Waugh DA, Alexander JH, Ibels LH: Filarial chyluria–associated 51. Meilof JF, Van der Lelij A, Rokeach LA, et al.: Autoimmunity and
glomerulonephritis and therapeutic consideration in the chyluric filariasis: autoantibodies against cytoplasmic cellular proteins in sera
patient. Aust N Z J Med 1980, 10:559–562. of patients with onchocerciasis. J Immunol 1993, 151:5800–5809.
28. Ayachi R, Ben Dhia N, Guediche N, et al.: The nephrotic syndrome in 52. Thomas MA, Frampton G, Isenberg DA, et al.: A common anti-DNA
kala-azar. Arch Fr Pediatr 1988, 45:493–495. antibody idiotype and anti-phospholipid antibodies in sera from
29. Sitprija V, Keoplung M, Boonpucknavig V, et al.: Renal involvement patients with schistosomiasis and filariasis with and without nephritis.
in human trichinosis. Arch Intern Med 1980, 140:544–546. J Autoimmune 1989, 2:803–811.
30. Okelo GBA, Kyobe J: A three-year review of human hydatid disease 53. Prina E, Lang T, Glaichenhaus N, et al.: Presentation of the protective
seen at Kenyata National Hospital. East Afr Med J 1981, parasite antigen LACK by Leishmania-infected macrophages. J
58:695–701. Immunol 1996, 156:4318–4327.
Renal Involvement in Tropical Diseases 6.21
54. Barsoum RS: Schistosomal glomerulopathies. Kidney Int 1993, 61. Logan JL, Ogden DA: Rhabdomyolysis and acute renal failure follow-
44:1–12. ing the bite of the giant desert centipede, Scolopendra heros. West J
55. Barsoum RS, Sersawy G, Haddad S, et al.: Hepatic macrophage Med 1985, 142:549.
function in schistosomal glomerulopathy. Nephrol Dial Transplant 62. Lin CT, Huang PC, Yen TS, et al.: Partial purification and some
1988, 3:612–616. characteristic nature of a toxic fraction of the grass carp bile. Clin
56. Chugh KS: Snake bite induced renal failure in India. Kidney Int Biochem Soc 1977, 6:1.
1989, 194. 63. Eiam-Ong S, Sitprija V, Saetang P, et al.: Djenkol bean nephrotoxicity
57. Waterman J: Some notes on scorpion poisoning in Trinidad. Trans R in Southern Thailand. Proceedings of the First Asia Pacific Congress
Soc Trop Med Hyg 1993, 32:607. on Animal, Plant and Microbial Toxins. Singapore; 1989:628.
58. Barss P: Renal failure and death after multiple stings in Papua New 64. McClain JL, Hause DW, Clark MA: Amanita phalloides mushroom
Guinea. Ecology, prevention and management of attacks by vespid poisoning: a cluster of four fatalities. J Forensic Sci 1989, 34:83.
wasps. Med J Aust 1989, 151:659. 65. Bye BN, Coetzer TH, Dutton MF: An enzyme immunoassay for
59. Spielman FJ, Bowe EA, et al.: Acute renal failure as a result of atractyloside, the nephrotoxin of Callilepis laureola (Impila).
Physalia physalis sting. South Med J 1982, 75:1425. Toxicology 1990, 28:997.
60. Kibukamusoke JW, Chugh KS, Sakhuja V: Renal effects of envenoma- 66. Matthai TP, Date A: Renal cortical necrosis following exposure to sap
tion. In Tropical Nephrology. Edited by Kibukamusoke JW. Canberra, of the marking nut tree (Semecarpus anacardium). Am J Trop Med
Australia: Citforge Pty; 1984:170. Hyg 1979, 28:773.
Renal Disease in
Patients Infected with
Hepatitis and Human
Immunodeficiency Virus
Jacques J. Bourgoignie
T.K. Sreepada Rao
David Roth
I
nfection with hepatitis B virus (HBV) may be associated with a
variety of renal diseases. In the past, HBV was the major cause of
viral hepatitis in patients with end-stage renal disease (ESRD).
Introduction of rigorous infection-control strategies has led to a
remarkable decline in the spread of HBV infection in dialysis units.
Physicians also are increasingly recognizing the association between
chronic hepatitis C virus (HCV) infection and glomerular disease,
both in native kidneys and renal allografts. Liver disease caused by
HCV is a major factor in morbidity and mortality among patients
with ESRD treated with dialysis and transplantation. The first part of
this chapter focuses mainly on issues related to HCV infection. The
second part of this chapter examines the renal complications in
patients with human immunodeficiency virus (HIV) infection.
Our knowledge about HIV has increased greatly, and dramatic
advances have occurred in the treatment of patients with acquired
immunodeficiency syndrome (AIDS). For the first time since the dis-
covery of the disease, deaths are decreasing. Nevertheless, in the CHAPTER
United States, as of June 30, 1997, there were over 600,000 cumula-
tive cases of HIV infection, with over 400,000 deaths. Worldwide,
7
the HIV epidemic continues to spread; an estimated 20 million per-
sons are infected with HIV. Recent advances in the clinical manage-
ment of these patients result from better understanding of the repli-
cation kinetics of HIV, assays to measure viral load, availability of
7.2 Systemic Diseases and the Kidney
new effective drugs against HIV, and demonstration that with HIV infection now is common. The incidence of renal
aggressive protocols combining antiviral drugs substantially complications in this population is expected to increase further
reduce HIV replication. Thus, prolonged survival of patients as patients live longer.
FIGURE 7-6
FIGURE 7-5 Prevalence of anti-HCV among dialysis patients. Patients receiving
Diagnostic tests for HCV infection. In 1989, hepatitis C virus (HCV) dialysis clearly are at greater risk for acquiring hepatitis C virus
was cloned and identified as the major cause of parenterally transmit- (HCV) infection than are healthy subjects, based on the seropreva-
ted non-A, non-B hepatitis [22]. The first serologic test for HCV lence of anti-HCV antibodies among patients with end-stage renal
employed an enzyme-linked immunosorbent assay (ELISA-1) that disease. These results of ELISA-1 testing likely underestimate true
detected a nonneutralizing antibody (anti-HCV) to a single recombi- positivity because studies have demonstrated a nearly twofold
nant antigen. Limitations of the sensitivity and specificity of this test increase in seropositivity when screening dialysis patients with the
led to development of second-generation tests, ELISA-2 and a recom- ELISA-2 assay [52]. Additional studies have demonstrated that
binant immunoblot assay (RIBA-2) [23]. The standard for identifying most patients receiving dialysis who have anti-HCV seropositive
active HCV infection remains the detection of HCV RNA by reverse test results have circulating HCV RNA by polymerase chain reac-
transcriptase polymerase chain reaction. (Adapted from Roth [24].) tion analysis, indicating active viral replication.
7.4 Systemic Diseases and the Kidney
FIGURE 7-7
RISK FACTORS IN THE Risk of HCV in the ESRD population. Numerous studies have demonstrated a strong
POPULATION WITH END-STAGE association between the prevalence of hepatitis C virus (HCV) infection among patients
RENAL DISEASE AND HEPATITIS receiving dialysis and both the number of transfusions received and duration of dialysis
C VIRUS INFECTION [53,61]. Although these two variables are related, the prevalence of anti-HCV in these
patients has been shown to be independently associated with both factors by regression
analysis. In contrast to patients receiving hemodialysis, patients receiving peritoneal dialy-
Transfusions [24,27,30,32,54–57] sis consistently have a lower prevalence of anti-HCV antibody [60–70]. Moreover, units
Duration of end-stage renal disease with a low prevalence of anti-HCV have been shown to have a lower seroconversion rate
[29,30,32,35,37,53–61] [71]. The latter two observations coupled with the independent association of duration of
Mode of dialysis [60–70] dialysis with seropositivity argue in favor of nosocomial transmission of HCV in hemo-
Prevalence of hepatitis C virus infection dialysis units. This conclusion is further supported by data showing a decreased incidence
in the dialysis unit [71,72] of HCV seroconversion in dialysis units employing isolation and dedicated equipment for
patients who test positive for HCV infection [72].
FIGURE 7-8
TRANSMISSION OF HEPATITIS C Transmission of HCV during dialysis. Convincing data are available that demonstrate an
VIRUS IN HEMODIALYSIS UNITS increased risk of anti-HCV seroconversion associated with both a failure to strictly follow
infection control procedures and the performance of dialysis at a station immediately adja-
cent to that of a patient testing positive for anti-HCV [71–75]. Units using dedicated
Breakdown in universal precautions [73,74] machines have shown a decreased incidence of seroconversion [51]. The literature provides
Dialysis adjacent to an infected patient [71,75] conflicting data on the likelihood of passage of HCV RNA into dialysis ultrafiltrate and
Dialysis equipment [46,60]
the risk of contamination by reprocessing filters [71,72,76–78]. At this time the Centers
for Disease Control does not recommend that patients who are HCV positive be isolated
Type of dialyzer membrane [76–78]
or dialyzed on dedicated machines and has no official policy concerning reuse of machines
Reuse [71,72]
in these patients [79].
FIGURE 7-9
Liver disease among anti-HCV–positive dialysis patients. Serum
alanine aminotransferase levels are elevated in only 24% to 67%
Chronic active of dialysis patients who test positive for the anti-hepatitis C virus
Cirrhosis hepatitis (HCV) [80]. Caramelo and colleagues [81] evaluated liver biopsies
Pericentral 9% 42% from 33 patients on hemodialysis who tested positive using ELISA-2
fibrosis and found a variety of histologic patterns; however, over 50% of
3%
these patients had chronic hepatitis or cirrhosis. No correlation has
been found between mean levels of serum aminotransferase and
Other Hemosiderosis severity of liver disease [81]. At this time, liver biopsy is the only
6% 15% Reactive reliable method to determine the extent of hepatic injury in patients
hepatitis Chronic with end-stage renal disease infected with HCV. Liver function tests
18% persistent
hepatitis
and HCV serology testing may help identify patients who are at risk
6% for liver disease. However, a liver biopsy should be obtained before
initiating therapy or as part of the evaluation before transplanta-
tion. Liver biopsy can identify patients with advanced histologic
liver injury who may not be good candidates for transplantation or
can be used as a baseline before starting -interferon therapy. (From
Caramelo and colleagues [81]; with permission.)
Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus 7.5
FIGURE 7-10
PREVALENCE OF LIVER DISEASE AFTER Liver disease after kidney transplant. Biochemical abnormalities
KIDNEY TRANSPLANTATION reflecting liver injury have been reported in 7% to 34% of kidney
recipients in the early period after transplantation [23,82–86].
Morbidity and mortality associated with liver disease, however, are
First decade, % Second decade, % rarely seen until the second decade after transplantation [87]. Liver
dysfunction can be secondary to viral infections, such as hepatitis B
Acute liver disease: 5–65 Chronic liver disease: 5–40 and C, herpes simplex virus, Epstein-Barr virus, and cyto-
Chronic liver disease: 5–15 Death from liver failure: 10–30 megalovirus, in addition to the hepatotoxicity associated with several
immunosuppressive agents (azathioprine, tacrolimus, and cyclo-
sporine) [88]. However, hepatitis C virus infection has been demon-
strated convincingly to be the primary cause of posttransplantation
liver disease in renal allograft recipients [89,90].
FIGURE 7-11
TRANSMISSION OF HEPATITIS C VIRUS INFECTION Organ donor hepatitis C virus (HCV) transmission. Most recipients
BY CADAVERIC DONOR ORGANS of a kidney from a donor positive for hepatitis C virus RNA will
become infected with HCV if the organ is preserved in ice. ELISA-
1 testing of serum samples from 711 cadaveric organ donors iden-
Posttransplantation HCV infection status tified 13 donors positive for anti-HCV infection; 29 recipients of
organs from these donors were followed [91,92]. The prevalence of
Reference Anti-HCV, n/n (%) HCV RNA, n/n (%) HCV RNA in these allograft recipients increased from 27% before
Pereira et al. [91,92] 16/24(67) 23/24(96) transplantation to 96% after transplantation. In contrast, studies
Roth et al. [93] 10/31(32) Not available from centers using pulsatile perfusion of the kidney during preser-
Tesi et al. [94] 15/43(35) 21/37(57) vation have confirmed transmission of HCV in only about 56% of
Vincente et al. [95] 1/7(14) 1/7(14) cases [93,94]. Several factors might explain the discrepancy in
Wreghtt et al. [96] 6/15(40) 12/14(86) transmission rates. One possibility may involve differences in organ
preservation. Zucker and colleagues [97] demonstrated that pul-
satile perfusion removed 99% of the estimated viral burden in the
kidney, and centers using pulsatile perfusion have consistently
reported lower transmission rates than do centers preserving
organs on ice. Additional factors could include geographic varia-
tion in HCV quasi-species and the magnitude of the circulating
viral titer in the donor at the time of harvesting.
FIGURE 7-12
Patterns of hepatitis C virus (HCV) infection after transplantation of
Recipient 3a (Donor 1a) Recipient strain
5 a kidney from a positive donor into a positive recipient. In a simple
Donor strain
Both strains
but important study, Widell and colleagues [98] demonstrated three
Recipient 1b (Donor 1a) differing virologic patterns of HCV infection emerging after kidney
4
transplantation from a donor infected with HCV into a recipient
Patient, n
FIGURE 7-13
IMPACT ON OUTCOME OF HEPATITIS C VIRUS INFECTION Pretransplant HCV infection effect on out-
CONTRACTED BEFORE TRANSPLANTATION come. Reports have varied from different
centers concerning the impact of pretrans-
plantation hepatitis C virus (HCV) infection
After transplantation* on outcome after transplantation. Patient
survival and graft survival were significant-
Anti–hepatitis C ly worse among patients with anti-HCV
Reference virus infection Actuarial graft survival, % Actuarial patient survival, % infection in some studies [99,100]; in other
Fritche et al. [99] ELISA-2 positive 32(10) 58(8) studies a measurable impact could not be
ELISA-2 negative 53(10) 82(8) detected [90,101]. Some of these differences
Pereira et al. [100] ELISA-2 positive 50 59 could be attributed to geographic variation
ELISA-2 negative 59 85 in the prevalence of various HCV genotypes,
Roth et al. [90] RIBA-2 positive 81(5) 63(5) differing immunosuppressive protocols, and
RIBA-2 negative 80(5) 63(5) length of follow-up after transplantation.
Ynares et al. [101] ELISA-1 positive 33(10) 53(10)
ELISA-1 negative 25(10) 54(10)
FIGURE 7-15
INTERFERON THERAPY FOR PATIENTS IN END-STAGE Interferon in HCV-positive end-stage renal
RENAL DISEASE WITH HEPATITIS C VIRUS INFECTION disease (ESRD) and transplant patients. -
Interferon therapy in patients infected with
hepatitis C virus (HCV) who have ESRD
Reference Study population Patients, n Clearing of HCV RNA, % Comments has been studied in both patients receiving
dialysis and transplantation recipients.
Pol et al. [107] HD 19 53 Some studies have reported encouraging
Casanovas et al. HD 10 10 early responses [107–111]. Relapses are
[108] common after cessation of treatment, how-
Koenig et al. [109] HD 37 65 ever, and many transplantation recipients
Duarte et al. [110] HD 5 NA have experienced deterioration in allograft
function [112–116]. Based on the poor out-
Raptopoulou-Gigi HD 19 77
et al. [111] comes reported in transplantation recipi-
ents, additional studies are needed. These
Magnone et al. [112] TX 7 NA 6/7 (86%) rejection
studies would evaluate the long-term bene-
Rostaing et al. [113] TX 16 33 6/16 (37%) acute renal failure fits of a strategy in which infected patients
Harihara et al. [114] TX 3 0 3/3(100%) renal failure who have ESRD are treated with -interfer-
Thervet et al. [115] TX 13 0 2/3 (67%) acute renal failure on while on dialysis in an effort to clear
Izopet et al. [116] TX 15 0 5/15 (33%) acute renal failure
viremia before the planned transplantation.
Further study of protocols using extended
Ozgur et al. [117] TX 5 NA All with improved liver histology
treatment periods coupled with differing
dosing regimens are necessary to determine
HD—hemodialysis; NA—not available; TX—transplantation. the optimal therapy for the patient infected
with HCV who has ESRD.
FIGURE 7-17
PATHOGENESIS OF HYPONATREMIA IN PATIENTS Hyponatremia pathogenesis in AIDS. Single and mixed acid-base
WITH ACQUIRED IMMUNODEFICIENCY SYNDROME disturbances, as well as all types of electrolyte disorders, can be
observed in patients with AIDS. These disturbances and disorders
develop spontaneously in patients with complications of AIDS or
Hypovolemia follow pharmacologic interventions and usually are not associated
Tubular dysfunction with structural lesions in the kidneys unless renal failure also is
Mineralocorticoid deficiency
present. Hyponatremia is the most prevalent electrolyte abnormality,
occurring in 36% to 56% of patients hospitalized with AIDS
Syndrome of inappropriate antidiuretic hormone
[118–122]. In the absence of an evident source of fluid loss, volume
Hemodilution
depletion may be related to renal sodium wasting as a result of
Addison’s disease or hyporeninemic hypoaldosteronism [123–125].
In euvolemic patients, hyponatremia is compatible with nonosmolar
inappropriate secretion of antidiuretic hormone [120,121,126].
Hyponatremia in patients with hypervolemia is dilutional in
origin as a result of excessive free water intake in a context of
renal insufficiency [122].
7.8 Systemic Diseases and the Kidney
30%, most often in patients with AIDS and prerenal azotemia from hypovolemia, hypotension,
severe hypoalbuminemia, superimposed sepsis, or drug nephrotoxicity (radiocontrast dyes, fos-
CAUSES OF ACUTE RENAL FAILURE
carnet, acyclovir, pentamidine, cidofovir, amphotericin B, nonsteroidal anti-inflammatory drugs,
and antibiotics) [129–138]. The clinical presentation, laboratory findings, and course of acute
tubular necrosis do not differ in patients with AIDS and those in other clinical settings.
Prerenal azotemia, acute tubular necrosis Prevention includes correction of fluid and electrolyte abnormalities and dosage adjustments of
Allergic interstitial nephritis potentially nephrotic drugs. Identification and withdrawal of the offending agents usually result
Obstructive nephropathy in recovery of renal function. Dialysis may be needed before renal function improves. Less
Rhabdomyolysis, myoglobinuric acute renal failure frequent causes of acute renal failure include allergic acute interstitial nephritis; complicating
Thrombotic thrombocytopenic purpura, hemolytic treatments with trimethoprim and sulfamethoxazole, rifampin, or acyclovir; and acute
uremic syndrome obstructive nephropathy, resulting from the intrarenal precipitation of crystals of sulfadiazine,
Rapidly progressive glomerulonephritis acyclovir, urate, or protease inhibitors [134,139–146]. Obstructive uropathy without
hydronephrosis also may develop in patients with lymphoma as a result of lymphomatous
ureteropelvic infiltration or retroperitoneal fibrosis [147–149]. Rhabdomyolysis with myoglo-
binuric acute renal failure usually occurs in the setting of cocaine use [150]. Instances of acute
FIGURE 7-19 renal failure associated with intravascular coagulation related to thrombotic thrombocytopenic
Causes of acute renal failure. Acute renal purpura (TTP) or hemolytic uremic syndrome (HUS) have been reported (vide infra). Rare
failure is related to complications of AIDS, its causes of acute renal failure include disseminated microsporidian infection or histoplasmosis
treatment, or the use of diagnostic agents in [151,152]. A clinical presentation of acute renal failure also can be seen in patients with acute
about 20% of patients [129,130]. Acute tubu- immunocomplex postinfectious glomerulonephritis, crescentic glomerulonephritis, or fulminant
lar necrosis occurs with a prevalence of 8% to HIV-associated glomerulosclerosis.
FIGURE 7-20
Acyclovir, g/d IV
5 5 the dose of acyclovir from 2.4 to 0.4 g/24 h. Patients infected with
HIV can exhibit a broad spectrum of conditions that may affect the
mg/dL
4 4
3 3 kidneys. Renal biopsy is useful for diagnostic and prognostic purpos-
2 2 es when the cause of acute renal failure is not clinically evident. In a
1 1 recent study of 60 patients with acute renal failure, a percutaneous
0 0 renal biopsy yielded a pathologic diagnosis in 13% that was not
1 2 3 4 5 6 7 8 expected clinically [154].
Day
Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus 7.9
FIGURE 7-21
MANAGEMENT OF SEVERE Acute renal failure management. Rao and Friedman [155] compared the course of 146
ACUTE RENAL FAILURE patients with severe acute renal failure (serum creatinine >6 mg/dL) infected with HIV
with a group of 306 contemporaneous persons not infected with HIV but with equally
severe acute renal failure. The patients infected with HIV were younger than those in the
HIV Non-HIV group not infected (mean age 38.4 and 55.2 years, respectively; P<0.001) and were more
often septic (52% and 24%, respectively; P<0.001). Over 80% of patients in each group
Conservative 20 (14%) 42 (14%) recovered renal function when conservative therapy alone was sufficient. When dialysis
Recovered 85% 83% NS intervention was needed, it was not initiated more often in the group with HIV than in the
Needing dialysis 126 264 control group (42% and 24%, respectively; P<0.003). In those patients in whom dialysis
Not initiated 42% 22% 0.003 was initiated, recovery occurred in about half in each group. Overall, the mortality in
Initiated 73 207 patients with severe acute renal failure was not significantly different in those with HIV
Recovered 56% 47% NS infection from those in the group not infected with HIV (immediate mortality, 60% and
56%, respectively; mortality at 3 months, 71% and 60%, respectively).
NS— not significant.
FIGURE 7-22
NEPHROPATHIES Nephropathies associated with HIV. The literature refers to the glomerulosclerosis associated
ASSOCIATED WITH with human immunodeficiency virus (HIV) as HIV-associated nephropathy. However, HIV-
HUMAN IMMUNODEFICIENCY associated nephropathies may include a spectrum of renal diseases, including HIV-associated
VIRUS INFECTION glomerulosclerosis, HIV-associated immune-complex glomerulonephritis (focal or diffuse
proliferative glomerulonephritis, immunoglobulin A nephropathy) and HIV-associated
hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Diffuse
Focal segmental or global glomerulosclerosis mesangial hyperplasia and minimal change disease also may be associated with HIV, particu-
Diffuse and global mesangial hyperplasia
larly in children. Therefore, the nomenclature of HIV-associated nephropathies should be
amended to list the associated qualifying histologic feature [156]. All types of glomeru-
Minimal change disease
lopathies have been observed in patients with HIV-infection. Their prevalence and severity
Others:
vary with the population studied. Focal segmental or global glomerulosclerosis is most preva-
Immune-complex glomerulopathies
lent in black adults. In whites, proliferative and other types of glomerulonephritis predomi-
Hemolytic uremic syndrome, thrombotic
nate. In children with perinatal acquired immunodeficiency syndrome, glomerulosclerosis,
thrombocytopenic purpura
diffuse mesangial hyperplasia, and proliferative glomerulonephritis are equally prevalent.
FIGURE 7-24
TWO CASE HISTORIES OF PATIENTS WITH HUMAN IMMUNODEFICIENCY These two patients illustrate typical presenting
VIRUS INFECTION ASSOCIATED WITH GLOMERULOSCLEROSIS features of HIV-associated glomerulosclerosis,
ie, proteinuria, usually in the nephrotic range;
normal-sized or large echogenic kidney; and
renal insufficiency rapidly progressing to end-
41-year-old black Jamaican woman 28-year-old black Haitian man
stage renal disease (ESRD). The onset of the
October 1985: A dockworker until 3 months before admission, when nephropathy is often abrupt, with uremia and
Viral syndrome. 135 lbs; proteinuria, 1+; serum creati- fevers began to occur. No identifiable risk factor. He massive nonselective proteinuria (sometimes
nine, 0.5 mg/dL; blood pressure, 130/70 mm Hg presented with a blood pressure of 110/80 mm Hg, in excess of 20 g/24 h). These fulminant
December 1986: periorbital and trace ankle edema, interstitial pneu-
monia, and diffuse adenopathies. Serum creatinine
lesions may present as acute renal failure in
Fever, fatigue, cough. 120 lbs; proteinuria, 1+; interstitial
increased from 5.3 to 9 mg/dL in 6 days; albumin, 1.6 patients who were well only a few weeks or
pneumonia; serum creatinine, 1.5 mg/dL; ex-husband months before hospitalization. In other
g/dL; proteinuria, 6.9 g/24 h; 15-cm, echogenic kid-
used intravenous drugs; 11-cm, echogenic kidneys patients, minimal proteinuria and azotemia at
neys. Renal biopsy showed focal segmental glomeru-
February 1987: losclerosis. Lymph node biopsy showed presentation increase insidiously over a period
3+ edema. 116 lbs; proteinura, 12.7 g/24 h; serum crea- Mycobacterium gordonae. This patient returned to of several months until a nephrotic syndrome
tinine, 11.4 mg/dL; albumin, 2.5 g/dL; blood pressure, Haiti after six hemodialyses. becomes evident, with rapid evolution there-
150/86; renal biopsy showed focal segmental
after to uremia and ESRD. Hypertension and
glomerulosclerosis
peripheral edema may be absent even in the
May 1987:
context of advanced renal insufficiency or
100 lbs; patient died after 3 months of hemodialysis
severe nephrotic syndrome. The status of the
from sepsis and cryptococcal meningitis
patient’s HIV infection rather than the pres-
ence of renal disease per se has the greatest
impact on survival.
FIGURE 7-26
Pathologic features of glomerulosclerosis. None of the features list-
FIGURE 7-25 ed is pathognomonic. The concomitant presence of glomerular and
Ultrasonography of a hyperechogenic 15-cm kidney in a patient tubular lesions with tubuloreticular inclusions in the glomerular
with HIV-associated glomerulosclerosis, nephrotic syndrome, and and peritubular capillary endothelial cells, however, is highly sug-
renal failure. gestive of glomerulosclerosis associated with human immunodefi-
ciency virus infection [134,166–171].
Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus 7.11
FIGURE 7-28
More advanced glomerulosclerosis. Micrograph of a more
FIGURE 7-27 advanced stage of glomerulosclerosis with large hyperplastic viscer-
Glomerulosclerosis. Micrograph of segmental glomerulosclerosis al epithelial cells loaded with hyaline protein droplets, interstitial
with hyperplastic visceral epithelial cells (arrows). infiltrate, and tubules filled with proteinaceous material.
FIGURE 7-31
Diffuse mesangial hyperplasia and nephrotic syndrome. Micrograph
of diffuse mesangial hyperplasia in a child with perinatal AIDS and
nephrotic syndrome. Both diffuse and global mesangial hyperplasia
are identified in 25% of children with perinatal AIDS and protein-
uria. The characteristic microcystic tubular dilations and the kidney
enlargement of glomerulosclerosis associated with human immun-
odeficiency virus infection are absent in patients with diffuse mesan-
gial hyperplasia.
FIGURE 7-32
Tubuloreticular cytoplasmic inclusions. Micrograph of tubuloreticular cytoplasmic inclusions in
glomerular endothelial cell. The latter are virtually diagnostic of nephropathy associated with
HIV infection, provided systemic lupus erythematosus has been excluded. On immunofluo-
rescent examination, findings in the glomeruli are nonspecific and similar in HIV-associated
glomerulosclerosis and idiopathic focal segmental glomerulosclerosis. These findings consist
largely of immunoglobulin M and complement C3 deposited in a segmental granular pattern
in the mesangium and capillaries. The same deposits also occur in 30% of patients with
AIDS without renal disease [134,163,167].
FIGURE 7-33
HIV infection Possible pathogenic mechanisms of glomerulosclerosis associated
with HIV infection. HIV-associated glomerulosclerosis is not the
result of opportunistic infections. Indeed, the nephropathy may be
the first manifestation of HIV infection and often occurs in patients
HIV in glomerular, tubular HIV in lymphocytes, before opportunistic infections develop. HIV-associated glomeru-
epithelial cells monocytes losclerosis also is not an immune-complex-mediated glomerulopathy
because immune deposits are generally absent. Three mechanisms
have been proposed: direct injury of renal epithelial cells by infective
HIV, although direct renal cell infection has not been demonstrated
Cytopathic HIV gene Cytokines,
conclusively and systematically; injury by HIV gene products; or injury
effects products growth factors
by cytokines and growth factors released by infected lymphocytes and
monocytes systemically or intrarenally or released by renal cells
after uptake of viral gene products. The variable susceptibility to
Glomerular epithelial cell proliferation
Tubular epithelial cell apoptosis and proliferation glomerulosclerosis also suggests that unique viral-host interactions
may be necessary for expression of the nephropathy
[132,156,166,173–175].
FIGURE 7-34
HIV proteins in glomerulosclerosis. HIV-associated glomerulosclero- FIGURE 7-35
sis has been viewed as a complication that occurs either as a direct Treatment of glomerulosclerosis. There have been no prospective
cellular effect of HIV infection or HIV gene products in the kidney, controlled randomized trials of any therapy in patients with nephropa-
as an indirect effect of the dysregulated cytokine milieu existing in thy associated with HIV infection. Thus, the optimal treatment is
patients with acquired immunodeficiency syndrome, or both. Studies unknown. Individual case reports and studies, often retrospective,
involving reciprocal transplantation of kidneys between normal and on a small number of patients suggest a beneficial effect of
mice transgenic of noninfectious HIV clearly show that the patho- monotherapy with azidothymidine (AZT) on progression of renal
genesis of HIV-glomerulosclerosis is intrinsic to the kidney [176]. In disease [177–179]. No reports exist on the effects of double or
these studies, HIV-glomerulosclerosis developed in kidneys of trans- triple antiretroviral therapy on the incidence or progression of
genic mice transplanted into nontransgenic littermates, whereas kid- renal disease in patients with HIV who have modest proteinuria or
neys from normal mice remained disease-free when transplanted into nephrotic syndrome. The incidence of HIV-associated glomeruloscle-
HIV-transgenic mice [176]. These findings suggest that HIV gene rosis may be declining as a result of prophylaxis with AZT,
proteins, rather than infective HIV, may induce the nephropathy trimethoprim and sulfamethoxazole, or other drugs. Using logistic
either through direct effects on target cells or indirectly through the regression analysis, Kimmel and colleagues [180] demonstrated an
release of cytokines and growth factors. improved outcome related specifically to antiretroviral therapy.
Steroids usually have been ineffective on proteinuria or progression
of renal disease in adults and children. Recently, 20 adult patients
with HIV-associated glomerulosclerosis or mesangial hyperplasia
with proteinuria over 2 g/24 h and serum creatinine over 2 mg/dL
were studied. These patients showed impressive decreases in pro-
teinuria and serum creatinine when given 60 mgd of prednisone for
2 to 6 weeks [181]. Complications of steroid therapy, however,
were common. These include development of new opportunistic
infections, steroid psychosis, and gastrointestinal bleeding. The
short-term improvement in renal function may correlate with an
improvement in tubulointerstitial mononuclear cell infiltration
[182]. In a single report of three children with perinatal AIDS,
HIV-associated glomerulosclerosis, and normal creatinine clearance,
cyclosporine induced a remission of the nephrotic syndrome [183].
This report has not been confirmed, and the use of cyclosporine in
adults with HIV-associated glomerulosclerosis has not been studied.
7.14 Systemic Diseases and the Kidney
FIGURE 7-36
4.0 Effect of angiotensin-converting enzyme (ACE) inhibitors on pro-
P=0.006
3.5 Fosinopril gression of glomerulosclerosis associated with HIV infection. Serum
Control ACE levels are increased in patients with HIV infection [184]. Kimmel
4.0
Serum creatinine, mg/dL
and colleagues [180], using captopril, and Burns and colleagues [185],
3.5
using fosinopril, demonstrated a renoprotective effect of ACE
3.0
inhibitors in patients with biopsy-proven HIV-associated glomeru-
2.5 losclerosis. In the former study, the median time to end-stage renal
2.0 disease was increased from 30 to 74 days in nine patients given
1.5 6.25 to 25 mg captopril three times a day. In the latter study, 10
1.0
mg of fosinopril was given once a day to 11 patients with early
renal insufficiency (serum creatinine <2 mg/dL). Serum creatinine
0.5 and proteinuria remained stable during 6 months of treatment with
0 fosinopril. In contrast, patients not treated with fosinopril exhibited
0 4 8 12 16 20 24 progressive and rapid increases in serum creatinine and proteinuria.
Week Similar outcomes prevailed in patients with proteinuria in the
9 nephrotic range and serum creatinine levels less than 2 mg/dL.
P=0.006 Captopril also is beneficial to the progression of the nephropathy
8 Fosinopril
Control
in HIV-transgenic mice [186]. The mechanism(s) of the renoprotective
7
effects of ACE inhibitors are unclear and may include hemodynamic
Urinary protein, g/24 h
3
2
1
0
0 4 8 12 16 20 24
Week
FIGURE 7-37
SURVIVAL OF PATIENTS WITH HUMAN Survival rates in dialysis patients. Once end-stage renal disease
IMMUNODEFICIENCY VIRUS INFECTION (ESRD) develops and supportive maintenance dialysis is needed, the
RECEIVING CHRONIC HEMODIALYSIS complications of HIV are the dominant factor in patient survival, as
they are in patients with HIV infection without renal involvement.
Asymptomatic patients on chronic hemodialysis survive longer than
do patients with AIDS on chronic hemodialysis. Patients with AIDS
Reference Year Patients Mean survival, mo
also may develop malnutrition, wasting, and failure to thrive that are
Rao et al. [187] 1987 79 AIDS <3 unresponsive to intensive nutritional support [131]. Recent studies,
Ortiz et al. [188] 1988 17 AIDS 3 however, show that the survival of patients with AIDS maintained on
12 carriers 16 chronic hemodialysis is improving. Enhanced survival has been
Feinfeld et al. [189] 1989 5 AIDS 13 attributed to antiviral drugs, better prophylaxis, and aggressive treat-
10 carriers 16 ment of opportunistic infections. We have seen four patients with
Ribot et al. [190] 1990 8 AIDS 88% <12 HIV infection survive for more than 10 years on hemodialysis.
28 carriers 96% >12 Chronic hemodialysis and chronic ambulatory peritoneal dialysis are
Schrivastava et al. [191] 1992 44 AIDS 41% >15 equally appropriate treatments for patients with HIV infection and
Kimmel et al. [192] 1993 23 AIDS 14.7 ESRD. Universal precautions should be used for peritoneal dialysis
Ifudu et al. [193] 1997 34 AIDS 57 and hemodialysis alike, because infectious HIV is present in peri-
toneal effluent and blood.
Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus 7.15
FIGURE 7-38
PREDICTORS OF SURVIVAL OF PATIENTS WITH Predictors of survival. Perinbasekar and colleagues [194] analyzed
HUMAN IMMUNODEFICIENCY VIRUS INFECTION those factors associated with better survival in patients infected
RECEIVING CHRONIC HEMODIALYSIS with HIV receiving chronic hemodialysis. A low CD4 lymphocyte
count, low systolic blood pressure, increased infection rate, nephrotic
range proteinuria, lack of edema, and lack of antiretroviral therapy
R P are associated with decreased survival.
FIGURE 7-39
RECOMMENDED ANTI- Antiretroviral therapy. Recommended antiretroviral therapy for patients with HIV infection
RETROVIRAL THERAPY without renal disease includes therapies with two drugs for all patients, combining two
reverse transcriptase inhibitors. Aggressive early intervention with triple antiviral drugs, one
of which is a protease inhibitor, should be offered to patients symptomatic of AIDS,
Combination of two reverse transcriptase inhibitors asymptomatic patients with CD4 counts under 500/µL, and asymptomatic patients with
Aggressive triple therapy, including a protease CD4 counts over 500/µL and plasma HIV RNA levels over 20,000 copies/mL [195].
inhibitor for patients who are Reduced dosages are required for reverse transcriptase inhibitors in renal insufficiency.
Symptomatic of acquired immunodeficiency Although the clearance information on these drugs is limited, additional dosing is not
syndrome necessary in patients receiving maintenance dialysis. No dosage reduction is needed for
Asymptomatic with CD4 <500 cells/µL protease inhibitors.
Asymptomatic with CD4 >500 cells/µL but viral
load > 20,000
FIGURE 7-41
RENAL INFECTIONS AND TUMORS ASSOCIATED WITH Other renal findings in patients with AIDS include infections and
HUMAN IMMUNODEFICIENCY VIRUS INFECTION tumors. Almost all opportunistic infections seen in patients with AIDS
may localize in the kidneys as manifestations of systemic disease.
However, rarely are these infections expressed clinically, and often
Pathogens Neoplasms they are found at autopsy. Cytomegalovirus infection is the most
common [209]. Referrals to a urologist are reported for renal and
Cytomegalovirus Kaposi’s sarcoma perirenal abscesses with uncommon organisms (Candida, Mucor
Candida Carcinoma mycosis, Aspergillus, and Nocardia). Nephrocalcinosis can occur in
Nocardia Lymphoma association with pulmonary granulomatosis, Mycobacterium
Cryptococcus Myeloma avium–intracellulare infection, or as a manifestation of extrapul-
Pneumocystis monary pneumocystis infection. Renal tuberculosis is a manifestation
Mycobacterium of miliary disease. Non-Hodgkin’s lymphoma and Kaposi’s sarcoma
Toxoplasma are the most frequently found renal neoplasms in patients with
Histoplasma AIDS, usually as a manifestation of disseminated involvement.
Aspergillus
Herpes
References
1. Johnson RJ, Couser WG: Hepatitis B infection and renal disease: 16. Johnson RJ, Willson R, Yamabe H, et al.: Renal manifestations of
clinical, immunopathogenetic and therapeutic considerations. Kidney hepatitis C virus infection. Kidney Int 1994, 46:1255.
Int 1990, 37:663. 17. Johnson RJ, Gretch DR, Couser WG, et al.: Hepatitis C virus associ-
2. Lai KN, Lai FM: Clinical features and natural history of hepatitis B ated glomerulonephritis: effect of -interferon therapy. Kidney Int
virus–related glomerulopathy in adults. Kidney Int 1991, 35(suppl):S40. 1994, 46:1700.
3. Takekoshi Y, Tochimaru H, Nagatta Y, Itami N: 18. Misiani R, Bellavita P, Fenili D, et al.: Interferon--2a therapy in
Immunopathogenetic mechanisms of hepatitis B virus–related cryoglobulinemia associated with hepatitis C virus. N Engl J Med
glomerulopathy. Kidney Int 1991, 35(suppl):S34. 1994, 330:751.
4. Lai KN, Li PK, Lui SF, et al.: Membranous nephropathy related to 19. Poynard T, Bedossa P, Chevallier M, et al.: A comparison of three
hepatitis B virus in adults. N Engl J Med 1991, 324:1457. interferon--2b regimens for the long-term treatment of chronic non-
5. Lin CY: Clinical features and natural course of HBV-related glomeru- A, non-B hepatitis. N Engl J Med 1995, 332:1457.
lopathy in children. Kidney Int 1991, 35(suppl):S46. 20. Poynard T, Leroy V, Cohard M, et al.: Meta-analysis of interferon
6. Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infec- randomized trials in the treatment of viral hepatitis C: effects of dose
tion in type II cryoglobulinemia. N Engl J Med 1992, 327:1490–1495. and duration. Hepatology 1996, 24:778.
7. Misiani R, Bellavita P, Fenili D, et al.: Hepatitis C virus infection in 21. Sarac E, Bastacky S, Johnson JP: Response to high-dose interferon-
patients with essential mixed cryoglobulinemia. Ann Intern Med after failure of standard therapy in MPGN associated with hepatitis
1992, 117:573–577. C virus infection. Am J Kidney Dis 1997, 30:113.
8. Disdier P, Harle JR, Weiller PJ: Cryoglobulinemia and hepatitis C 22. Choo Q, Kuo G, Weiner AJ, et al.: Isolation of a cDNA clone derived
infection. Lancet 1991, 338:1151–1152. from a blood-borne non-A, non-B viral hepatitis genome. Science
1989, 244:358–362.
9. Dammacco F, Sansono D: Antibodies to hepatitis C virus in essential
mixed cryoglobulinemia. Clin Exp Immunol 1992, 87:352–356. 23. Pereira BJG: Hepatitis C infection and post-transplantation liver dis-
ease. Nephrol Dial Transplant 1995, 10(suppl 1):58–67.
10. Galli M, Monti G, Monteverde A: Hepatitis C virus and mixed cryo-
globulinemias. Lancet 1992, 1:989. 24. Roth D: Hepatitis C virus: The nephrologist’s view. Am J Kidney Dis
1995, 25:3–16.
11. Ferri C, Greco F, Longobardo G: Antibodies to hepatitis C virus in
patients with mixed cryoglobulinemia. Arthritis Rheum 1991, 25. Zeldis JB, Depner TA, Kuramoto IK, et al.: The prevalence of hepatitis
34:1606–1610. C virus antibodies among hemodialysis patients. Ann Intern Med 1990,
112:958–960.
12. Sansono D, Gesualdo L, Mano C, et al.: Hepatitis C virus related
proteins in kidney tissue from hepatitis C virus–infected patients 26. Hardy NM, Sandroni S, Danielson S, Wilson WJ: Antibody to hepatitis
with cryoglobulinemic membranoproliferative glomerulonephritis. C virus increases with time on dialysis. Clin Nephrol 1992, 38:44–48.
Hepatology 1997, 25:1237–1244. 27. Jeffers LJ, Perez GO, de Medina MD, et al.: Hepatitis C infection in
13. Johnson RJ, Gretch DR, Yamabe H, et al.: Membranoproliferative two urban hemodialysis units. Kidney Int 1990, 38:320–322.
glomerulonephritis associated with hepatitis C virus infection. N Engl 28. Getzung T, Lindsay K, Brezina M, et al.: Hepatitis C virus antibody
J Med 1993, 328:465–470. in hemodialysis patients: prevalence and risk factors. Lancet 1990,
14. Rollino C, Roccatello D, Giachino O, et al.: Hepatitis C virus infec- 335:A589.
tion and membranous glomerulonephritis. Nephron 1991, 29. Niu MT, Coleman PJ, Alter MJ: Multicenter study of hepatitis C
59:319–320. virus infection in chronic hemodialysis patients and hemodialysis cen-
15. Davda R, Peterson J, Weiner R, et al.: Membranous glomerulonephri- ter staff members. Am J Kidney Dis 1993, 22:568–573.
tis in association with hepatitis C virus infection. Am J Kidney Dis 30. Muller GY, Zabaleta ME, Arminio A, et al.: Risk factors for dialysis-
1993, 22:452–455. associated hepatitis C in Venezuela. Kidney Int 1992, 41:1055–1058.
Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus 7.17
31. Esteban JI, Esteban RK, Viladomiu L, et al.: Hepatitis C virus anti- 56. Mosconi G, Campieri C, Miniero R, et al.: Epidemiology of hepatitis C
bodies among risk groups in Spain. Lancet 1989, ii:294–296. in a population of hemodialysis patients. Nephron 1992, 61:298–299.
32. Mondelli MU, Smedile V, Piazza V, et al.: Abnormal alanine amino- 57. Scotto G, Savastano AM, Forcella M, et al.: HCV infections in dialysis
transferase activity reflects exposure to hepatitis C virus in hemodialy- patients. Nephron 1992, 61:320–321.
sis patients. Nephrol Dial Transplant 1991, 6:480–483. 58. Ponz E, Campistol JM, Barrera JM, et al.: Hepatitis C virus antibodies
33. Mortimer PP, Cohen BJ, Litton PA, et al.: Hepatitis C virus antibody. in patients on hemodialysis and after transplantation. Transplant
Lancet 1989, 2:798. Proc 1991, 23:1371–1372.
34. Roggendorf M, Deinhard F, Rasshofer R, et al.: Antibodies to hepatitis 59. Yamaguchi K, Nishimura Y, Fukuoka N, et al.: Hepatitis C virus
C virus. Lancet 1989, 2:324–335. antibodies in hemodialysis patients. Lancet 1990, 335:1409–1410.
35. Schlipkoter U, Roggendorf M, Ernst G, et al.: Hepatitis C virus anti- 60. Brugnano R, Francisci D, Quintaliani G, et al.: Antibodies against
bodies in hemodialysis patients. Lancet 1990, 335:1409. hepatitis C virus in hemodialysis patients in the central Italian region of
36. Kallinowski B, Theilmann L, Gmelin K, et al.: Prevalence of antibod- Umbria: evaluation of some risk factors. Nephron 1992, 61:263–265.
ies to hepatitis C virus in hemodialysis patients. Nephron 1991, 61. Cantu P, Mangano S, Masini M, et al.: Prevalence of antibodies
59:236–238. against hepatitis C virus in a dialysis unit. Nephron 1992,
37. Elisa M, Tsianos E, Mavridis M, et al.: Antibodies against hepatitis C 61:337–338.
virus (anti-HCV) in hemodialysis patients: association with hepatitis 62. Cendoroglo-Neto M, Draibe SA, Silva AE, et al.: Incidence of and
B serological markers. Nephrol Dial Transplant 1991, 6:476–479. risk factors for hepatitis B virus and hepatitis C infection among
38. Conway M, Catterall AP, Brown EA, et al.: Prevalence of antibodies to hemodialysis and CAPD patients: evidence for environmental trans-
hepatitis C in dialysis patients and transplant recipients with possible mission. Nephrol Dial Transplant 1995, 102:240–246.
routes of transmission. Nephrol Dial Transplant 1992, 7:1226–1229. 63. Selgas R, Martinez-Zapico R, Bajo MA, et al.: Prevalence of hepatitis
39. Malaguti M, Capece R, Marciano M, et al.: Antibodies to hepatitis C C antibodies (HCV) in a dialysis population at one center. Perit Dial
virus (anti-HCV): prevalence in the same geographical area in dialysis Int 1992, 12:28–30.
patients, staff members, and blood donors. Nephron 1992, 61:346. 64. Chan TM, Lok ASF, Cheng IKP: Hepatitis C infection among dialysis
40. Mondelli MU, Cristina G, Pazza V, et al.: High prevalence of antibod- patients: a comparison between patients on maintenance hemodialysis
ies to hepatitis C virus in hemodialysis units using a second genera- and continuous ambulatory peritoneal dialysis. Nephrol Dial
tion assay. Nephron 1992, 61:350–351. Transplant 1991, 6:944–947.
41. Chauveau P, Courouce AM, Lemarec N, et al.: Antibodies to hepatitis 65. Dussol B, Berthezene P, Brunet P, et al.: Hepatitis C virus infection
C virus by second generation test in hemodialyzed patients. Kidney among chronic dialysis patients in the south-east of France. Nephrol
Int 1993, 46(suppl 43):S149–S152. Dial Transplant 1995, 10:477–478.
42. Sheu JC, Lee SH, Wang JT, et al.: Prevalence of anti-HCV and HCV 66. McIntyre PG, McCrudden EA, Dow BC, et al.: Hepatitis C virus
viremia in hemodialysis patients in Taiwan. J Med Virol 1992, infection in renal dialysis patients in Glasgow. Nephrol Dial
37:108–112. Transplant 1994, 9:291–295.
43. Ayoola EA, Huraib S, Arif M, et al.: Prevalence and significance of 67. Huang CC, Wu MS, Lin DY, et al.: The prevalence of hepatitis C
antibodies to hepatitis C virus among Saudi hemodialysis patients. antibodies in patients treated with continuous ambulatory peritoneal
J Med Virol 1991, 35:155–159. dialysis. Perit Dial Int 1992, 12:31–33.
44. Korksal I, Biberoglu K, Biberoglu S, et al.: Hepatitis C virus antibodies 68. Jonas MM, Zilleruelo GE, Larue SI, et al.: Hepatitis C infection in a
among risk groups in Turkey. Infection 1991, 19:228–229. pediatric dialysis population. Pediatrics 1992, 89:707–709.
45. Bahakim H, Bakir TMF, Arif M, et al.: Hepatitis C virus antibodies 69. Barril G, Traver JA: Prevalence of hepatitis C virus in dialysis patients
in high-risk Saudi groups. Vox Sang 1991, 60:162–164. in Spain. Nephrol Dial Transplant 1995, 10(suppl 6):78–80.
46. Mitwalli A, Al-Mohaya S, Al Wakeel J, et al.: Hepatitis C in chronic 70. Yoshida CFT, Takahashi C, Gaspar AMC, et al.: Hepatitis C virus in
renal failure patients. Am J Nephrol 1992, 12:228–291. chronic hemodialysis patients with non-A, non-B hepatitis. Nephron
47. Alfuray O, Sobh M, Buali AR, et al.: Hepatitis C virus infection in 1992, 60:150–153.
chronic hemodialysis patients, a clinicopathologic study. Nephrol 71. Jadoul M, Cornu C, Van Ypersele de Strihou C, et al.: Incidence and
Dial Transplant 1992, 7:327–332. risk factors for hepatitis C seroconversion in hemodialysis: a prospec-
48. Oguchi H, Miyassaka M, Tokunaga S, et al.: Hepatitis virus infection tive study. Kidney Int 1993, 44:1322–1326.
(HBV and HCV) in eleven Japanese hemodialysis units. Clin Nephrol 72. Pinto dos Santos J, Loureiro A, Cendoroglo Meto M, et al.: Impact
1992, 38:36–43. of dialysis room and reuse strategies on the incidence of HCV infec-
49. Lin DY, Lin HH, Huang CC, et al.: High incidence of hepatitis C tion in HD units. Nephrol Dial Transplant 1996, 11:7017–7022.
virus infection in hemodialysis patients in Taiwan. Am J Kidney Dis 73. Gilli P, Moretti M, Soffritti S, et al.: Non-A, non-B hepatitis and anti-
1993, 21:288–291. HCV antibodies in dialysis patients. Int J Artif Organs 1990,
50. Blackmore TK, Maddocks P, Stace NH, et al.: Prevalence of antibodies 13:737–741.
to hepatitis C virus in patients receiving renal replacement therapy, 74. Okuda K, Hayashi H, Yokozeki KEA: Mode of nosocomial HCV
and in the staff caring for them. Aust N Z J Med 1992, 22:353–357. infection among chronic hemodialysis patients and its prevention.
51. Roger SD, Cunningham A, Crewe E, et al.: Hepatitis C virus infec- Hepatology 1994, 19:293.
tion in heamodialysis patients. Aust N Z J Med 1991, 21:22–24. 75. Da Porto A, Adami A, Susanna F, et al.: Hepatitis C virus in dialysis
53. Natov SN, Pereira BJG: Hepatitis C infection in patients on dialysis. units: a multicenter study. Nephron 1992, 61:309–310.
Semin Dial 1994, 7:360–368. 76. Hubmann R, Zazgornik J, Gabriel C, et al.: Hepatitis C virus: Does it
54. Dussol B, Chicheporttiche C, Cantaloube JF, et al.: Detection of hepati- penetrate the hemodialysis membrane? PCR analysis of hemodialysis
tis C infection by polymerase chain reaction among hemodialysis ultrafiltrate and whole blood. Nephrol Dial Transplant 1995,
patients. Am J Kidney Dis 1993, 22:574–580. 10:541–542.
55. Kundsen F, Wantzin P, Rasmussen K, et al.: Hepatitis C in dialysis 77. Caramelo C, Navas S, Alberola ML, et al.: Evidence against transmis-
patients: relationship to blood transfusions, dialysis and liver disease. sion of hepatitis C virus though hemodialysis ultrafiltrate and peritoneal
Kidney Int 1993, 43:1353–1356. fluid. Nephron 1994, 66:470–473.
55. Dentico, P, Buongiorno R, Volpe A, et al.: Prevalence and incidence 78. Lombardi M, Cerrai T, Dattolo P, et al.: Is the dialysis membrane a
of hepatitis C virus (HCV) in hemodialysis patients: study of risk fac- safe barrier against HCV infection? Nephrol Dial Transplant 1995,
tors. Clin Nephrol 1992, 61:49–52. 10:578–579.
7.18 Systemic Diseases and the Kidney
79. Alter MJ, Favero MS, Moyer LA, et al.: National surveillance of dialy- 104. Morales JM, Fernandez-Zatarain G, Munoz MA, et al.: Clinical pic-
sis-associated diseases in the United States, 1989. ASAIO Trans 1991, ture and outcome allograft membranous glomerulonephritis in renal
37:97–109. transplant patients with hepatitis C virus infection. J Am Soc Nephrol
80. Natov SN, Pereira BJG: Hepatitis C infection in patients on dialysis. 1995, 6:1107.
Semin Dial 1994, 7:360–368. 105. Roth D, Cirocco R, Zucker K, et al.: De novo membranoproliferative
81. Caramelo C, Ortiz A, Aguilera B, et al.: Liver disease patterns in glomerulonephritis in hepatitis C virus-infected renal allograft recipients.
hemodialysis patients with antibodies to hepatitis C virus. Am J Transplantation 1995, 59:1676–1682.
Kidney Dis 1993, 22:822–823. 106. Morales JM, Capdevila JP, Campistol JM, et al.: Membranous
82. LaQuaglia MP, Tolkoff-Rubin NE, Dienstag JL, et al.: Impact of glomerulonephritis associated with hepatitis C virus infection in renal
hepatitis on renal transplantation. Transplantation 1981, 32:504–507. transplant patients. Transplantation 1997, 63:1634–1639.
83. Boyce NW, Hodsworth SR, Hooke D, et al.: Nonhepatitis B-associated 107. Pol S, Thiers V, Carnot F, et al.: Efficacy and tolerance of -2b inter-
liver disease in a renal transplant population. Am J Kidney Dis 1988, feron therapy on HCV infection of hemodialyzed patients. Kidney Int
11:307–312. 1985, 47:1412–1418.
84. Weir MR, Kirkman RL, Strom TB, et al.: Liver disease in recipients 108. Casanovas TT, Baliellas C, Sese E, et al.: Interferon may be useful in
of long-functioning renal allografts. Kidney Int 1985, 28:839–844. hemodialysis patients with hepatitis C virus chronic infection who are
85. Ware AJ, Luby JP, Hollinger B, et al.: Etiology of liver disease in candidates for kidney transplant. Transplant Proc 1995, 27:2229–2230.
renal-transplant patients. Ann Intern Med 1979, 91:364–371. 109. Koenig P, Vogel W, Umlauft F, et al.: Interferon treatment for chronic
86. Debure A, Degos F, Pol S, et al.: Liver diseases and hepatic complica- hepatitis C virus infection in the uremic patient. Kidney Int 1994,
tions in renal transplant patients. Adv Nephrol 1988, 17:375–400. 45:1507–1509.
87. Mahony JF: Long term results and complications of transplantation: 110. Duarte R, Huraib S, Said R, et al.: Interferon- facilities renal trans-
the kidney. Transplant Proc 1989, 21:1433–1434. plantation in hemodialysis patients with chronic viral hepatitis. Am J
88. Rao KV, Anderson WR, Kasiske BL, et al.: Value of liver biopsy in the Kidney Dis 1995, 25:40–45.
evaluation and management of chronic liver disease in renal transplant 111. Raptopoulou-Gigi M, Spaia S, Garifallos A, et al.: Interferon--2b
recipients. Am J Med 1993, 94:241–250.
treatment of chronic hepatitis C in hemodialysis patients. Nephrol
89. Pereira BJG, Wright TL, Schmid CH, et al.: The impact of pretrans- Dial Transplant 1995, 10:1834–1837.
plantation hepatitis C infection on the outcome of renal transplanta-
112. Magnone M, Hollet JL, Shapiro R, et al.: Interferon- induced acute
tion. Transplantation 1995, 60:799–805.
renal allograft rejection. Transplantation 1995, 59:1068.
90. Roth D, Zucker K, Cirocco R, et al.: The impact of hepatitis C virus
infection on renal allograft recipients. Kidney Int 1994, 45:238–244. 113. Rostaing L, Izopet J, Baron E, et al.: Preliminary results of treatment
of chronic hepatitis C with recombinant interferon- in renal trans-
91. Pereira BJG, Milford EL, Kirkman RL, et al.: Prevalence of hepatitis plant patients. Nephrol Dial Transplant 1995, 10:93–96.
C virus RNA in organ donors positive for hepatitis C antibody and in
the recipients of their organs. N Engl J Med 1992, 327:910–915. 114. Harihara Y, Kurooka Y, Yanagisawa T, et al.: Interferon therapy in
renal allograft recipients with chronic hepatitis C. Transplant Proc
92. Pereira BJG, Wright TL, Schmid CH, et al.: A controlled study of hepati-
tis C transmission by organ transplantation. Lancet 1995, 345:484–487. 1994, 26:2075.
93. Roth D, Fernandez JA, Babischkin S, et al.: Detection of hepatitis C 115. Thervet E, Pol S, Legendre C, et al.: Low dose recombinant leukocyte
virus infection among cadaver organ donors: evidence for low trans- interferon alpha treatment of hepatitis C viral infection in renal trans-
mission of disease. Ann Intern Med 1992, 117:470. plant recipients. Transplantation 1994, 58:625.
94. Tesi RJ, Waller K, Morgan CJ, et al.: Transmission of hepatitis C virus 116. Izopet J, Rostaing L, Cazabet M, et al.: Failure of HCV RNA clear-
by kidney transplantation: the risks. Transplantation 1994, 57:826. ance in kidney transplant recipients treated with -interferon. J Am
Soc Nephrol 1994, 5:1013A.
95. Vincente F, Lake J, Wright T, et al.: Nontransmission of hepatitis C
from cadaver organ donors to transplant recipients. Transplantation 117. Ozgur O, Boyacioglu S, Telatar H, et al.: Recombinant -interferon
1993, 55:674–675. in renal allograft recipients with chronic hepatitis C. Nephrol Dial
96. Wreghtt TG, Gray JJ, Allain JP, et al.: Transmission of hepatitis C Transplant 1995, 10:2104–2106.
virus by organ transplantation in the United Kingdom. J Hepatol 118. Glassock RJ, Cohen Ah, Danovitch G, et al.: Human immunodeficien-
1994, 20:768–772. cy virus (HIV) infection and the kidney. Ann Intern Med 1990,
97. Zucker K, Cirocco R, Roth D, et al.: Depletion of hepatitis C virus 112:35–49.
from procured kidneys using pulsatile perfusion preservation. 119. Seney FD Jr, Burns DK, Silva FG: Acquired immunodeficiency syndrome
Transplantation 1994, 54:832. and the kidney. Am J Kidney Dis 1990, 16:1–13.
98. Widell A, Mansson S, Persson NH, et al.: Hepatitis C superinfection 120. Vitting KE, Gardenswartz MH, Zabetakis PM, et al.: Frequency of
in hepatitis C virus (HCV)-infected patients transplanted with an hyponatremia and nonosmolar vasopressin release in the acquired
HCV-infected kidney. Transplantation 1995, 60:642–647. immunodeficiency syndrome. JAMA 1990, 263:973–976.
99. Fritsche C, Brandes JC, Delaney SR, et al.: Hepatitis C is a poor 121. Agarwal A, Soni A, Ciechanowsky M, et al.: Hyponatremia in
prognostic indicator in black kidney transplant recipients. patients with the acquired immunodeficiency syndrome. Nephron
Transplantation 1993, 55:1283–1287.
1989, 53:317–321.
100. Pereira BJG, Wright TL, Schmid CH, et al. for the New England Organ
122. Tang WW, Kapstein, EM, Feinstein EI, et al.: Hyponatremia in hospi-
Bank Hepatitis C Study Group: the impact of pretransplantation
talized patients with acquired immune deficiency syndrome and the
hepatitis C infection on the outcome of renal transplantation.
Transplantation 1995, 60:799–805. AIDS related complex. Am J Med 1993, 94:169–174.
101. Ynares C, Johnson HK, Kerlin T, et al.: Impact of pretransplant hepatitis 123. Greene LW, Cole W, Greene JB, et al.: Adrenal insufficiency as a com-
C antibody status upon long-term patient and renal allograft survival: a plication of the acquired immunodeficiency syndrome. Ann Intern
5- and 10-year follow-up. Transplant Proc 1993, 25:1466–1468. Med 1984, 101:497–498.
102. Cockfield SM, Prieksaitis JK: Infection with hepatitis C virus increas- 124. Kalin G, Torensky L, Seras DS, et al.: Hyporeninemic hypoaldostero-
es the risk of de novo glomerulonephritis in renal transplant recipi- nism associated with the acquired immunodeficiency syndrome. Am J
ents. J Am Soc Nephrol 1995, 6:1078. Med 1987, 82:1035–1038.
103. Huraib S, Al Khudair W, Abu Romeh S, et al.: Pattern and prevalence 125. Guenthner EE, Rabinowe SL, Van Niel A, et al.: Primary Addison’s
of glomerulonephritis in renal transplant hepatitis C (HCV ) patients disease in a patient with the acquired immunodeficiency syndrome.
(PTS). J Am Soc Nephrol 1995, 6:1093. Ann Intern Med 1984, 100:847–848.
Renal Disease in Patients Infected with Hepatitis and Human Immunodeficiency Virus 7.19
126. Santos GI, Garcia PI, del Arco GC, et al.: Sindrome de secrecion 150. Roth D, Alarcon FJ, Fernandez JA, et al.: Acute rhabdomyolysis asso-
inapropiada asociado con el sindrome de immunodeficiencia adquirida. ciated with cocaine intoxication. N Engl J Med 1988, 319:673–677.
Rev Clin Esp 1991, 188:120–122. 151. Aarons EJ, Woodrow D, Hollister WS, et al.: Reversible renal failure
127. Berns JS, Cohen RM, Stumacher RJ, et al.: Renal aspects of therapy caused by a microsporidian infection. AIDS 1994, 8:1119–1121.
for human immunodeficiency virus and associated opportunistic 152. Clinicopathologic Conference: Fever and acute renal failure in a
infections. J Am Soc Nephrol 1991, 1:1061–1080. 31-year-old male with AIDS. Am J Med 1997, 102:310–315.
128. Berns JS, Cohen RM, Rudnick MR, et al.: Renal aspects of antimicro- 153. Becker BN, Fall P, Hall C, et al.: Rapidly progressive acute renal
bial therapy for HIV infection. In Renal and Urologic Aspects of HIV failure due to acyclovir: case report and review of the literature.
Infection. Comtemp Issues Nephrol 1996, 29:195–235. Am J Kidney Dis 1993, 22:611–615.
129. Valeri A, Neusy AJ: Acute and chronic renal disease in hospitalized 154. Peraldi MN, Ovali N, Rondeau E, et al.: Is biopsy useful in HIVJ-
AIDS patients. Clin Nephrol 1991, 35:110–118. infected patients with acute renal failure? A retrooperative study.
130. Genderini A, Bertoli S, Scorza D, et al.: Acute renal failure in patients J Am Soc Nephrol 1997, 8:130A.
with acquired immune deficiency syndrome. J Nephrol 1991, 1:45–47. 155. Rao TK, Friedman EA: Outcome of severe acute renal failure in patients
131. Rao TK, Friedman EA: Renal syndromes in the acquired immunode- with acquired immunodeficiency syndrome. Am J Kidney Dis 1995,
ficiency syndrome (AIDS): lessons learned from analysis over 5 years. 25:390–398.
Artif Organs 1988, 12:206–209. 156. Bourgoignie J: Glomerulosclerosis associated with HIV infection.
132. Bourgoignie JJ: Renal complications of human immunodeficiency Contemp Issues Nephrol 1996, 29:59–75.
virus type 1. Kidney Int 1990, 37:1571–1584. 157. Rao TK, Filippone EJ, Nicastri AD, et al.: Associated focal and segmen-
133. Cantor ES, Kimmel PL, Bosch JP: Effect of race on expression of tal glomerulosclerosis in the acquired immunodeficiency syndrome. N
acquired immunodeficiency syndrome–associated nephropathy. Arch Engl J Med 1984, 310:669–673.
Intern Med 1991, 151:125–128. 158. Pardo V, Aldana M, Colton RM, et al.: Glomerular lesions in the
134. D’Agati V, Cheng JI, Carbone L, et al.: The pathology of HIV- acquired immunodeficiency syndrome. Ann Intern Med 1984,
nephropathy: a detailed morphologic and comparative study. Kidney 101:429–434.
Int 1989, 35:1358–1370. 159. Gardenswartz MH, Lerner CW, Seligson GR, et al.: Renal disease in
135. Polis MA, Spooner KM, Baird BF, et al.: Anticytomegaloviral activity patients with AIDS: a clinicopathologic study. Clin Nephrol 1984,
and safety of cidofovir in patients with human immunodeficiency 21:197–204.
virus infection and cytomegalovirus viruria. Antimicrob Agents 160. Mazbar SA, Schoenfeld PY, Humphreys MH: Renal involvement in
Chemother 1995, 39:882–886. patients infected with HIV: experience at San Francisco General
136. Seidel EA, Koenig S, Polis MA: A dose escalation study to determine Hospital. Kidney Int 1990, 37:1325–1332.
the toxicity and maximally tolerated dose of foscarnet. AIDS 1993, 161. Humphreys MH: Human immunodeficiency virus–associated
7:941–945. nephropathy: east is east and west is west? Arch Intern Med 1990,
137. Rao TKS, Berns JS: Acute renal failure in patients with HIV infections. 150:253–255.
Contemp Issues Nephrol 1996, 29:41–57. 162. Bourgoignie JJ, Ortiz-Interian C, Green DF, et al.: The epidemiology
138. Jabs DA, David MD, Kuriniji et al.: Parenteral cidofovir for cyto- of human immunodeficiency virus–associated nephropathy. In
megalovirus retinitis in patients with AIDS: the HPMC peripheral Nephrology, vol 1. Edited by Hatano M. Tokyo: Springer-Verlag;
cytomegalovirus retinitis trial. A randomized controlled trial. Ann 1991:484–492.
Intern Med 1997, 126:264–275. 163. Pardo V, Meneses R, Ossa L, et al.: AIDS-related glomerulopathy:
139. Rashed A, Azadeh B, Abu Romeh SH: Acyclovir-induced acute tubu- occurrence in specific risk groups. Kidney Int 1989, 31:1167–1173.
lo-interstitial nephritis. Nephron 1990, 56:436–438. 164. Strauss J, Abitbol C, Zilleruelo G, et al.: Renal disease in children
140. Christin S, Baumelou A, Bahri S, et al.: Acute renal failure due to with the acquired immunodeficiency syndrome. N Engl J Med 1989,
sulfadiazine in patients with AIDS. Nephron 1990, 55:233–234. 321:625–630.
141. Carbone LG, Bendixen B, Appel GB: Sulfadiazine-associated obstruc- 165. Nochy D, Gotz D, Dosquet P, et al.: Renal disease associated with
tive nephropathy occurring in a patient with the acquired immunodefi- HIV infection: a multicentric study of 60 patients from Paris hospitals.
ciency syndrome. Am J Kidney Dis 1988, 12:72–75. Nephrol Dial Transplant 1993, 8:11–19.
142. Molina JM, Belenfant X, Doco-Lecompte T, et al.: Sulfadiazine- 166. D’Agati V, Appel GB: HIV infection and the kidney. J Am Soc
induced crystalluria in AIDS patients with toxoplasma encephalitis. Nephrol 1997, 8:138–152.
AIDS 1991, 5:587–589. 167. Cohen AH, Nast CC: HIV-associated nephropathy: a unique com-
143. Becker K, Jablonowski H, Haussinger D: Sulfadiazine-associated bined glomerular, tubular and interstitial lesion. Modern Pathol
nephrotoxicity in patients with the acquired immunodeficiency 1988, 1:87–97.
syndrome. Medicine 1996, 75:185–194. 168. Soni A, Agarwal A, Chander P, et al.: Evidence for an HIV-related
144. Sawyer MH, Webb DE, Balow JE, et al.: Acyclovir-induced acute renal rephropathy: a clinicopathological study. Clin Nephrol 1989, 31:12–17.
failure. clinical course and histology. Am J Med 1988, 84:1067–1071. 169. Bourgoignie JJ, Pardo V: The nephropathology in human immuno-
145. Tashima KT, Horowitz JD, Rosen S: Indinavir nephropathy [letter]. deficiency virus (HIV-1) infection. Kidney Int 1991, 35:S19–S23.
N Engl J Med 1997, 336:138–139. 170. Cohen AH: Renal pathology of HIV-associated nephropathy.
146. Kopp JB, Miller KD, Micam JAM, et al.: Crystoalluria and urinary Contemp Issues Nephrol 1996, 27:155–180.
tract abnormalities associated with Indinovir. Ann Intern Med 1997, 171. Pardo V, Strauss J, Abitbol C: Renal disease in children with HIV
127:119–125. infection. Contemp Issues Nephrology 1996, 29:135–154.
147. Spector DA, Katz RS, Fuller H, et al.: Acute non-dilating obstructive 172. Langs C, Gallo GR, Schacht RG, et al.: Rapid renal failure in AIDS-
renal failure in a patient with AIDS. Am J Nephrol 1989, 9:129–132. associated focal glomerulosclerosis. Arch Intern Med 1990,
148. Comiter S, Glasser J, Al-Askari S: Ureteral obstruction in a patient 150:287–292.
with Burkitt’s lymphoma. Urology 1992, 39:277–289. 173. Humphreys MH: Human immunodeficiency virus–associated
149. Kuhlman JE, Browne D, Shermak M, et al.: Retroperitoneal and glomerulosclerosis. Kidney Int 1995, 48:311–320.
pelvic CT of patients with AIDS: primary and secondary involvement 174. Shuka RR, Kimmel PL, Jumar A: Molecular biology of HIV-1 and
of the genitourinary tract. Radiographics 1991, 11:473–483. kidney disease. Contemp Issues Nephrol 1996, 29:329–389.
7.20 Systemic Diseases and the Kidney
175. Barisoni L, Bruggeman L, Schwartz E, et al.: Pathogenesis of HIV-asso- 192. Kimmel PL, Umana WO, Simmens SJ, et al.: Continuous ambulatory
ciated nephropathy in transgenic mice. J Am Soc Nephrol 1997, peritoneal dialysis and survival of HIV infected patients with end-
8:492A. stage renal disease. Kidney Int 1993, 44:373–378.
176. Bruggeman LA, Dikman S. Meng C, et al.: Nephropathy in human 193. Ifudu O, Mayers JD, Matthew JJ, et al.: Uremia therapy in patients with
immunodeficiency virus-1 transgenic mice is due to renal transgene end-stage renal disease and human immunodeficiency virus infection:
expression. J Clin Invest 1997, 100:84–92. Has the outcome changed in the 1990s? Am J Kidney Dis 1997,
29:549–552.
177. Babut-Gay ML, Echard M, Kleinknecht D, et al.: Zidovudine and
nephropathy with human immunodeficiency virus (HIV) infection 194. Perinbasekar S, Brod-Miller S, Pal S, et al.: Predictors of survival in
[letter]. Ann Intern Med 1989, 111:856–857. HIV-infected patients on hemodialysis. Am J Nephrol 1996,
16:280–286.
178. Harrer T, Hunzelmann N, Stoll R, et al.: Therapy for HIV-1 related
nephritis with zidovudine. AIDS 1990, 4:815–817. 195. Carpenter C, Fischl M, Hammer S, et al.: Antiretroviral therapy for
HIV infection in 1996. JAMA 1996, 276:146–154.
179. Ifudu O, Rao TK, Tan CC, et al.: Zidoudine is beneficial in human
immunodeficiency virus associated nephropathy. Am J Nephrol 1995, 196. Casanova S, Mazzucco G, Barbiano di Belgiojoso G, et al.: Pattern of
15:217–221. glomerular involvement in human immunodeficiency virus-infected
patients: an Italian study. Am J Kidney Dis 1995, 26:446–453.
180. Kimmel PL, Mishkin GJ, Umana WO: Captopril and renal survival in
patients with human immunodeficiency virus nephropathy. Am J 197. Korbet SM, Schwartz MM: Human immunodeficiency virus infection
Kidney Dis: 1996, 28:202–208. and nephrotic syndrome. Am J Kidney Dis 1992, 20:97–103.
198. Stokes MB, Chawla H, Brody RI, et al.: Immune complex glomeru-
181. Smith MC, Austen JL, Carey JT, et al.: Prednisone improves renal
lonephritis in patients co-infected with human immunodeficiency
function and proteinuria in human immunodeficiency virus-associat-
virus and hepatitis C virus. Am J Kidney Dis 1997, 29:514–525.
ed nephropathy. Am J Med 1996, 101:41–48.
199. Kimmel PL, Phillips TM: Immune-complex glomerulonephritis associ-
182. Watterson MK, Detwiler RD, Bolin P Jr: Clinical response to pro-
ated with HIV infection. Contemp Issues Nephrol 1996, 29:77–110.
longed corticosteroids in a patient with human immunodeficiency
virus-associated nephropathy. Am J Kidney Dis 1997, 29:624–626. 200. Guerra IL, Abraham AA, Kimmel PL, et al.: Nephrotic syndrome
associated with chronic persistent hepatitis B in an HIV antibody
183. Ingulli E, Tejani A, Fikrig S, et al.: Nephrotic syndrome associated positive patient. Am J Kidney Dis: 1987, 10:385–388.
with acquired immunodeficiency syndrome in children. J Pediatr
1991, 119:710–716. 201. Schectman JM, Kimmel PL: Remission of hepatitis B–associated mem-
branous glomerulonephritis in human immunodeficiency virus infection.
184. Ouelette DR, Kelly JW, Anders JT: Serum angiotensin converting Am J Kidney Dis 1991, 17:716–718.
enzyme level is elevated in patients with HIV-infection. Arch Intern
202. Kusner DJ, Ellner JJ: Syphilis, a reversible cause of nephrotic syn-
Med 1992, 152:321–324.
drome in HIV infection [letter]. N Engl J Med 1991, 324:341–342.
185. Burns G, Paul SK, Sivak SL, et al.: Effect of angiotensin-converting
203. D’Agati V, Seigle R: Coexistence of AIDS and lupus nephritis: a case
enzyme inhibition in HIV-associated nephropathy. J Am Soc Nephrol
report. Am J Nephrol 1990, 10:243–247.
1997, 8:1140–1146.
204. Contreras G, Green DF, Pardo V, et al.: Systemic lupus erythematosus
186. Bird JE, Kopp JB, Gitlitz P, et al.: Captopril intervention is of benefit in two adults with human immunodeficiency virus. Am J Kidney Dis
in HIV-transgenic mice. J Am Soc Nephrol 1997, 8:611A. 1996, 28:292–295.
187. Rao TKS, Friedman EA, Micastri AD: The types of renal disease in 205. Kimmel PL, Phillips TM, Farkas-Szallasi T, et al.: Idiotypic IgA
human acquired immunodeficiency syndrome. N Engl J Med 1987, nephropathy in patients with HIV infection. N Engl J Med 1992,
316:1062–1068. 327:702–706.
188. Ortiz C, Meneses R, Jaffe D, et al.: Outcome of patients with human 206. Bourgoignie JJ, Pardo V: Human immunodeficiency virus: associated
immunodeficiency virus on maintenance hemodialysis. Kidney Int nephropathies [editorial]. N Engl J Med 1992, 327:729–730.
1988, 34:248–253.
207. Peraldi MN, Berrou J, Flahaut A, et al.: Elevated plasma tissue type
189. Feinfeld DA, Kaplan R, Dressler R, et al.: Survival of human plasminogen activator (tPA) in HIV-infected patients with thrombotic
immunodeficiency virus infected patients on maintenance dialysis. microangiopathy [abstract]. J Am Soc Nephrol 1996, 7:1377.
Clin Nephrol 1989, 32:221–224. 208. Berns JS: Hemolytic uremic syndrome and thrombotic thrombocy-
190. Ribot S, Dean D, Goldblat M, et al.: Prognosis of HIV positive dialysis topenic purpura associated with HIV infection. Contemp Issues
patients [abstract]. Kidney Int 1990, 37:315. Nephrol 1996, 29:111–133.
191. Schrivastava D, Delano BG, Lundin P, et al.: Factors affecting survival 209. Nadasdy T, Miller KW, Johnson LD, et al.: Is cytomegalovirus associ-
of HIV+ patients undergoing maintenance hemodialysis [abstract]. ated with renal disease in AIDS patients? Modern Pathol 1992,
J Am Soc Nephrol 1992, 3:320. 5:277–282.
Renal Involvement
in Sarcoidosis
Garabed Eknoyan
S
arcoidosis is a clinicopathologic syndrome resulting from dis-
persed organ involvement by a noncaseating granulomatous
process of unknown cause. The clinical manifestations of sar-
coidosis are protean, depending on the affected organs; however, the
principal targets of sarcoidosis are the lungs and thoracic lymph
nodes, which almost always are involved. As a rule, it is a disease of
insidious onset that pursues a chronic course, with episodic remis-
sions and exacerbations. The severity and diversity of its clinical
manifestations depend on the extent of infiltrating granulomatous
lesions of the involved organs and that of the number of affected
organs. When diffuse and widespread the disease may pursue an
acute fulminant course. Diagnosis depends on demonstration of the
characteristic pathologic lesion of noncaseating granulomas within
the affected organ.
Sarcoidosis is a common (1 to 40 cases per 100,000 population)
disease of the relatively young (mean age 40 years), with a proclivity
for racial (3.5 times more in blacks), ethnic (Scandinavian), and sea-
sonal occurrence (summer rather than winter). Reports of community
outbreaks, work-related risks, familial clustering, occurrence after
organ transplantation, and experimental induction in animals by
injection of affected tissue homogenates from humans strongly sug-
gests an infective cause that remains to be identified.
Two associated metabolic abnormalities of diagnostic and clinical
import are elevated levels of calcitriol (1,25-dihydroxy-vitamin D3)
and angiotensin-converting enzyme (ACE). Neither is unique to sar-
coidosis. Elevated levels of calcitriol are consequent to the capacity of
the infiltrating macrophages of the granulomas to synthesize calcitriol. CHAPTER
Elevated levels of ACE are consequent to that of the multinucleated
giant and epithelioid cells that ultimately develop in the granulomas,
8
along with that of the infiltrating macrophages, to produce ACE. Of
these, the elevated levels of calcitriol are the more important because
they account for the abnormal calcium metabolism that occurs in most
patients. Elevated levels of ACE are of no known clinical consequence
8.2 Systemic Diseases and the Kidney
and are of limited value in diagnosis; however, they can be use- the active granulomatous lesions. Close monitoring of patients
ful in follow-up of the course of the disease and patient response is essential during tapering and after discontinuation of steroid
to treatment. therapy, because 25% of treated patients experience relapse.
In symptomatic cases, steroids are highly effective in sup- Other drugs that have been used in cases unresponsive to
pressing the cellular inflammatory reaction of sarcoidosis and steroids are methotrexate, chloroquine, azathioprine, and
in reversing most forms of organ dysfunction caused by granu- cyclophosphamide. Of these, methotrexate seems to be more
lomatous infiltration. Therapy with prednisone (30 to 40 mg/d) effective.
for 8 to 12 weeks, with gradual tapering of the dose (10 to The prognosis is worse in blacks, the elderly, and those
20 mg/d) over 6 to 12 months, is usually sufficient. Persistent patients who fail to respond to steroids or have extensive multi-
dysfunction can result from residual fibrosis after reversal of organ involvement.
A B
C D
FIGURE 8-1 (see Color Plate)
Pathology of granulomatous lesions in lungs affected by sarcoidosis. teristic of sarcoidosis are shown. (Hematoxylin-eosin stain 10.)
The diagnosis of sarcoidosis depends on demonstration of the charac- C and D, Lesions in the lung are illustrated, showing their course from
teristic lesion of noncaseating granulomas within the affected organs. a cellular inflammatory response, which may be asymptomatic (panel
As with other epithelioid granulomas, the more commonly involved C), to that of the fibrotic resolution (panel D). The fibrotic response
organs are the lungs and liver. A, A section of a normal lung is shown. usually accounts for the permanent loss of normal parenchyma and
(Pentachrome stain 10.) B, Multiple noncaseating granulomas and organ function. (Hematoxylin-eosin stain 10 and pentachrome
areas of mononuclear cell infiltration of the lung interstitium charac- 10, respectively.) (From Newman et al. [1]; with permission.)
Renal Involvement in Sarcoidosis 8.3
FIGURE 8-2
Pathogenesis of granulomatous
lesions Pathogenesis of granulomatous lesions. Mononuclear cell infiltra-
tion is the initial step in the sequence of events that leads to granu-
loma formation. Recruited macrophages then differentiate into
Mononuclear cell infiltration epithelioid and multinucleated giant cells. Activated lymphocytes
are interspersed in the evolving lesion and come to form a rim
around the granulomas. In time, fibroblasts, mast cells, and colla-
Macrophage aggregation ↑ Synthesis of 1,25-dihydroxy-vitamin D3 gen fibers begin to encapsulate the mature sarcoid granuloma.
Cultured granulomatous homogenates exhibit 1-hydroxylase
activity and are capable of converting 25-hydroxy-vitamin D3 to its
active 1,25-dihydroxylated form, calcitriol. This capacity resides in
Epithelioid and multinucleated ↑ Synthesis of angiotensin-converting
giant cells the infiltrating macrophages and is not unique to sarcoidosis but a
enzyme
feature of most other granulomatous disorders. Although lacking
in specificity to be of diagnostic merit, radioactive gallium scans
Encapsulating rim can be used as noninvasive methods of assessing the activity of sar-
CD4>CD8 (except in rare cases) coid granulomas. The uptake of radioactive gallium by the
B cells, few macrophages and lymphocytes reflects the activity of the infiltrat-
Fibroblasts ing cells in affected organs.
Mast cells
FIGURE 8-4
CYTOKINES IMPLICATED IN SARCOIDOSIS FREQUENCY OF ORGAN INVOLVEMENT Frequency of organ
PERPETUATING GRANULOMAS involvement.
Sarcoidosis is a
Patients, % multisystem disease.
Interferon- Parenchymal
Thoracic 90–100 involvement by
Interleukin-2, 6, and 1
Stage I: hilar adenopathy granulomatous
Chemoattractants
Stage II: hilar adenopathy plus lesions is most
Adhesion molecules pulmonary infiltration common in the
Tumor necrosis factor- Stage III: pulmonary infiltration lungs, whereas that
Dermatologic 25 of renal involvement
Erythema nodosum, lupus pernio, papules, macules, plaques is relatively rare.
Ophthalmic 25
FIGURE 8-3 Uveitis, iritis, conjunctivitis
Cytokines implicated in perpetuating granu- Nervous system 10
lomas. Cytokines released by the infiltrating Peripheral neuropathy, Bell’s palsy
mononuclear cells and T-cell lymphocytes Central nervous system
initiate the cascade of inflammatory reaction Gastrointestinal 40–70
that results in subsequent formation of the Liver
noncaseating granulomas that characterize Spleen
sarcoidosis. It is the loss of the otherwise
Cardiac 5–10
balanced ability of cytokines to modulate
Renal 1–20
the inflammatory response that accounts for
Musculoskeletal 10–15
the progression of the initial inflammatory
Polyarthritis, lower > upper
reaction to granulomatous formation, and
ultimately to the more detrimental process
of fibrosis. Macrophages are critical in
inducing fibroblasts to proliferate and
deposit fibronectin and collagen in the
extracellular matrix.
8.4 Systemic Diseases and the Kidney
FIGURE 8-5
DIFFERENTIAL DIAGNOSIS OF Differential diagnosis of pulmonary sarcoidosis. The lungs are the principal organs involved
PULMONARY SARCOIDOSIS in sarcoidosis. Pulmonary involvement may or may not be associated with hilar lym-
phadenopathy. In contrast to the pulmonary diseases listed, pulmonary symptoms may be
absent in sarcoidosis even in the presence of extensive pulmonary lesions seen on chest radi-
Sarcoidosis ographs. Pulmonary symptoms develop when the disease is in its late fibrotic phase and are
Beryllium exposure associated with airway obstruction.
Hypersensitivity pneumonitis
Idiopathic pulmonary fibrosis
Mycobacterial infection
Fungal infections
Methotrexate-induced pneumonitis
Wegener’s granulomatosis
FIGURE 8-6
LABORATORY FINDINGS Laboratory findings in sarcoidosis. The diagnosis of sarcoidosis depends on the demon-
IN SARCOIDOSIS stration of the characteristic pathologic lesion of noncaseating granulomas within the
affected organs. Several laboratory abnormalities characterize sarcoidosis and are useful in
supporting but not establishing the diagnosis. Hyperglobulinemia is a principal feature,
Hyperglobulinemia being present in two thirds of cases. About half of patients have liver involvement, with
Abnormal liver function tests some abnormality of liver function tests; anergy is present in about half of patients;
Anergy leukopenia is present in 25% to 30%. Hypercalciuria is common because of increased lev-
Leukopenia els of calcitriol. In 50% to 60% of patients levels of angiotensin-converting enzymes are
Hyperuricemia elevated. Fever is present in about one third of patients.
Hypercalciuria
Hypercalcemia
Elevated calcitriol (1,25-dihydroxy-vitamin D3)
Elevated angiotensin-converting enzyme
Cryoglobulinemia
FIGURE 8-7
RENAL INVOLVEMENT IN SARCOIDOSIS Renal involvement in sarcoidosis. The principal manifestations of
renal involvement in sarcoidosis are the functional abnormalities
resulting from the altered metabolism of calcium as a result of the
Patients, % increased synthesis of 1,25-dihydroxy-vitamin D3 by the
macrophages of the granulomatous lesions. The consequent
Calcium metabolism increased calcium absorption from the gastrointestinal tract results
Hypercalciuria 50–60 in the hypercalciuria that can be detected in more than half of
Hypercalcemia 10–20 patients. The frequency of hypercalciuria depends on the extent of
Nephrolithiasis ≈10 granulomatous lesions and on the time of the year, being more
Nephrocalcinosis 5–10 common in spring and summer when exposure to the sun is great-
Tubulointerstitial nephritis est. Hypercalcemia is less common and usually depends on coexis-
Granulomatous 15–40 tent deterioration of renal function when the capacity of the kidney
Fibrotic 10–20 to excrete calcium is compromised. In most patients, hypercalciuria
Glomerulopathy Rare is asymptomatic. Its principal manifestations are inability to con-
Membranous centrate the urine and polyuria. Nephrolithiasis occurs in about
Proliferative 10% of patients; another 10% develop nephrocalcinosis.
Focal segmental glomerulosclerosis
Arteritis Rare
Granulomatous angiitis
Obstructive nephropathy Rare
Retroperitoneal lymphadenopathy
Retroperitoneal fibrosis
Renal Involvement in Sarcoidosis 8.5
FIGURE 8-10
DIFFERENTIAL DIAGNOSIS OF Differential diagnosis of granulomatous lesions in renal sarcoidosis. Once considered rare,
GRANULOMATOUS LESIONS granulomatous interstitial nephritis is now observed in 10% of kidney biopsy results. Most
IN RENAL SARCOIDOSIS of these are seen in cases of drug hypersensitivity. The commonly implicated drugs are anti-
biotics and nonsteroidal anti-inflammatory drugs. Sarcoidosis and Wegener’s granulomatosis
each account for 5% to 10% of cases observed on kidney biopsy. Other less common and
Lesion Patients, % rather rare causes include tuberculosis, angiitis, and lupus erythematosus. In some 15% to
20% of cases, the cause of the granulomatous lesions is never established.
Drug-induced 55–70
Sarcoid 5–10
Wegener’s granulomatosis 5–10
Other (less common):
Tuberculosis
Brucellosis
Vasculitis
Systemic lupus
erythematosus
Idiopathic 15–20
Clinical Course
FIGURE 8-11
Micrograph of fibrosis. As a rule, abnormal renal function in
patients with sarcoidosis is due to tubulointerstitial nephritis rather
than granulomatous infiltration, which certainly is true in patients
with progressive loss of renal function. Fibrosis may occur in the
absence of granulomas but generally reflects the residual fibrosis of
granulomatous lesions that have subsided or responded to steroid
therapy. It is important to monitor renal function closely in such
patients and initiate proper measures to retard the course of pro-
gressive renal failure.
As with all other forms of tubulointerstitial nephritis, tubular
dysfunction is a common finding in such cases. The reduction in
the glomerular filtration rate usually is modest but can progress to
end-stage renal disease. Progression to end-stage disease tends to
occur in older men who have minimal pulmonary involvement.
Renal Involvement in Sarcoidosis 8.7
FIGURE 8-12
8 Pre-R R Clinical course of granulomatous nephritis. Extensive granulomatous
infiltration of the kidneys can result in acute renal failure as a pre-
Serum creatinine, mg/100mL
7
senting clinical feature of sarcoidosis in the absence of any evidence
6
of other organ involvement. As a rule, improvement in renal func-
5 tion occurs after steroid therapy (R), as shown here, in the clinical
4 course of one such patient. (From Bolton et al. [2]; with permission.)
3
2
1
60
50
Creatinine clearance, mL/min
40
30
20
10
40
30
Hematocrit, %
20
10
60
Prednisone
qod, mg 30
September October Nov. Dec. Jan. Feb. Mar. April May June July
Time, mo
FIGURE 8-13
CASE REPORT OF A PATIENT WITH SARCOIDOSIS Obstructive nephropathy due to sarcoidosis. Acute deterioration of
HAVING RETROPERITONEAL FIBROSIS renal function in sarcoidosis very rarely results from obstructive
nephropathy caused by intrarenal granulomatous infiltrates or
from extensive retroperitoneal lymphadenopathy or fibrosis caus-
Patient profile ing obstruction of the renal vasculature or ureteral outflow [3,4].
(From Grodin et al. [3]; with permission.)
A man aged 40 years with established diagnosis of pulmonary sarcoidosis that had
responded to steroids
Presentation: hypertension (200/140 mm Hg) and proteinuria (4 g/d)
Intravenous pyelogram: asymmetric kidneys with delayed appearance of contrast on right
Surgery: sclerotic matrix affecting aorta and proximal renal artery
Kidney biopsy: focal and global glomerulosclerosis, interstitial fibrosis
Postoperative course: persistent hypertension
8.8 Systemic Diseases and the Kidney
CASE REPORT OF A PATIENT WITH SARCOIDOSIS CASE REPORT OF A PATIENT WITH RECURRENT
HAVING GLOMERULOPATHY GRANULOMATOUS SARCOID NEPHRITIS IN A
TRANSPLANTED KIDNEY
Patient profile
Aged 13 y Sarcoidosis with pulmonary, hepatic, and ophthalmic symptoms
A man aged 57 years with 3 months’ history of progressive edema
Responded to steroids
Past history: pulmonary sarcoidosis, treated with steroids for 10 years, on 5 mg 4 times Steroids discontinued due to cataract and hypertension
a day on admission
Aged 19 y Renal involvement progressive to end-stage renal disease
Physical examination: blood pressure, 180/95 mm Hg; peripheral edema Cadaveric transplantation after 3 months of dialysis
Laboratory test results: blood urea nitrogen, 32 mg/dL; creatinine, 4.3 mg/dL; albumin, Medications: azathioprine, 75 mg per day; prednisone tapered to
2.9 g/dL; cholesterol, 543 mg/dL; urinalysis, 6–8 erythrocyte/high-power field, 3 + 15 mg 4 times a day
protein; 24-h urine protein, 1.5 g Aged 26 y Creatinine, 3.1 mg/dL; creatinine clearance, 20 mL/min;
Kidney biopsy: membranous glomerulopathy; no granulomas blood pressure, 150/84 mm Hg
Transplanted kidney biopsy: diffuse granulomatous infiltration
Treatment: prednisone increased to 60 mg/d for 6 wk
Response: creatine, 2.5 mg/dL; creatinine clearance, 35 mL/min
FIGURE 8-14
Sarcoid-associated glomerulopathy. Whereas renal involvement in
sarcoidosis primarily is due to abnormalities of calcium metabolism
and tubulointerstitial nephritis, rare cases of glomerulopathy have FIGURE 8-15
been associated with sarcoidosis. The detection of an abnormal urine Recurrent granulomatous sarcoid nephritis in a transplanted kid-
sediment and proteinuria in a patient with sarcoidosis should always ney. In patients with sarcoidosis having renal involvement whose
lead to consideration of glomerular disease. A variety of glomerular renal failure has progressed to end-stage renal disease, kidney
lesions have been reported in patients with sarcoidosis, including transplantation can be successful. However, due consideration
membranous glomerulopathy, minimal change disease, membrano- should be given to the fact that recurrence of sarcoidosis in renal
proliferative glomerulonephritis, focal glomerulosclerosis, immuno- allografts have been reported. Conversely, documented cases exist
globulin A nephropathy, and crescentic glomerulonephritis. Of these, in which sarcoidosis was transmitted by cardiac or bone marrow
membranous glomerulopathy is more common. These rare cases may transplantation. This observation has been taken as evidence of an
represent a chance coexistence of two separate diseases; however, infectious or transmissible cause of sarcoidosis that highlights the
their occurrence in a disease of altered immunity may reflect a problem of transplantation in patients with sarcoidosis. (From
causative association. Mesangial deposits of C3 have been observed Shen et al. [6]; with permission.)
in cases of sarcoid granulomatous nephritis in the absence of any clin-
ical evidence of glomerular disease. Circulating immune complexes
are detected in about half of cases of sarcoidosis in the absence of
any evidence of renal involvement by granulomatous nephritis or
glomerular lesions. As such, the presence of immune-mediated
glomerulopathy may well be more than coincidental in occasional
cases in which the patient may be predisposed by genetic or other
as yet unidentified factors. (From Taylor et al. [5]; with permission.)
References
1. Newman LS, Rose CS, Maier LA: Sarcoidosis. N Engl J Med 1997, 4. Cuppage FE, Emmott DF, Duncan KA: Renal failure secondary to sar-
336:1224–1234. coidosis. Am J Kidney Dis 1990, 11:519–521.
2. Bolton WK, Atuk NO, Rametta C, et al.: Reversible renal failure from 5. Taylor RG, Fisher C, Hoffbrand BI: Sarcoidosis and membranous
isolated granulomatous renal sarcoidosis. Clin Nephrol 1976, glomerulonephritis: a significant association. Br Med J 1982,
5:88–92. 284:1297–1298.
3. Grodin M, Filastre JP, Ducastelle T, et al.: Sarcoidosis retroperitoneal 6 Shen SY, Hall-Craggs M, Posner JN, Shalozz B: Recurrent sarcoid
fibrosis, renal arterial involvement and unilateral focal glomeruloscle- granulomatous nephritis and reactive tuberculin test in a renal trans-
rosis. Arch Intern Med 1980, 140:1240–1242. plant recipient. Am J Med 1986, 80:699–702.
Selected Bibliography
Casella FJ, Allon M: The kidney in sarcoidosis. J Am Soc Nephrol Fuss M, Pepersack T, Gillet C, et al.: Calcium and vitamin D metabo-
1993, 3:1555–1562. lism in granulomatous diseases. Clin Rheumatol 1992, 11:28–36.
Romer FK: Renal manifestations and abnormal calcium metabolism in Hanedouche T, Grateau G, Noel LH, et al.: Renal granulomatous sar-
sarcoidosis. Quart J Med 1980, 49:233–247. coidosis: Report of 6 cases. Nephrol Dial Transplant 1990, 5: 18–24.
Renal Involvement in
Essential Mixed
Cryoglobulinemia
Giuseppe D’Amico
Franco Ferrario
U
p to the end of the 1980s, the cause of about 30% of both type
II and III mixed cryoglobulinemias (MC) in patients was not
known, and this subgroup of patients were referred to as hav-
ing essential mixed cryoglobulinemia. Essential mixed cryoglobuline-
mia was characterized clinically by systemic signs, mainly purpura,
arthralgias, and fever, together with hepatic, neurologic, and renal
symptoms. During this decade, antibodies against hepatitis C virus
(HCV) antigens and HCV RNA (which is a marker of active viremia)
have been detected in the serum of up to 90% of these patients.
Only when a monoclonal rheumatoid factor, usually an
immunoglobulin Mk (IgMk), is the anti-IgG component of the mixed
cryoglobulinemia (type II MC) does this distinctive glomerular and vas-
cular involvement of the kidney occur. The most frequent histologic pic-
ture, especially in the acute stages, is a membranoproliferative glomeru-
lonephritis (MPGN) with subendothelial deposits, with some character-
izing features both by light and electron microscopy. However, a less
distinctive picture of lobular MPGN is found at biopsy in 20% of
patients, and of a mesangioproliferative glomerulonephritis in another
20%. In all cases, the two components of MC, IgG, and IgM, together
with complement, are found by immunofluoroscopy.
The clinical picture varies during the long-term course of the dis-
ease, being characterized by periods of temporary reactivation CHAPTER
(nephritic or nephrotic syndrome, sometimes with rapidly occurring
renal insufficiency) and long-lasting periods of partial remission. Only
9
infrequently does end-stage renal failure develop; however, mortality
as a result of the other complications of the systemic disease (mainly
cardiovascular) is rather frequent.
9.2 Systemic Diseases and the Kidney
During acute flare-ups, antiviral treatment (interferon-) is insuf- ized events might induce the shift to abnormal proliferation of
ficient to control the renal disease, even when it reduces viremia. a clone of B cells, producing a monoclonal IgM rheumatoid fac-
Steroids, usually associated with immunosuppressive drugs tor. Thus, a type II MC is induced that can be considered a lym-
(cyclophosphamide), are then necessary to control renal disease. phoproliferative disorder. It has been suggested that the IgMk
Hepatitis C virus can infect B lymphocytes and stimulate produced by this permanent clone of B cells has affinity for the
them to synthesize the cryoprecipitating polyclonal rheumatoid glomerular matrix and can deposit, in the glomerulus together
factors responsible for type III MC. In some patients with this with the IgG to which it binds in the blood, IgG that probably
polyclonal B-cell activation, additional but as yet uncharacter- acts as an anti-HCV antigen antibody.
*Usually IgM.
From Brouet and coworkers [1]; with permission.
FIGURE 9-1
Classification of cryoglobulinemias and associated diseases as proposed not clear, and this group of mixed cryoglobulinemias was called essential
by Brouet and coworkers in 1974 [1]. Up to the end of the 1980s, the [2,3]. As indicated in Figure 9-4, it now is evident that most essential
cause of about 30% of both types II and III mixed cryoglobulins was mixed cryoglobulinemias are associated with hepatitis C virus infection.
FIGURE 9-2
DETECTION OF CIRCULATING CRYOGLOBULINS AND Correct methodology for detecting circulating cryoglobulins.
DETERMINATION OF CRYOPRECIPITATE Cryoglobulins are immunoglobulins that precipitate reversibly from
cooled serum.
Study Types of mixed cryoglobulinema Serum HCV antibodies Serum HCV RNA
Patients tested, n Positive patients, % Patients tested, n Positive patients, %
Ferri et al. [5] II and III EMC 52 54
Galli et al. [6] II and III EMC 129 80
63 70
Pechère-Bertschi et al. [7] II and III EMC 15 87 7 71
Agnello et al. [8] II EMC 19 42 19 84
Misiani et al. [9] II EMC 75 96 28 93
Pasquariello et al. [10] II EMC with GN 26 100 7 100
Cacoub et al. [11] II and III EMC 63 52 16 63
SMC 52 27
Bichard et al. [12] II and III EMC — — 15 93
D’Amico, Unpublished data II EMC 41 95 41 95
II EMC wtih GN 28 93 28 93
III EMC 13 77 13 77
FIGURE 9-4
Second-generation enzyme-linked immunosorbent assay has antibodies. The prevalence of positivity of HCV RNA
been used by all the authors listed here (with the exception in the 15 patients studied by Bichard and coworkers [12]
of Agnello and coworkers [9], who used a recombinant increased from 60% to 93% when cryoprecipitate from
immunoblot assay) to measure anti–hepatitic C virus (HCV) serum was tested.
9.4 Systemic Diseases and the Kidney
FIGURE 9-7
DISTINCTIVE FEATURES OF MEMBRANOPROLIFERATIVE The distinctive features of the membra-
GLOMERULONEPHRITIS, OR CRYOGLOBULINEMIC GLOMERULONEPHRITIS noproliferative glomerulonephritis. This dis-
order, called cryoglobulinemic glomeru-
lonephritis, occurs only in patients with
Exudative component type II mixed cryoglobulinemia, especially
The major constituent of intracapillary proliferation is an infiltration of leukocytes, mainly monocytes, that in the acute stage of the disease [4,14]. In
sometimes is massive. about 20% of patients with type II mixed
Intraluminal thrombi cryoglobulinemia, a less distinctive picture
Huge deposits of cryoglobulins called intraluminal thrombi sometimes fill the capillary lumen. of lobular membranoproliferation is found,
Interposition of monocytes in the double contour of the capillary wall whereas an additional 20% exhibit mild
Monocytes, in close contact with the subendothelial deposits of cryoglobulins, are interposed between the glomerular
mesangial proliferation. These various types
basement membrane and the newly formed membranelike material, to give the double-contoured appearance of the of histologic lesions can be found by repeat
capillary wall, whereas peripheral interposition of mesangial matrix and cells is moderate. biopsies in the same patient during different
Structured crystalloid deposits on electron microscopy stages of the disease.
Intraluminal and subendothelial deposits of cryoglobulins sometimes show a specific fibrillar structure on
electron microscopy.
Vasculitis of small and medium-sized arteries
Necrotizing arteritis, without concomitant features of segmental necrotizing glomerulonephritis, is found in one
third of patients.
Renal Involvement in Essential Mixed Cryoglobulinemia 9.5
FIGURE 9-12
Electron microscopy of subendothelial and endocapillary deposits showing an amorphous
structure. In a minority of cases, as illustrated here, a specific annular and cylindrical
structure is shown. This structure is identical to that seen in the in vitro precipitate of the
same patients and consists of cylinders 100- to 1000-µm long, with a hollow axis, appear-
ing in cross-sections as annular bodies [16]. (Uranyl acetate–lead citrate 22,000.)
(Courtesy of Department of Pathology, San Carlo Borromeo Hospital, Milan, Italy.)
FIGURE 9-15
Morphologic pattern of lobular glomerulonephritis. This pattern is
present in 20% of cases, characterized by intense mesangial prolif-
eration and peripheral mesangial matrix expansion associated with
centrolobular sclerosis. This histologic picture is indistinguishable
from that of idiopathic membranoproliferative glomerulonephritis
type I, except for the presence of some degree of monocyte infiltra-
tion. (Trichrome 250.)
Renal Involvement in Essential Mixed Cryoglobulinemia 9.7
FIGURE 9-16
The glomerulus showing only mild mesangial proliferation and
mesangial matrix expansion. Thickening of the glomerular base-
ment membrane is not evident. This picture frequently is present in
cases clinically characterized only by mild urinary abnormalities
(inactive phase). Moreover, in many cases in which a biopsy is taken
during the acute phase of the disease with typical membranoprolif-
erative patterns with or without thrombi, a second renal biopsy will
show clear regression of the morphologically acute lesions with only
mild mesangioproliferative alteration. (Trichrome 250.)
A B
FIGURE 9-17 (see Color Plate)
The pattern of immunohistologic glomerular staining varies
according to the different glomerular patterns seen on light
microscopy. A, Diffuse granular subendothelial deposits along the
capillary walls, with or without very rare intraluminal thrombi.
(Immunoglobulin M 250). B, Intense massive staining of the
deposits totally filling the capillary lumina. Faint and irregular
parietal deposits also are present. (Immunoglobulin 250.)
C, Parietal deposits with more evident peripheral lobular distribu-
tion. (Immunoglobulin 250.) The components of mixed cryo-
globulinemia immunoglobulin M and G, usually associated with
C3, are the most frequently found immunoreactants.
C
9.8 Systemic Diseases and the Kidney
FIGURE 9-20
RENAL SYNDROME AT PRESENTATION IN PATIENTS Renal syndrome at presentation in patients
WITH CRYOGLOBULINEMIC GLOMERULONEPHRITIS with cryoglobulinemic glomerulonephritis
AND ASSOCIATED HISTOLOGIC LESION and associated histologic lesion. During the
course of this disease, both the systemic and
renal signs may vary remarkably, with peri-
Renal syndrome Patients, % Frequent histologic features ods of exacerbation alternating with peri-
ods of quiescence. Very often, exacerbation
Isolated proteinuria with microscopic hema- ≈55 Membranoproliferative glomerulonephritis of the extrarenal signs is associated with
turia, sometimes associated with moderate (MPGN), with moderate infiltration of monocytes exacerbation of renal disease (recurrent
chronic renal insufficiency Lobular MPGN episodes of nephritic or nephrotic syn-
Mesangioproliferative glomerulonephritis drome); however, a flare-up of renal disease
Acute nephritic syndrome, sometimes com- ≈25 MPGN with leukocytic infiltration, or intraluminal may occur even in the absence of exacerba-
plicated by acute oliguric renal failure thrombi owing to abrupt massive precipitation tion of the extrarenal signs. Partial or total
of cryoglobulins, usually associated with renal
and systemic vasculitis, or both
prolonged remission occurs spontaneously
or after treatment in 10% to 15% of
Nephrotic syndrome ≈20 MPGN, frequently of lobular type, with some
infiltration of monocytes patients. Arterial hypertension frequently is
severe and is present in most patients with
cryoglobulinemic nephropathy.
Renal Involvement in Essential Mixed Cryoglobulinemia 9.9
Circulating cryoglobulins 49% cumulative 10-year probability of survival, without renal failure
Cryocrits ranging from 2% to 70%, with large variations during the course of the disease 40% of patients died, mostly from cardiovascular diseases, liver failure, or infections
Hypocomplementemia 14% of patients progressed to chronic renal failure and required dialysis
Very low levels of early C components (C1q and C4) and CH50; slightly low levels of 14% of patients achieved complete and prolonged remission of renal symptoms
C3; and high levels of late C components, C5 and C9
FIGURE 9-22
FIGURE 9-21 The clinical outcomes in 105 patients studied in three hospitals in
Relevant laboratory abnormalities in “essential” mixed cryoglobu- Milan, Italy, between 1966 and 1990. The medial total follow-up
linemia. During the course of this disease, cryoglobulins may tem- time from clinical onset was approximately 11 years [19].
porarily become undetectable. Low levels of serum C4 cannot be
corrected by treatment. Low levels of C3 frequently are found dur-
ing clinical flare-ups and can be corrected by treatment.
FIGURE 9-23
TREATMENT OF ACUTE RENAL EXACERBATIONS This approach to treatment of the acute renal exacerbations of
OF CRYOGLOBULINEMIC GLOMERULONEPHRITIS cryoglobulinemia and vasculitis used previously when the viral
AND VASCULITIS cause of the disease was unknown is still valid now that the viral
cause is evident. It is a common experience that the antiviral agent
interferon-, when given alone, does not control renal complica-
Steriods are used to control inflammatory renal and systemic involvement tions in the acute stage of the disease [20].
Cytotoxic drugs are used to block production of new cryoglobulins by the specific
lymphocytic clone that produces the monoclonal immunoglobulin Mk RF, and
therefore, the precipitating cryoglobulins
Plasma exchange is used to remove circulating cryoglobulins from the blood before
they deposit in the glomerulus and arterial walls
FIGURE 9-24
PROPOSED TREATMENT FOR MIXED The proposed treatment for mixed cryoglobulinemia associated with
CRYOGLOBULINEMIA ASSOCIATED WITH HEPATITIS hepatitis C virus infection in the presence of severe acute signs of
C VIRUS INFECTION renal involvement, ie, glomerulonephritis and vascultits. Plasma
exchange is used only when acute renal insufficiency caused by mas-
sive precipitation of cryoglobulins is present. Interferon- is given
Drug Dosage Duration for more than 6 months only when negation of hepatitis C virus
RNA is achieved in the first months, suggesting a beneficial effect
Interferon- 3.0–6.0 MU, 3 times weekly 6–12 mo on the viremia. Only the antiviral treatment with interferon- even-
Steriods Methylprednisolone, 0.75–1.0 g/d, intravenously 3d tually associated with low doses of steriods to conrol the systemic
Prednisone, 0.5 mg/kg of body weight tapered 6 mo signs of mixed cryoglobulinemias should be given if renal involve-
over a few weeks until maintenance dose of ment is mild. The association of interferon- with another antiviral
10–15 mg/d is achieved
agent ribavirin, 0.6 to 1.0 g/d orally, now is being tested in patients
Cyclophosphamide 2 mg/kg of body weight 3–4 mo
with hepatitis C virus infection, with promising results [20].
Plasmapheresis Exchanges of 3 L of plasma, 3 times weekly 2–3 wk
9.10 Systemic Diseases and the Kidney
FIGURE 9-25
– Infection by HCV The mechanisms of renal complications induced by hepatitis C virus
– Emergence of a B lymphocyte (HCV) infection, with or without associated mixed cryoglobulinemia,
permanent clone
producing IgMk RF according to our hypothesis. As illustrated, the prevalent pathogenetic
mechanism is the deposition in the glomerulus of a monoclonal IgM
rheumatoid factor (RF) with particular affinity for the glomerular
matrix, which is produced by permanent clones of B lymphocytes
IgMk RF
HCV IgG Ab
infected by HCV. It is unknown whether the IgM RF deposits in the
Serum glomerulus alone, with subsequent in situ binding of IgG (perhaps
bound already to viral antigens, or as a complex composed of HCV
HCV-IgG HCV-IgG-IgMk antigens, IgG anti-HCV antibodies, and IgMk RF). Only recently
have specific HCV-related proteins been detected in glomerular struc-
tures using indirect immunochemistry. As depicted on the left, it is
Deposition of anti-HCV Precipitation of In situ binding of possible that in a minority of cases immune complexes composed of
immune complexes the circulating HCV-IgG Ab to HCV antigens and anti-HCV IgG antibodies can deposit directly in
type II cryo predeposited IgMk Glomerulus the glomerular structures, in the absence of a concomitant type II MC
MPGN without with a monoclonal IgM RF. This deposition induces an immune-com-
cryoglobulinemia Cryoglobulinemic GN
plex glomerulonephritis similar to that described in patients infected
with the hepatitis B virus. (Adapted from D’Amico [21].)
Acknowledgments
We thank Dr. M.P. Rastaldi of the Division of Nephrology and Drs. E. Schiaffino and R. Boeri of the
Department of Pathology of the Hospital of San Carlo Borromeo for their help.
References
1. Brouet JC, Clauvel JP, Danon F, et al.: Biological and clinical significance 13. D’Amico G, Ferrario F, Colasanti G, Bucci A: Glomerulonephritis in
of cryoglobulins: a report of 86 cases. Am J Med 1974, 57:775–778. essential mixed cryoglobulinemia (EMC). In Proceedings of the XXI
2. Meltzer M, Franklin EC, Elias K, et al.: Cryoglobulinemia: a clinical Congress of the European Dialysis and Transplant Association. Edited
and laboratory study. II. Cryoglobulins with rheumatoid factor by Davison PJ, Guillou PJ. London: Pitman; 1985:527–547.
activity. Am J Med 1966, 40:837–856. 14. D’Amico G, Colasanti G, Ferrario F, Sinico RA: Renal involvement in
3. Gorevic PD, Kassab HJ, Levo Y, et al.: Mixed cryoglobulinemia: essential mixed cryoglobulinemia. Kidney Int 1989, 35:1004–1014.
clinical aspects and long-term follow-up of 40 patients. Am J Med 15. Castiglione A, Bucci A, Fellin G, et al.: The relationship of infiltrating
1980, 69:287–308. renal leukocytes to disease activity in lupus and cryoglobulinemic
4. D’Amico G: Cryoglobulinemic glomerulonephritis: a membranoprolif- glomerulonephritis. Nephron 1988, 50:14–23.
erative glomerulo-nephritis induced by hepatitis C virus. Am J Kidney 16. Cordonnier D, Martin H, Groslambert P, et al.: Mixed IgG-IgM cryo-
Dis 1995, 25:361–369. globulinemia with glomerulonephritis. Immunochemical fluorescent
5. Ferri C, Greco F, Longobardo G: Antibodies to hepatitis C virus in patients and ultrastructural study of kidney and in vitro cryoprecipitate. Am J
with mixed cryoglobulinemia. Arthritis Rheum 1991, 34:1606–1610. Med 1975, 59:867–872.
6. Galli M, Monti G, Munteverde A: Hepatitis C virus and mixed cryo- 17. Mazzucco G, Monga G, Casanova S, Cagnoli L: Cell interposition in
globulinemias. Lancet 1992, 1:989. glomerular capillary walls in cryoglobulinemic glomerulonephritis:
ultrastructural investigation of 23 cases. Ultrastruct Pathol 1986,
7. Pechère-Bertschi A, Perrin L, De Sassure P, et al.: Hepatitis C: a 10:355–361.
possible etiology for cryoglobulinemia type II. Clin Exp Immunol
1992, 89:419–422. 18. D’Amico G, Colasanti G, Ferrario F et al.: L’atteinte rénale dans la
cryoglobulinémie mixte essentielle: un type particulier de néphropathie
8. Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infection à médiation immunologique. In Actualités Néphrologiques. Edited by
in type II cryoglobulinemia. N Engl J Med 1992, 327:1490–1495. Flammarion Médecine Sciences; 1987:201–219.
9. Misiani R, Bellavita P, Fenili D: Hepatitis C virus and cryoglobuline- 19. Tarantino A, Campise M, Banfi G, et al.: Long-term predictors of sur-
mia [letter]. N Engl J Med 1993, 328:1121. vival in essential mixed cryoglobulinemic glomerulonephritis. Kidney
10. Pasquariello A, Ferri C, Moriconi L, et al.: Cryoglobulinemic Int 1995, 47:618–623.
membranoproliferative glomerulonephritis associated with hepatis C 20. D’Amico G, Fornasieri A: Cryoglobulinemia. In Current Therapy in
virus [letter]. Am J Nephrol 1993, 13:300–304. Nephrology and Hypertension: A Companion to Brenner and Rector’s
11. Cacoub P, Lunel Fabiani F, Musset L, et al.: Mixed cryoglobulinemia the Kidney. Edited by Brady HR, Wilcox CS. Philadelphia: WB
and hepatitis C virus. Am J Med 1994, 96:124–132. Saunders Company; 1998 (in press).
12. Bichard P, Ounanian A, Girard M, et al.: High prevalence of hepatitis C virus 21. D’Amico G: Is type II mixed cryoglobulinaemia an essential part of
RNA in the supernatant and the cryoprecipitate of patients with essential and hepatitis C virus (HCV)-associated glomerulonephritis? Nephrol Dial
secondary type II mixed cryoglobulinemia. J Hepatol 1994, 21:58–63. Transplant 1995, 1279–1282.
Kidney Disease and
Hypertension in Pregnancy
Phyllis August
K
idney disease and hypertensive disorders in pregnancy are dis-
cussed. Pregnancy in women with kidney disease is associated
with significant complications when renal function is impaired
and hypertension predates pregnancy. When renal function is well
preserved and hypertension absent, the outlook for both mother and
fetus is excellent. The basis for the close interrelationship between
reproductive function and renal function is intriguing and suggests
that intact renal function is necessary for the physiologic adjustments
to pregnancy, such as vasodilation, lower blood pressure, increased
plasma volume, and increased cardiac output.
The renal physiologic adjustments to pregnancy are reviewed,
including hemodynamic and metabolic alterations. The common
primary and secondary renal diseases that may occur in pregnant
women also are discussed. Some considerations for the management of
end-stage renal disease in pregnancy are given.
Hypertensive disorders in pregnancy are far more common than is
renal disease. Almost 10% of all pregnancies are complicated by
either preeclampsia, chronic hypertension, or transient hypertension.
Preeclampsia is of particular interest because it is associated with
life-threatening manifestations, including seizures (eclampsia), renal
failure, coagulopathy, and rarely, stroke. Significant progress has been
made in our understanding of some of the pathophysiologic manifes-
tations of preeclampsia; however, the cause of this disease remains
unknown. The diagnostic categories of hypertension in pregnancy,
pathophysiology of preeclampsia, and important principles of preven-
tion and treatment also are reviewed.
CHAPTER
10
10.2 Systemic Diseases and the Kidney
PRA
120 Postpartum angiotensinogen values
14
110
12 *
Blood pressure, mmHg
PRA, ng/mL/h
100 10
90 Sitting 8
Standing
80 6
*
70 4 **
**
*
60 2 * *
(N) (7) (16) (18) (18) (18) (19) (18) (18)(15) (19)
50 0
4 8 12 16 20 24 28 32 36 40 PP 4 8 12 16 20 24 28 32 36 38 PP
A Gestation, wk B Gestation, wk
FIGURE 10-4
Blood pressure and the renin-aldosterone system in pregnancy. pregnancy and often approaches prepregnancy levels at term.
Normal pregnancy is associated with profound alterations in B, Despite the decrease in blood pressure, plasma renin activity
cardiovascular and renal physiology. These alterations are (PRA) increases during the first few weeks of pregnancy; on
accompanied by striking adjustments of the renin-angiotensin- average, close to a fourfold increase in PRA occurs by the end of
aldosterone system. A, Blood pressure and peripheral vascular the first trimester, with additional increases until at least 20
resistance decrease during normal gestation. The decrease in weeks. The source of the increased renin is thought to be the
blood pressure is apparent by the end of the first trimester of maternal renal release of renin.
(Continued on next page)
10.4 Systemic Diseases and the Kidney
120
150
100
80 80
60 60
50
40 40
0
20 20
8 12 16 20 24 28 32 36 38 PP
C 0 0 D Gestation, wk
*
75 15 P < .05 dose of captopril to normotensive pregnant women in their first
and second trimesters and age-matched normotensive women who
70 10 were not pregnant. We then measured mean arterial pressure (MAP)
P < 0.005 and plasma renin activity (PRA) before and 60 minutes after the dose.
65 5
* A, Despite similar baseline blood pressures, blood pressure decreased
60 0 more in pregnant women compared with those who were not preg-
T=0 T = 60 T=0 T = 60 nant in response to captopril. This observation suggests that the
A B RAS plays a greater role in supporting blood pressure in pregnan-
cy. B, Baseline PRA was higher in pregnant women compared with
those who were not pregnant, and pregnant women had a greater
increase in renin after captopril compared with those who were not
pregnant. T—time. (From August and coworkers [8]; with permission.)
Kidney Disease and Hypertension in Pregnancy 10.5
FIGURE 10-6
INTERRELATIONSHIPS BETWEEN Pregnancy may influence the course of renal disease. Some women
PREGNANCY AND RENAL DISEASE with intrinsic renal disease, particularly those with baseline azotemia
and hypertension, suffer more rapid deterioration in renal function
after gestation. In general, as kidney disease progresses and function
Impact of pregnancy on renal disease Impact of renal disease on pregnancy deteriorates, the ability to sustain a healthy pregnancy decreases. The
Hemodynamic changes → hyperfiltration Increased risk of preeclampsia
presence of hypertension greatly increases the likelihood of renal
deterioration [2]. Although hyperfiltration (increased glomerular
Increased proteinuria Increased incidence of prematurity,
intrauterine growth retardation filtration rate) is a feature of normal pregnancy, increased intra-
Intercurrent pregnancy-related illness,
eg, preeclampsia glomerular pressure is not a major concern because the filtration
Possibility of permanent loss
fraction decreases. Possible factors related to the pregnancy-related
of renal function deterioration in renal function include the gestational increase in
proteinuria and intercurrent pregnancy-related illnesses, such as
preeclampsia, that might cause irreversible loss of renal function.
Women with renal disease are at greater risk for complications
related to pregnancy such as preeclampsia, premature delivery,
and intrauterine growth retardation.
AFLP—acute fatty liver of pregnancy; HELLP—hemolysis, elevated liver enzymes, and low platelet count;
HUS–hemolytic uremic syndrome; TTP—thrombotic thrombocytopenic purpura.
Adapted from Saltiel et al. [18].
10.10 Systemic Diseases and the Kidney
Hemorrhage
13%
100–800/100,000 12/100,000
(deaths, births) (deaths, births)
Kidney Disease and Hypertension in Pregnancy 10.11
Historical:
3- to 6-fold increase in stillbirths Preeclampsia, eclampsia Nulliparity
5- to 15-fold increase in intrauterine growth restriction Chronic hypertension Multiple gestations
Family history
Premature delivery Chronic hypertension with superimposed preeclampsia
Preexisting renal or vascular decrease
Long-term developmental and neurologic problems Transient hypertension
Hypertension:
140/90 mm Hg after 20 wk or
30 mm Hg increase in systolic pressure or
15 mm Hg increase in diastolic pressure
FIGURE 10-21 FIGURE 10-22 Sudden appearance of edema,
Hypertensive disorders in pregnancy are Several classification systems exist for hyper- especially in hands and face
associated with increased incidences of still- tensive disorders of pregnancy. The one used Rapid weight gain
birth, fetal growth restriction, premature most commonly in the United States is that Headache, visual disturbances,
delivery, and long-term developmental prob- proposed in 1972 by the American College abdominal or chest pain
lems secondary to prematurity. These com- of Obstetricians and Gynecologists and
plications are more frequent when hyperten- endorsed by the National High Blood
sion is due to preeclampsia. Pressure Education Program. The distinction
is made between the pregnancy-specific FIGURE 10-23
hypertensive disorder (preeclampsia, and the The diagnosis of preeclampsia is strength-
convulsive form, eclampsia) and chronic ened when one or more of the risk factors
hypertension that precedes pregnancy, which are present. Hypertension develops after 20
usually is due to essential hypertension. weeks, with normal blood pressures in the
Women with chronic hypertension are at first half of pregnancy. Although edema is a
greater risk for preeclampsia (20–25%). feature of many normal pregnancies, its
Transient hypertension refers to late preg- sudden appearance in the face and hands in
nancy elevations in blood pressure, without association with a rapid weight gain, is sug-
any of the laboratory or clinical features of gestive of preeclampsia. Headache, visual
preeclampsia. This disorder may recur with disturbances, and abdominal or chest pain
each pregnancy (in contrast to preeclampsia, are signs of impending eclampsia.
which usually is a disease of first pregnancy)
and usually indicates a genetic predisposition
to essential hypertension.
FIGURE 10-24
CLINICAL FEATURES OF CHRONIC Women with chronic hypertension are usually older and may be
HYPERTENSION IN PREGNANCY multiparous. Although hypertension often is detectable before
20 weeks, in some women the pregnancy-mediated vasodilation
is sufficient to normalize blood pressure so that women with
Women are older, more likely to be multiparous stage 1 or 2 hypertension may have normal blood pressures by
Hypertension: present before 20 wk, or documented previous pregnancy the time of their first antepartum visit. The risk of preeclampsia
Blood pressure may be significantly lower or normal in mid pregnancy
is substantially increased in women with chronic hypertension.
Risk of superimposed preeclampsia of 15–30%
10.12 Systemic Diseases and the Kidney
FIGURE 10-25
LABORATORY ABNORMALITIES IN PREECLAMPSIA Laboratory tests are helpful in making the diagnosis of preeclampsia.
AND CHRONIC HYPERTENSION In addition to proteinuria, which may occur late in the course of the
disease, hyperuricemia, mild azotemia, hemoconcentration, and hypo-
calciuria are observed commonly. Some women with preeclampsia
Chronic hypertension Preeclampsia may develop a microangiopathic syndrome with hemolysis, elevated
liver enzymes, and low platelet counts (HELLP). The presence of the
Renal: HELLP syndrome usually reflects severe disease and is considered an
Creatinine Normal Increased; increased indication for delivery. Women with uncomplicated chronic hyperten-
blood urea nitrogen, sion have normal laboratory test results unless superimposed
creatinine
preeclampsia or underlying renal disease exists.
Uric acid Normal Increased (>5.5 mg/dL)
Urinary protein <300 mg/d >300 mg/d
Urinary calcium >200 mg/d <150 mg/d
Heme:
Hematocrit Normal Increased (>38%)
Platelets Normal Decreased
Liver function tests:
Aspartate aminotransferase Normal Increased
Alanine aminotransferase Normal Increased
Albumin Normal Decreased
FIGURE 10-26
Pathophysiology of preeclampsia Preeclampsia is a syndrome with both maternal and fetal manifes-
tations. Current evidence suggests that an underlying genetic pre-
disposition leads to abnormalities in placental adaptation to the
maternal spiral arteries that supply blood to the developing feto-
Fetal placental unit. These abnormalities in the maternal spiral arteries
syndrome
(IUGR, IUD, prematurity) lead to inadequate perfusion of the placenta and may be the earli-
est changes responsible for the maternal disease. The maternal dis-
ease is characterized by widespread vascular endothelial cell dys-
function, resulting in vasospasm and intravascular coagulation and,
ultimately, in hypertension (HTN), renal, hepatic, and central ner-
Maternal vous system (CNS) abnormalities. The fetal syndrome is a conse-
syndrome quence of inadequate placental circulation and is characterized by
(HTN, renal, CNS)
growth restriction and, rarely, demise. Premature delivery may
occur in an attempt to ameliorate the maternal condition. IUD—
intrauterine death; IUGR—intrauterine growth retardation.
Genetic susceptibility
(maternal x fetal)
Kidney Disease and Hypertension in Pregnancy 10.13
FIGURE 10-27
GENETICS OF PREECLAMPSIA A positive family history is a risk factor for preeclampsia, and the incidence is approxi-
mately 4 times greater in first-degree relatives of index cases [23]. Cooper and coworkers
[24] also noted an increased incidence in relatives by marriage (eg, daughter-in-laws), and
Increased incidence observed in mothers, daughters, 10 instances in which the disease occurred in one but not the other monozygotic twin.
granddaughters of probands These data raise the possibility of paternal or fetal genetic influence [24]. The mode of
Mode of inheritance unknown: inheritance of preeclampsia is not known. Several possibilities have been suggested, includ-
Single recessive gene ? ing a recessive gene with the possibility of a maternal-fetal genotype-by-genotype interac-
Shared maternal-fetal recessive gene ? tion or a dominant maternal gene with incomplete penetrance.
Dominant gene with incomplete penetrance ?
Syncytiotrophoblast
Maternal
blood
FV space
Invasion
FIGURE 10-30
Placental
ischemia Pathophysiology of preeclampsia. A major unresolved issue in the
Lipid peroxides
Cytokines pathophysiology of preeclampsia is the mechanism whereby abnor-
malities in placental modulation of the maternal circulation lead to
maternal systemic disease. The current schema, which is a hypothe-
Endothelial cell damage Platelet aggregation sis, depicts a scenario whereby placental ischemia leads to the
release of substances that might be toxic to maternal endothelial
cells. The resulting endothelial cell dysfunction also results in
increased platelet aggregation. These events lead to the widespread
Thromboxane A2 ↑ systemic vasospasm, intravascular coagulation and decreased organ
Serotonin, PDGF ↑
flow that are characteristic of preeclampsia. NO—nitric oxide;
PGI2 ↓ Systemic PDGF—platelet-derived growth factor; PGI2—prostacyclin 2.
NO ↓ vasoplasm
Thrombin ↑
Endothelin ↑
Mitogenic factors↑
(eg, PDGF) ↓ Organ flow
Intravascular
coagulation
Kidney Disease and Hypertension in Pregnancy 10.15
Visual disturbances
Seizures
Hyperemia, focal anemia Cardiac
Thrombosis, hemorrhage
↓ Cardiac output
↓ Plasma volume
↑ Atrial natriuretic factor
Pulmonary edema
Hepatic
Vasospasm
Reduced flow
Periportal hemorrhagic necrosis Intravascular coagulation
Subcapsular hematoma
↑ Aspartate aminotransferase Vascular
↑ Alanine aminotransferase
↑ Systemic vascular resistance
↑ Blood pressure
↑ Angiotensin II sensitivity
Renal Endotheliosis
Proteinuria
↓ Glomerular filtration rate
↓ Renal blood flow
↓ Urinary sodium, uric acid,
and calcium excretion
↓ Plasma renin activity
FIGURE 10-31
Maternal manifestations of preeclampsia. Preeclampsia is a multisystem maternal disorder, with dramatic alterations in
heart, kidney, circulation, liver, and brain. Interestingly, all of these abnormalities resolve within a few weeks of delivery.
10.16 Systemic Diseases and the Kidney
of vasoconstrictors
The endothelium such as endothelin (ET).
and platelet-vessel Compensatory suppres-
wall interaction
↓ Placental hormones Platelets sion of the renin-
+
Endothelial Thr angiotensin system
(eg, estrogen, progesterone) +
cells PThr occurs, suggesting that
cGMP excess angiotensin II
− TXA2 (AII) does not play a
↑ Circulating endothelial toxins
5-HT 5-HT Compensatory major role in preeclamptic
AII
responses: hypertension (HT).
A ↓ Plasma renin Finally, sodium retention
S
NO/PGl2 1 ↓ Aldosterone
Endothelin owing to renal vasocon-
Relaxation Contraction
Proliferation
striction may further
↑ Sympathetic nervous system Antiproliferation
S2 increase blood pressure.
cGMP/cAMP TX ET cAMP—cyclic adenosine
Vascular smooth
muscle cells monophosphate; cGMP—
cyclic guanosine
monophosphate; 5-HT—
serotonin; PThr—
parathyroid hormone;
FIGURE 10-32
S2—serotonergic receptors;
Hypertension in preeclampsia. Although the mechanism of the increased blood pressure in preeclampsia is Thr—thombin TX—
not established, evidence suggests it may involve multiple processes. A possible scenario involves the following: thromboxane; TXA2—
decreased placental production of estrogen and progesterone, both of which have hemodynamic effects; thromboxane A2.
increased circulating endothelial toxins, possibly released from a poorly perfused placenta; and increased (Adapted from Lüscher
activity of the sympathetic nervous system. These processes may then result in alterations in platelet– vascular and Dubey [28];
endothelial cell function, with decrease in vasodilators such as nitric oxide and prostacyclin and increased production with permission.)
↓ Renin
FIGURE 10-35
Trial Number of trials Antiplatelet Control Odds ratio and 95% Cl (horizontal line) Prevention of preeclampsia with low-dose
therapy therapy (antiplatelet: placebo)
aspirin. Investigators have sought methods
to prevent preeclampsia (eg, salt restriction,
prophylactic diuretics, and high-protein
Smaller studies 11 10/319 50/284
(<200 women) (3.1%) (17.6%) diets). One approach that has been exten-
sively investigated in the last 10 years is
Larger studies: therapy with low-dose aspirin. It was
EPHREDA (1990) 5/156 8/74 hypothesized that such therapy reversed the
Hauth (1993) 5/303 17/303
Italian (1993) 12/565 9/477
imbalance between prostacyclin and throm-
Sibai (1993) 69/1570 94/1565 boxane that may be responsible for some of
Viinikka (1993) 9/103) 11/105) the manifestations of the disease. Several
CLASP (1994) 313/4659 352/4650 large trials now have been completed, and
All larger trials 6 413/7356 491/7174
Odds ratio most have had negative results. Shown here
Overall results
is an overview of the effects of aspirin on
25% SD 6 proteinuric preeclampsia reported from all
All trials 17 423/7675 541/7458 odds reduction
(5.5%) (7.3%) (2p = 0.00002) trials of antiplatelet therapy (through 1994)
as analyzed by the Collaborative Low-dose
0 0.5 1.0 1.5 Aspirin in Pregnancy (CLASP) Collaborative
Antiplatelet Antiplatelet
Group [28]. Odds ratios (area proportional
therapy therapy to amount of information contributed) and
better worse 99% confidence interval (CI) are plotted for
various trials. A black square to the left of
the solid vertical line suggests a benefit (how-
ever, this indication is significant at 2p >0.01
only if the entire CI is to the left of solid ver-
tical line). (From CLASP Collaborative
Group [29]; with permission.)
FIGURE 10-36
Prevention of preeclampsia using calcium
Study
Favors calcium Favors control supplementation. Another preventive strategy
that has been extensively investigated, with
Marya et al.,1987 0.65 (0.31–1.38)
Villar et al.,1987 0.43 (0.06–3.14) conflicting outcomes, is calcium supplemen-
Lopez-Jaramillo et al.,1989 0.03 (0.002–0.49) tation. The rationale for this approach is
Lopez-Jaramillo et al.,1990 0.07 (0.004–1.27) based on the observations that low dietary
Montanaro et al.,1990 0.25 (0.06–1.03) calcium intake may increase the risk for
Villar and Repke,1990 0.13 (0.007–2.65) preeclampsia, and that preeclampsia is charac-
Belizan et al.,1991 0.66 (0.34–1.27) terized by abnormalities in calcium metabolism
Cong et al.,1993 0.19 (0.009–4.10)
that suggest a calcium deficit, eg, decreased
Sanchez-Ramos et al.,1994 0.22 (0.07–0.74)
Pooled estimate 0.38 (0.22–0.65) vitamin D and hypocalciuria [31]. A recent
meta-analysis of 14 trials of calcium supple-
0.001 0.01 0.1 1.0 10.0 mentation in pregnancy concluded that calci-
um supplementation during pregnancy leads
OR to reductions in blood pressure and a lower
incidence of preeclampsia. In contrast, a
large randomized trial of calcium supple-
mentation in 4589 low-risk women failed to
demonstrate a benefit of calcium therapy
[31]. CI—confidence interval; OR—odds
ratio. (From Bucher and coworkers [30];
with permission.)
10.18 Systemic Diseases and the Kidney
FIGURE 10-37
TREATMENT OF PREECLAMPSIA Treatment of preeclampsia requires close monitoring of both the maternal and fetal condi-
tion to maximize chances of avoiding catastrophes such as seizures, renal failure, and fetal
demise. Close surveillance is best accomplished in the hospital in all but the mildest cases.
Close monitoring of maternal and fetal conditions Maternal hypertension should be treated to avoid cerebrovascular and cardiovascular
Hospitalization in most cases complications. Magnesium sulfate is the treatment of choice for seizure prophylaxis and
Lower blood pressure for maternal safety
usually is instituted immediately after delivery. When the fetus is mature, delivery is indi-
cated in all cases. When the fetus is immature, the decision to deliver is made after careful-
Seizure prophylaxis with magnesium sulfate
ly assessing both the maternal and fetal condition. When maternal health is in jeopardy,
Timely delivery
delivery is necessary, even with a premature fetus.
FIGURE 10-38
ANTIHYPERTENSIVE THERAPY Some controversy exists regarding when to institute antihypertensive therapy in women
IN PREECLAMPSIA with preeclampsia. The basis for this controversy is that decreased uteroplacental perfusion
is believed to be important in the pathophysiology of this disorder, and concern exists that
lowering maternal blood pressure may compromise uteroplacental blood flow and lead to
Decreased uteroplacental blood flow and placental fetal distress. Furthermore, lowering maternal blood pressure does not cure preeclampsia.
ischemia are central to the pathogenesis of Thus, antihypertensive therapy is instituted when the blood pressure reaches a level at
preeclampsia. which the physician considers the maternal condition to be in danger from hypertension.
Lowering blood pressure does not prevent or cure For most physicians, this treatment threshold is at approximately 150/100 mm Hg.
preeclampsia and does not benefit the fetus unless Aggressive lowering of blood pressure is not advisable.
delivery can be safely postponed.
Lowering blood pressure is appropriate for maternal safety:
maintain blood pressure at 130–150/85–100 mm Hg.
FIGURE 10-39
ANTIHYPERTENSIVE THERAPY IN PREECLAMPSIA When blood pressure increases acutely and delivery is likely within
the next 24 hours, use of a parenteral antihypertensive agent is
preferable. Intravenous hydralazine or labetalol are acceptable
Imminent delivery Delivery postponed agents for pregnant women, and both have been used successfully
in preeclampsia. Calcium channel blockers should be used with
Hydralazine (intravenous, intramuscular) Methyldopa caution because they may act synergistically with magnesium sul-
Labetalol (intravenous) Labetalol, other blockers fate, resulting in precipitous decreases in blood pressure. Rarely,
Calcium channel blockers Calcium channel blockers agents such as diazoxide may be needed; however, when hyperten-
Diazoxide (intravenous) Hydralazine sion is severe, maternal safety takes priority over pregnancy status.
blockers When delivery can be postponed safely for several days, an oral
Clonidine agent is indicated. Methyldopa is one of the safest drugs in preg-
nancy and has been used extensively with excellent maternal and
fetal outcome. Labetalol and other blockers have been used suc-
cessfully in preeclampsia. Calcium channel blockers also may be
used as either second- or third-line agents. Oral hydralazine is safe
in pregnancy. Limited experience exists with blockers or cloni-
dine, although anecdotal reports suggest these agents are safe.
Kidney Disease and Hypertension in Pregnancy 10.19
90 Diastolic BP, mm Hg
Diastolic
FIGURE 10-42
ANTIHYPERTENSIVE THERAPY The overall treatment goals of chronic hypertension in pregnancy are to ensure a success-
FOR CHRONIC HYPERTENSION ful full-term delivery of a healthy infant without jeopardizing maternal well-being. The
DURING PREGNANCY level of blood pressure control that is tolerated in pregnancy may be higher, because the
risk of exposure of the fetus to additional antihypertensive agents might outweigh the ben-
efits to the mother (for the duration of pregnancy) of having a normal blood pressure.
Methyldopa Most antihypertensive agents have been evaluated only sporadically during gestation, and
blockers (labetalol) careful follow-up of children exposed in utero to many of the agents is lacking. The only
Calcium channel blockers
antihypertensive agent for which such follow-up exists is methyldopa. Because no adverse
effects have been documented in offspring of exposed mothers, methyldopa is considered
Hydralazine
to be one of the safest drugs during pregnancy. blockers and calcium channel blockers
Diuretics
are acceptable second- and third-line agents. Diuretics can be used at low doses, particu-
larly in salt-sensitive hypertensive patients on chronic diuretic therapy. Angiotensin-con-
verting enzyme inhibitors are contraindicated in pregnancy because they adversely affect
fetal renal function. Angiotensin II receptor antagonists are presumed to have similar
effects but have not been evaluated in human pregnancy.
10.20 Systemic Diseases and the Kidney
References
1. Baylis C: Glomerular filtration and volume regulation in gravid animal 19. Sibai BM, Kustermann L, Velasco J: Current understanding of severe
models. Clin Obstet Gynaecol 1987, 1:789. preeclampsia, pregnancy-associated hemolytic uremic syndrome,
2. Lindheimer MD, Katz AI: The kidney and hypertension in pregnancy. thrombotic thrombocytopenic purpura, hemolysis, elevated liver
In The Kidney, edn 4. Edited by Brenner BM, Rector FC. Philadelphia: enzymes, and low platelet syndrome, and postpartum acute renal
WB Saunders Co; 1991:1551–1595. failure: different clinical syndromes or just different names? Curr
Opinion Nephrol Hypertens 1994, 3:436–445.
3. Davison JM, Shiells EA, Philips PR, Lindheimer MD: Serial evaluation
20. Hou S: Peritoneal dialysis and hemodialysis in pregnancy. Clin Obstet
of vasopressin release and thirst in human pregnancy: role of chorionic
Gynaecol (Balliere) 1994, 8:491–510.
gonadotropin in the osmoregulatory changes of gestation. J Clin
Invest 1988, 81:798. 21. Davison JM: Pregnancy in renal allograft recipients: problems, prognosis,
and practicalities. Clinc Obstet Gynaecol (Balliere) 1994, 8:511–535.
4. Lindheimer MD, Richardson DA, Ehrlich EN, Katz AI: Potassium
homeostasis in pregnancy. J Reprod Med 1987, 32:517. 22. Douglas KA, Redman CW: Eclampsia in the United Kingdom. BMJ
1994, 309:1395–1400.
5. Brown MA, Sinosich MJ, Saunders DM, Gallery EDM: Potassium
regulation and progesterone-aldosterone interrelationships in human 23. Chesley LC, Annitto JE, Cosgrove RA: Pregnancy in the sisters and
pregnancy. A prospective study. Am J Obstet Gynecol 1986, 155:349. daughters of eclamptic women. Pathol Microbiol 1961, 24:662.
24. Cooper DW, Brenneckes SP, Wilton AN: Genetics of pre-eclampsia.
6. Lim VS, Katz AI, Lindheimer MD: Acid-base regulation in pregnancy.
Hypertens Preg 1993, 12:1.
Am J Physiol 1976, 231:1764.
25. Khong TY, WF De, Robertson WB, Brosens I: Inadequate maternal
7. Wilson M, Morganti AA, Zervoudakis I, et al.: Blood pressure, the renin-
vascular response to placentation in pregnancies complicated by
aldosterone system and sex steroids throughout normal pregnancy. Am J
preeclampsia and small for gestational age infants. Br J Obstet
Med 1980, 68:97. Gynaecol 1986, 93:1049–1059.
8. August P, Mueller FB, Sealey JE, Edersheim TG: Role of renin- 26. Zhou Y, Fisher SJ, Janatpour M: Human cytotrophoblasts adopt a
angiotensin system in blood pressure regulation in pregnancy. vascular phenotype as they differentiate. A strategy for successful
Lancet 1995, 345:896–897. endovascular invasion? J Clin Invest 1997, 99:2139–2151.
9. Diabetic nephropathy. Pregnancy performance and fetal-maternal 27. Zhou Y, Damsky CH, Fisher SJ: Preeclampsia is associated with failure
outcome. Am J Obstet Gynecol 1988, 159:56. of human cytotrophoblasts to mimic a vascular adhesion phenotype.
10. Hayslett JP, Lynn RI: Effect of pregnancy in patients with lupus One cause of defective endovascular invasion in this syndrome? J Clin
nephropathy. Kidney Int 18:207, 1980. Invest 1997, 99:2152–2164.
11. Houser MT, Fish AJ, Tagatz GE, et al.: Pregnancy and systemic lupus 28. Lüscher TF, Dubey RK: Endothelium and platelet=derived vasoactive
erythematosus. Am J Obstet Gynecol 1980, 138:409. substances: role in the regulation of vascular tone and growth. In
Hypertension: Pathophysiology, Diagnosis and Management, edn 2.
12. Fine LG, Barnett EV, Danovitch GM, et al.: Systemic lupus erythematosus
New York: Raven Press; 1995: 609–630.
in pregnancy. Ann Intern Med 1981, 94:667.
29. CLASP Collaborative Group. CLASP: A randomized trial of low-dose
13. Imbasciati E, Surian M, Bottino S, et al: Lupus nephropathy and
aspirin for the prevention and treatment of preeclampsia among 9364
pregnancy. A study of 26 pregnancies in patients with systemic pregnant women. Lancet 1994, 343:619–629.
lupus erythematosus and nephritis. Nephron 1984, 36:46.
30. Bucher HC, Guyatt GH, Cook RJ, et al.: Effect of calcium supplemen-
14. Jungers P, Dougodos M, Pelissier C, et al.: Lupus nephropathy and tation on pregnancy-induced hypertension and preeclampsia: a meta-
pregnancy. Report of 104 cases in 36 patients. Arch Intern Med 1982, analysis of randomized controlled trials. JAMA 1996,
142:771. 275:1113–1117.
15. Lockshin MD, Druzin MC, Goel S, et al.: Antibody to cardiolipin as a 31. Hojo M, August P: Calcium metabolism in normal and hypertensive
predictor of fetal distress on death in pregnant patients with systemic pregnancy. Semin Nephrol 1995, 15:504–511.
lupus erythematosus. N Engl J Med 1985, 313:152.
32. Levine RJ, Hauth JC, Curet LB, et al.: Trial of calcium to prevent
16. Chapman AB, Johnson AM, Gabow PA: Pregnancy outcome and its preeclampsia. N Engl J Med 1997, 337:69–76.
relationship to progression of renal failure in autosomal dominant 33. August P, Lenz T, Ales KL, et al.: Longitudinal study of the renin
polycystic kidney disease. J Am Soc Nephrol 1994, 5:1178–1185. angiotensin system in hypertensive women: deviations related to the
17: Lindheimer MD, Davison JM. Renal biopsy during pregnancy: development of superimposed preeclampsia. Am J Obstet Gynecol
“To b... or not to b...” Br J Obstet Gynecol 1987, 94:932. 1990, 163:1612–1621.
18. Saltiel C, Legendre, Grunfeld JP, et al.: Hemolytic uremic syndrome in
association with pregnancy. In Hemolytic Uremic Syndrome and
Thrombotic Thrombocytopenic Purpura. Edited by Kaplan BS,
Trompeter RS, Moake JL. New York: Marcel Dekker; 1992:241–254.
Renal Involvement in
Collagen Vascular Diseases
and Dysproteinemias
Jo H.M. Berden
Karel J.M. Assmann
R
enal involvement in systemic lupus erythematosus (SLE), dys-
proteinemias, and certain rheumatic diseases, namely rheuma-
toid arthritis, Sjögren’s syndrome, and scleroderma (systemic
sclerosis), is discussed. SLE is a systemic autoimmune disease that can
lead to disease manifestations in almost every organ. SLE is charac-
terized by the formation of a wide array of autoantibodies mainly
directed against nuclear autoantigens, of which antibodies against
double-stranded DNA (dsDNA) are the most prominent. Although
the cause is still obscure, considerable progress has been made recent-
ly by identification of the nucleosome as the major driving autoanti-
gen in SLE and the possible role of disturbances in apoptosis in dis-
ease development. The section on SLE reviews the major clinical and
serologic features of the disease, the serologic analysis, new insights
into the pathophysiology of lupus nephritis, and the histologic assess-
ment of kidney biopsies. The therapeutic options for treatment of
lupus nephritis are discussed as are the results of treatment of end-
stage renal disease in patients with SLE.
The second part of this chapter deals with the renal involvement in
dysproteinemias. The renal lesions of these diseases, characterized by
an overproduction of abnormal immunoglobulins or their subunits,
are quite heterogeneous. Because the kidney often is affected in these
disorders, it is not unusual for examination of a kidney biopsy speci-
CHAPTER
men to reveal clues for the diagnosis. On immunofluorescence, the
distribution of the light or heavy chain isotype, or both, can be detect-
11
ed in the tissue deposits, whereas electron microscopy can define the
ultrastructural organization. Incidence and types of renal involve-
ment, the pathogenesis and risk factors for the various types of renal
lesions, the histology of the different renal manifestations, and an
11.2 Systemic Diseases and the Kidney
overview of the therapy are given. The renal manifestations of The third part of this chapter presents a concise review of
cryoglobulinemias and fibrillary and immunotactoid glomeru- renal involvement in rheumatoid arthritis, Sjögren’s syndrome,
lonephritis also are discussed. and scleroderma.
Epidemiology Genetics
Percent Prevalence: between 25 and 250 per 100,000 Concordancy in twins
Frequency of major clinical symptoms persons, depending on racial and geographic Monozygotic: 50–60%
Musculoarticular symptoms 60–95 background Dizygotic: 5–10%
Cutaneous manifestations 55–80 Race: more prevalent in Asians and blacks Familial aggregation in 10%
Renal involvement 40–55 Gender: female preponderance; gender ratio Association with the following:
Neuropsychiatric disease 30–60 between 20 and 40 years; male:female, 1:9 HLA: B7, B8, DR2, DR3, DQW1
Pulmonary and cardiac disease 20–40
Age: onset mainly between 20–40 y Complement:
Hematologic abnormalities 60–85 C4A Q0
Occurrence of major autoantibody specificities C1q or C4 deficiency
Antinuclear autoantibody 95 Fc receptor IIA low-affinity
Anti–double-stranded DNA 60–75 phenotype
Antihistone 50–70 X chromosome ?
Antinucleosome Up to 80
Anti-Sm 10–30
Anti-ribonucleoprotein (RNP) 10–30
Anti–Sjögren’s syndrome (SS-A) (Ro) 20–60
Anti-SS-B (La) 15–40 FIGURE 11-2
Anticardiolipin 10–30 The major epidemiologic characteristics of systemic lupus erythe-
Antierythrocyte 50–60 matosus are listed. The prevalence of the disease depends on ethnic
Antilymphocyte 50–70 background. The highest prevalence is seen in Asians and Blacks.
Antithrombocyte 10–30
As in other systemic autoimmune diseases, there is a striking prepon-
derance in women, especially during childbearing age. This prepon-
derance is related to hormonal status. Animal studies have shown
that estrogens have a facilitating effect on disease expression, where-
FIGURE 11-1 as androgens have a suppressive effect. The importance of estrogens
This overview of the major clinical symptoms illustrates the systemic is further substantiated by the fact that changes in the hormonal
character of lupus erythematosus. Depending on patient selection, homeostasis (eg, at onset of puberty, during use of oral anticontra-
renal involvement occurs in up to half of patients. In almost all ceptives, and during pregnancy and puerperium) are associated with
patients, antibodies are formed against nuclear antigens, as detected an increased frequency of lupus onset and disease flare-up. The
by antinuclear antibody (ANA) testing. These ANAs are either directed genetic susceptibility is illustrated by the concordance of the disease
against nucleic acids (DNA), nuclear proteins (histones, Sm, ribonu- in twins, occurrence of familial aggregation, and association with
cleoprotein, Sjögren’s syndrome-A [SS-A], and SS-B) or nucleosomes certain genes, mainly human leukocyte antigens (HLA).
that consist of DNA and the DNA binding proteins histones. In
addition, antibodies can be formed against the anionic phospholipid
cardiolipin. This latter antibody specificity is characteristic for the
antiphospholipid syndrome either primary or secondary to systemic
lupus erythematosus. All these antigens recognized by lupus autoan-
tibodies share the property that they are present in apoptotic blebs at
the surface of cells undergoing apoptosis. In addition to these ANAs,
autoantibodies against blood cells frequently develop in lupus, giving
rise to hemolytic anemia positive on Coombs testing, lymphopenia,
or thrombopenia.
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.3
ANA test
THE 1982 REVISED AMERICAN RHEUMATISM
ASSOCIATION CRITERIA FOR CLASSIFICATION
OF SYSTEMIC LUPUS ERYTHEMATOSUS Negative Positive
No further evaluation
unless strong clinical
suspicion
Criterion Sensitivity, %* Specificity, %*
1. Malar rash 57 96
?
2. Discoid rash 18 99 Western blot test
Negative Crithidia lucillae
3. Photosensitivity 43 96 on nuclear extracts
4. Oral ulcers 27 96 ?
5. Arthritis (two or more joints) 86 37
anti-ENA Positive
6. Serositis: 56 86
Pleuritis or pericarditis Ouchterlony
7. Renal disorder: 51 94 immunodiffusion
Proteinuria > 0.5 g/24 h or cellular casts (red, using ENAs Farr assay
hemoglobin, granular, tubular, or mixed)
8. Neurologic disorder:
Seizures or psychosis 20 98
9. Hematologic disorder:
FIGURE 11-4
Hemolytic anemia or leukopenia (<4 59 89 Algorithm for analysis of antinuclear antibodies (ANA) in systemic
109/L) or lymphopenia (<1.5 109/L) lupus erythematosus. To demonstrate the presence of antinuclear
or thrombopenia (<100 109/L) antibodies the ANA test is used as a screening procedure. Details
10. Immunologic disorder: 85 93 of this ANA test and the different ANA patterns are given in Figure
Positive LE cell test result or positive
anti–double-stranded DNA or positive
11-5. A positive ANA test result indicates the presence of antinuclear
anti-Sm or false-positive TPI/VDRL test antibodies. Although the pattern of ANA can give an indication
11. Antinuclear antibody 99 49 about the specificity of the antinuclear antibody, additional tests
are needed to define this specificity. Antibody specificity to double-
stranded DNA (dsDNA) can be identified by the Crithidia assay
*The sensitivity was calculated as the percentage of patients with SLE who were positive (Fig. 11-6), in which a single-celled organism is used that has pure-
for this criterion over those in whom this criterion was analyzed. The specificity was
ly dsDNA in the kinetoplast. When this test result is positive, the
calculated as the percentage of the number of patients in the control group who were
negative or normal for that criterion over those in whom this criterion was analyzed. titer of anti-dsDNA antibodies can be determined using the Farr
TPI—treponemal immobilization; VDRL—Venereal Disease Research Laboratory.
assay (Fig. 11-7). When these anti-dsDNA test results are negative,
ANA positivity is most likely caused by antibodies directed against
Data from Tan et al. [1].
nuclear proteins. Autoantibodies can be analyzed by the Western
blot test on nuclear extracts (Fig. 11-8). The advantage of this
FIGURE 11-3 technique over the Ouchterlony technique using extractable nuclear
These criteria were selected for their sensitivity and specificity in antigens (ENA), is that the Western blot test allows identification
classifying patients with systemic lupus erythematosus (SLE). In the of a large number of autoantibody specificities in one test, although
selection process, these criteria were analyzed in 177 patients with both tests do not completely overlap.
SLE and 162 patients in the control group matched for age, gender,
and race. Patients in the control group had a nontraumatic nondegen-
erative connective tissue disease, mainly rheumatoid arthritis (n = 95).
The presence of four of these criteria for the diagnosis of SLE has a
sensitivity of 96% and specificity of 96% in patients with SLE. For
the purpose of identifying patients in clinical studies, it is determined
that a patient has SLE when at least four of these criteria are present,
serially or simultaneously, during any interval of observation.
FIGURE 11-5
Patterns of antinuclear antibody (ANA)
staining. The ANA test is carried out by incu-
bation of the serum with either preparations
of cultured cells (eg, human cervical carcino-
ma cells [HeLa cells]) or sections of normal
tissue (mostly liver). Antibodies bound to the
nucleus are detected by a fluorescinated anti–
human immunoglobulin antibody that can
reveal four distinctive staining patterns:
A, homogeneous; B, rim or peripheral;
FIGURE 11-6
Nucleus + Screening for anti–doubled-stranded DNA (dsDNA) antibodies
+
Mitochondrion using the Crithidia assay. The hemoflagellate Crithidia luciliae con-
tains in its kinetoplast pure dsDNA, not complexed to proteins [3].
Kinetoplast Anti-dsDNA Fluorescent Serially diluted serum samples are added to the slide carrying
+ dsDNA labeled Crithidia cells. Binding of antibodies is visualized by fluorescinated
Crithidia luciliae antihuman anti–immunoglobulin G antibodies. Antibodies to dsDNA are
immunoglobulin almost pathognomonic for systemic lupus erythematosus and there-
fore can be regarded as marker antibodies [4]. (From Klippel and
Croft [5]; with permission.)
Fluorescence of kinetoplast
FIGURE 11-7
Farr assay for quantitative measurement of anti-double-e-stranded DNA (dsDNA) anti-
bodies. The serum to be tested is added to a tube containing radiolabeled dsDNA. When
Test serum containing anti-dsDNA antibodies to dsDNA are present, they bind to the dsDNA. Eventually, formed complexes
are precipitated in 50% ammonium sulfate. By testing several dilutions of the serum and
comparing them with a standard curve the results can be expressed in units per milliliter.
Because high salt conditions are used, this assay detects only high avidity anti-dsDNA
antibodies [4]. Positivity and titer in this Farr assay are correlated with renal disease in
patients with systemic lupus erythematosus. This titer can be used to monitor lupus dis-
ease activity together with complement levels and clinical parameters. In 80% to 90%
of cases, disease onset or flare-up is associated with increases in anti-dsDNA titers in the
Farr assay [6]. (From Maddison [2]; with permission.)
Radiolabeled dsDNA added
FIGURE 11-8
Western blot test of autoantibodies on nuclear extracts. Nuclear pro-
Topo I Scl-55 teins extracted from human cervical carcinoma cells (HeLa cells) are
RNP 70,000 separated on polyacrylamide gel and transferred to nitrocellulose.
Subsequently, identical strips of the blot are incubated with various
SS-B SS-50 patient sera. Binding of autoantibodies can be visualized with peroxi-
dase or alkaline phosphatase–labeled antihuman immunoglobulin.
Lane 1: anti-ribonucleoprotein (RNP)
A and centromere (CR-17) activity
B Lane 2: anti-Sm (B/B-D)
Sm
B’ Lane 3: anti-RNP and anti-Sm
C Lane 4: anti–Sjögren’s syndrome (SS-B) (La)
Lane 5: anticentromere
Centromere CR-17 Lane 6: antitopoisomerase I (Topo I)
D
Antibodies against Sm are rather specific for systemic lupus ery-
thematosus (SLE) and can be used as marker antibody, anti-ribonu-
cleoprotein for mixed connective tissue disease (MCTD), cen-
1 2 3 4 5 6 tromere (CR17) for the limited variant of scleroderma, SS-B for
Sjögren’s syndrome and SLE, and topoisomerase I for systemic scle-
roderma. The Western blot test is a simplified version of the cur-
rently available technique, which allows identification of autoanti-
bodies to much more autoantigens. Reference 7 provides a full
description of the diagnostic possibilities. (From Van Venrooij et al.
[8]; with permission.)
FIGURE 11-10
INDICATIONS FOR A DISTURBED APOPTOSIS IN On the one hand, indications exist that apoptosis is increased in
HUMAN SYSTEMIC LUPUS ERYTHEMATOSUS human systemic lupus erythematosus (SLE) (eg, increased Fas expres-
sion and increased in vitro apoptosis). On the other hand, some find-
ings suggest that apoptosis is decreased (eg, increased levels of solu-
Finding Study ble Fas, increased bcl-2 expression, and decreased anti-CD3–induced
apoptosis). Bcl-2 is a physiologic inhibitor of apoptosis, and trans-
Increased expression of Fas receptor Mysler et al. [28], Lorenz et al. [29] genic induction of bcl-2 overexpression leads to lupuslike autoimmu-
Circulating levels of soluble Fas nity [27]. Although presently it is difficult to reconcile these findings,
Increased Cheng et al. [30] it is clear that changes in the delicate balances governing apoptosis
Normal Goel et al. [31], Knipping et al. [32] can lead to apoptosis at the wrong moment (too late) or at the
Increased in vitro apoptosis of lymphocytes Lorenz et al. [29], Emlen et al. [33] wrong place (systemically instead of locally).
Abnormal anti-CD3–induced apoptosis Kovacs et al. [34]
Apoptosis-induced alterations of autoantigens
Proteolysis Casciola-Rosen et al. [35],
Casiano et al. [36],
Rosen and Casciola-Rosen [37],
Casiano [38]
Phosphorylation Utz et al. [39]
Reactive oxygen species–mediated damage Cooke et al. [40]
Apoptosis-induced surface expression Casciola-Rosen et al. [41],
of autoantigens Jordan and Kuebler [42]
Decreased phagocytosis of apoptotic cell Herrmann et al. [43]
FIGURE 11-11
Chromatin Central role of T cells specific for nucleosomal histone peptides in
the generation of the antinuclear autoantibody repertoire in sys-
temic lupus erythematosus. The cascade begins with the uptake of
nucleosomes by B cells by way of their antigen receptor. After
endosomal antigen processing, these B cells present histone pep-
Anti-HMG
Anti-DNA B cell
tides to T cells. After activation of the T cell, it provides help to the
B cell presenting B cell, leading to the formation of nucleosome-specific
autoantibodies. Binding of B cells to other determinants on the
nucleosome (B cells specific for DNA, histones, or the nonhistone
chromosomal peptides high-mobility group proteins [HMG]) and
MHC II-Peptide antigen-processing by these B cells, can generate additional antinu-
clear autoantibody responses (anti–doubled-stranded DNA, antihis-
Histone-
peptide TCR tone, and anti-HMG). This intramolecular antigen-spreading owing
Th cell to different endosomal antigen-processing revealing cryptic neoepi-
CD40L topes, is now known for a number of autoimmune responses [44].
Anti-nucleosome
B cell MHC—major histocompatibility complex; TCR—T-cell receptor.
CD40 (From Datta and Kaliyaperumal [45]; with permission.)
Anti-Histone CD4
B cell
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.7
FIGURE 11-13
NATIONAL INSTITUTES OF HEALTH HISTOLOGIC The value of the analysis of lupus glomerulonephritis according to
SCORING SYSTEM FOR ACTIVITY AND CHRONICITY the World Health Organization (WHO) classification for prognosis
IN LUPUS NEPHRITIS and treatment can be enhanced by including indices of activity and
chronicity. These indices were proposed in the National Institutes
of Health (NIH) index [49]. The extent of the active and chronic
Activity index Chronicity index lesions is assessed according to the scoring system here. A chronici-
ty index of 3 or higher and an activity index of 12 or higher are
Glomerular Endocapillary hypercellularity Glomerular sclerosis associated with a significantly greater risk for the development of
Leukocyte infiltration Fibrous crescents end-stage renal disease [14].
Fibrinoid necrosis, karyorrhexis*
Cellular crescents*
Hyalin deposits, wire loops
Tubulointerstitial Mononuclear cell infiltration Fibrosis
Tubular atrophy
Maximal score 24 12
Scoring per item from 0 to 3; for parameters with asterisks, the score is doubled.
A C
FIGURE 11-14
Lupus nephritis class II. A, A moderate increase of mesangial cells is seen on light micro-
scopy. B, Immunofluorescence. Mesangial deposits of immunoglobulin G. C, Electron
microscopy shows electron-dense deposits restricted to the mesangial area. L—capillary
lumen; U—urinary space. (Panel A, methenamine silver. Original magnification 400,
520, 10,000, respectively.)
B
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.9
A B C
FIGURE 11-15
Lupus nephritis class III. A, Segmental necrotizing lesion surrounded by deposits in a necrotizing lesion. According to the 1995 modified World
an increased number of epithelial cells. B, Immunofluorescence. Next Health Organization classification, this is a characteristic immuno-
to mesangial deposits of immuno-globulin G there also are deposits in pathologic lesion of class III lupus nephritis. (Panel A, methenamine
the periphery of some loops (arrows). C, Immunofluorescence. Fibrin silver. Original magnification 400, 400, 520, respectively.)
FIGURE 11-16
Lupus nephritis class IV on light micro-
scopy and immunofluorescence. A and B,
Diffuse endocapillary proliferative pattern
of injury with an increase of mesangial
cells and an influx of mononuclear cells
and some granulocytes. Panel B shows a
necrotizing lesion (arrow). C, A mesangio-
capillary pattern of injury with duplication
of the glomerular basement membrane
(GBM), an increase of mesangial cells and
matrix, and massive subendothelial deposits
(wire loops). In addition, spikes (membra-
nous component) can be found on the
epithelial side of the GBM (arrow). D,
Immunofluorescence. The characteristic
pattern of the immune deposits
A B (immunoglobulin G) of class IV lupus
nephritis, predominantly localized along
the capillary wall. (Panels A, B, C,
methenamine silver. Original magnification
360, 360, 740, 300, respectively.)
C D
11.10 Systemic Diseases and the Kidney
FIGURE 11-17
Lupus nephritis class IV. A representative electron micrograph
shows diffuse lupus nephritis with subendothelial and mesangial
electron-dense deposits with additional massive subepithelial
deposits (asterisk). GBM—glomerular basement membrane;
U—urinary space. (Original magnification 12,000.)
GBM
U S
S L
A C
FIGURE 11-18
Lupus nephritis class V. A, Discrete spikes on the epithelial side of the glomerular basement
membrane (GBM) (arrows), and a moderate increase of mesangial cells. B, Immunofluore-
scence. Fine granular deposits of immunoglobulin G along the capillary wall in a characteristic
membranous pattern. C, Electron micrograph reveals electron-dense deposits on the epithelial
side of the GBM between spikes. Between an increased number of mesangial cells small
deposits also are present (arrows). L—capillary lumen; S—spikes; U—urinary space. (Panel A,
methenamine silver, original magnification 700, 400, 3100, respectively.)
B
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.11
FIGURE 11-19
Lupus nephritis class VI. Sclerosing glomerulonephritis with exten-
sive sclerosis of most of the capillary tuft. (Methenamine silver,
original magnification 700.)
FIGURE 11-20
Chronic tubulointerstitial nephritis.
A, Extensive interstitial fibrosis accompa-
nied by tubular atrophy and a mononuclear
cell infiltration B, Immunofluorescence.
Granular deposits of immunoglobulin G
in tubular basement membranes. (Panel A,
methenamine silver, original magnification
100, 400, respectively.)
A B
FIGURE 11-21
Incidence of the different forms Incidence of the different forms of lupus nephritis classified according to the World Health
of lupus nephritis, % Organization (WHO) classification. The incidence of the different forms categorized accord-
ing to the WHO classification depends on patient selection and ethnic background. The
Class IV 57 Class III 15
percentages represent an average of the data reported in the literature. Most patients have
a diffuse proliferative form of lupus nephritis (WHO class IV).
Class II 10
Class I 1
Class VI 2
Class V 15
11.12 Systemic Diseases and the Kidney
100
Class II
Class III
Class IV
Class V
80
60
Percentage
40
20
0
ent
3
uri
rom
wC
ctio
sio
im
tein
ten
/lo
un
ynd
sed
per
Pro
A+
al f
ic s
tive
ren
Hy
sDN
rot
Ac
red
ph
ti-d
pai
Ne
An
Im
FIGURE 11-22
Incidence of renal manifestations and serologic class V, nephritic sediment for WHO class IV), it is
abnormalities in the different forms of lupus nephri- clear that on the basis of clinical symptoms it is not
tis. The clinical manifestations of lupus nephritis are possible to classify the form of nephritis correctly.
not different from other forms of glomerulonephritis This inability underlines the necessity for obtaining a
and include a nephritic sediment (dysmorphic ery- renal biopsy specimen. In addition, listed are the
throcytes and erythrocyte casts), proteinuria or occurrence of both a positive result on performing a
nephrotic syndrome, impaired renal function, and Farr assay and a low complement 3 level for the dif-
hypertension. Although certain clinical manifesta- ferent forms of lupus nephritis. Anti-dsDNA—
tions are more prevalent in certain forms (nephrotic anti–double-stranded DNA. (Adapted from Appel
syndrome for World Health Organization (WHO) et al. [50]).
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.13
FIGURE 11-24
Change in chronicity index in repeat biopsies after treatment
8
with prednisone (PRED) alone or prednisone and cytotoxic drugs
(CTD). The addition of cytotoxic drugs to the treatment regimen
6
of patients with World Health Organization (WHO) class III or IV
nephritis clearly improves renal and patient survival [56,57]. The
pathophysiologic basis for this beneficial effect is illustrated, dis-
4 playing the change in chronicity index between the first and sec-
ond kidney biopsies over time. As can be seen during prednisone
∆ Chronicity index
PRED
-2
-4
0 33 66 99 132
A Time interval, m
11.14 Systemic Diseases and the Kidney
4
∆ Chronicity index
-2
CTD
-4
0 33 66 99 132
B Time interval, m
Probability of end-stage renal disease
0 100
IVCY
AZCY
20 80
POCY
Cumulative survival, %
40 AZ 60
60 CPM
40
80
PRED
20 } AZA
100 0
0 20 40 60 80 100 120 140 160 180 200 220 0 24 48 72 96 120
A Months B Months
FIGURE 11-25
A, The probability of end-stage renal disease in patients with prolifer- effects of both drugs are not identical. Cyclophosphamide has
ative lupus nephritis treated with different drug regimens. This update a greater bone marrow toxicity, leads to amenorrhea in many
of the prospective trial by the National Institutes of Health (NIH) on patients, is teratogenic, and displays an unique urothelial toxicity
the treatment of these patients clearly demonstrates that prednisone (hemorrhagic cystitis and bladder carcinoma). Therefore, prospec-
monotherapy, in a significantly greater proportion of patients, leads tive studies comparing cyclophosphamide with azathioprine are
to the development of end-stage renal disease compared with patients warranted but not available. The results of the NIH trial are com-
on regimens containing cytotoxic drugs. The results between azathio- pared with those reported for azathioprine [57,60–62]. This analy-
prine and drug regimens containing cyclophosphamide are not signifi- sis, carried out by Cameron [57], does not reveal a significant dif-
cantly different. Note that in up to 7 years the results do not differ ference between cyclophosphamide and azathioprine. A recent
between the different treatment groups. From these studies it is clear meta-analysis [63] again showed that monotherapy with prednisone
that although the therapeutic efficacy is equal for the three treatment was inferior to treatment with cytotoxic drugs in combination with
regimens containing cyclophosphamide, less side effects occurred in steroids. However, as in the NIH trial and the analysis by Cameron,
patients treated with intravenous pulses of cyclophosphamide. no differences were found between cyclophosphamide and azathio-
B, Renal survival in patients with World Health Organization prine in preserving renal function. AZ—azathioprine; AZCY—
(WHO) class IV lupus nephritis treated with either cyclophos- combined therapy with azathioprine and cyclophosphamide;
phamide (CPM) or azathioprine (AZ). The NIH trial [56,59] did IVCY—intravenous pulses of cyclophosphamide; POCY—oral
not reveal a significant difference between the therapeutic efficacy cyclophosphamide. (Panel A from Steinberg and Steinberg [59];
of cyclophosphamide and azathioprine (A). However, the side with permission. Panel B from Cameron [57]; with permission.)
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.15
RISK FACTORS FOR DEVELOPMENT OF END-STAGE RENAL DISEASE IN SYSTEMIC LUPUS ERYTHEMATOSUS
FIGURE 11-26
These risk factors were identified in different analyzes in follow-up, and so on. The most powerful predictors seem to be
different patient groups. Not all these parameters were con- an elevated serum creatinine level at entry into the trial, a
firmed in all studies, probably because of differences in defini- chronicity index of 3 or higher, and persistent or remitting renal
tions used, composition of the cohort studied, duration of disease activity [14,64].
100
100
Hemodialysis
80 80 CAPD
Survival, %
Patients, %
60 60
40 40
All patients
Hemodialysis
20 CAPD 20
0 0
0 12 24 36 48 60 0 1–10 >10
Months on dialysis Maximal Nonrenal SLEDAI
25
100 Before dialysis
During dialysis
20 After transplantation
80
Number of patients
Actuarial Survival, %
60 15
40 10
Patient/SLE
Patient/non-SLE
20 Graft/SLE 5
Graft/non-SLE
0 0
0 12 24 36 0 1–10 >10
Months after transplantation Maximal nonrenal SLEDAI score
FIGURE 11-32
100 Incidence of renal involvement in dysproteinemias. This incidence
is not identical for all paraproteinemias. The reason is directly
related to the frequency and degree of light chain proteinuria [71].
90
Ig—immunoglobulin. (From Pruzanski [72]; with permission.)
80
70
Cumulative incidence, %
60
50
40
30
20
10
0
IgG IgA IgD κ λ
Paraproteinemia
B C
FIGURE 11-36
U Light chain amyloidosis on electron micro-
scopy. A, Characteristic fibrillar pattern of
amyloid deposits. Long, randomly distrib-
uted, nonbranching fibrils with diameters
Pod of 8 to 12 nm. B, Amyloid fibrils in the
capillary lumen and capillary wall with
extension through the glomerular basement
membrane (GBM) into the subepithelial
space (arrow) fibrils arranged in parallel
forming spicules). (Original magnification
GBM 48,000, 20,000, respectively.)
A B
GBM
L
TBM
C D
A B C
FIGURE 11-38
Cast nephropathy. The casts have a homogeneous, fractured, or crystalline appearance with
sharp angular or irregular edges and are present in the distal and collecting tubules [73].
These casts are composed of aggregated or light chains mixed with Tamm-Horsfall pro-
tein (THP). Sometimes the tubular cells shows necrosis accompanied by disruptions of the
tubular basement membrane (TBM). Proximal tubular cells show hyaline droplets or vac-
uoles with needlelike, tubular, or complex crystalline material. Casts are surrounded by
macrophages and multinucleated giant cells. On electron microscopy, the casts have a gran-
ular, homogeneous, or fibrillary appearance with occasional needlelike crystals. The fibrils
that surround the casts are probably THP. In most cases, a varying degree of interstitial
fibrosis exists, accompanied by mononuclear cell infiltration and tubular atrophy. Congo
red staining for amyloid is usually negative. The glomeruli are normal.
A, Low magnification with casts in the distal tubules, and interstitial fibrosis with
atrophic tubules (chronic tubulointerstitial nephritis). B, Brown-colored cast surrounded
by macrophages. C, Eosinophilic homogeneous cast. D, Immunofluorescence. Casts are
stained for light chains. (Panels A, B, C, methenamine silver. Original magnification
D 160, 400, 600, 200, respectively.)
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.21
FIGURE 11-39
Fanconi’s syndrome in a patient with
light chain proteinuria. A, Vacuolization
of proximal tubular epithelial cells. Vacuoles
contain light-brown-colored material.
B, Immunofluorescence. The granular materi-
al in tubular cells is stained for light chains.
C, Low-power view of a proximal tubular
epithelial cell with vacuoles containing orga-
nized or crystalline material. D, High-power
view of the vacuoles containing tubular or
ladderlike crystalline structures. BB—brush
border. (Panel A, methenamine silver.
Original magnification 600, 400, 7000,
19,000, respectively.)
A B
BB
C D
11.22 Systemic Diseases and the Kidney
C
FIGURE 11-40
A Glomerular deposition of immunoglobulin A- paraproteins. No paraproteins or cryoglobulins
could be found in the serum of this patient. In addition, the urinary excretion of light chains
was not detectable. A, A mesangiocapillary pattern of injury with deposition of eosinophilic
material in the capillary wall and mesangium. B, Immunofluorescence. The deposits were
positive for light chains (and immunoglobulin A). C, Ultrastructurally, below the glomerular
basement membrane, organized deposits composed of parallel arranged fibrils or gridlike
structures can be seen. (Panel A, methenamine silver, original magnification 400, 400,
25,000, respectively.)
A B
FIGURE 11-41 (see Color Plate)
Glomerular deposition of immunoglobulin G– in a patient closely packed tubules arranged in parallel. (Panel A,
with multiple myeloma. A, Glomerulus with many intracapil- toluidine blue. Original magnification 600, 130,000,
lary protein thrombi. B, The material was composed of respectively.)
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.23
A B C
FIGURE 11-42
Mixed cryoglobulinemia. Of the three types of cryoglobulins, types I and II contain mono-
clonal immunoglobulins (Ig). Type I cryoglobulins occur in monoclonal gammopathies and
lymphomas and consist of a single monoclonal immunoglobulin. Type II cryoglobulins (also
called mixed cryoglobulinemia) occur in systemic infections, autoimmune diseases, and malig-
nancies. Type II cryoglobulins consist of two components, a monoclonal immunoglobulin,
most frequently IgM, with rheumatoid factor activity directed to the polyclonal IgG compo-
nent. Various patterns of glomerular injury can be found, such as a diffuse endocapillary pro-
liferative glomerulonephritis with a prominent influx of monocytes, or a mesangiocapillary
glomerulonephritis. Less frequently, a diffuse mesangial proliferative, sclerosing glomeru-
lonephritis, or both can be seen. Eosinophilic aggregates along the glomerular basement mem-
brane (GBM) or in the lumina designated as thrombi frequently are present. Type II cryoglob-
ulinemia is sometimes accompanied by a vasculitis. The aggregates in the glomeruli of type I,
as seen on immunofluorescence, have a composition identical to that of the cryoglobulins in
the serum. The deposits in type II contain IgG, IgM, and complement. Ultrastructurally, the
deposits usually demonstrate an organized or crystalline appearance. In type I, the deposits
D frequently are organized in closely packed fibrils, long tubules, or crystals. In type II, short
tubulo-annular structures can be found. Sometimes aggregates in the glomeruli composed of
a single monoclonal immunoglobulin component can be demonstrated in patients without
evidence of a monoclonal immunoglobulin or cryoglobulins in the serum.
A, Diffuse endocapillary proliferative glomerulonephritis with prominent influx of
mononuclear cells. B, Mixed pattern of injury in a patient with Sjögren’s syndrome.
Intracapillary thrombi, increase of mesangial cells and matrix, and occasionally duplication
of the GBM. C, Immunofluorescence with staining for IgM. D, Electron microscopy of tubu-
lar and annular structures in the glomerular deposits. (Parts A, B, methenamine silver.
Original magnification 400, 400, 200, 120,000, respectively.)
FIGURE 11-43
Biopsy specimen of immunotactoid glomeru-
lonephritis with immunoglobulin A–
deposits. The patient had no signs of a mon-
oclonal gammopathy or lymphoma. A, Mild
increase of mesangial matrix with segmental
irregularity of the capillary wall. B,
Immunofluorescence. The deposits are posi-
tive for (and immunoglobulin A) C, Below
the glomerular basement membrane, seen is
an accumulation of short microtubules with a
diameter of about 30 nm. (Part A,
methenamine silver. Original magnification
400, 400, 25,000, respectively.)
A B (Continued on next page)
11.24 Systemic Diseases and the Kidney
A C
FIGURE 11-44
Fibrillary glomerulonephritis. A, Moderate widening of mesangial areas by increase of
matrix. B, Immunofluorescence. Heavy staining for IgG (and complement, and light
chains). C, Ultrastructurally, randomly distributed long fibrils with diameters of 18 to
22 nm are localized in the capillary wall. (Panel A, methenamine silver. Original magni-
fication 400, 300, 27,000, respectively.)
B
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.25
CLINICAL PRESENTATION, FREQUENCY, AND CAUSES RISK FACTORS FOR RENAL INVOLVEMENT
OF RENAL INVOLVEMENT IN DYSPROTEINEMIAS IN DYSPROTEINEMIAS
*VAD protocol has the advantage that drug metabolism is independent of kidney function, whereas the melphalan dose must be adjusted to renal function.
FIGURE 11-47
Treatment should be directed at ameliorating the renal lesion and plasmapheresis that do those without cast formation and intersti-
reduction of the production of paraproteins. In patients with myelo- tial changes [81]. Of two controlled studies, only one showed a
ma it is very important to prevent situations that could precipitate beneficial effect of addition of plasmapheresis to chemotherapy
acute renal failure. In this respect, dehydration and hypercalcemia [82,83]. The major determinant for success seems to be a good
are very harmful. Measures should be taken to maintain a high fluid response to chemotherapy [83]. Furthermore, patients with exten-
intake. When radiocontrast agents are necessary, hydration before sive cast formation and interstitial changes seem to respond less
the study decreases the chance of intratubular cast formation well to chemotherapy than do those without cast formation and
between light chains and the contrast agent. Alkalization of the interstitial changes [81,83]. The patient with end-stage renal dis-
urine can reduce the interaction between light chains and Tamm- ease can be treated with dialysis, although survival is poor and
Horsfall protein (THP). Nephrotoxic drugs (such as nonsteroidal dependent on the success of chemotherapy.
anti-inflammatory drugs and gentamycin) should not be used The experience of renal transplantation in patients with dyspro-
because they further enhance tubular dysfunction. Experimental teinemias is, for obvious reasons, rather limited. The results are rather
studies suggest that colchicine may be helpful in reducing cast for- disappointing with a high mortality rate, especially in patients with
mation either by decreasing THP secretion or modifying the interac- multiple myeloma and amyloidosis. Patients surviving for more than
tion between THP and light chains. Presently, no data exist that 1 year show a high recurrence rate [84–87]. Discussion of antitumor
document the clinical efficacy of this treatment. therapy is beyond the scope of this review. Briefly, treatment with
Plasmapheresis has the potential to remove the toxic light chains melphalan and prednisone is considered to be the first choice, where-
from the circulation, although in certain patients the serum concen- as more aggressive treatment with vincristine-adriamycin-dexametha-
tration can be rather low. Plasmapheresis alone does not reduce the sone is given to patients who do not respond to or who relapse after
rate of production of the paraprotein; therefore, this treatment melphalan and prednisone therapy. Recently, more encouraging
should be combined with chemotherapy. Patients with extensive results have been obtained with ablative chemotherapy and stem-cell
cast formation and interstitial changes seem to respond less well to reinfusion [88]. PD—peritoneal dialysis.
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.27
FIGURE 11-49
RENAL MANIFESTATIONS IN SJÖGREN’S SYNDROME The clinical manifestations of the tubulointerstitial nephritis in
Sjögren’s syndrome can vary and depend on localization of the
functional impairment. Occasionally, symptoms of tubular dysfunc-
Manifestation % tion precede development of symptoms of Sjögren’s syndrome. It is
unclear what causes these tubular dysfunctions. When the degree
Interstitial nephritis with or without tubular dysfunction 30–60 of tubulointerstitial damage is not chronic, corticosteroids are benefi-
Tubular dysfunction (distal > proximal) associated with 20–25 cial. Glomerular involvement is rare in Sjögren’s syndrome. When
interstitial infiltrates and granuloma formation a glomerulonephritis is present, the patient should be evaluated for
Clinical symptoms: the presence of cryoglobulins and existence of systemic lupus ery-
Type 1 renal tubular acidosis thematosus. Reference 95 provides a more detailed description of
Fanconi’s syndrome this subject.
Nephrogenic diabetes insipidus
Hypokalemia
Glomerulonephritis 3–5
Mesangiocapillary glomerulonephritis
Membranous glomerulonephritis
Vasculitis <5
Mostly extrarenal (skin, muscle, nerve);
occasionally in the kidney
11.28 Systemic Diseases and the Kidney
Incidence of renal involvement Risk factors for renal crisis Clinical characteristics of renal crisis Therapy for renal crisis
Based on autopsy studies, 60–70% Diffuse form of scleroderma Acute onset Prevention of reduction of renal perfusion
Based on clinical symptoms, 30–50% Rapid progression of skin lesions Marked to severe (malignant) hypertension (eg, dehydration, diuretics, cyclosporin A,
Scleroderma renal crisis, 10–15% HLA BW35, DR3, DR5 (10% of patients remain normotensive) nonsteroidal anti-inflammatory drugs)
Race (Blacks > whites) Features of malignant hypertension Angiotensin-converting enzyme inhibitors
Micro-angiopathic hemolytic anemia and (even in patients with normotension)
Use of corticosteroids or cyclosporine A?
thrombopenia Renal replacement therapy
Cold exposure ?
Mostly normal urinary sediment
(in cases with malignant hypertension
hematuria possible)
Progressive decline of renal function
FIGURE 11-50
The main features of renal involvement in scleroderma are summa- the mainstay of treatment for patients with scleroderma renal crisis,
rized. The major manifestation is the so-called renal crisis. Besides because it will significantly reduce progression to renal failure,
this often life-threatening manifestation, other patients may display increase the chance of recovery if renal failure has already developed,
milder forms of renal involvement, clinically characterized by mild and improve the 1-year patient survival rate. Renal replacement ther-
proteinuria or slight deterioration of kidney function. Renal involve- apy (hemodialysis or continuous ambulatory peritoneal dialysis)
ment is more common in patients with the diffuse form of scleroder- should be offered to patients whose renal function does not recover.
ma that is serologically characterized by antibodies against topoiso- The patient survival rate, however, is lower than in patients with
merase I or RNA polymerase III. Patients with progressive skin dis- other collagen-vascular diseases such as lupus nephritis. Limited
ease should be monitored carefully for hypertension and signs of experience with renal transplantation indicates that successful trans-
renal involvement. Early institution of angiotensin-converting enzyme plantation is possible, especially in patients with quiescent disease.
(ACE) inhibition in patients with micro-albuminuria can prevent fur- Recurrence in the transplanted kidney has been reported [84].
ther deterioration of kidney function [96,97]. ACE inhibition is also References 96 to 98 provide more extensive reviews on the subject.
FIGURE 11-51
Scleroderma. In the acute phase, small- and
medium-sized renal arteries show mucoid
thickening of the intima with severe narrow-
ing of the lumen. Sometimes these lesions are
accompanied by thrombosis and fibrinoid
necrosis of the arterioles and glomeruli.
Morphologically, the vascular alterations
resemble malignant nephrosclerosis (malig-
nant hypertension) or hemolytic-uremic syn-
drome. In the chronic phase, the mucoid
intimal material is replaced by fibrous tissue.
A, Severe narrowing of a small-sized
renal artery owing to extensive endothelial
widening with ischemia of glomeruli.
B, Accumulation of mucopolysaccharide
material in the widened endothelial layer.
(Continued on next page)
A B
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.29
References
1. Tan EM, Cohen AS, Fries JF, et al.: The 1982 revised criteria for the 15. Mohan C, Adams S, Stanik V, Datta SK: Nucleosome, a major
classification of systemic lupus erythematosus. Arthritis Rheumatol immunogen for pathogenic autoantibody-inducing T cells of lupus.
1982, 25:1271–1277. J Exp Med 1993, 177:1367–1381.
2. Maddison PJ: Systemic lupus erythematosus variants. In Slide Atlas of 16. Kaliyaperumal A, Mohan C, Wu W, Datta SK: Nucleosomal peptide
Rheumatology. Edited by Dieppe PA, Bacon PA, Bamji AN, Watt I. epitopes for nephritis-inducing T helper cells of murine lupus. J Exp
London: Gower; 1984:9.1–9.14. Med 1996, 183:2459–2469.
3. Aarden LA, De Groot ER, Feltkamp TEW: Immunology of DNA. III. 17. Burlingame RW, Rubin RL, Balderas RS, Theofilopoulos AN: Genesis
Crithidia luciliae: a simple substrate for the detection of anti-dsDNA and evolution of anti-chromatin autoantibodies in murine lupus impli-
with the immunofluorescence technique. Ann NY Acad Sci 1975, cates T-dependent immunization with self antigen. J Clin Invest 1993,
254:505–509. 91:1687–1696.
4. Smeenk RJT, Berden JHM, Swaak AJG: dsDNA autoantibodies. In 18. Amoura Z, Chabre H, Koutouzov S, et al.: Nucleosome-restricted
Autoantibodies. Edited by Peter JB, Shoenfeld Y. Amsterdam: Elsevier; antibodies are detected before anti-dsDNA and/or antihistone anti-
1996:227–236.
bodies in serum of MRL-Mp lpr/lpr and +/+ mice, and are present in
5. Klippel JH, Croft JD: Systemic lupus erythematosus. In Slide Atlas of kidney eluates of lupus mice with proteinuria. Arthritis Rheumatol
Rheumatology. Edited by Dieppe PA, Bacon PA, Bamji AN, Watt I. 1994, 37:1684–1688.
London: Gower; 1984:8.1–8.14.
19. Burlingame RW, Boey ML, Starkebaum G, Rubin RL: The central role
6. ter Borg EJ, Horst G, Hummel EJ, et al.: Predictive value of rises in of chromatin in autoimmune responses to histones and DNA in sys-
anti–double-stranded DNA antibody levels for disease exacerbations temic lupus erythematosus. J Clin Invest 1994, 94:184–192.
in systemic lupus erythematosus: a long term prospective study.
Arthritis Rheumatol 1990, 33:634–643. 20. Chabre H, Amoura Z, Piette JC, et al.: Presence of nucleosome-
restricted antibodies in patients with systemic lupus erythematosus.
7. Verheyen R, Salden M, Van Venrooij WJ: Protein blotting. In Manual
Arthritis Rheumatol 1995, 38:1485–1491.
of Biological Markers of Disease. Edited by van Venrooij WJ, Maini
RN. Dordrecht: Kluwer; 1997:A4.1–A4.25. 21. Kramers C, Hylkema MN, van Bruggen MCJ, et al.: Anti-nucleosome
antibodies complexed to nucleosomal antigens show anti-DNA reac-
8. Van Venrooij WJ, De Rooij DJ, van de Putte LBA, Habets WJ: De
serologische herkenning van gedefinieerde kernantigenen bij collageen- tivity and bind to rat glomerular basement membrane in vivo. J Clin
ziekten: immunoblotting als nieuw diagnostisch middel. Ned Tijdschr Invest 1994, 94:568–577.
Geneeskd 1985, 129:1124–1129. 22. van Bruggen MCJ, Kramers C, Hylkema MN, et al.: Significance of anti-
9. Watanabe-Fukunaga R, Brannan CI, Copeland NG, et al.: Lympho- nuclear and anti-extra cellular matrix auto-antibodies for albuminuria in
proliferation disorder in mice explained by defects in Fas antigen that MRL/l mice. A longitudinal study on plasma and glomerular eluates.
mediates apoptosis. Nature 1992, 356:314–317. Clin Exp Immunol 1996, 105:132–139.
10. Singer GG, Carrera AC, Marshak-Rothstein A, et al.: Apoptosis, Fas 23. van Bruggen MCJ, Kramers C, Walgreen B, et al.: Nucleosomes and
and systemic autoimmunity: the MRL/lpr model. Curr Opinion histones are present in glomerular deposits in human lupus nephritis.
Immunol 1994, 6:913–920. Nephrol Dial Transplant 1997, 12:57–66.
11. Tax WJM, Kramers C, van Bruggen MCJ, Berden JHM: Apoptosis, 24. van den Born J, van den Heuvel LPWJ, Bakker MAH, et al.:
nucleosomes, and nephritis in systemic lupus erythematosus. Kidney Distribution of GBM heparan sulphate proteoglycan core protein and
Int 1995, 48:666–673. side chains in human glomerular diseases. Kidney Int 1993, 43:454–463.
1. Berden JHM: Systemic lupus erythematosus: disturbed apoptosis? 25. van Bruggen MCJ, Kramers C, Hylkema MN, et al.: Decrease of
Ned Tijdschr Geneeskd 1997, 141:1848–1854. heparan sulfate staining in the glomerular basement membrane in
13. Rumore PM, Steinman CR: Endogenous circulating DNA in systemic murine lupus nephritis. Am J Pathol 1995, 146:753–763.
lupus erythematosus. Occurrence as multimeric complexes bound to 26. van Bruggen MCJ, Walgreen B, Rijke GPM, et al.: Heparin and
histone. J Clin Invest 1990, 86:69–74. heparinoids prevent the binding of immune complexes containing
14. Berden JHM: Lupus nephritis. Nephrology Forum. Kidney Int 1997, nucleosomal antigens to the GBM and delay nephritis in MRL/l mice.
52:538–558. Kidney Int 1996, 50:1555–1564.
11.30 Systemic Diseases and the Kidney
27. Strasser A, Whittingham S, Vaux DL, et al.: Enforced bcl-2 expression in 49. Austin III HA, Muenz LR, Joyce KM, et al.: Diffuse proliferative
B-lymphoid cells prolongs antibody responses and exhibits autoimmune lupus nephritis: identification of specific pathologic features affecting
diseases. Proc Natl Acad Sci USA 1991, 88:8661–8665. renal outcome. Kidney Int 1984, 25:689–695.
28. Mysler E, Bini P, Drappa J, et al.: The apoptosis-1/Fas protein in human 50. Appel GB, Silva FG, Pirani CL, et al.: Renal involvement in systemic
systemic lupus erythematosus. J Clin Invest 1994, 93:1029–1034. lupus erythematosus. Medicine 1975, 57:371–410.
29. Lorenz H, Gruenke M, Hieronymus T, et al.: In vitro apoptosis and 51. Sloan RP, Schwartz MM, Korbet SM, Borok RZ, and the Lupus
expression of apoptosis related molecules in lymphocytes from Nephritis Collaborative Study Group: Long-term outcome in systemic
patients with systemic lupus erythematosus and other autoimmune lupus erythematosus membranous glomerulonephritis. J Am Soc
diseases. Arthritis Rheumatol 1997, 40:306–317. Nephrol 1996, 7:299–305.
30. Cheng J, Zhou T, Liu C, et al.: Protection from Fas-mediated apoptosis 52. Bruns FJ, Adler S, Fraley DS, Segel DP: Sustained remission of mem-
by a soluble form of the Fas molecule. Science 1994, 263:1759–1762. branous glomerulonephritis after cyclophosphamide and prednisone.
Ann Intern Med 1991, 114:725–730.
31. Goel N, Ulrich DT, St.Clair EW, et al.: Lack of correlation between
serum soluble Fas/APO-1 levels and autoimmune disease. Arthritis 53. Reichert LJM, Huysmans FTM, Assmann KJM, et al.: Preserving
Rheumatol 1995, 38:1738–1743. renal function in patients with membranous nephropathy: daily oral
chlorambucil compared with intermittent monthly pulses of
32. Knipping E, Krammer PH, Onel KB, et al.: Levels of soluble Fas/APO- cyclophosphamide. Ann Intern Med 1994, 121:328–333.
1/CD95 in systemic lupus erythematosus and juvenile rheumatoid
arthritis. Arthritis Rheumatol 1995, 38:1735–1737. 54. Falk RJ, Hogan SL, Muller KE, Jenette C, and the Glomerular Disease
Collaborative Network: Treatment of progressive membranous
33. Emlen W, Niebur J, Kadera R: Accelerated in vitro apoptosis of lym- glomerulopathy. A randomized trial comparing cyclophosphamide
phocytes from patients with systemic lupus erythematosus. J Immunol and corticosteroids with corticosteroids alone. Ann Intern Med 1992,
1994, 152:3685–3692. 116:438–445.
34. Kovacs B, Vassilopoulos D, Vogelgesang SA, Tsokos GC: Defective CD3- 55. Appel GB, Valeri A: The course and treatment of lupus nephritis. Ann
mediated cell death in activated T cells from patients with systemic lupus Rev Med 1994, 45:525–537.
erythematosus: role of decreased intracellular TNF-. Clin Immunol
56. Austin III HA, Klippel JH, Balow JE, et al.: Therapy of lupus nephri-
Immunopathol 1996, 81:293–302.
tis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med
35. Casciola-Rosen LA, Anhalt G, Rosen A: DNA-dependent protein kinase 1986, 314:614–619.
is one of a subset of autoantigens specifically cleaved early during apop-
57. Cameron JS: What is the role of long-term cytotoxic agents in the
tosis. J Exp Med 1995, 182:1625–1634.
treatment of lupus nephritis? J Nephrol 1993, 6:172–176.
36. Casiano CA, Martin SJ, Green DR, Tan EM: Selective cleavage of nuclear
58. Balow JE, Austin III HA, Muenz LR, et al.: Effect of treatment of the
autoantigens during CD95(Fas/APO-1)-mediated T cell apoptosis. J Exp
evolution of renal abnormalities in lupus nephritis. N Engl J Med
Med 1996, 183:765–770. 1984, 311:491–495.
37. Rosen A, Casciola-Rosen LA: Macromolecular substrates for the ICE- 59. Steinberg AD, Steinberg SC: Longterm preservation of renal function
like proteases during apoptosis. J Cell Biochem 1997, 64:50–54. in patients with lupus nephritis receiving treatment that includes
38. Casiano C, Tan EM: Recent developments in the understanding of anti- cyclophosphamide versus those treated with prednisone only. Arthritis
nuclear autoantibodies. Int Arch Allergy Immunol 1996, 111:308–313. Rheumatol 1991, 34:945–950.
39. Utz P, Hottelet M, Schur PH, Anderson P: Proteins phosphorylated 60. Esdaile JM, Levinton C, Federgreen W, et al.: The clinical and renal
during stress-induced apoptosis are common targets for autoantibody biopsy predictors of long term outcome in lupus nephritis. Q J Med
production in patients with systemic lupus erythematosus. J Exp Med 1989, 72:779–833.
1997, 185:843–854. 61. Ponticelli C, Zucchelli P, Moroni G, et al.: Long-term prognosis of
40. Cooke MS, Mistry N, Wood C, et al.: Immunogenicity of DNA dam- diffuse lupus nephritis. Clin Nephrol 1987, 28:263–271.
aged by reactive oxygen species. Implications for anti-DNA antibodies 62. Cameron JS, Turner BR, Ogg CS, et al.: Systemic lupus with nephritis:
in lupus. Free Rad Bio Med 1997, 22:151–159. a long term study. Q J Med 1979, 48:1–24.
41. Casciola-Rosen LA, Anhalt G, Rosen A: Autoantigens targeted in sys- 63. Bansal VK, Beto JA: Treatment of lupus nephritis: a meta-analysis of
temic lupus erythematosus are clustered in two populations of surface clinical trials. Am J Kidney Dis 1997, 29:193–199.
structures on apoptotic keratinocytes. J Exp Med 1994, 179:1317–1330. 64. Nossent HC, Henzen-Logmans SC, Vroom TM, et al.: Contribution
42. Jordan P, Kuebler D: Autoimmune diseases: nuclear autoantigens can of renal biopsy data in predicting outcome in lupus nephritis. Arthritis
be found at the cell surface. Mol Biol Rep 1996, 22:63–66. Rheumatol 1990, 33:970–977.
43. Hermann M, Voll RE, Zoller RM, et al.: Impaired phagocytosis of 65. Nossent JC, Swaak AJG, Berden JHM: Systemic lupus erythematosus:
apoptotic cell material by monocyte-derived macrophages from analysis of disease activity in 55 patients with end stage renal failure
patients with systemic lupus erythematosus. Arthritis Rheum 1998, treated with hemodialysis or continuous ambulatory peritoneal dialysis.
41:1241–1250. Am J Med 1990, 89:169–174.
44. Mamula MJ: Lupus autoimmunity: from peptides to particles. 66. Bombardier C, Gladman DD, Urowitz MB, et al.: Derivation of the
Immunol Rev 1995, 144:301–314. SLEDAI. A disease activity index for lupus patients. Committee on
45. Datta SK, Kaliyaperumal A: Nucleosome-driven autoimmune response Prognosis Studies in SLE. Arthritis Rheumatol 1992, 35:630–640.
in lupus. Pathogenic T helper cell epitopes and co-stimulatory signals. 67. Nossent JC: End stage renal disease in patients with systemic lupus
In B Lymphocytes and Autoimmunity. Edited by Chiorazzi N, Lahita erythematosus. In Lupus Nephritis. Edited by Lewis EJ. Oxford:
RG, Pavelka K, Ferrarini M. New York: New York Academy of Oxford University Press; 1998: in press.
Sciences; 1997:155–170. 68. Nossent JC, Swaak AJG, Berden JHM: Systemic lupus erythematosus
46. Churg J, Sobin LH: Lupus nephritis. In Renal Diseases. Classification after renal transplantation: patient and graft survival and disease
and Atlas of Glomerular Diseases. Edited by Churg J. Tokyo: Igaku- activity. Ann Intern Med 1991, 114:183–188.
Shoin; 1982:127–149. 69. Winearls CG: Acute myeloma kidney. Nephrology Forum. Kidney Int
47. Churg J, Bernstein J, Glassock RJ: Lupus nephritis. In Renal Diseases. 1995, 48:1347–1361.
Classification and Atlas of Glomerular Diseases, edn 2. Edited by Churg 70. Kyle RA: Multiple myeloma. Review of 869 cases. Mayo Clin Proc
J, Bernstein J, Glassock RJ. New York: Igaku-Shoin; 1995:151–180. 1975, 50:29–40.
48. D’Agati VD: Systemic lupus erythematosus. In Renal Biopsy 71. Alexanian R, Barlogie B, Dixon D: Renal failure in multiple myeloma.
Interpretation. Edited by Silva FG, D’Agati VD, Nadasdy T. New Pathogenesis and prognostic implications. Arch Int Med 1990,
York: Churchill Livingstone; 1996:181–220. 150:1693–1695.
Renal Involvement in Collagen Vascular Diseases and Dysproteinemias 11.31
72. Pruzanski W: Clinical manifestations of multiple myeloma: relation 85. Harrison KL, Alpers CE, Davis CL: De novo amyloidosis in a renal
to class and type of the M component. Can Med Assoc J 1976, allograft: a case report and review of the literature. Am J Kidney Dis
114:896–897. 1993, 22:468–476.
73. Gallo G, Kumar V: Hematopoietic disorders. In Renal Biopsy 86. Sammett D, Dagher F, Abbi R, et al.: Renal transplantation in multiple
Interpretation. Edited by Silva FG, D’Agati VD, Nadasdy T. New myeloma. Transplantation 1996, 62:1577–1580.
York: Churchill Livingstone; 1996:259–282. 87. Gerlag PGG, Koene RAP, Berden JHM: Renal transplantation in light
74. Enlitz M, Weiss DT, Solomon A: Immunoglobulin heavy-chain-associ- chain nephropathy: case report and review of the literature. Clin
ated amyloidosis. Proc Natl Acad Sci USA 1990, 87:6542–6546. Nephrol 1986, 25:101–104.
75. Preudhomme JL, Aucouturier P, Touchard G, et al.: Monoclonal 88. Varet B, Choukroun G, Grunfeld JP: Multiple myeloma. Part II: treat-
immunoglobulin deposition disease (Randall type). Relationship with ment. Nephron 1995, 70:18–20.
structural abnormalities of immunoglobulin chains. Kidney Int 1994, 89. Iskander SS, Falk RJ, Jenette JC: Clinical and pathologic features of
46:965–972. fibrillary glomerulonephritis. Kidney Int 1992, 42:1401–1407.
76. Sanders PW, Herrera GA: Monoclonal immunoglobulin light chain- 90. Fogo A, Qureshi N, Horn RG: Morphologic and clinical features of
related renal diseases. Semin Nephrol 1993, 13:324–341. fibrillary versus immunotactoid glomerulonephritis. Am J Kidney Dis
77. Buxbaum JN, Chuba JV, Hellman GC, et al.: Monoclonal immuno- 1993, 22:367–377.
globulin deposition disease: light chain and light and heavy chain 91. Alpers CE: Fibrillary glomerulonephritis and immunotactoid glomeru-
deposition diseases and their relation to light chain amyloidosis: clinical lopathy. Curr Opinion Nephrol Hyperts 1994, 3:349–355.
features, immunopathology, and molecular analyses. Ann Intern Med
92. Pasternack A, Ahonen J, Kuhlback B: Renal transplantation in 45
1990, 112:455–464.
patients with amyloidosis. Transplantation 1986, 42:598–601.
78. Autocouterier P, Khamlichi AA, Touchard G, et al.: Brief report: heavy- 93. Helin H, Korpela M, Mustonen J, Pasternack A: Rheumatoid arthritis
chain deposition disease. Nucl Acids Res 1993, 329:1389–1393. and ankylosing spondylitis. In The Kidney in Collagen-Vascular Diseases.
79. Solomon A, Weiss DT, Kattine AA: Nephrotoxic potential of Bence Edited by Grishman E, Churg J, Needle MA, Vankataseshan VS. New
Jones proteins. N Engl J Med 1991, 324:1845–1851. York: Raven Press; 1993:149–166.
80. Sanders PW, Booker BB: Pathobiology of cast nephropathy from 94. Emery P, Adu D: The patient with rheumatoid arthritis, mixed con-
human Bence Jones proteins. J Clin Invest 1992, 89:630–639. nective tissue disease or polymyositis. In Oxford Textbook of Clinical
81. Johnson WJ, Kyle RA, Pineda AA, et al.: Treatment of renal failure Nephrology, edn 2. Edited by Davison AM, Cameron JS, Grunfeld JP,
associated with multiple myeloma. Plasmapheresis, hemodialysis and et al. Oxford: Oxford University Press; 1998:975–993.
chemotherapy. Arch Intern Med 1990, 150:863–869. 95. Winer RL: Sjögren’s syndrome. In The Kidney in Collagen-Vascular
82. Zucchelli P, Pasquali S, Cagnoli L, Ferrari G: Controlled plasma Diseases. Edited by Grishman E, Churg J, Needle MA, Venkataseshan
exchange trial in acute renal failure due to multiple myeloma. Kidney VS. New York: Raven Press; 1993:179–187.
Int 1988, 33:1175–1180. 96. Donohue JF: Scleroderma and the kidney. Kidney Int 1992, 41:462–477.
83. Misiani R, Tiraboschi G, Mingardi G, Mecca G: Management of 97. Steen VD: Scleroderma renal crisis. Rheumatol Dis Clin North Am
myeloma kidney: an anti–light chain approach. Am J Kidney Dis 1996, 22:861–878.
1987, 10:28–33. 98. D’Agati VD, Cannon PJ: Scleroderma (systemic sclerosis). In The Kidney
84. Ramos EL, Tisher CC: Recurrent disease in the kidney transplant. in Collagen-Vascular Diseases. Edited by Grishman E, Churg J, Needle
Am J Kidney Dis 1994, 24:142–154. MA, Venkataseshan VS. New York: Raven Press; 1993:121–147.
Principles of Dialysis:
Diffusion, Convection,
and Dialysis Machines
Robert W. Hamilton
C
hronic renal failure is the final common pathway of a number
of kidney diseases. The choices for a patient who reaches the
point where renal function is insufficient to sustain life are
1) chronic dialysis treatments (either hemodialysis or peritoneal dialysis),
2) renal transplantation, or 3) death. With renal failure of any cause,
there are many physiologic derangements. Homeostasis of water and
minerals (sodium, potassium, chloride, calcium, phosphorus, magne-
sium, sulfate), and excretion of the daily metabolic load of fixed
hydrogen ions is no longer possible. Toxic end-products of nitrogen
metabolism (urea, creatinine, uric acid, among others) accumulate in
blood and tissue. Finally, the kidneys are no longer able to function as
endocrine organs in the production of erythropoietin and 1,25-dihy-
droxycholecalciferol (calcitriol).
Dialysis procedures remove nitrogenous end-products of catabo-
lism and begin the correction of the salt, water, and acid-base derange-
ments associated with renal failure. Dialysis is an imperfect treatment
for the myriad abnormalities that occur in renal failure, as it does not
correct the endocrine functions of the kidney.
Indications for starting dialysis for chronic renal failure are empiric
and vary among physicians. Some begin dialysis when residual glomerular
filtration rate (GFR) falls below 10 mL/min /1.73 m2 body surface
area (15 mL/min/1.73 m2 in diabetics.) Others institute treatment
when the patient loses the stamina to sustain normal daily work and
activity. Most agree that, in the face of symptoms (nausea, vomiting, CHAPTER
anorexia, fatigability, diminished sensorium) and signs (pericardial
friction rub, refractory pulmonary edema, metabolic acidosis, foot or
1
wrist drop, asterixis) of uremia, dialysis treatments are urgently indicated.
1.2 Dialysis as Treatment of End-Stage Renal Disease
Function Dysfunction
Salt, water, and acid-base balance Salt, water, and acid-base balance
Water balance Fluid retention and hyponatremia
Sodium balance Edema, congestive heart failure, hypertension
Potassium balance Hyperkalemia
Bicarbonate balance Metabolic acidosis, osteodystrophy
Magnesium balance Hypermagnesemia
Phosphate balance Hyperphosphatemia, osteodystrophy
Excretion of nitrogenous end products Excretion of nitrogenous end products
Urea ?Anorexia, nausea, pruritus, pericarditis, polyneuropa-
Creatinine thy, encephalopathy, thrombocytopathy
Uric acid
Amines
Guanidine derivatives
Endocrine-metabolic Endocrine-metabolic
Conversion of vitamin D to active metabolite Osteomalacia, osteodystrophy
Production of erythropoietin Anemia
Renin Hypertension
FIGURE 1-2
Statue of Thomas Graham in George
Square, Glasgow, Scotland. The physico-
FIGURE 1-1 chemical basis for dialysis was first
Functions of the kidney and pathophysiology of renal failure. described by the Scottish chemist Thomas
Graham. In his 1854 paper “On Osmotic
Force” he described the movements of
various solutes of differing concentrations
through a membrane he had fashioned
from an ox bladder. (From Graham [1].)
FIGURE 1-3
Blood Membrane Dialysate Membrane fluxes in dialysis. Dialysis is the process of separating elements in a solution by
diffusion across a semipermeable membrane (diffusive solute transport) down a concentra-
tion gradient. This is the principal process for removing the end-products of nitrogen
Na+ Na+ metabolism (urea, creatinine, uric acid), and for repletion of the bicarbonate deficit of the
metabolic acidosis associated with renal failure in humans. The preponderance of diffusion
as the result of gradient is shown by the displacement of the arrow.
K+ K+
Ca2+ Ca2+
HCO3– HCO3–
Creatinine Creatinine
Urea Urea
Principles of Dialysis: Difusion, Convection, and Dialysis Machines 1.3
FIGURE 1-4
Simplified schematic of typical hemodialysis system. In hemodialysis, pumps that mix a concentrated salt solution with water purified by
blood from the patient is circulated through a synthetic extracorporeal reverse osmosis and/or deionization to produce the dialysate, a means
membrane and returned to the patient. The opposite side of that of removing excess fluid from the blood (mismatching dialysate
membrane is washed with an electrolyte solution (dialysate) contain- inflow and outflow to the dialysate compartment), and a series of
ing the normal constituents of plasma water. The apparatus contains pressure, conductivity, and air embolus monitors to protect the
a blood pump to circulate the blood through the system, proportioning patient. Dialysate is warmed to body temperature by a heater.
FIGURE 1-5
Dialysate The hemodialysis membrane. Most membranes are derived from
cellulose. (The earliest clinically useful hemodialyzers were made
from cellophane sausage casing.) Other names of these materials
include cupraphane, hemophan, cellulose acetate. They are usually
sterilized by ethylene oxide or gamma irradiation by the manufac-
Blood Blood
turer. They are relatively porous to fluid and solute but do not
allow large molecules (albumin, vitamin B12) to pass freely. There
is some suggestion that cupraphane membranes sterilized by ethylene
oxide have a high incidence of biosensitization, meaning that the
patient may have a form of allergic reaction to the membrane.
Dialysate Polysulfone, polyacrylonitrile, and polymethylmethacrylate membranes
are more biocompatible and more porous (high flux membranes).
They are most often formed into hollow fibers. Blood travels down
Blood the center of these fibers, and dialysate circulates around the outside
of the fibers but inside a plastic casing. Water for dialysis must meet
Dialysate
critical chemical and bacteriologic standards. These are listed in
Figures 1-6 and 1-7.
1.4 Dialysis as Treatment of End-Stage Renal Disease
FIGURE 1-6
ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL Association for the Advancement of Medical Instrumentation
INSTRUMENTATION CHEMICAL STANDARD FOR (AAMI) chemical standards for water for hemodialysis. Before
WATER FOR HEMODIALYSIS hemodialysis can be performed, water analysis is performed.
Water for hemodialysis generally requires reverse osmosis treat-
ment and a deionizer for “polishing” the water. Organic materials,
Substance Concentration (mg/L) chlorine, and chloramine are removed by charcoal filtration.
(From Vlchek [2]; with permission.)
Aluminum 0.01
Arsenic 0.005
Barium 0.1
Cadmium 0.001
Calcium 2.0
Chloramine 0.1
Chlorine 0.5
Chromium 0.014
Copper 0.1
Fluoride 0.2
Lead 0.005
Magnesium 4.0
Mercury 0.0002
Nitrate 2.0
Potassium 8.0
Selenium 0.009
Silver 0.005
Sodium 70
Sulfate 100
Zinc 0.1
FIGURE 1-7
ASSOCIATION FOR THE ADVANCEMENT OF MEDICAL Association for the Advancement of Medical Instrumentation
INSTRUMENTATION BACTERIOLOGIC STANDARDS (AAMI) bacteriologic standards for dialysis water and prepared
FOR DIALYSIS WATER AND PREPARED DIALYSATE dialysate. Excess bacteria in water can lead to pyrogen reactions.
Treated water supply systems are designed so that there are no
dead-end connections. Because the antiseptic agents (chlorine and
Colony-forming units/mL chloramine) have been removed in water treatment, the water is
prone to develop such problems if stagnation is allowed. (From
Dialysis water <200 Bland and Favero [3]; with permission.)
Prepared dialysate <2000
kΤ 3 4πN
FIGURE 1-9
D=
6πη 3Μυ Fick’s diffusion constant, where D = Fick’s diffusion coefficient, k = Boltzman’s constant;
T = absolute temperature; = viscosity; N = Avogadro’s number; M = molecular weight;
and = partial molal volume. The diffusion constant is proportional to the temperature of
the solution and inversely proportional to the viscosity and the size of the molecule removed.
FIGURE 1-10
250 Effect of blood flow on clearance of various solutes, Fresenius F-5 membrane. The amount
Urea
Creatinine of solute cleared by a dialyzer depends on the amount delivered to the membrane. The
200 Phosphate usual blood flow is 300–400 mL/min, which is adequate to deliver the dialysis prescrip-
Clearance, mL/min
Vitamin B12 tion. On institution of dialysis to a very uremic patient the blood flow is decreased to 160
150 to 180 mL/min to avoid disequilibrium syndrome. As time goes on, blood flow can be
increased to standard flows as the patient adjusts to dialysis. Most patients require
100 hemodialysis at least thrice weekly. From this graph it is also evident that small molecules
such as urea (molecular weight 60 D) are cleared more easily than large molecules such as
vitamin B12 (molecular weight 1355 D).
50
0
0 100 200 300 400
Blood flow, mL/min
–300
–400
Blood Dialysate Net transmembrane
compartment compartment pressure
1.6 Dialysis as Treatment of End-Stage Renal Disease
FIGURE 1-12
35 Dialysis membranes differ in their ability to remove fluid. Differences in ultrafiltration
30 coefficient (UFR) are shown for two different membranes, F-5 and F-50. The F-50 is
considered a high-flux membrane.
UFR, mL/h/mmHg
25
20
15
10
5
0
F–5 F–50
References
1. Graham T: The Bakerian lecture—on osmotic force. Philos Trans R 3. Bland LA, Favero MS: Microbiologic aspects of hemodialysis systems. In
Soc Lond 1854, 144:177–228. AAMI Standards and Recommended Practices, vol. 3. Arlington, VA:
2. Vlchek DL: Monitoring a hemodialysis water treatment system. In AAMI Association for the Advancement of Medical Instrumentation; 1993:257–265.
Standards and Recommended Practices, vol. 3. Arlington, VA: Association 4. Daniels F, Alberty RA: Physical Chemistry. New York : John Wiley &
for the Advancement of Medical Instrumentation; 1993:267–277. Sons; 1955.
Dialysate Composition
in Hemodialysis and
Peritoneal Dialysis
Biff F. Palmer
T
he goal of dialysis for patients with chronic renal failure is to
restore the composition of the body’s fluid environment toward
normal. This is accomplished principally by formulating a
dialysate whose constituent concentrations are set to approximate
normal values in the body. Over time, by diffusional transfer along
favorable concentration gradients, the concentrations of solutes that
were initially increased or decreased tend to be corrected. When an
abnormal electrolyte concentration poses immediate danger, the
dialysate concentration of that electrolyte can be set at a nonphysio-
logic level to achieve a more rapid correction. On a more chronic basis
the composition of the dialysate can be individually adjusted in order
to meet the specific needs of each patient.
2
concentration—and more specifically changes in serum osmolality—
were contributing to the development of this hemodynamic instability.
fluid shift from the extracellular space to the intracellular erbate hemodynamic instability during the dialysis procedure
[21]. In this regard, the intradialysis drop in blood pressure
space, thus exacerbating the volume-depleting effects of dialy- noted in patients dialyzed against a low-calcium bath, while
sis. With the advent of high-clearance dialyzers and more effi- statistically significant, is minor in degree [22,23]. Nevertheless,
for patients who are prone to intradialysis hypotension avoid-
cient dialysis techniques, this decline in plasma osmolality ing low calcium dialysate concentration may be of benefit. On
the other hand, the use of a lower calcium concentration in the
becomes more apparent, as solute is removed more rapidly. dialysate allows the use of increased doses of calcium-containing
phosphate binders and lessens dependence on binders containing
Use of dialysate of low sodium concentration would tend fur-
aluminum. In addition, use of 1,25-dihydroxyvitamin D can be
ther to enhance the intracellular shift of fluid, as plasma tends liberalized to reduce circulating levels of parathyroid hormone
and, thus, the risk of inducing hypercalcemia. With dialysate
to become calcium concentrations below 1.5 mmol/L, however, patients
need close monitoring to ensure that negative calcium balance
even more hyposmolar consequent to the movement of sodi-
does not develop and that parathyroid hormone levels remain
um from in an acceptable range [24].
plasma to dialysate. The use of a higher sodium concentration Dialysate Composition for Peritoneal Dialysis
To meet the ultrafiltration requirements of patients on peritoneal
dialysate (>140 mEq/L) has been among the most efficacious
dialysis, the peritoneal dialysate is deliberately rendered hyper-
and best tolerated therapies for episodic hypotension [1–3]. osmolar relative to plasma, to create an osmotic gradient that
favors net movement of water into the peritoneal cavity. In
The high sodium concentration prevents a marked decline in commercially available peritoneal dialysates, glucose serves as
the osmotic agent that enhances ultrafiltration. Available con-
the plasma osmolality during dialysis, thus protecting the extra- centrations range from 1.5% to 4.25% dextrose. Over time, the
cellular volume by minimizing osmotic fluid loss into the cells. osmolality of the dialysate declines as a result of water moving
In the early 1960s acetate became the standard dialysate into the peritoneal cavity and of absorption of dialysate glucose.
buffer for correcting uremic acidosis and offsetting the diffusive The absorption of glucose contributes substantially to the calorie
losses of bicarbonate during hemodialysis. Over the next several intake of patients on continuous peritoneal dialysis. Over time,
years reports began to accumulate that linked routine use of this carbohydrate load is thought to contribute to progressive
acetate with cardiovascular instability and hypotension during obesity, hypertriglyceridemia, and decreased nutrition as a
dialysis. As a result, dialysate containing bicarbonate began to result of loss of appetite and decreased protein intake. In addition,
re-emerge as the principal dialysate buffer, especially as advances the high glucose concentrations and high osmolality of currently
in biotechnology made bicarbonate dialysate less expensive and available solutions may have inhibitory effects on the function
less cumbersome to use. For the most part, the bicarbonate con- of leukocytes, peritoneal macrophages, and mesothelial cells
centration used consistently in most dialysis centers is 35 [25]. In an attempt to develop a more physiologic solution, various
mmol/L. Emphasis is now being placed on individually adjusting new osmotic agents are now under investigation. Some of these
the dialysate bicarbonate concentration so as to maintain the may prove useful as alternatives to the standard glucose solutions.
predialysis tCO2 concentration above 23 mmol/L [12–16]. Those that contain amino acids have received the most attention.
Increasing evidence suggests that correction of chronic acidosis The sodium concentration in the ultrafiltrate during peri-
is of clinical benefit in terms of bone metabolism and nutrition. toneal dialysis is usually less than that of extracellular fluid, so
Dialysis assumes a major role in the maintenance of a normal there is a tendency toward water loss and development of hyper-
serum potassium concentration in patients with end-stage renal natremia. Commercially available peritoneal dialysates have a
disease. Excess potassium is removed by using a dialysate with a sodium concentration of 132 mEq/L to compensate for this ten-
lower potassium concentration, so that a gradient is achieved dency toward dehydration. The effect is more pronounced with
that favors movement of potassium. In general, one can expect increasing frequency of exchanges and with increasing dialysate
only up to 70 to 90 mEq of potassium to be removed during a glucose concentrations. Use of the more hypertonic solutions
typical dialysis session. As a result, one should not overestimate and frequent cycling can result in significant dehydration and
the effectiveness of dialysis in the treatment of severe hyper- hypernatremia. As a result of stimulated thirst, water intake and
kalemia. The total amount removed varies considerably and is weight may increase, resulting in a vicious cycle.
affected by changes in acid-base status, in tonicity, in glucose and Potassium is cleared by peritoneal dialysis at a rate similar to
insulin concentration, and in catecholamine activity [17–20]. that of urea. With chronic ambulatory peritoneal dialysis and
The concentration of calcium in the dialysate has implications 10 L of drainage per day, approximately 35 to 46 mEq of potas-
for metabolic bone disease and hemodynamic stability. Like the sium is removed per day. Daily potassium intake is usually
other constituents of the dialysate, the calcium concentration greater than this, yet significant hyperkalemia is uncommon in
should be tailored to the individual patient [21]. Some data suggest these patients. Presumably potassium balance is maintained by
that lowering the dialysate calcium concentration would exac- increased colonic secretion of potassium and by some residual
Dialysate Composition in Hemodialysis and Peritoneal Dialysis 2.3
renal excretion. Given these considerations, potassium is not absorption. The pH of commercially available peritoneal dialysis
routinely added to the dialysate. solutions is purposely made acidic by adding hydrochloric acid
The buffer present in most commercially available peritoneal to prevent dextrose from caramelizing during the sterilization
dialysate solutions is lactate. In patients with normal hepatic procedure. Once instilled, the pH of the solution rises to values
function, lactate is rapidly converted to bicarbonate, so that greater than 7.0. There is some evidence that the acidic pH of
each mM of lactate absorbed generates one mM of bicarbonate. the dialysate, in addition to the high osmolality, may impair the
Even with the most aggressive peritoneal dialysis there is no host’s peritoneal defenses [25,26].
appreciable accumulation of circulating lactate. The rapid To avoid negative calcium balance—and possibly to suppress
metabolism of lactate to bicarbonate maintains the high circulating parathyroid hormone—commercially available peri-
dialysate-plasma lactate gradient necessary for continued toneal dialysis solutions evolved to have a calcium concentration
150
Baseline Low-sodium dialysate High-sodium dialysate Step
Linear
Interstitial Exponential
space
BUN H2O BUN H2O
Cell Cell
space osmolality
Hypotension
1 2 3 4
Time, h
of 3.5 mEq/L (1.75 mmol/L). This concentration is equal to or
slightly greater than the ionized concentration in the serum of
most patients. As a result, there is net calcium absorption in of administered calcium, contributing to the development of
most patients treated with a conventional chronic ambulatory hypercalcemia. As a result, there has been increased interest in
peritoneal dialysis regimen. As the use of calcium-containing using a strategy similar to that employed in hemodialysis,
phosphate binders has increased, hypercalcemia has become a namely, lowering the calcium content of the dialysate. This
common problem when utilizing the 3.5 mEq/L calcium strategy can allow increased use of calcium-containing phosphate
dialysate. This complication has been particularly common in binders and more liberal use of 1,25-dihydroxyvitamin D to
patients treated with peritoneal dialysis, since they have a much effect decreases in the circulating level of parathyroid hormone.
greater incidence of adynamic bone disease than do hemodialysis In this way, development of hypercalcemia can be minimized.
patients [27]. In fact, the continual positive calcium balance
associated with the 3.5-mEq/L solution has been suggested to
Dialysate Na in Hemodialysis
be a contributing factor in the development of this lesion. The
low bone turnover state typical of this disorder impairs accrual
2.4 Dialysis as Treatment of End-Stage Renal Disease
FIGURE 2-1
INDICATIONS AND CONTRAINDICATIONS FOR USE Use of a low-sodium dialysate is more often associated with intra-
OF SODIUM MODELING (HIGH/LOW PROGRAMS) dialysis hypotension as a result of several mechanisms [4]. The
drop in serum osmolality as urea is removed leads to a shift of
water into the intracellular compartment that prevents adequate
Indications refilling of the intravascular space. This intracellular movement of
Intradialysis hypotension
Cramping
Initiation of hemodialysis in setting of severe azotemia
Hemodynamic instability (eg, intensive care setting)
Contraindications
Intradialysis development of hypertension
Large interdialysis weight gain induced by high-sodium dialysate
Hypernatremia
hypertonicity and any resultant excessive thirst, fluid gain, and hypertension in the interdialysis period. In some but not all studies, sodi-
um modeling has been shown to be effective in treating intradialysis hypotension
4.0
3.5
3.0
End hemodialysis
2.5
0 1 2 3 4 5
Time, h
FIGURE 2-5
FIGURE 2-6
Dialysate component
and adjustment Advantages Disadvantages
Sodium:
Increased More hemodynamic stability, less cramping Dipsogenic effect, increased interdialytic weight gain,
? chronic hypertension
Decreased (rarely used) Less interdialytic weight gain Intradialytic hypotension and cramping more common
Calcium:
Increased Suppression of PTH, promotes hemodynamic stability in HD Hypercalcemia with vitamin D and high-dose calcium-containing
phosphate binders, ? contribution to adynamic bone disease in PD
Decreased Permits greater use of vitamin D and calcium containing Potential for negative calcium balance, stimulation of PTH,
phosphate binders slight decrease in hemodynamic stability
Potassium:
Increased Less arrhythmias in setting of digoxin or coronary heart disease Limited by hyperkalemia
? improved hemodynamic stability
Decreased Permits greater dietary intake of potassium with less hyperkalemia Increased arrhythmias, may exacerbate autonomic insufficiency
? improvement in myocardial contractility
Bicarbonate:
Increased Corrects chronic acidosis thereby benefits nutrition and bone metabolism Post-dialysis metabolic alkalosis
Decreased Less metabolic alkalosis Potential for chronic acidosis
Magnesium:
Increased ? Less arrhythmias, ? hemodynamic benefit Potential for hypermagnesemia
Decreased Permits greater use of magnesium containing phosphate binders which in tum Symptomatic hypomagnesemia
permits reduced dose of calcium binders and results in less hypercalcemia
Plasma potassium concentration can be expected to fall rapidly in the early stages of dialy-
sis, but as it drops, potassium removal becomes less efficient [17,18]. Since potassium is
freely permeable across the dialysis membrane, movement of potassium from the intracellular space to the extracellular space appears to be
the limiting factor that accounts for the smaller fractional decline in potassium concentration at lower plasma potassium concentrations.
Presumably, the movement of potassium out of cells and into the extracellular space is
slower than the removal of potassium from the extracellular space into the dialysate, so a
COMPOSITION OF A
disequilibrium is created. The rate of potassium removal is largely a function of its predialysis
COMMERCIALLY AVAILABLE
concentration. The higher the initial plasma concentration, the greater is the plasma-dialysate
PERITONEAL DIALYSATE
gradient and, thus, the more potassium is removed. After the completion of a standard
dialysis treatment there is an increase in the plasma concentration of potassium secondary
to continued exit of potassium from the intracellular space to the extracellular space in an
Solute Dianeal PD-2 attempt to re-establish the intracellular-extracellular potassium gradient.
Sodium, mEq/L 132 FIGURE 2-7
Potassium, mEq/L 0
Chloride , mEq/L 96
Calcium , mEq/L 3.5
Magnesium, mEq/L 0.5
D, L-Lactate, mEq/L 40
Glucose, g/dL 1.5, 2.5, 4.25
Osmolality 346, 396, 485
pH 5.2
2.8 Dialysis as Treatment of End-Stage Renal Disease
H
emodialysis remains the major modality of renal replacement
therapy in the United States. Since the 1970s the drive for
shorter dialysis time with high urea clearance rates has led to
the development of high-efficiency hemodialysis. In the 1990s, certain
biocompatible features and the desire to remove amyloidogenic 2-
microglobulin has led to the popularity of high-flux dialysis. During
the 1990s, the use of high-efficiency and high-flux membranes has
steadily increased and use of conventional membrane has declined [1].
In 1994, a survey by the Centers for Disease Control showed that
high-flux dialysis was used in 45% and high-efficiency dialysis in 51%
of dialysis centers (Fig. 3-1) [1].
Despite the increasing use of these new hemodialysis modalities the
clinical risks and benefits of high-performance therapies are not well-
defined. In the literature published over the past 10 years the definitions
of high-efficiency and high-flux dialysis have been confusing.
Currently, treatment quantity is not only defined by time but also by
dialyzer characteristics, ie, blood and dialysate flow rates. In the past,
when the efficiency of dialysis and blood flow rates tended to be low,
treatment quantity was satisfactorily defined by time. Today, however,
treatment time is not a useful expression of treatment quantity because
efficiency per unit time is highly variable.
CHAPTER
3
3.2 Dialysis as Treatment of End-Stage Renal Disease
Dialyzers
FIGURE 3-2
50
HIGH-PERFORMANCE EXTRA- The four high-
CORPOREAL THERAPIES FOR performance extra-
END-STAGE RENAL DISEASE corporeal therapies
40
for end-stage renal
disease are listed [2].
30 High-efficiency hemodialysis
Centers, %
High-flux hemodialysis
Hemofiltration, intermittent
20 Hemodiafiltration, intermittent
10
0
1986 1988 1990 1992 1994 1996
Year
FIGURE 3-1
Centers using high-flux dialyzers have increased threefold from
1986 to 1996 because of their ability to remove middle molecules.
(From Tokars and coworkers [1]; with permission.)
FIGURE 3-3
DEFINITIONS OF FLUX, PERMEABILITY, AND EFFICIENCY Definitions of flux, permeability, and efficiency. The urea value KoA,
as conventionally defined in hemodialysis, is an estimate of the clear-
ance of urea (a surrogate marker of low molecular weight uremic
Flux toxins) under conditions of infinite blood and dialysate flow rates.
Measure of ultrafiltration capacity The following equation is used to calculate this value:
Low and high flux are based on the ultrafiltration coefficient (Kuf)
QbQd 1-Kd/Qb
KoA= ln
Low flux: Kuf <10 mL/h/mm Hg
Qb-Qd 1-Kd/Qd
where Ko = mass transfer coefficient
High flux: Kuf >20 mL/h/mm Hg
A = surface area
Permeability
Qb = blood flow rate
Measure of the clearance of the middle molecular weight molecule (eg, 2-microglobulin)
Qd = dialysate flow rate
General correlation between flux and permeability
ln = natural log
Low permeability: 2-microglobulin clearance <10 mL/min
Kd = mean of blood and dialysate side urea clearance
High permeability: 2-microglobulin clearance >20 mL/min As conventionally defined in hemodialysis, flux is the rate of water
Efficiency transfer across the hemodialysis membrane. Dissolved solutes are
Measure of urea clearance removed by convection (solvent drag effect).
Low and high efficiency are based on the urea KoA value Permeability is a measure of the clearance rate of molecules of
Low efficiency: KoA <500 mL/min middle molecular weight, sometimes defined using 2-microglobulin
High efficiency: KoA >600 mL/min (molecular weight, 11,800 D) as the surrogate [3,4]. Dialyzers that
permit 2-microglobulin clearance of over 20 mL/min under usual
Ko—mass transfer coefficient; A—surface area. clinical flow and ultrafiltration conditions have been defined as high-
permeability membrane dialyzers. Because of the general correlation
between water flux and the clearance rate of molecules of middle
molecular weight, the term high-flux membrane has been used
commonly to denote high-permeability membrane.
High-Efficiency and High-Flux Hemodialysis 3.3
FIGURE 3-4
1000
Theoretic KoA profile of high- and low-flux dialyzers and high-
High flux and low-efficiency dialyzers. Note that here the definition of KoA
100 applies to the product of the mass transfer coefficient and surface
area for solutes having a wide range of molecular weights, and is
not limited to urea. Note also the logarithmic scales on both axes
[3]. Ko—mass transfer coefficient; A—surface area. (From Cheung
10
KOA, mL/min
High efficiency
0.1 Low efficiency
0.01
10 100 1000 10,000 100,000
FIGURE 3-5
CLASSIFICATION OF HIGH- Classification of high-performance dialysis. Some authors have defined high-efficiency
PERFORMANCE DIALYSIS hemodialysis as treatment in which the urea clearance rate exceeds 210 mL/min. High-flux
dialysis, arbitrarily defined as a 2-microglobulin clearance of over 20 mL/min, is achieved
using high-flux membranes [3,4].
High-efficiency low-flux hemodialysis
High-efficiency high-flux hemodialysis
Low-efficiency high-flux hemodialysis
400
CHARACTERISTICS OF HIGH-EFFICIENCY DIALYSIS
350 KOA=1000
Urea clearance rate, mL/min
300
Urea clearance rate is usually >210 mL/min
250
KOA=500 Urea KoA of the dialyzer is usually >600 mL/min
200 Ultrafiltration coefficient of the dialyzer (Kuf) may be high or low
Clearance of middle molecular weight molecules may be high or low
150
Dialysis can be performed using either cellulosic or synthetic membrane dialyzers
100
0
0 50 150 250 350 450 500 FIGURE 3-7
Blood flow rate, mL/min Characteristics of high-efficiency dialysis. High-efficiency dialysis is
arbitrarily defined by a high clearance rate of urea (>210 mL/min).
High-efficiency membranes can be made from either cellulosic or
FIGURE 3-6 synthetic materials. Depending on the membrane material and surface
Comparison of urea clearance rates between low- and high-efficiency area, the removal of water (as measured by the ultrafiltration coeffi-
hemodialyzers (urea KoA = 500 and 1000 mL/min, respectively). cient or Kuf) and molecules of middle molecular weight (as measured
The urea clearance rate increases with the blood flow rate and by 2-microglobulin clearance) may be high or low [3,4,6,7].
gradually reaches a plateau for both types of dialyzers. The plateau
value of KoA is higher for the high-efficiency dialyzer. At low blood
flow rates (<200 mL/min), however, the capacity of the high-efficien-
cy dialyzer cannot be exploited and the clearance rate is similar to
that of the low-flux dialyzer [3,6]. Ko—mass transfer coefficient;
A—surface area. (From Collins [6]; with permission.)
3.4 Dialysis as Treatment of End-Stage Renal Disease
FIGURE 3-8
DIFFERENCES BETWEEN HIGH- AND Differences between high- and low-efficiency hemodialysis.
LOW-EFFICIENCY HEMODIALYSIS Conventional hemodialysis refers to low-efficiency low-flux
hemodialysis that was the popular modality before the 1980s [3,6].
FIGURE 3-15
CHARACTERISTICS OF HIGH-FLUX DIALYSIS Characteristics of high-flux dialysis. Because of the high ultrafiltra-
tion coefficients of high-flux membranes, high-flux dialysis requires
an automated ultrafiltration control system to avoid accidental
Dialyzer membranes are characterized by a high ultrafiltration coefficient profound intravascular volume depletion. Because high-flux mem-
(Kuf > 20 mL/h/mm Hg) branes tend to have larger pores, clearance of middle molecular
High clearance of middle molecular weight molecules occurs (eg, 2-microglobulin) weight molecules is usually high. Urea clearance rates for high-flux
Urea clearance can be high or low, depending on the urea KoA of the dialyzer dialyzers are still dependent on urea KoA values, which can be
Dialyzers are made of either synthetic or cellulosic membranes either high (ie, high-flux high-efficiency) or low (ie, high-flux low-
High-flux dialysis requires an automated ultrafiltration control system efficiency) [3,4,10]. Ko—mass transfer coefficient; A—surface area.
3.6 Dialysis as Treatment of End-Stage Renal Disease
High-flux dialyzer Delayed onset and risk of dialysis-related amyloidosis Enhanced drug clearance, requiring supplemental
Automated ultrafiltration control system because of enhanced 2-microglobulin clearance dose after dialysis
[11,12] High cost of dialyzers
Increased patient survival resulting from higher
clearance of middle molecular weight molecules
[12,13,15,16]
FIGURE 3-16
Reduced morbidity and hospital admissions [14,16]
Technical requirements for high-flux dialysis. FIGURE 3-18
Improved lipid profile [16,17]
Because of the potential for reverse filtration Limitations of high-flux dialysis. The
Higher clearance of aluminum [18]
(movement of fluid from dialysate to the enhanced clearance of drugs depends on
Improved nutritional status [19,20]
blood compartment) to occur, use of a the physicochemical characteristics of
Reduced risk of infection [16,21]
pyrogen-free dialysate is preferred but not the specific drug and dialysis membrane.
Preserved residual renal function [22] Because of their relative high costs, high-
mandatory. Bicarbonate concentrate used
to prepare dialysate is particularly prone to flux dialyzers are usually reused.
bacterial overgrowth when stored for more
than 2 days [5,8].
FIGURE 3-17
Potential benefits of high-flux dialysis.
Data are accumulating that support many
potential benefits of high-flux dialysis.
Large-scale randomized prospective trials,
however, are unavailable.
FIGURE 3-19
EXAMPLES OF COMMONLY USED DIALYZERS Examples of commonly used dialyzers.
“Efficiency” refers to the capacity to remove
urea; “flux” refers to the capacity to remove
Dialyzer type Material KoA (in vitro), mL/min water, and indirectly, the capacity to remove
Surface area, m2
molecules of middle molecular weight.
Low-flux low-efficiency Cellulosic membranes can be either low flux
CA90 Cellulose acetate 0.9 410 or high flux. Similarly, synthetic membranes
CF12 Cuprammonium 0.7 418 can be either low flux or high flux. High-
Low-flux high-efficiency efficiency membranes usually have large
CA150 Cellulose acetate 1.5 660 surface areas.
T150 Cuprammonium 1.5 730
High-flux low-efficiency
F50 Polysulfone 0.9 520
PAN 150P Polyacrylonitrile 1.0 420
High-flux high-efficiency
CT190 Cellulose triacetate 1.9 920
F80 Polysulfone 1.8 945
Solutes
Cb Cb Cb Postdilution
Ultrafiltrate
Solute flux
Fluid flux
Cd Solute flux
Predilution
Blood Membrane Ultrafiltrate Blood Membrane Ultrafiltrate
Blood
FIGURE 3-23
Addition of diffusive transport in hemodiafiltration. In hemodiafiltration, diffusive transport
Postdilution is added to hemofiltration to augment the clearance of solutes (usually small solutes such
as urea and potassium). Solute clearance is accomplished by circulating dialysate in the
dialysate-ultrafiltrate compartment. Hemodiafiltration is particularly useful in patients
Ultrafiltrate who have hypercatabolism with large urea generation.
Dialysate
Predilution
Blood
3.8 Dialysis as Treatment of End-Stage Renal Disease
Membranes
Bacteria FIGURE 3-24
Backfiltration, or reverse filtration, of endotoxins (ET) from dialysate to blood. Reverse
filtration of ET is particularly prone to occur when high-flux membranes are used and the
Macrophage dialysate is heavily contaminated with bacteria (>2000 CFU/mL) and may result in pyrogenic
ET
reactions. The dialysis membranes are impermeable to intact ET; however, their fragments
(some of which still are pyrogenic) may be small enough to traverse the membrane. Although
the membrane is impermeable to bacteria and blood cells, a mechanical break in the membrane
could result in bacteremia.
ET fragments
FIGURE 3-25
H 2O
Dialysis membranes with small and large pores. Although a general correlation exists
H 2O
between the (water) flux and the (middle molecular weight molecule) permeability of dialysis
H 2O membranes, they are not synonymous. A, Membrane with numerous small pores that allow
H 2O high water flux but no 2-microglobulin transport. B, Membrane with a smaller surface
H 2O area and fewer pores, with the pore size sufficiently large to allow 2-microglobulin transport.
The ultrafiltration coefficient and hence the water flux of the two membranes are equivalent.
H 2O
H 2O
H 2O
H 2O
A
FIGURE 3-26
Scanning electron microscopy of a conventional low-flux-membrane
hollow fiber (panel A) and a synthetic high-flux-membrane hollow fiber
(panel B). The low-flux membrane consists of a single layer of relatively
homogenous material. The high-flux membrane has a three-layer struc-
ture, ie, finger, sponge, and skin. The skin is a thin semipermeable layer B
that functions as the selective barrier; it is mechanically supported by
the sponge and finger layers. (Magnification: finger, 14,000; sponge
17,000; skin 85,000.) (Courtesy of Goehl H, Gambrogroup).
High-Efficiency and High-Flux Hemodialysis 3.9
Backfiltration
FIGURE 3-28
Pressure inside the blood compartment (dark colored arrow) and
Blood flow Dialysate flow the dialysate compartment (light colored arrow) with a fixed net
zero ultrafiltration rate. The pressure gradually decreases in the
Blood /Dialysate Blood /Dialysate blood compartment as blood travels from the inlet toward the outlet.
150 inlet outlet outlet inlet
Pbi Beyond a certain point along the dialyzer length (x, where the two
pressure lines intersect), the pressure in the dialysate compartment
140 exceeds that in the blood compartment, forcing fluid to move from
Pressure, mm Hg
Pdi
the dialysate to the blood compartment. This movement of fluid
in the direction opposite to that of the designed ultrafiltration is
130
Ultrafiltrate x called backfiltration. Backfiltration may carry with it contaminants
Back filtrate (eg, endotoxins) from the dialysate. Increasing the net ultrafiltra-
120 tion rate shifts the pressure intersection point to the right and
Pdo
diminishes backfiltration.
110
Pbo
100
3.10 Dialysis as Treatment of End-Stage Renal Disease
References
1. Tokars JI, Alter MJ, Miller E, et al.: National surveillance of dialysis 13. Chandran PKG, Liggett R, Kirkpatrick B: Patient survival on
associated disease in the United States: 1994. ASAIO J 1997, PAN/AN 69 membrane hemodialysis: a ten year analysis. J Am Soc
43:108–119. Nephrol 1993, 4:1199–1204.
2. United States Renal Data System, 97: Treatment modalities for ESRD 14. Hornberger JC, Chernew M, Petersen J, Garber AM: A multivariate
patients. Am J Kidney Dis 1997, 30:S54–S66. analysis of mortality and hospital admissions with high-flux dialysis.
3. Cheung AK, Leypoldt JK: The hemodialysis membranes: a historical J Am Soc Nephrol 1992, 3:1227–1236.
perspective, current state and future prospect. Sem Nephrol 1997, 15. Hakim RM, Held PJ, Stannard DC, et al.: Effect of the dialysis membrane
17:196–213. on mortality of chronic hemodialysis patients. Kidney Int 1996,
4. Leypoldt JK, Cheung AK, Agodoa LY, et al.: Hemodialyzer mass 50:566–570.
transfer–area coefficients for urea increase at high dialysate flow rates. 16. Churchill DN: Clinical impact of biocompatible dialysis membranes
Kidney Int 1997, 51:2013–2017. on patient morbidity and mortality: an appraisal of evidence. Nephrol
5. Collins AJ, Keshaviah P: High-efficiency, high flux therapies in Dial Trans 1995, 10(suppl):52–56.
clinical dialysis. In Clinical Dialysis, edn 3. Edited by Nissenson AR. 17. Seres DS, Srain GW, Hashim SA, et al.: Improvement of plasma
1995:848–863. lipoprotein profiles during high flux dialysis. J Am Soc Nephrol 1993,
6. Collins AJ: High-flux, high-efficiency procedures. In Principles and 3:1409–1415.
Practice of Hemodialysis. Edited by Henrich W. Norwalk, CT: 18. Mailloux LU: Dialysis modality and patient outcome. UpToDate Med
Appleton & Large; 1996:76–88. 1995.
7. von Albertini B, Bosch JP: Short hemodialysis. Am J Nephrol 1991, 19. Parker TF III, Wingard RL, Husni L, et al.: Effect of the membrane
11:169–173. biocompatibility on nutritional parameters in chronic hemodialysis
8. Keshaviah P, Luehmann D, Ilstrup K, Collins A: Technical requirements patients. Kidney Int 1996, 49:551–556.
for rapid high-efficiency therapies. Artificial Organs 1986, 10:189–194. 20. Ikizler TA, Hakim RM: Nutrition in end-stage renal disease. Kidney
9. Shinaberger JH, Miller JH, Gardner PW: Short treatment. In Int 1996, 50:343–357.
Replacement of Renal Function by Dialysis, edn 3. Edited by Maher 21. Hakim RM, Wingard RL, Parker RA, et al.: Effects of biocompatibility
JF. Norwell, MA: Kluwer Academic Publishers; 1989:360–381. on hospitalizations and infectious morbidity in chronic hemodialysis
10. Barth RH: High flux hemodialysis: overcoming the tyranny of time. patients. J Am Soc Nephrol 1994, 5:450.
Contrib Nephrol 1993, 102:73–97. 22. Van Stone JC: Hemodialysis apparatus. In Handbook of Dialysis, edn 2.
11. Van Ypersele, De Strihou C, Jadoul M, et al.: The working party on Edited by Daugirdas JT, Ing TS. Boston/New York: Little, Brown &
dialysis amyloidosis: effect of dialysis membrane and patient’s age on Co.; 1994:31–52.
signs of dialysis-related amyloidosis. Kidney Int 1991, 39:1012–1019.
12. Koda Y, Nishi S, Miyazaki S, et al.: Switch from conventional to high-
flux membrane reduces the risk of carpal tunnel syndrome and mor-
tality of hemodialysis patients. Kidney Int 1997, 52:1096–1101.
Principles of
Peritoneal Dialysis
Ramesh Khanna
Karl D. Nolph
P
eritoneal dialysis is a technique whereby infusion of dialysis solu-
tion into the peritoneal cavity is followed by a variable dwell
time and subsequent drainage. Continuous ambulatory peri-
toneal dialysis (CAPD) is a continuous treatment consisting of four to
five 2-L dialysis exchanges per day (Fig. 4-1A). Diurnal exchanges last
4 to 6 hours, and the nocturnal exchange remains in the peritoneal
cavity for 6 to 8 hours. Continuous cyclic peritoneal dialysis, in real-
ity, is a continuous treatment carried out with an automated cycler
machine (Fig. 4-1B). Multiple short-dwell exchanges are performed at
night with the aid of an automated cycler machine. Other peritoneal
dialysis treatments consist of intermittent regimens (Fig. 4-2A-C).
During peritoneal dialysis, solutes and fluids are exchanged between
the capillary blood and the intraperitoneal fluid through a biologic
membrane, the peritoneum. The three-layered peritoneal membrane
consists of 1) the mesothelium, a continuous monolayer of flat cells,
and their basement membranes; 2) a very compliant interstitium; and
3) the capillary wall, consisting of a continuous layer of mainly non-
fenestrated endothelial cells, supported by a basement membrane. The
mesothelial layer is considered to be less of a transport barrier to fluid
and solutes, including macromolecules, than is the endothelial layer
[1]. The capillary endothelial cell membrane is permeable to water
through aquaporins (radius of approximately 0.2 to 0.4 nm) [2]. In
addition, small solutes and water are transported through ubiquitous
small pores (radius of approximately 0.4 to 0.55 nm). Sparsely popu-
lated large pores (radius of approximately 0.25 nm, perhaps mainly
venular) transport macromolecules passively. Diffusion and convection CHAPTER
move small molecules through the interstitium with its gel and sol
phases, which are restrictive owing to the phenomenon of exclusion
4
[3,4]. The splanchnic blood flow in the normal adult ranges from 1.0
to 2.4 L/min, arising from celiac and mesenteric arteries [5]. The lym-
phatic vessels located primarily in the subdiaphragmatic region drain
fluid and solutes from the peritoneal cavity through bulk transport.
4.2 Dialysis as Treatment of End-Stage Renal Disease
The extent of lymph drainage from the peritoneal cavity is a sub- fraction of glucose absorbed from the dialysate at specific times can
ject of controversy owing to the lack of a direct method to mea- be determined by the ratio of dialysate glucose concentrations
sure lymph flow. at specific times to the initial level in the dialysis solution. Tests
Dialysis solution contains electrolytes in physiologic con- are standardized for the following: duration of the preceding
centrations to facilitate correction of acid-base and electrolyte exchange before the test; inflow volume; positions during
abnormalities. High concentrations of glucose in the dialysis inflow, drain, and dwell; durations of inflow and drain; sam-
solution generate ultrafiltration in proportion to the overall pling methods and processing; and laboratory assays [7].
osmotic gradient, the reflection coefficients of small solutes Creatinine and urea clearance rates are the most commonly used
relative to the peritoneum, and the peritoneal membrane indices of dialysis adequacy in clinical settings. Contributions
hydraulic permeability. Removal of solutes such as urea, creati- of residual renal clearances are significant in determining the
nine, phosphate, and other metabolic end products from the body adequacy of dialysis. The mass-transfer area coefficient (MTAC)
depends on the development of concentration gradients between represents the clearance rate by diffusion in the absence of ultrafil-
blood and intraperitoneal fluid, and the transport is driven by the tration and when the rate of solute accumulation in the dialysis
process of diffusion. The amount of solute removal is a function solution is zero. Peritoneal clearance is influenced by both blood
of the degree of its concentration gradient, the molecular size, and dialysate flow rates and by the MTAC [8]. Therefore, the
membrane permeability and surface area, duration of dialysis, and maximum clearance rate can never be higher than any of these
charge. Ultrafiltration adds a convective component proportion- parameters. At infinite blood and dialysate flow rates, the clearance
ately more important as the molecular size of the solute increases. rate is equal to the MTAC and is mass-transfer–limited. Large mol-
The peritoneal equilibration test is a clinical tool used to charac- ecular weight solutes are mass-transfer–limited; therefore, their
terize the peritoneal membrane transport properties [6]. Solute clearance rates do not increase significantly with high dialysate flow
transport rates are assessed by the rates of their equilibration rates [9]. In CAPD, blood flow and MTAC rates are higher than is
between the peritoneal capillary blood and dialysate (see Fig. 4-8). the maximum achievable urea clearance rate. However, the urea
The ratio of solute concentrations in dialysate and plasma at specif- clearance rate approximately matches the dialysate flow rate, sug-
ic times during the dwell signifies the extent of solute transport. The gesting that the dialysate flow rate limits CAPD clearances.
Right
2.0
1.0
0.0
B Exchanges, n
Principles of Peritoneal Dialysis 4.3
FIGURE 4-2
Day Night Day Night Intermittent peritoneal dialysis regimens.
Left Peritoneal dialysis is performed every day
2.0
but only during certain hours. A, In daytime
ambulatory peritoneal dialysis (DAPD),
1.0 multiple manual exchanges are performed
during the waking hours. B, Nightly peri-
0.0 toneal dialysis (NPD) is also performed
while patients are asleep using an automated
A
cycler machine. One or two additional day-
time manual exchanges are added to
enhance solute clearances.
2.0
1.0
0.0
B
Solute Removal
24
Blood urea nitrogen, mg/dL
100
20
80
Creatinine, mg/dL
16
60
40 12
20 8
0 Dialysate
Blood 4 Dialysate
–20 Blood
0 80 160 240 320 400 480 560 0
0 40 80 120 160 200 240 280 320 360
A Time, min B Time, min
FIGURE 4-3
Solute removal. Solute concentration gradients are at maximum at rate by either increasing the intraperitoneal dialysate volume per
the beginning of dialysis and diminish gradually as dialysis progress- exchange or increasing the frequency of exchange. By convection
es. As the gradients diminish, the solute removal rates decrease. or enhanced diffusion, solutes are able to accompany the bulk flow
Solute removal can be enhanced by increasing the dialysate flow of water. (From Nolph and coworkers [10]; with permission.)
4.4 Dialysis as Treatment of End-Stage Renal Disease
1.0 1.0
0.9 0.9
0.8
0.7 0.7
0.6 0.6
0.5 0.5
0.4 Urea 0.4 Urea
0.3 Creatinine 0.3 Creatinine
Uric acid Uric acid
0.2 Phosphorus 0.2 Phosphorus
0.1 Inulin 0.1 Inulin
Calcium Calcium
0 100 200 300 400 500 0 100 200 300 400 500
A Dwell time, min B Dwell time, min
FIGURE 4-4
Solute removal. The rates of change of solute concentrations are is near 1.0. Smaller size solutes (ie, urea and creatinine) diffuse
similar for 1.5% dextrose dialysis solutions (panel A) and 4.25% across the membrane faster, equilibrate sooner, and are influenced
dextrose dialysis solutions (panel B). Hypertonic exchanges enhance more by exchange frequency as compared with larger size solutes
solute removal owing to larger drain volumes. Net solute diffusion (ie, uric acid, phosphates, inulin, and proteins). (From Nolph and
ceases at equilibration when the dialysate to plasma solute ratio (D/P) coworkers [10]; with permission.)
Total dialysate volume (V)
Creatinine clearance
per exchange (Ccr)
Creatnine dialysate to
D/P=1
plasma ratio (D/P)
High transport
1.0 2600 Ccr=V
2
Low transport
2300
0.5 1
2000
NIPD DAPD CAPD Ccr=V × D/P
1700 NTPD CCPD CCPD
0 (NE) (DE) 0
1 2 3 4 5 6 7 0 1 2 3 4 5 6 7
1 2 3 4 5 6 7
A Dwell time, h B Dwell time, h C Dwell time, h
FIGURE 4-5
Solute removal. In a highly permeable membrane, smaller molecules Consequently, intraperitoneal volume peaks later. Ultrafiltration in
(ie, urea and creatinine) are transported at a faster rate from the a low transporter peaks late during dwell time. Therefore, a low
blood to dialysate than are larger molecules, enhancing solute removal. transporter continues to generate ultrafiltration even after 8 to 10
Similarly, glucose (a small solute used in the peritoneal dialysis solution hours of dwell. The solute creatinine dialysate to plasma ratio
to generate osmotic force for ultrafiltration across the peritoneal mem- (D/P) increases linearly during the dwell time. Patients with average
brane) is also transported faster, but in the opposite direction. This solute transfer rates have ultrafiltration and mass transfer patterns
high transporter dissipates the osmotic force more rapidly than does between those of high and low transporters. NIPD—nightly inter-
the low transporter. Both osmotic and glucose equilibriums are mittent peritoneal dialysis; NTPD—nighttime tidal peritoneal dialy-
attained eventually in both groups, but sooner in the high trans- sis; DAPD—daytime ambulatory peritoneal dialysis; CAPD—con-
porter group. Intraperitoneal volume peaks and begins to diminish tinuous ambulatory peritoneal dialysis; CCPD (NE)—continuous
earlier in the high transporter group. When the membrane is less cyclic peritoneal dialysis (night exchange); CCPD (DE)—continu-
permeable, solute removal is lower, ultrafiltration volume is larger ous cyclic peritoneal dialysis (day exchange). (From Twardowski
at 2 hours or more, and glucose equilibriums are attained later. [11]; with permission.)
Principles of Peritoneal Dialysis 4.5
FIGURE 4-6
150 Solute sieving. A, Dialysate sodium concentration is initially reduced and tends to return
Serum and dialysate to baseline later during a long dwell exchange of 6 to 8 hours. B, Dialysate sodium con-
Sodium, mLq/L
140
130 centration decreases, particularly when using 4.25% dextrose dialysis solution, because of
120 1.5% dextrose
dialysis solutions the sieving phenomenon. Removal of water during ultrafiltration unaccompanied by sodium,
110 in proportion to its extracellular concentration, is called sodium sieving [7,12]. The peri-
100 toneum offers greater resistance to the movement of solutes than does water. This probably
90
Inflow
relates to approximately half the ultrafiltrate being generated by solute-free water movement
0 100 200 300 400 500
through aquaporins channels. Therefore, ultrafiltrate is hypotonic compared with plasma.
A Dwell time, min Dialysate chloride is also reduced below simple Gibbs-Donnan equilibrium, particularly
during hypertonic exchanges. Patients with a low peritoneal membrane transport type tend
to reduce dialysate sodium concentration more than do other patients. Therefore, during a
short dwell exchange of 2 to 4 hours, net electrolyte removal per liter of ultrafiltrate is
well below the extracelluar fluid concentration. As a result, severe hypernatremia, excessive
150 thirst, and hypertension may develop. This hindrance can be overcome by lowering the
Serum and
Sodium, mLq/L
140 dialysate dialysate sodium concentration to 132 mEq/L. In patients who use cyclers with short dwell
130
4.25% dextrose exchanges and who generate large ultrafiltration volumes, lower sodium concentrations
120
110
dialysis solutions may need to be used (such as 118 mEq/L for 2.5% glucose solutions or 109 mEq/L for
100 4.25% solutions). In continuous ambulatory peritoneal dialysis with long dwell exchanges
90 of 6 to 8 hours, significant sieving usually does not occur, whereas in automated peritoneal
Inflow dialysis with short dwell exchanges, sieving may occur. Sieving predisposes patients to
0 100 200 300 400 500 thirst and less than optimum blood pressure control, especially in those who have low-nor-
B Dwell time, min mal serum sodium levels, those with low peritoneal membrane transporter rates, or both.
(From Nolph and coworkers [10]; with permission.)
FIGURE 4-7
Transcapillary ultrafiltration Fluid removal by ultrafiltration. During peritoneal dialysis, hyperosmolar glucose solution
Lymphatic absorption
600 generates ultrafiltration by the process of osmosis. Water movement across the peritoneal
membrane is proportional to the transmembrane pressure, membrane area, and membrane
hydraulic permeability. The transmembrane pressure is the sum of hydrostatic and osmotic
500 pressure differences between the blood in the peritoneal capillary and dialysis solution in
the peritoneal cavity. Net transcapillary ultrafiltration defines net fluid movement from the
peritoneal microcirculation into the peritoneal cavity primarily in response to osmotic
400 pressure. Net ultrafiltration would equal the resulting increment in intraperitoneal fluid
volume if it were not for peritoneal reabsorption, mostly through the peritoneal lymphatics.
mL/h
2600
2400
0 1 2 3 4
B Dwell time, h
4.6 Dialysis as Treatment of End-Stage Renal Disease
2000 Dialysate
Glucose, mOsm/L
Serum
Hypothetical
1000 glucose
equilibrium
0 1 2 3 4
D Dwell time, h
FIGURE 4-8
STANDARDIZED 4-HOUR PERITONEAL EQUILIBRATION TEST Standardized 4-hour peritoneal equilibra-
tion test. Dt/D0 glucose—final to initial
dialysate glucose ratio.
1. Perform an overnight 8- to 12-h preexchange.
2. Drain the overnight exchange (drain time not to exceed 25 min) with patient in the upright position.
3. Infuse 2 L of dialysis solution over 10 min with patient in the supine position. Roll the patient from side to side after
every 400-mL infusion.
4. After the completion of infusion (0 time) and at 120 min, drain 200 mL of dialysate. Take a 10-mL sample, and
reinfuse the remaining 190 mL into the peritoneal cavity.
5. Position the patient upright, and allow patient ambulation if able.
6. Obtain a serum sample at 120 min.
7. At the end of study (240 min), drain the dialysate with the patient in the upright position
(drain time not to exceed 20 min).
8. Measure the drained volume, and take a 10-mL sample from the drained volume after a good mixing.
9. Analyze the blood and dialysate samples for creatinine and glucose concentrations.
10. Correct the serum and dialysate creatinine concentrations for high glucose level (correction factor 0.000531415).
11. Calculate the dialysate to plasma ratios for creatinine, and so on, and calculate the Dt/D0 glucose.
FIGURE 4-9
Correction of creatinine levels
Equation to correct the creatinine levels in dialysate and serum.
Corrected creatinine (mg/dL) The creatinine levels in dialysate and serum need to be corrected
= Observed creatinine (mg/dL) – (glucose [mg/dL] x 0.000531415) for high glucose levels, which contribute to formation of noncreatinine
chromogens during the creatinine assay. The correction factor may
vary from one laboratory to another. In our laboratory at the University
of Missouri–Columbia, the correction factor is 0.000531415.
Accordingly, the corrected creatinine is calculated as in the equation.
The correction in the serum is minimal due to low blood sugar levels;
however, it is significant in dialysate, especially during the early
phase of dwell (0- and 2-hour dialysate samples).
Principles of Peritoneal Dialysis 4.7
FIGURE 4-10
Intraperitoneal residual volume Equation to calculate the intraperitoneal residual volume. Residual volume is the volume
Vin(S3 – S2) of dialysate remaining in the peritoneal cavity after drainage over 20 minutes. The residual
R=
(S1 – S3) volume can be determined by knowing the dilution factor for solutes such as potassium, urea,
and creatinine during the next instillation. The calculation of residual volumes is based on
the assumption that the mixing of fluid in the peritoneal cavity is instantaneous and com-
plete. This equation is used for the calculation, where Vin is instillation volume; S1 is solute
concentration in pretest exchange dialysate; S2 is solute concentration in instilled dialysis
solution; and S3 is solute concentration immediately after instillation (0 dwell time). The
residual volumes by urea, creatinine, glucose, potassium, and protein are calculated and
averaged for accuracy. The measurement of residual volumes is of limited clinical useful-
ness; however, it is of great value in a research setting in which accurate determination of
intraperitoneal volume is required.
FIGURE 4-11
1.1 1.1
Urea Creatinine Classification of peritoneal transport func-
tion. Based on the peritoneal equilibrium
0.9 0.9 test results, peritoneal transport function
Dialysis to plasma ratio
Dialysis to plasma ratio
1.1 35
Glucose Protein
Final to initial dialysate glucose ratio
30
Dialysate to plasma ratio × 1000
0.9
25
0.7
20
0.5
15
0.3 10
5
0.1
0
0 1/ 1 2 3 4
0 1/
2 1 2 3 4 2
C Hours D Hours
4.8 Dialysis as Treatment of End-Stage Renal Disease
0.90
ers [6]; with permission.)
0.7
0.5
0.80
0.3
Max H
+SD HA
0.1 –SD LA
Min L
0 0.70
1/ 0 1/ 1 2 3 4
0 2 1 2 3 4 2
E Hours F Hours
ADK vol05 ch p04 fig11F
1.1 3500
Corrected creatinine Max
+SD
3000 x
0.9 –SD
Min
2500
Dialysate to plasma ratio
0.7
2000
mL
0.5 1500
1000
0.3
H 500
HA
0.1 LA
L 0
0 Drain Residual Volume
0 1/
2 1 2 3 4 volume pre-eq post-eq
G Hours H
FIGURE 4-12
CLINICAL APPLICATIONS OF THE In clinical practice it is customary to perform the baseline standard-
PERITONEAL EQUILIBRATION TEST ized peritoneal equilibrium test (PET) approximately 3 to 4 weeks
after catheter insertion. The PET is repeated when complications
occur. The standardized test for clinical use measures dialysate
Peritoneal membrane transport classification creatinine and glucose levels at 0, 2, and 4 hours of dwell time
1. Choose peritoneal dialysis regimen. and serum levels of creatinine and glucose at any time during
2. Monitor peritoneal membrane function.
the test. The extensive unabridged test, as originally proposed
by Twardowski and coworkers [6], has become a very important
3. Diagnose acute membrane injury.
research tool.
4. Diagnose causes of inadequate ultrafiltration.
5. Diagnose causes of inadequate solute clearance.
6. Estimate dialysate to plasma ratio of a solute at time t.
7. Diagnose early ultrafiltration failure.
8. Predict dialysis dose.
9. Assess influence of systemic disease on peritoneal membrane function.
Principles of Peritoneal Dialysis 4.9
FIGURE 4-13
Baseline peritoneal equilibrium test Population distribution of peritoneal membrane transport types.
Baseline peritoneal equilibrium test results of patients on long-term
peritoneal dialysis in the United States suggest that approximately
High High average Low average Low
transporter transporter transporter transporter 68% have average transport rates, 16% have high transport rates,
D/P creatinine D/P creatinine D/P creatinine D/P creatinine and another 16% have low transport rates [6]. Similar distributions
of transport types have been documented worldwide [14–16].
D/P—dialysate to plasma ratio.
16% 68% 16%
FIGURE 4-14
Baseline peritoneal equilibrium test Using transport type to select a peritoneal dialysis regimen. Because
clearance rates continue to increase with time, patients with low
High High average Low average Low transport rates are treated with long dwell exchanges, ie, continu-
ous cyclic peritoneal dialysis (CCPD). Owing to the low rate of
NIPD NIPD High-dose CAPD increase in the dialysate to plasma ratio (D/P), the clearance rate
High-dose CCPD
DAPD CAPD High-dose CCPD only when significant per unit of time is augmented relatively little by rapid exchange
residual renal techniques such as nightly intermittent peritoneal dialysis (NIPD).
function is present On the contrary, the clearance per exchange rate over long dwell
exchanges would be less in patients with high transport rates.
During the short dwell time, patients with high transport rates
capture maximum ultrafiltration and small solutes are completely
equilibrated. Therefore, these patients are best treated with tech-
niques using short dwell exchanges, ie, NIPD or daytime ambulato-
ry peritoneal dialysis (DAPD). Patients with average transport rates
can be effectively treated with either short or long dwell exchange
techniques. CAPD—continuous ambulatory peritoneal dialysis.
FIGURE 4-15
1.0
0.97 Diagnosis of early ultrafiltration failure. The dialysate to plasma ratio (D/P) curve of sodi-
um, during the unabridged peritoneal equilibrium test (2.5% dextrose dialysis solution),
typically shows an initial decrease owing to the high ultrafiltration rate. Because of sodium
Dialysate to plasma ratio
0.92 sieving, the ultrafiltrate is low in sodium. Consequently, the dialysate sodium is lowered,
0.9 resulting in a lower D/P ratio of sodium. Later, during the dwell when ultrafiltration ceas-
0.88
es, dialysate sodium tends to equilibrate with that of capillary blood, returning the D/P
ratio of sodium to baseline. Absence of the initial decrease of the D/P of sodium is an indi-
0.85
cation of ultrafiltration failure and is typically seen in the early phase of sclerosing encap-
0.8 0.80
sulating peritonitis. (From Dobbie and coworkers [17]; with permission.)
High
High average
Low average
Low
0.7
0.0 1.0 2.0 3.0 4.0
4.10 Dialysis as Treatment of End-Stage Renal Disease
FIGURE 4-16
(DxV)
C= Creatinine and urea clearances rates. These rates are estimated by dividing the amount of
P
where C = clearance in mL/min: solute removed per unit of time by the plasma solute concentration. Alternatively, clearance
DxV = dialysate solute removed per minute; also can be estimated by multiplying the solute equilibration rate per unit of time by the
D = dialysate solute concentration; volume of dialysate into which equilibration occurred over the same unit of time. By con-
V = volume of dialysate in mL/min; and vention, the creatinine clearance rate is normalized to body surface area.
P = plasma solute concentration
The urea clearance is normalized to total body water (volume of urea distribution in the
or body) and is expressed as Kt/V. The Kt/Vvalue is a number without a unit ([mL/min min]/
C=(D/P) x V
mL). During intermittent dialysis, with a dialysate flow rate of 30 mL/min, the typical urea
where C = clearance in mL/exchange at time t; clearance is about 18 to 20 mL/min [18]. Increasing the dialysate flow rates to 3.5 to 12
D/P = solute equilibrium rate at time t; and
V = volume of dialysate at time t L/h by rapid exchanges increases the urea clearance rate to a maximum of 30 to 40 mL/min.
A Beyond this maximum rate, the clearance rate begins to decrease owing to the loss of mem-
brane-fluid contact time with infusion and drainage; inadequate mixing may also occur
Kt/V [19–22]. Clearance could be enhanced by increasing the membrane-solution contact [23].
where K = urea clearance in mL/min; Continuous dialysate flow techniques using either two catheters or double-lumen catheters
t = minutes of therapy; and also have enhanced the urea clearance rate to a maximum of 40 mL/min. At these high flow
V = volume of urea distribution or total
body water rates, poor mixing, channeling, abdominal pain, and poor drainage limit successful applica-
B tion. Maintaining a fluid reservoir in the peritoneal cavity (called tidal peritoneal dialysis)
and then replacing only a fraction of the intraperitoneal volume rapidly, increases clearance
rates by about 30% compared with the standard technique using the same doses owing to
maintaining fluid-membrane contact at higher dialysis-solution flow rates [24–29]. During
continuous ambulatory peritoneal dialysis (CAPD) in adults, the optimum volume that
ensures complete membrane-solution contact is about 2 L [30,32]. Successful use of 2.5-
and 3.0-L volumes has been reported in adult patients undergoing CAPD; however, hernial
complications are increased [32,33].
FIGURE 4-17
Mass-transfer area coefficient
The mass-transfer area coefficient (MTAC). The MTAC represents the clearance rate by
The diffusive mass transfer is estimated by
diffusion in the absence of ultrafiltration and when the solute accumulation in the dialysis
solution is zero [34–39]. MTAC is equal to the product of peritoneal membrane perme-
A ability (P) and effective peritoneal membrane surface area (S). Thus, when both capillary
M=I (C – C )
R P D
blood and dialysate flows are infinite, the clearance rate is directly proportional to the
where M = diffusive mass transfer: effective peritoneal surface area and inversely proportional to the overall membrane resis-
A = effective membrane surface area;
tance. However, infinite blood and dialysate flows cannot be achieved, and the maximum
I = coefficient of proportionality;
R = sum of all resistances; clearance rate is unattainable. The closest measurable value, the MTAC, was introduced.
Cp = solute concentration in the potential The MTAC represents an instantaneous clearance without being influenced by ultrafiltra-
capillary blood; and tion and solute accumulation in the dialysate. The MTAC is measured over a test exchange
CD = solute concentration in the dialysate during which at least two blood and dialysate samples are obtained at different dwell
A
times. The precision of the measurement is enhanced with more data points. The MTAC
is seldom used clinically; however, it is a very useful research tool.
Dividing both sides of the equation by solute
concentration in peripheral blood (CB) will
yield instantaneous clearance or the MTAC;
M A CP CD
CB
=K=I (
–
R CB CB (
B
References
1. Clough G, Michel CC: Quantitative comparisons of hydraulic perme- 22. Tenckhoff H, Ward G, Boen ST: The influence of dialysate volume
ability and endothelial intercellular cleft dimensions in single form and flow rate on peritoneal clearance. Proc Eur Dial Transplant Assoc
capillaries. J Physiol 1988, 405:563–576. 1965, 2:113–117.
2. Pannekeet MM, Mulder JB, Weening JJ, et al.: Demonstration of 23. Trivedi HS, Twardowski ZJ: Long-term successful nocturnal intermittent
aquaporin-CHIP in peritoneal tissue of uremic and CAPD patients. peritoneal dialysis: a ten-year case study. In Advances in Peritoneal
Peritoneal Dial Int 1996, 16(suppl 1):S54. Dialysis. Edited by Khanna R. Toronto, Canada: Peritoneal Dialysis
3. Flessner MF, Dedrick RL, Schultz JS: Exchange of macromolecules Publications; 1994:81–84.
between peritoneal cavity and plasma. Am J Physiol 1985, 248:H15. 24. Di Paolo N: Semicontinuous peritoneal dialysis. Dial Transplant
4. Flessner MF, Fenstermacher JD, Blasberg RG, Dedrick RL: Peritoneal 1978, 7:839–842.
absorption of macromolecules studied by quantitative autoradiography. 25. Finkelstein FO, Kliger AS: Enhanced efficiency of peritoneal dialysis
Am J Physiol 1985, 248:H26. using rapid, small-volume exchanges. ASAIO J 1979, 2:103–106.
5. Wade OL, Combes B, Childs AW, et al.: The effect of exercise on the 26. Twardowski ZJ, Nolph KD, Khanna R, et al.: Tidal peritoneal dialysis.
splanchnic blood flood and splanchnic blood volume in normal man. In Ambulatory Peritoneal Dialysis: Proceedings of the IVth Congress
Clin Sci 1956, 15:457. of the International Society for Peritoneal Dialysis, Venice, Italy, June
6. Twardowski ZJ, Nolph KD, Khanna R, et al.: Peritoneal equilibration 1987. Edited by Avram MM, Giordano C. New York: Plenum;
test. Peritoneal Dial Bull 1987, 7:138–147. 1990:145–149.
7. Ahearn DJ, Nolph KD: Controlled sodium removal with peritoneal 27. Twardowski ZJ, Prowant BF, Nolph KD, et al.: Chronic nightly tidal
dialysis. Trans Am Soc Artif Intern Organs 1972, 28:423. peritoneal dialysis (NTPD). ASAIO Trans 1990, 36:M584–M588.
8. Popovich RP, Moncrief JW: Kinetic modeling of peritoneal transport: 28. Twardowski ZJ: Tidal peritoneal dialysis: acute and chronic studies.
In Today’s Art of Peritoneal Dialysis. Edited by Trevino-Bacerra A, Eur Dial Transplant Nurses Assoc Eur Renal Care Assoc September
Boen FST. Basel, Switzerland: Karger; 1979:59–72. [Contributions to 1990, 15:4–9.
Nephrology, 1.] 29. Twardowski ZJ: Tidal peritoneal dialysis. In Dialysis Therapy. Edited
9. Twardowski ZJ: Physiology of peritoneal dialysis. In Clinical Dialysis. by Nissenson AR, Fine RN. Philadelphia: Hanley & Belfus;
Edited by Nissenson AR, Fine RN, Gentile DE, edn 3. Norwalk, CT: 1993:153–156.
Appleton & Lange; 1995:322. 30. Twardowski ZJ, Nolph KD, Prowant BF, et al.: Efficiency of high vol-
10. Nolph KD, Twardowski ZJ, Popovich RP, et al.: Equilibration of peri- ume low frequency continuous ambulatory peritoneal dialysis
toneal dialysis solutions during long dwell exchanges. J Lab Clin Med (CAPD). ASAIO Trans 1983, 29:53–57.
1979, 93:246–256. 31. Krediet RT, Boeschoten EW, Zuyderhoudt FMJ, et al.: Differences in
11. Twardowski ZJ: Nightly peritoneal dialysis (why? who? how? and the peritoneal transport of water, solutes and proteins between dialy-
when?). Trans Am Soc Artif Intern Organs 1990, 36:8–16. sis with two- and with three-litre exchanges [thesis]. In Peritoneal
Permeability in Continuous Ambulatory Peritoneal Dialysis Patients.
12. Nolph KD, Hano JE, Teschan PE: Peritoneal sodium transport during Edited by Krediet RT. Amsterdam, Holland: University of Amsterdam;
hypertonic peritoneal dialysis: physiologic mechanisms and clinical 1986:129–146.
implications. Ann Intern Med 1969; 70:931.
32. Twardowski Z, Janicka L: Three exchanges with a 2.5 liter volume
13. Mactier RA, Khanna R, Twardowski ZJ, et al.: Contribution of lym- for continuous ambulatory peritoneal dialysis. Kidney Int 1981,
phatic absorption to loss of ultrafiltration and solute clearances in 20:281–284.
continuous ambulatory peritoneal dialysis. J Clin Invest 1987,
80:1311–1316. 33. Twardowski ZJ, Prowant BF, Nolph KD, et al.: High volume, low fre-
quency continuous ambulatory peritoneal dialysis. Kidney Int 1983,
14. Zabetakis PM, Krapf R, DeVita MV, et al.: Determining peritoneal 23:64–70.
dialysis prescriptions by employing a patient-specific protocol.
Peritoneal Dial Int 1993, 13:189–193. 34. Randerson DH: Continuous ambulatory peritoneal dialysis-a critical
appraisal [thesis]. Sydney, Australia: University of New South Wales;
15. Wolf CJ, Polsky J, Ntoso KA, et al.: Adequacy of dialysis in CAPD and 1980.
cycler PD; the PET is enough. Peritoneal Dial Bull 1992, 8:208–211.
35. Pyle WK: Mass transfer in peritoneal dialysis [thesis]. Austin: University
16. Struijk DG, Krediet RT, Koomen GCM, et al.: A prospective study of of Texas; 1981.
peritoneal transport in CAPD. Kidney Int 1994, 1739–1744.
36. Farrell PC, Randerson DH: Mass transfer kinetics in continuous ambu-
17. Dobbie JW, Krediet RT, Twardowski ZJ, et al.: A 39-year-old man latory peritoneal dialysis. In Proceedings of the First International
with loss of ultrafiltration. Peritoneal Dial Int 1994, 14:384–394. Symposium on Continuous Ambulatory Peritoneal Dialysis. Edited by
18. Nolph KD, Popovich RP, Ghods AJ, et al.: Determinants of low Legrain M. Amsterdam, Holland: Excerpta Medica; 1980:34–41.
clearances of small solutes during peritoneal dialysis. Kidney Int 37. Pyle WK, Moncrief JW, Popovich RP: Peritoneal transport evaluation
1978, 13:117–123. in CAPD. In CAPD Update. Edited by Moncrief JW, Popovich RP.
19. Boen ST: Kinetics of Peritoneal Dialysis. Baltimore, MD: Medicine; New York: Masson; 1981:35–52.
1961:243–287. 38. Pyle WK, Popovich RP, Moncrief JW: Mass transfer in peritoneal dial-
20. Penzotti SC, Mattocks AM: Effects of dwell time, volume of dialysis ysis. In Advances in Peritoneal Dialysis. Edited by Gahl GM, Kessel
fluid, and added accelerators on peritoneal dialysis of urea. J Pharm M, Nolph KD. Amsterdam, Holland: Excerpta Medica; 1981:41–46.
Sci 1971, 60:1520–1522. 39. Garred LF, Canaud B, Farrell PC: A simple kinetic model for assessing
21. Pirpasopoulos M, Lindsay RM, Rahman M, et al.: A cost-effectiveness peritoneal mass transfer in continuous ambulatory peritoneal dialysis.
study of dwell time in peritoneal dialysis. Lancet 1972, 2:1135–1136. ASAIO J 1983, 6:131–137.
Dialysis Access
and Recirculation
Toros Kapoian
Jeffrey L. Kaufman
John Nosher
Richard A. Sherman
S
ince its inception, hemodialysis has been bedeviled by problems
of vascular access. Access, from the time of creation and through-
out a patient’s dialysis life, consumes significant time, effort, and
expense and creates much anxiety and risk for patient and family.
Vascular access complications remain the single leading cause of hos-
pitalization and expense for dialysis patients. Some, such as infected
access sites, are potentially life threatening. It is common for an access
problem to precipitate a crisis related to the end of a patient’s dialysis
life. Despite the advances made in hemodialysis technology, the same
vascular access problems that plagued dialysis pioneers continue
today to confound patient care teams.
CHAPTER
5
5.2 Dialysis as Treatment of End-Stage Renal Disease
FIGURE 5-2
Creation of a Brescia-Cimino (radial-cephalic) fistula. The native
vein arteriovenous fistula is the preferred choice for hemodialysis
access. This simple and effective procedure, in which an artery is
connected to an adjacent vein to provide a large volume of blood
flow into the superficial venous system, has become less common
in recent years. The ideal artery has minimal wall calcification, so
that dilation can occur with time and allow unimpeded flow. In
addition, the artery should not be affected by proximal stenosis,
the most common site being an ostial lesion in the subclavian
artery. Ideally, the outflow vein is subjected to minimal dissection
or manipulation during the surgical procedure. Forcible distension
of veins and rough handling of arteries leads to formation of
neointimal fibrous hyperplasia and localized stenosis.
The first autogenous access site described was radial-cephalic at
the level of the radial styloid process. These can be constructed end-
vein to side-artery, A and B, or side-to-side, C, between the two ves-
sels. The exposure is conveniently obtained using a transverse inci-
sion at the wrist, just proximal to the radial styloid process, where
the artery and cephalic vein lie close to one another. In general, the
two vessels are just far enough apart so that an end-to-side tech-
nique is best. When the vessels overlie each other, some surgeons
prefer the side-to-side technique, which allows reversal of blood
flow into the dorsum of the hand and then via collaterals into the
forearm, theoretically leading to better flow volume over time.
Dialysis Access and Recirculation 5.3
incidence of steal is likely the result of the lower flow rate associat-
ed with these accesses. Additionally, such accesses have low rates
of thrombosis and infection. The photograph shows a mature
Brescia-Cimino fistula in a patient with longstanding diabetes. The
fistula outflow vein has numerous aneurysmal segments, and,
although they are associated with some tendency toward flow stag-
nation, they are of no harm to the patient’s dialysis life. They do,
however, become obvious targets for the dialysis technical staff,
who have a tendency to puncture them repeatedly rather than to
utilize new needle insertion sites. The patients arm also demon-
strates marked muscle atrophy secondary to advanced diabetic neu-
ropathy, which particularly involves the thenar eminence and the
FIGURE 5-3 interosseus muscle groups. Complaints of weakness and loss of
The Brescia-Cimino (radial-cephalic) fistula. The radial-cephalic fis- grip strength in the arm are common and may represent symptoms
tula offers many advantages. It is simple to create and preserves of steal. In this case, however, the symptoms are due to the intrin-
more proximal vessels for future access construction. The lower sic loss of muscle mass, rather than to steal.
A
FIGURE 5-4
The brachial-cephalic vein fistula. If a radial-cephalic vein fistula cannot be constructed,
the next best choice for vascular access is the brachial-cephalic vein fistula. Accesses that
utilize the brachial artery have the advantage of higher blood flow rates than those that
use the radial artery. Although this may improve the efficiency of hemodialysis, it is also
associated with increased risk of arm edema and steal. A, The native anatomy of the ante-
cubital veins somewhat resembles the letter M. A more complete depiction is seen in B.
The medial volar venous flow enters the basilic system; lateral volar flow enters the
cephalic system; and the central connector, which includes a deep tributary, connects the
brachial (venae comitantes) system at the brachial artery bifurcation. To create an antecu-
bital autogenous site, there are two general approaches; the surgeon either mobilizes the
cephalic vein directly into the brachial artery (C) or “anastomoses” the deep connector
between the median antecubital vein and the brachial veins directly to the adjacent artery.
It is also possible to prepare a native vein arteriovenous fistula in the antecubital fossa by
transposing brachial or basilic veins from the deeper compartment of the brachium to the
subcutaneous tissue.
C
5.4 Dialysis as Treatment of End-Stage Renal Disease
FIGURE 5-6
Trends in dialysis access sites. Despite our understanding of
hemodialysis access and the advantages and disadvantages of the
various options available, there is an alarming trend away from
the use of native vein fistulas. Of even more concern is the increas-
ing number of patients who begin dialysis without a permanent
vascular access in place and the increasing prevalence of central
vein catheters. It is not clear whether these trends are the result of
age, comorbid conditions such as diabetes and peripheral vascular
disease, or simply the untoward effect of late nephrology referral.
Although central vein catheters were initially designed for tempo-
rary use while an arteriovenous vascular access was being con-
structed, improvements in design have led to their being used for
permanent dialysis access. Nevertheless, central vein catheters,
while popular with patients because they obviate “being stuck,”
are the source of a variety of access complications, including infec-
tion, central vein stenosis, and thrombosis.
Dialysis Access and Recirculation 5.5
A B
FIGURE 5-7
Arteriovenous fistula anastomotic stenosis. Arteriovenous fistulas most common site for a stenotic lesion in native vein fistulas.
exhibit better long-term patency compared with polytetrafluoroeth- B, Angioplasty successfully eliminated the anastomotic stenosis.
ylene (PTFE) grafts. A, This arteriogram, performed by injecting Limitations on balloon size are often encountered when treating
the brachial artery, demonstrates an end-to-side arteriovenous fistu- lesions in arteriovenous fistulas because a portion of the balloon
la involving the brachial artery and the cephalic vein. The arrow must often extend into the donor artery, which typically is of
indicates an area of narrowing adjacent to the anastomosis, the smaller diameter than the outflow vein.
FIGURE 5-8
Exposed polytetrafluoroethylene (PTFE) graft. Proper placement of
a PTFE graft is crucial for its long-term survival. The graft cannot
be too short, as it will deteriorate quickly from puncture limited to
only a few sites; if it is too long, however, it will have a greater
impedance to flow and a tendency toward thrombosis. The graft
should be neither too deep to the skin nor too shallow. When the
graft is too shallow, puncture by the dialysis staff is easier, but the
skin may be eroded with scarring from repeated use. This photo-
graph shows a linear forearm graft with a segment of exposed
PTFE. An exposed graft is a serious problem for several reasons.
First, exposure of actual puncture holes eventually leads to hemor-
rhage. Second, an exposed graft is, by definition, infected.
Although some cases have been treated successfully with rotational
skin flaps and a long course of antibiotics, the majority do not
heal. The ideal treatment is removal of the segment of exposed
graft, splicing a segment of new PTFE away from the site of expo-
sure, and allowing secondary wound healing.
5.6 Dialysis as Treatment of End-Stage Renal Disease
A B
FIGURE 5-9
Extravasation injury to the access site. A, A relatively fresh seg- potentially huge volume of fluid can enter the soft tissue before
ment of polytetrafluoroethylene graft was removed during a revi- the pump stops in response to the alarm for elevated venous pres-
sion procedure. There is virtually no fibrosis or calcification (asso- sure. In many cases, the graft is unusable for weeks after such an
ciated with repeated puncture). The luminal surface displays the episode. Continued use of the access in this setting may result in
results of multiple sites of puncture and healing. Among the most loss of the access site. B, In this example, the infiltration was com-
dramatic and troublesome complications of dialysis is access infil- posed of approximately 400 mL of priming crystalloid and blood,
tration. In most cases the infiltration is minor and usually results located both deep and superficial to the investing fascia of the
from either inadequate hemostasis at the end of dialysis or needle arm. The access remained patent and was eventually restored to
perforation through the access site. Extravasation injury to the function; however, a series of percutaneous drainage procedures
access is more likely when a needle errantly transfixes a graft or and open drainage were necessary. Compartment syndrome, with
vein or when it accidentally becomes dislodged into the subcuta- loss of distal motor function or sensation in the arm, is another
neous tissue. The venous return needle presents the biggest prob- concern in this setting, and drainage must be performed to treat
lem. In the face of typical pump speeds of 400 to 500 mL/min a this surgical emergency.
FIGURE 5-10
Outflow vein stenosis. Stenotic lesions are most often found
at a polytetrafluoroethylene (PTFE) graft’s venous anastomotic
site or within its outflow vein. A, Radiograph depicting an
angioplasty balloon inflated across an outflow vein with a
stenotic lesion. The “waist” in the balloon (arrow) indicates the
location of the stenosis. With increasing inflation pressure the
waist disappears, an indication of successful angioplasty. Failure
to eliminate the waist in the balloon indicates incomplete dilata-
tion of the lesion. Occasionally, outflow vein stenoses are very
resistant to dilatation and require high inflation pressures. This
is not surprising given the amount of scarring and intimal hyper-
plasia that can develop in a dialysis access site. B, Resected
graft-venous anastomosis from a one-year-old PTFE graft. The
A vein wall seen here is enormously thickened. Angioplasty of
lesions such as these is often unsuccessful, as this rigid material
is likely to rebound to its stenotic state with any manipulation.
B
Dialysis Access and Recirculation 5.7
A B
C D
be necessary to permit removal of this material under direct visual-
ization. Failure to remove this meniscus invariably leads to rethrom-
bosis. B, This type of clot is demonstrated in an arteriogram per-
formed through the brachial artery following thrombolytic therapy.
The arterial end of this polytetrafluoroethylene (PTFE) graft demon-
strates a residual intraluminal thrombus (arrow), which is typical of
the platelet-rich plug or arterial type thrombus. A third type of clot
(not shown) consists of a white laminar material that lines the graft
over time, especially in sites of repeated puncture. This material can
create a stenosis along the body of the graft and may be removed by
curettage at the time of thrombectomy using an atherectomy
catheter. Failure to remove this material decreases blood flow
through the graft and may lead to rethrombosis. According to
Poiseuille’s law, if blood pressure remains constant, a 6-mm graft
with 1 mm of circumferential laminar clot accommodates only 20%
of the flow originally present, since flow is inversely related to the
fourth power of the radius.
E Eighty percent of thrombosed accesses have an associated stenotic
lesion. C, An eccentric focal stenosis is demonstrated at the anasto-
FIGURE 5-11 mosis of a PTFE forearm graft and its outflow vein (arrow), which
Graft thrombosis due to outflow vein stenosis requiring use of an did not respond to percutaneous transluminal angioplasty. The lesion
atherectomy catheter. Thrombectomy of a dialysis access site involves was subsequently resected using a Simpson atherectomy catheter,
removal of three types of clot. A, The body of a thrombosed access which consists of a concealed cutting chamber that is deflected into
contains a red or purplish thrombus that is often gelatinous. It is eas- contact with the stenotic lesion of the vessel wall by inflating the
ily removed with a balloon-tipped thrombectomy/embolectomy associated balloon. With the lesion projecting into the cutting cham-
catheter. This photograph also demonstrates the small meniscus of ber, a high-speed cylindrical cutting blade resects tissue into a collect-
firm, laminar, platelet-rich clot that usually obstructs arterial inflow. ing chamber. This chamber is rotated sequentially until the circum-
On occasion, it is also found at the venous end. This type of clot can ference of the lesion has been treated. D, The Simpson atherectomy
be tenacious and may not be removed with thrombolytic therapy or catheter is placed across the stenotic lesion. E, The postprocedure
the balloon catheter. A cutdown at the arterial end of the graft may venogram shows that the lesion was successfully resected.
5.8 Dialysis as Treatment of End-Stage Renal Disease
FIGURE 5-12
Pulse spray catheter. To increase the efficiency of drug thrombolysis,
pulse spray catheters are often used. The technique involves embed-
ding the catheter within the clot and intentionally obstructing the
catheter end hole with a guidewire. When the fibrinolytic agent is
injected, it is forced out through the catheter sideholes in jets and
permeates the clot. With this method, a larger surface area of clot
is exposed to the fibrinolytic agent.
FIGURE 5-13
Thrombectomy brush. Several types of mechanical thrombectomy
devices have been developed as alternatives to pharmaceutical
fibrinolysis. All mechanically macerate or disrupt clot into small
fragments that embolize into the central veins and, eventually, the
pulmonary vascular bed. This photograph demonstrates a brush
attached to a motor drive that imparts high-speed rotary motion
to disrupt the thrombus. The danger of most mechanical devices
is the risk of vascular injury.
A B
C D
FIGURE 5-14
Outflow vein stenosis with stenting. A, Arteriography in this develop vigorous fibrosis at the venous site of a stent. D, This
patient with a Brescia-Cimino fistula demonstrates stenosis of the photograph demonstrates what had occurred only 1 month after
outflow vein approximately 15 cm central to the fistula (arrow). stent placement. Stents can be a problem when dealing with sub-
B, Percutaneous transluminal angioplasty was performed in this sequent vascular access dysfunction. During thrombectomy, the
patient; however, because of immediate elastic recoil, the lesion tiny wires of a stent can puncture balloon catheters. When stent-
looks no different after angioplasty. C, Following stent placement ed segments restenose, it is impossible to perform open patch
(arrow), there is no residual stenosis, and good flow through the angioplasty over such segments, and it becomes necessary to
stent is apparent. Stents have proven controversial in access sites. jump to a different venous outflow site. It is not clear whether
Although they may improve patency in central vein stenoses (vide stents in or adjacent to dialysis grafts are cost effective in main-
infra), in the periphery they may be a hindrance. Some patients taining graft patency.
Dialysis Access and Recirculation 5.9
A B
FIGURE 5-15
Intragraft stenosis. A, This arteriogram demonstrates a forearm atherectomy or surgical revision. Since this region of the access is
loop polytetrafluoroethylene (PTFE) graft with an intragraft stenosis subject to needle cannulation, the placement of a stent would be
(arrow). Stenotic lesions in this site are less common than those inadvisable. Intragraft stenoses may be located between the sites of
involving either the venous anastomosis or the outflow vein. the arterial and venous needle placements during dialysis. If so, the
B, These lesions can be treated successfully with percutaneous trans- most common screening studies, namely venous pressure measure-
luminal angioplasty (arrow). In cases where angioplasty is unsuccess- ments and recirculation, do not have abnormal findings and the
ful, intragraft stenoses can also be treated using percutaneous lesion may remain undetected until access thrombosis develops.
A B
FIGURE 5-16
Aneurysmal degeneration. Severe aneurysmal degeneration poses a significant surgical prob-
lem for both patient and surgeon. A, Photograph demonstrating an anastomotic aneurysm
in a loop forearm polytetrafluoroethylene (PTFE) graft. This aneurysm is an example of the
type of degenerative changes that occasionally occur in both arteries and veins subjected to
turbulence and high tangential wall stress. This is common in the native circulation in areas
of poststenotic dilatation. The PTFE graft with high flow volumes manifested the enlarge-
ment of the venous outflow. This bulge, which constitutes a segment of flow stagnation, is
associated with increased risk of thrombosis over time. Since this would jeopardize the
long-term function of the access, the area was revised by interposing a short segment of
PTFE to a new venous outflow adjacent to the aneurysmal segment. B, Radiograph demon-
strating a pseudoaneurysm in the midportion of a forearm loop PTFE graft (arrow). This
lesion represents a communication between the graft and a confined space in the tissue sur-
rounding the graft and is a common finding in dialysis patients. C, A pseudoaneurysm in a
patient with a 3-year-old left groin PTFE graft. Because of the patient’s severe phobia of
central vein catheters, this access was revised in two separate procedures to maintain dialy-
sis continuity. The lateral area of the loop was initially replaced, and when this was healed
C and functioning well the medial segment was replaced.
5.10 Dialysis as Treatment of End-Stage Renal Disease
FIGURE 5-17
Vascular steal. Vascular steal is a common problem of dialysis access sites. The principle
of steal is related to two phenomena: 1) calcification or stenosis in the inflow arterial seg-
ment proximal to an access site (so that the native artery cannot dilate to meet the increas-
ing demands for flow volume); 2) and an outflow arterial bed in parallel to the fistula origin
with higher net vascular resistance than the fistula conduit. If both of these are present,
blood flow is diverted to the access site in association with a drop in perfusion pressure to
the most acral tissues, the fingers. When steal is severe, trauma to the digits leads to gan-
grene. Several treatment strategies are available to the surgeon. The access can be “band-
ed,” or purposefully stenosed at its origin to divert flow to the ischemic site. The access
can be revised using a tapered graft or the point of origin of the access can be moved more
proximally in the arterial tree, in the hope of allowing full flow without diverting distal
perfusion pressure. Additionally, one can perform a variety of bypass procedures to divert
higher-pressure proximal blood to increase distal perfusion pressure. In severe cases, either
the access or the distal digits may be sacrificed to preserve the other.
screening methods may help detect grafts at high risk for thrombo-
sis at a point where graft revision (surgical or radiologic) may
increase its longevity.
Measurement of graft blood flow (using Doppler imaging, ultra-
sound dilution, or another method) is increasingly available and
may be the best screening method. When graft flow declines below
dialyzer blood flow (E), blood flows between the needles (F) in a
retrograde direction. This development is called recirculation, since
it results in repeated uptake and dialysis of blood that has just been
dialyzed. Recirculation can be detected by finding evidence that
blood from the venous cannula is being taken up by the arterial
cannula. This is most often recognized by the finding of an arterial
blood urea nitrogen value below that in blood entering the graft.
A stenotic lesion in an outflow vein tends to increase the pressure
in the vein and graft (G) between the stenosis and the venous nee-
dle. This pressure usually ranges from 25 to 50 mm Hg but may
increase to more than 70 mm Hg in the presence of stenosis. This
pressure can be measured directly or can be estimated from the
venous pressure monitor on the dialysis machine at zero blood
FIGURE 5-18 flow (adjusting for the difference in height between the graft and
Vascular access screening methods. Dialysis grafts have a high inci- the transducer). To increase accuracy, this pressure can be normal-
dence of thrombosis, the risk of which increases when graft flow ized by dividing it by the mean arterial pressure. More commonly,
rates (A) fall below 600 to 700 mL/min, particularly with stenotic this intragraft pressure is determined indirectly by using the dialysis
lesions in or near the graft. Most often, stenoses occur just distal to machine’s pressure transducer and a pump speed of 200 mL/min.
the graft-vein anastomosis (B) but they can occur proximal to the In this case the measured pressure often exceeds 100 mm Hg in a
graft-artery anastomosis (C) or within the graft itself (D). Various normal graft, owing to the resistance in the venous needle.
Dialysis Access and Recirculation 5.11
FIGURE 5-20
Central vein steno-
sis. A, Venogram of
the central outflow
veins performed in
a patient with a left
upper extremity
polytetrafluoroeth-
ylene graft and arm
edema, B.
(Continued on
next page)
A B
5.12 Dialysis as Treatment of End-Stage Renal Disease
A B
FIGURE 5-21
Stent deployment. When angioplasty fails, metal stents are intro-
duced to treat outflow vein occlusion. These stents are either balloon
expandable or self-expanding. The stages of deployment of the self-
expanding Wallstent (Schneider, Inc, Division of Pfizer Hospital
Products, Minneapolis, MN) are seen in these radiographs. A, The
radiopaque stent is positioned across the lesion to be treated. B, As
the deployment envelope is gradually withdrawn, the stent begins to
expand (arrow). These stents shorten during deployment, and this
factor must be taken into consideration for proper placement. C, An
angioplasty balloon (arrow) is placed in the proximal portion of this
completely deployed stent to achieve further expansion.
(Continued on next page)
C
Dialysis Access and Recirculation 5.13
D E
FIGURE 5-22
Central vein catheter complications. A, This
radiograph demonstrates the tip of this dialy-
sis catheter abutting the wall of the left
innominate vein at its junction with the supe-
rior vena cava. To maintain adequate dialysis
flow rates and minimize fibrin sheath forma-
tion, it is important for the catheter tip to be
in the superior vena cava, near or in the right
atrium. B and C, Injection of contrast
through these dialysis catheters demonstrates
the contrast outlining the outside of the distal
portion of the catheter (arrows). This finding
is characteristic of a fibrin sheath with con-
trast medium trapped between the fibrin
sheath and the outer wall of the catheter.
Fibrin sheaths are associated with a reduction
(often severe) in the achievable blood flow
A rate and, as a result, inadequate dialysis
delivery. They can be lysed by instilling large
doses of urokinase (typically 250,000 units)
through the catheter ports. If thrombolytic
therapy is unsuccessful, the fibrin sheath can
be stripped using a snare loop. Although
these catheters can function remarkably well,
they are prone to thrombosis.
(Continued on next page)
B C
5.14 Dialysis as Treatment of End-Stage Renal Disease
FIGURE 5-23
Translumbar catheter placement. Patients receiving chronic hemodialysis may exhaust
potential sites for permanent vascular access. Additionally, after long-term use of central
vein catheters, these sites also develop irreversible occlusion. In most cases, these patients
are trained for peritoneal dialysis; however, some patients cannot tolerate this modality.
This patient failed all attempts at arteriovenous and central vein access placement, includ-
ing those involving the vessels of the lower extremity. Peritoneal dialysis was not possible
owing to recurrent disabling pleural effusions. Translumbar placement of tunneled
catheters (arrow) into the inferior vena cava can provide a long-term solution for the
patient with no apparent remaining access sites.
The Dialysis Prescription
and Urea Modeling
Biff F. Palmer
H
emodialysis is a life-sustaining procedure for the treatment of
patients with end-stage renal disease. In acute renal failure the
procedure provides for rapid correction of fluid and electrolyte
abnormalities that pose an immediate threat to the patient’s well-being. In
chronic renal failure, hemodialysis results in a dramatic reversal of uremic
symptoms and helps improve the patient’s functional status and increase
patient survival. To achieve these goals the dialysis prescription must
ensure that an adequate amount of dialysis is delivered to the patient.
Numerous studies have shown a correlation between the delivered dose
of hemodialysis and patient morbidity and mortality [1–4]. Therefore, the
delivered dose should be measured and monitored routinely to ensure
that the patient receives an adequate amount of dialysis. One method
of assessing the amount of dialysis delivered is to calculate the Kt/V. The
Kt/V is a unitless value that is indicative of the dose of hemodialysis.
The Kt/V is best described as the fractional clearance of urea as a func-
tion of its distributional volume. The fractional clearance is opera-
tionally defined as the product of dialyzer clearance (K) and the treat-
ment time (t). Recent guidelines suggest that the Kt/V be determined by
either formal urea kinetic modeling using computational software or
by use of the Kt/V natural logarithm formula [5]. The delivered dose
also may be assessed using the urea reduction ratio (URR).
A number of factors contribute to the amount of dialysis delivered
as measured by either the Kt/V or URR. Increasing blood flow rates
to 400 mL/min or higher and increasing dialysate flow rates to 800
mL/min are effective ways to increase the amount of delivered dialysis.
When increases in blood and dialysate flow rates are no longer effective,
use of a high-efficiency membrane can further increase the dose of CHAPTER
dialysis (KoA >600 mL/min, where KoA is the constant indicating the
efficiency of dialyzers in removing urea). Eventually, increases in blood
6
and dialysate flow rates, even when combined with a high-efficiency
membrane, result in no further increase in the urea clearance rate. At
this point the most important determinant affecting the dose of dialysis
is the amount of time the patient is dialyzed.
6.2 Dialysis as Treatment of End-Stage Renal Disease
Ultrafiltration during dialysis is performed to remove volume that has been used as a marker of biocompatibility is evidence of
that has accumulated during the interdialytic period so that complement activation. Cellulosic membranes generally tend to be
patients can be returned to their dry weight. Dry weight is bioincompatible, whereas noncellulosic or synthetic membranes
determined somewhat crudely, being based on clinical findings. have more biocompatible characteristics. Whether any clinical
The patient’s dry weight is the weight just preceding the devel- difference exists in acute or chronic outcomes between biocom-
opment of hypotension. The patient should be normotensive patible and bioincompatible membranes is still a matter of debate.
and show no evidence of pulmonary or peripheral edema. A Trials designed to address this issue have been mostly uncon-
patient’s dry weight frequently changes over time and therefore trolled, limited in sample size, and often retrospective in nature.
must be assessed regularly to avoid hypotension or progressive Nevertheless, some evidence exists to suggest that bioincompati-
volume overload. ble membranes may have a greater association with 2 microglob-
During ultrafiltration the driving force for fluid removal is the ulin-induced amyloidosis, susceptibility to infection, enhanced
establishment of a pressure gradient across the dialysis membrane. protein catabolism, and increased patient mortality [5–9].
The water permeability of a dialysis membrane is a function of Another aspect of the dialysis prescription is the composition
membrane thickness and pore size and is indicated by its ultrafil- of the dialysate. The concentrations of sodium, potassium,
tration coefficient (KUf). During ultrafiltration additional solute calcium, and bicarbonate in the dialysate can be individualized
removal occurs by solvent drag or convection. Because of such that ionic composition of the body is restored toward
increased pore size, high-flux membranes (KUf >20 mL/h/mm Hg) normal during the dialytic procedure. This topic is discussed in
are associated with much higher clearances of average to high mol- detail in chapter 2.
ecular weight solutes such as 2 microglobulin. Because blood Although hemodialysis is effective in removing uremic toxins
flow rates over 50 to 100 mL/min result in little or no further and provides adequate control of fluid and electrolyte abnor-
increase in the clearance of these molecules, clearance is primarily malities, the procedure does not provide for the endocrine or
membrane-limited. In contrast, clearance values for urea are not metabolic functions of the normal kidney. Therefore, the dialy-
significantly greater with a high-flux membrane compared with a sis prescription often includes medications such as erythropoi-
high-efficiency membrane because the blood flow rate, and not the etin and 1,25(OH)2 vitamin D. The dose of erythropoietin
membrane, is the principal determinant of small solute clearance. should be adjusted to maintain the hematocrit between 33%
The biocompatibility of the dialysis membrane is another and 36% (hemoglobin of 11 g/dL and 12 g/dL, respectively)
consideration in the dialysis prescription. A biocompatible dialysis [10]. Vitamin D therapy is often used in patients undergoing
membrane is one in which minimal reaction occurs between the dialysis to help limit the severity of secondary hyperparathy-
humoral and cellular components of blood as they come into roidism. Dosages usually range from 1 to 2 µg given intra-
contact with the surface of the dialyzer [6]. One such reaction venously with each treatment.
Treatment
FIGURE 6-1
Diffusion Diffusional and convective flux in hemodialysis. Dialysis is a
Blood Dialysate process whereby the composition of blood is altered by exposing it to
dialysate through a semipermeable membrane. Solutes are transported
Urea, 100 mg/dL Urea, 0 mg/dL across this membrane by either diffusional or convective flux. A, In
diffusive solute transport, solutes cross the dialysis membrane in a
direction dictated by the concentration gradient established across
the membrane of the hemodialyzer. For example, urea and potassi-
Potassium, 5.0 mEq/L Potassium, 2.0 mEq/L um diffuse from blood to dialysate, whereas bicarbonate diffuses
from dialysate to blood. At a given temperature, diffusive transport
is directly proportional to both the solute concentration gradient
across the membrane and the membrane surface area and inversely
proportional to membrane thickness.
Bicarbonate, 20 mEq/L Bicarbonate, 35 mEq/L
(Continued on next page)
A Dialysis membrane
The Dialysis Prescription and Urea Modeling 6.3
Ultrafiltration
Blood Dialysate TREATMENT OF HEMODYNAMIC INSTABILITY
90 mm Hg –150 mm Hg
Exclude nondialysis-related causes (eg, cardiac ischemia, pericardial effusion, infection)
Set the dry weight accurately
H 2O
Optimize the dialysate composition
Use a sodium concentration of ≥140 mEq/L
H 2O
Use sodium modeling
Use a bicarbonate buffer
H 2O Avoid low magnesium dialysate
Avoid low calcium dialysate
Optimize the method of ultrafiltration
Use volume-controlled ultrafiltration
Use ultrafiltration modeling
Use sequential ultrafiltration and isovolemic dialysis
B Dialysis membrane Use cool temperature dialysate
Maximize cardiac performance
Have patients avoid food on day of dialysis
FIGURE 6-1 (Continued) Have patients avoid antihypertensive medicines on day of dialysis
B, During hemodialysis water moves from blood to dialysate Pharmacologic prevention
driven by a hydrostatic pressure gradient between the blood and Erythropoietin therapy to keep hematocrit >30%
dialysate compartments, a process referred to as ultrafiltration. Experimental (eg,caffeine, midodrine, ephedrine, phenylephrine, carnitine)
The rate of ultrafiltration is determined by the magnitude of this
pressure gradient. Movement of water tends to drag solute across
the membrane, a process referred to as convective transport or sol-
vent drag. The contribution of convective transport to total solute FIGURE 6-2
transport is only significant for average-to-high molecular weight
The common treatments for hemodynamic instability of patients
solutes because they tend to have a smaller diffusive flux.
undergoing dialysis. It is important to begin by excluding reversible
causes associated with hypotension because failure to recognize
these abnormalities can be lethal. Perhaps the most common rea-
son for hemodynamic instability is an inaccurate setting of the dry
weight. Once these conditions have been dealt with, the use of a
high sodium dialysate, sodium modeling, cool temperature dialysis,
and perhaps the administration of midodrine may be attempted.
All of these maneuvers are effective in stabilizing blood pressure in
dialysis patients.
FIGURE 6-3
ACCEPTABLE METHODS TO MEASURE Acceptable methods to measure hemodialysis adequacy as recom-
HEMODIALYSIS ADEQUACY* mended in the Dialysis Outcomes Quality Initiative (DOQI)
Clinical Practice Guidelines. These guidelines may change as new
information on the benefit of increasing the dialysis prescription
becomes available. For the present, however, they should be con-
• Formal urea kinetic modeling (Kt/V) using computational software
sidered the minimum targets.
• Kt/V = -LN (R0.008 t)
+ (4-3.5 R)
Uf/wt
• Urea reduction ratio
300 dialyzer
KoA 650 the relationship between the type of dialysis membrane used, blood
flow rate, and clearance rate of a given solute. For a small solute
KoA 300 Conventional such as urea (molecular weight, 60) initially a linear relationship
200 dialyzer
e-lim ited exists between clearance and blood flow rates. Small solutes are
Membran
therefore said to be flow-limited because their clearance is highly
d
100
lim
FIGURE 6-5
2000 Water permeability of a membrane and control of volumetric
ultrafiltration in hemodialysis. The water permeability of a dialysis
1800 membrane can vary considerably and is a function of membrane
thickness and pore size. The water permeability is indicated by its
1600 ultrafiltration coefficient (KUf). The KUf is defined as the number
KUf=60 mL/h/mm Hg
KUf=4 mL/h/mm Hg of milliliters of fluid per hour that will be transferred across the
1400 membrane per mm Hg pressure gradient across the membrane.
A high-flux membrane is characterized by an ultrafiltration coeffi-
Ultrafiltration, mL/h
1200 cient of over 20 mL/h /mm Hg. With such a high water permeabili-
ty value a small error in setting the transmembrane pressure can
1000 KUf=3 mL/h/mm Hg result in excessively large amounts of fluid to be removed. As a
result, use of these membranes should be restricted to dialysis
800 machines that have volumetric ultrafiltration controls so that the
amount of ultrafiltration can be precisely controlled.
600
400
200
0
0 100 200 300 400 500 600
Transmembrane pressure, mm Hg
The Dialysis Prescription and Urea Modeling 6.5
FIGURE 6-6
High-efficiency dialyzer High-efficiency and high-flux membranes in hemodialysis. These
High-flux dialyzer membranes have similar clearance values for low molecular weight
Normal kidney solutes such as urea (molecular weight, 60). In this respect both
types of membranes have similar KoA values (over 600 mL/min),
150 where KoA is the constant indicating the efficiency of the dialyzer
in removing urea. As a result of increased pore size, use of high-
flux membranes can lead to significantly greater clearance rates of
high molecular weight solutes. For example, 2-microglobulin is not
removed during dialysis using low-flux membranes (KUf <10
mL/h/mm Hg, where KUf is the ultrafiltration coefficient). With
Clearance, mL/min
50
0
0 10 100 1000 10,000 100,000
60)
11, ulin
35 2
(m Urea
β - w=1 B1
(m icrog 5)
w=
(m amin
)
w= lob
800
Vit
2 m
FIGURE 6-7
80
Effects of membrane biocompatibility in hemodialysis. Another
consideration in the choice of a dialysis membrane is whether it is
Patients recovering renal function, %
FIGURE 6-8
300
Dialysate flow rate in hemodialysis. The clearance of urea also
280 is influenced by the dialysate flow rate. Increased flow rates help
QD=800 maximize the urea concentration gradient along the entire length of
260 Dialyzer the dialysis membrane. Increasing the dialysate flow rate from 500
KoA=800
240
to 800 mL/min can be expected to increase the urea clearance rate
QD=500 on the order of 10% to 15%. This effect is most pronounced at
Clearance, mL/min
220 high blood flow rates and with use of high KoA dialyzers. KoA—
constant indicating the efficiency of the dialyzer in removing urea;
200 QD=800 QD—dialysate flow rate.
Dialyzer
180 KoA=400
QD=500
160
140
120
100
200 250 300 350 400 450 500
Blood flow rate, mL/min
3. Volume of distribution
(K), dialysis treatment time (t), and the volume of urea distribution
(V). The dialyzer urea clearance rate (K) is influenced by the charac-
teristics of the dialysis membrane (KoA), blood flow rate, dialysate
1. Urea generation rate flow rate, and convective urea flux that occurs with ultrafiltration.
Protein catabolic rate
2. Volume of distribution
The gradual increase in urea during the interdialytic period depends
3. Residual renal function on the rate of urea generation that, in an otherwise stable patient,
reflects the dietary protein intake, distribution volume of urea, and
presence or absence of residual renal function.
Dialysis Interdialytic
time time
FIGURE 6-10
FACTORS RESULTING IN A REDUCTION OF THE Each of the factors listed may play a major role in the reduction of
PRESCRIBED DOSE OF HEMODIALYSIS DELIVERED delivered dialysis dose. Particular attention should be paid to the
vascular access and to a reduction in the effective surface area of
the dialyzer. Perhaps the most important cause for reduction in
Compromised urea clearance dialysis time has to do with premature discontinuation of dialysis
Access recirculation for the convenience of the patient or staff. Delays in starting dialysis
Inadequate blood flow from the vascular access
treatment are frequent and may result in a significant loss of dialysis
prescription. Finally, particular attention should be paid to the correct
Dialyzer clotting during dialysis (reduction of effective surface area)
sampling of the blood urea nitrogen level and the site from which
Blood pump or dialysate flow calibration error
the sample is drawn.
Reduction in treatment time
Premature discontinuation of dialysis for staff or unit convenience
Premature discontinuation of dialysis per patient request
Delay in starting treatment owing to patient or staff tardiness
Time on dialysis calculated incorrectly
Laboratory or blood sampling errors
Dilution of predialysis BUN blood sample with saline
Drawing of predialysis BUN blood sample after start of the procedure
Drawing postdialysis BUN >5 minutes after the procedure
FIGURE 6-11
Increasing
ultrafiltation Monitoring the delivered dose in hemodialysis. Use of the urea reduc-
tion ratio (URR) is the simplest way to monitor the delivered dose of
0.0 0
0.0 8
1.80 0.02 formal urea kinetic modeling is that the URR does not account for the
contribution of ultrafiltration to the final delivered dose of dialysis.
0.00 During ultrafiltration, convective transfer of urea from blood to
dialysate occurs without a decrease in urea concentration. As a result,
1.60 with increasing ultrafiltration volumes the Kt/V, as determined by
formal urea kinetic modeling, progressively increases at any given
URR. For example, a URR of 65% may correspond to a Kt/V as
Kt/v by formal urea kinetic modeling
1.20
1.00
0.80
0.60
0.40 0.50 0.60 0.70 0.80
Urea reduction ratio, %
6.8 Dialysis as Treatment of End-Stage Renal Disease
FIGURE 6-12
Correction of anemia in chronic renal failure. Anemia is a pre- FIGURE 6-13
dictable complication of chronic renal failure that is due partly All these components are important as contributors to a successful
to reduction in erythropoietin production. Use of recombinant ery- dialysis prescription. The Dialysis Outcomes Quality Initiative
thropoietin to correct the anemia in patients with chronic renal (DOQI) recommendations should be followed to achieve an adequate
failure has become standard therapy. The rate of increase in hemat- dialysis prescription, and the time on dialysis should be monitored
ocrit is dose-dependent. The indicated doses were given intra- carefully. When the delivered dialysis dose is less that prescribed,
venously three times per week. Current guidelines for the initiation the reversible factors listed in Figure 6-10 should be addressed first.
of intravenous therapy suggest a starting dosage of 120 to 180 Subsequently, an increase in blood flow to 400 mL/min should be
U/kg/wk (typically 9000 U/wk) administered in three divided doses. attempted. Increases in dialyzer surface area and treatment time
Administration of erythropoietin subcutaneously has been shown also may be attempted. In addition, attention should be paid to the
to be more efficient than is intravenous administration. That is, on correct dialysis composition and to the ultrafiltration rate to make
average, any given increment in hematocrit can be achieved with certain that patients achieve a weight as close as possible to their
less erythropoietin when it is given subcutaneously as compared dry weight. Hematocrit should be sustained at 33% to 36%. Finally,
with intravenously. In adults, the subcutaneous dosage of erythro- vitamin D supplementation to prevent secondary hyperparathyroidism
poietin is 80 to 120 U/kg/wk (typically 6000 U/wk) in two to three and use of normal saline or other volume expanders are encouraged
divided doses. rHuEpo—recombinant human erythropoietin. Data to treat hypotension during dialysis. KoA—constant indicating the
from Eschbach and coworkers [12]; with permission. efficiency of the dialyzer in removing urea.
References
1. Owen WF, Lew NL, Liu Y, Lowrie EG: The urea reduction ratio and 7. Vanholder R, Ringoir S, Dhondt A, et al.: Phagocytosis in uremic and
serum albumin concentration as predictors of mortality in patients hemodialysis patients: a prospective and cross sectional study. Kidney
undergoing hemodialysis. N Engl J Med 1993, 329:1001–1006. Int 1991, 39:320–327.
2. Hakim RM, Breyer J, Ismail N, Schulman G: Effects of dose of dialysis 8. Gutierrez A, Alvestrand A, Bergstrom J: Membrane selection and
on morbidity and mortality. Am J Kidney Dis 1994, 23:661–669. muscle protein catabolism. Kidney Int 1992, 42:S86–S90.
3. Held PJ, Port FK, Wolfe RA, et al.: The dose of hemodialysis and 9. Hornberger JC, Chernew M, Petersen J, Garber AM: A multivariate
patient mortality. Kidney Int 1996, 50:550–556. analysis of mortality and hospital admissions with high-flux dialysis.
J Am Soc Nephrol 1992, 3:1227–1237.
4. Parker TF III, Husni L, Huang W, et al.: Survival of hemodialysis
10. Hemodialysis Adequacy Work Group: Dialysis Outcomes Quality
patients in the United States is improved with a greater quantity of Initiative (DOQI). Am J Kidney Dis 1997, 30(suppl 3:S199–S201.
dialysis. Am J Kidney Dis 1994, 23:670–680.
11. Hakim RM, Wingard RL, Parker RA: Effect of the dialysis membrane
5. Hemodialysis Adequacy Work Group: Dialysis Outcomes Quality in the treatment of patients with acute renal failure. N Engl J Med
Initiative (DOQI). Am J Kidney Dis 1997, 30(suppl 2:S22–S31. 1994, 331:1338–1342.
6. Hakim, RM: Clinical implications of hemodialysis membrane biocom- 12. Eschbach JW, Egrie JC, Downing MR, et al.: Correction of the anemia
patibility. Kidney Int 1993, 44:484–494. of end-stage renal disease with recombinant human erythropoietin.
N Engl J Med 1987, 316:73–78.
Complications of Dialysis:
Selected Topics
Robert W. Hamilton
C
omplications observed in end-stage renal disease may be due to
the side effects of treatment or to the alterations of pathophys-
iology that go with kidney failure.
CHAPTER
7
7.2 Dialysis as Treatment of End-Stage Renal Disease
Complications of Hemodialysis
COMPLICATIONS OF HEMODIALYSIS
FIGURE 7-6
Dialysis-associated amyloidosis. Multiple carpal bone cysts without joint space narrowing
in a patient treated with dialysis for 11 years. This phenomenon has been attributed to
inadequate clearance of b-2microglobulin using low-permeability, cellulose dialysis membranes.
(From van Ypersele de Strihou and coworkers [2]; with permission.)
FIGURE 7-10
Sclerosing encapsulating peritonitis. This patient had several bouts
of peritonitis during the course of her treatment on peritoneal dialysis.
She developed partial small bowel obstruction. Abdominal computed
tomography revealed a homogeneous mass filling the anterior peri-
toneum. At laparotomy the mesentery was encased in a “marble-
like” fibrotic mass. The patient required long-term home parenteral
hyperalimentation for recovery. (From Pusateri and coworkers [3];
with permission.)
Complications of Dialysis: Selected Topics 7.5
Pericardial effusion
Ventricular septum
Right ventricle
Left ventricle
FIGURE 7-11
Pericardial tamponade. Narrow pulse pressure and a pain. Pericardial tamponade may present as dialysis-induced
pericardial friction rub suggest pericarditis (a frequent hypotension. (Courtesy of T. Pappas, MD, Medical College
complication of uremia) especially in patients with chest of Ohio.)
FIGURE 7-14
15 Malnutrition. Malnutrition is an important risk factor for dialysis patients, as reflected in this
graph depicting the relation of death to serum albumin values. Albumin may have antioxidant
properties. Low concentrations of serum albumin may favor oxidation of lipids, which
renders them more atherogenic. (Data from Owens and coworkers [4].
10
Risk of death
0
>4.5 4.0–4.4 3.5–3.9 3.0–3.4 2.5–2.9 <2.5
Serum albumin, g/dL
10 min 30 30
FIGURE 7-17 50 1 hr 2 hr
Radiograph of the hands of a patient who has renal osteodystrophy.
The hands demonstrate diffuse bilateral osteoporosis. The resorption FIGURE 7-18
of the distal phalanges is best seen in the first and second digits of Parathyroid scan. The patient was injected with 24.6 mCi of 99m
the right hand. The radial side of the middle phalanges of the second Tc Cardiolite. Hyperfunction of four parathyroid glands is seen.
and third digits bilaterally demonstrates subperiosteal bone resorption. This technique is often useful to determine the location and number
Soft tissue calcification is present on the radial side of the proximal of parathyroid glands before performing subtotal parathyroidectomy.
interphalangeal joint of the second digit of the left hand. At operation, diffuse hyperplasia of four parathyroid glands was
found. (From Ishibashi and coworkers [5].)
References
1. Caruana RJ, Hamilton RW, Pearson FC: Dialyzer hypersensitivity syn- 4. Owens WF, Lew NL, Liu L, et al.: The urea reduction ratio and serum
drome: possible role of allergy to ethylene oxide. Am J Nephrol 1985, albumin concentration as predictors of mortality in patients undergoing
5:271–274. hemodialysis. N Engl J Med 1993, 329:1001–1006.
2. van Ypersele de Strihou C, Jadoul M, Malghem J, et al.: Effect of dialysis 5. Ishibashi M, Nishida H, Hiromatsu Y, et al.: Localization of ectopic
membrane and patient’s age on signs of dialysis-related amyloidosis. parathyroid glands using technetium-99m sestamibi imaging: comparison
The working party on dialysis amyloidosis. Kidney Int 1991, with magnetic resonance and computed tomographic imaging. Eur J
39:1012–1019. Nuclear Med 1997, 24:197–201.
3. Pusateri R, Ross R , Marshall R, et al.: Sclerosing encapsulating
peritonitis: report of a case with small bowel obstruction managed
by long-term home parenteral hyperalimentation and a review of the
literature. Am J Kidney Dis 1986, 8:56–60.
Histocompatibility Testing
and Organ Sharing
Lauralynn K. Lebeck
Marvin R. Garovoy
H
istocompatibility and its current application in kidney trans-
plantation are discussed. Both theoretic and clinical aspects of
human leukocyte antigen testing are described, including anti-
gen typing, antibody detection, and lymphocyte crossmatching. Living
related, living unrelated, and cadaveric donor-recipient matching algo-
rithms are discussed with regard to mandatory organ sharing and
graft outcomes.
CHAPTER
8
8.2 Transplantation as Treatment of End-Stage Renal Disease
Chromosome 6
(short arm) Class II Class III Class I HLA complex
Glyoxylase DP DQ DR B C A
DZ DO Cyp21 TNF
A
DQB2
DQB1
TAP 1
TAP 2
DRB
DPA1
DPA2
DMA
DPB1
DPB2
DMB
DNA
DRA
H
G
A
C
X
B
F
J
500 3000
CYP 21-A
CYP 21-B
HSP 70
TNF α
TNF β
C4A
C4B
C2
BF
B 1500
FIGURE 8-1
The major histocompatibility complex (MHC) is a group of closely region encode the a or heavy chain of the class I antigens, HLA-A,
linked genes that was first appreciated because it was found to B, and C. The class I region is composed of other genes, most of
contain the structural genes for transplantation antigens. A, The which are pseudogenes and are not expressed. The MHC class II
MHC, located on the short arm of chromosome 6, is now recog- region is more complex, with structural genes for both the a and
nized to include many other genes important in the regulation of b chains of the class II molecules. The class II region includes four
immune responses. B, Regions of the MHC classes I, II, and III. DP genes, one DN gene, one DO gene, five DQ genes, and a vary-
The MHC can be divided into three regions, of which the class I ing number of DR genes (two to 10), depending on the halotype.
and II regions contain the loci for the human histocompatibility Many other immune response genes are coded within the class III
antigen or human leukocyte antigen (HLA). Genes in the class I region. TNF—tumor necrosis factor.
FIGURE 8-2
Specific locus
Nomenclature of human leukocyte antigen (HLA) specificities. HLA
nomenclature may be confusing to the newcomer, but the format is
logical. The prefix HLA precedes all antigens or alleles to define
the major histocompatibility complex (MHC) of the species. The
HLA C w 8
designation, A, B, C, DR, and so on, is next and defines the locus.
The locus is followed by a number that denotes the serologically
defined antigen or a number with an asterisk that denotes the
molecularly defined allele. In some cases the letter w is placed
The major histocompatibility Provisional before the serologic antigen, indicating it is a workshop designation
complex in humans specificity and the specific assignment is provisional.
Specific antigen
HLA DRB1 * 04 03
FIGURE 8-3
PRETRANSPLANTATION In an immunogenetics and transplantation laboratory, three major types of renal pretrans-
TESTING FOR RENAL PATIENTS plantation testing are performed routinely. The human leukocyte antigen (HLA) assignments
are assigned by serologic methods (ie, complement-dependent cytotoxicity); however, molec-
ular-based methodologies are becoming widely accepted. Most laboratories now have the
HLA phenotype capability of reporting at least low-resolution molecular class II types.
Patient cells tested with known antisera The sera of patients awaiting cadaveric donor kidney transplantation are tested for the
HLA antibody screen
degree of alloimmunization by determining the percentage of panel reactive antibodies
(PRAs). Current federal regulations require that the serum screening test use lymphocytes
Known cells tested with patient sera
as targets; however, because these same regulations no longer mandate monthly screening,
HLA crossmatch
assays using soluble antigens may be used as adjuncts to the classic lymphocytotoxic assays.
Donor cells tested with patient sera
The purpose of cross-match testing is to detect the presence of antibodies in the patients’
serum that are directed against the HLA antigens of the potential donor. When present,
the antibodies indicate that the immune system of the recipient has been sensitized to the
donor antigens. The various test methods differ in sensitivity, including the multiple variations
of the lymphocytotoxicity text, flow cytometry, and enzyme-linked immunosorbent assay
(ELISA). The degree of acceptable risk is one factor to be considered in selecting a method
of appropriate sensitivity. For example, when the only risk considered unacceptable is that
of hyperacute rejection, a technique having lower sensitivity is adequate. A second approach
may be to consider the degree to which an individual patient or type of patient is at risk
for graft rejection. The patient having a repeat graft is at higher risk for graft rejection
than is the patient receiving a primary graft. Because patients differ in their degree of risk,
it is appropriate to use different techniques to offset that risk.
FIGURE 8-4
MHC I AND II CHARACTERISTICS Human leukocyte antigens (HLAs) are heterodimeric cell-surface
glycoproteins. HLAs are divided into two classes, according to
their biochemical structure and respective functions. Class I antigens
Class I Class II (A, B, and C) have a molecular weight of approximately 56,000 D
and consist of two chains: a glycoprotein heavy chain (a) and a
Composed of HLA-A, -B, and -C Composed of HLA-DR, -DQ, and -DP light chain (b2-microglobulin). The a chain is attached to the cell
Ubiquitous distribution Restricted distribution membrane, whereas b2-microglobulin is associated with the a
Autosomal codominant Autosomal codominant chain but is not covalently bonded. The HLA class I molecules are
Target for immune effector mechanism Major role in immune response found on almost all cells; however, only vestigial amounts remain
Serologic and molecular detection induction on mature erythrocytes. Class II antigens (HLA-DR, DQ, and DP)
Heterodimer noncovalently linked Serologic, molecular, and cellular have a molecular weight of approximately 63,000 D and consist of
Heavy chain (a): detection two dissimilar glycoprotein chains, designated a and b, both of
Contains variable regions Heterodimer noncovalently linked which are attached to the membrane. Each chain consists of two
Confers human leukocyte antigen a Chain: extramembranous amino acid domains, and the outer domains of
specificity Nonvariable in HLA-DR each molecule contain the variable regions corresponding to class II
Light chain (b2-microglobulin): Contains variable regions in HLA-DQ alleles. Although class I antigens are expressed on all nucleated cells
Invariant and -DP of the body, the expression of class II antigens is more restricted. Class
b Chain: II antigens are found on B lymphocytes, activated T lymphocytes,
Contains variable regions monocyte-macrophages, dendritic cells, and early hematopoietic
Confers most of HLA-DR specificity cells, and of importance in transplantation, endothelial cells.
8.4 Transplantation as Treatment of End-Stage Renal Disease
FIGURE 8-5
MHC T-cell
protein receptor Biology of the major histocompatibility complex (MHC). A, The
biologic function of MHC antigens is to present antigenic peptides
α chain to T lymphocytes. In fact, it is an absolute requirement of T-lym-
phocyte activation for the T cells to “see” the antigenic peptide
bound to an MHC molecule. This MHC restriction has been
defined on a molecular basis with the elucidation of the crystalline
structures of classes I and II MHC molecules. B, The N-terminal
Processed β chain domains of the MHC molecules are formed by the folding of por-
antigen tions of their component chains in b-pleated sheets and a helices.
C, The sheet portions form a floor, and the helices form the sides
of a peptide-binding groove.
A
α1 α2
β2m α3
B C
FIGURE 8-6
Peptide
Peptide The structure of class I and II molecules.
Comparison of the crystalline structures of
classes I and II molecules has revealed overall
structural similarity, with a few significant
differences. A, Class I molecules have a
groove with deep anchor pockets at each
end (a “pita pocket”). These pockets restrict
the binding of peptides to those of eight to
nine amino acid residues in length. B, The
peptide-binding groove of class II molecules
Heavy β2m subunit α subunit β subunit is more flexible and relatively open at one
subunit
end, more like a “hotdog bun,” permitting
larger peptides from 13 to 25 amino acid
residues in length to bind.
A B
Histocompatibility Testing and Organ Sharing 8.5
FIGURE 8-7
HLA SPECIFICITIES Allelic polymorphism. Allelic polymorphism
is a hallmark of the human leukocyte antigen
(HLA) system. The extreme polymorphism of
A B B C DR DQ DP the HLA system is seen in the large numbers
of different alleles that exist for the multiple
A1 B5 B51(5) Cw1 DR1 DQ1 DPw1 major histocompatibility complex (MHC)
A2 B7 B5102 Cw2 DR103 DQ2 DPw2 loci. At any given locus, one of several
A203 B703 B5103 Cw3 DR2 DQ3 DPw3 alternative forms or alleles of a gene can
A210 B8 B52(5) Cw4 DR3 DQ4 DPw4 exist. Because so many alleles are possible
A3 B12 B53 Cw5 DR4 DQ5(1) DPw5 for each HLA locus, the system is extremely
A9 B13 B54(22) Cw6 DR5 DQ6(1) DPw6 polymorphic. The currently accepted World
A10 B14 B55(22) Cw7 DR6 DQ7(3) Health Organization serologically defined
A11 B15 B56(22) Cw8 DR7 DQ8(3) alleles are shown here. Established HLA
A19 B16 B57(17) Cw9(w3) DR8 DQ9(3) antigens are designated by a number following
A23(9) B17 B58(17) Cw10(w3) DR9 the letter that denotes the HLA locus (eg,
A24(9) B18 B59 DR10 HLA-A1 and HLA-B8). For example, by
A2403 B21 B60(40) DR11(5) serologic techniques, 28 distinct antigens
A25(10) B22 B61(40) DR12(5) are recognized at the HLA-A locus, and
A26(10) B27 B62(15) DR13(6) 59 defined antigens at the HLA-B locus.
A28 B2708 B63(15) DR14(6) Sequencing studies of the HLA-DRB1 gene
A29(19) B35 B64(14) DR1403
have identified over 100 distinct alle