Chronic Renal Failure and Uremia

Objectives
1. Be able to identify differences between acute and chronic renal failure.
2. Be able to describe the factors that lead to a progressive decline in GFR irrespective of the inciting cause.
3. Be able to recognize antihypertensives that decrease glomerular capillary pressure and understand the
rationale for their use in patients with chronic glomerular disease.
4. Be able to describe the adaptations that occur at the level of the nephron to maintain sodium, potassium,
and acid-base balance.
5. Be able to characterize the pathogenesis of renal osteodystrophy and the basic methods of managing
altered calcium-phosphorus metabolism in chronic renal failure.
6. Be able to understand the pathogenesis and treatment of anemia in chronic renal failure.
7. Be able to recognize the clinical features of the uremic syndrome.

Outline
I. Chronic renal failure

A. Acute versus chronic renal failure

B. Etiology
C. Progression of renal failure
1. Histologic features
2. Pathogenesis
D. Treatment of hypertension in chronic renal failure
1. Antihypertensive medications and glomerular capillary pressure
2. Treatment recommendations
E. Nephron adaptation in chronic renal failure
1. Sodium balance
2. Potassium balance
3. Urinary concentration and dilution in chronic renal failure
4. Acid-base homeostasis
F. Calcium-phosphorus metabolism in chronic renal failure
1. Pathogenesis of renal osteodystrophy
2. Management of altered calcium-phosphorus metabolism
G. Anemia of chronic renal failure

II. The Uremic Syndrome

A. Symptoms of uremia
B. Clinical features of uremia
C. Pathogenesis of uremia
I. Chronic renal failure

Estimates of U.S. Pre-ESRD Population

USRDS 1998

1,600,000
The incidence of End Stage Renal Disease
Pre-ESRD (ESRD) in the U.S. is projected to increase five fold over
the next ten years. Currently there are an estimated 1.6
million patients at risk for developing renal failure over
the next 10 years (figure 1).
215,557
78,810
Dialysis Transplant
Figure 1

This obviously will place an enormous burden on health

care system. Currently there are limited therapies available to delay progression of renal failure. Hopefully
new therapies will emerge as new research efforts focus on understanding the pathogenesis of progressive
renal failure. The role of both the primary care physician and nephrologist is to identify patients at risk for
progressive renal failure and implement therapies that will both delay the progression of renal failure as
well as minimize the morbidity and mortality.
Table 1 A. Acute versus chronic renal failure
Differentiating Chronic Renal Failure
From Acute Renal Failure Chronic renal failure often follows an insidious
Acute Chronic asymptomatic course until the GFR declines to less than
• Physical exam 10 ml/min. It is not unusual, therefore, for patients with
• Oliguria – impaired growth in children chronic renal failure to initially present with advanced
– hyperpigmentation
• Normal or large kidneys
– uremic fetor
azotemia One is then left with the question whether the
on ultrasound
• Small echogenic kidneys patient is suffering from an acute versus chronic process
• Unstable azotemia
• Urinalysis (Table 1).
– Broad casts
• Renal osteodystrophy

Patients with acute renal failure often present with an

acute systemic illness. Patients with oliguria are more likely to have acute renal failure. Laboratory
studies, unfortunately, are generally not helpful is distinguishing between acute and chronic renal failure.
Anemia, hyperphosphatemia and hypocalcemia are commonly seen in both settings. Serial increases in
BUN and creatinine, however, suggest a diagnosis of acute renal failure. Patients with chronic renal failure
tend to have small echogenic kidneys on ultrasound. Because renal osteodystrophy develops over years,
the presence of this disorder as seen on radiographs of the hands is strong evidence that the renal failure has
a chronic component.

Table 2
Etiology of Chronic Renal Failure
• Diabetes mellitus
• Hypertension
• Unknown
• Glomerulonephritis
• Obstructive uropathy
• Polycystic kidney disease
Table 3
Anatom ic and H istologic Features Due to
G lom erular H ypertension
• Glom erular hypertrophy
• Focal segm ental glom erulosclerosis with
hyalinosis
• Interstitial fibrosis
• Vascular sclerosis
• Epithelial foot process fusion
Table 4
Physiologic Changes Observed
in Chronic Renal Failure
• Increased single nephron GFR
• Vasodilation of the afferent arteriole with
impaired autoregulation
• Intraglomerular hypertension
• Loss of glomerular permselectivity
Pathogenesis of Secondary
Glomerulosclerosis
Primary Insult
Nephron Mass
Glomerular Sclerosis Glomerular Volume and
and Hyalinosis Glomerular Hypertension
Epithelial Cell Density and
Foot Process Fusion
Proteinuria
Figure 2
B. Etiology
In the U.S. and in most Western countries,
diabetes mellitus remains the leading cause of ESRD.
This is in contrast to underdeveloped nations, where
31.5% glomerulonephritis remains the most common cause of
27.4% ESRD. The prevalence of the various causes of ESRD in
18.5% the U.S. is summarized in table 2. Many patients are
13.8% probably erroneously categorized as hypertensive
5.4% glomerulosclerosis when presenting with ESRD. This
3.4% stems from the fact that many patients will present with
small fibrotic kidneys, and thus no further diagnostic
workup can be performed.
C. Progression of renal failure
Over the past 20 years, considerable insight
has been gained into factors that may contribute to the
progression of chronic renal failure. It was initially
observed that there are common histologic features
seen on renal biopsy specimens in all patients with
chronic renal failure regardless of the initial insult
(Table 3).
At the same time, there are common
physiologic changes that have been demonstrated in
animal models of chronic renal failure (table 4).
Loss of nephron mass leads to glomerular
hypertension even in the absence of systemic
hypertension. Experimental models of chronic renal
failure have demonstrated an increase in single
nephron GFR (SNGFR) in the remaining nephrons.
Vascular resistance is decreased in both the afferent
and efferent arterioles, thus resulting in an increase
in glomerular capillary plasma flow rate. The
decrease in afferent arteriolar resistance is
proportionately greater than that in the efferent
arteriole, leading to an increase in glomerular
capillary pressure. As a result, there is epithelial cell
injury and glomerular sclerosis. Proteinuria ensues,
which results in worsening glomerular hypertension
and sclerosis. A relentless cycle of decreased
nephron mass and progressive glomerular sclerosis
ultimately leads to ESRD (Figure 2).
 D. Treatment of hypertension in chronic renal failure

Control of hypertension remains the mainstay of management of patients with chronic renal
failure. Recent studies have demonstrated the importance of maintaining stringent blood pressure control
in these patients to minimize progression of renal failure. The target blood pressure goal, for example, is
approximately 125-130 mmHg systolic and 75-80 mmHg diastolic, compared with a target blood pressure
of 140/90 mmHg in the general population.

Figure 3
Effects of Various Anti-hypertensives on
Glomerular Capillary Pressure

The ultimate goal is to restore normal

Afferent Efferent glomerular capillary pressure. This is achieved by
Arteriole Pressure
Arteriole employing drugs that preferentially vasodilate the
Pressure Vasodilate efferent arteriole. Examples include ACE inhibitors,
Vasodilate
angiotensin II receptor antagonists, and non-
Dihydropyridines ACE inhibitors dihydropyridine calcium blockers (figure 3).
Nifedipine AII Antagonists
Felodipine Verapamil
Amlodipine Diltiazem

Treatment of hypertension for patients with

chronic renal failure, then, is indicated at any stage of the disease. Drugs that lower the glomerular
capillary pressure should be used as first line agents, especially when there is more than 1 gram of urinary
protein excretion in 24 hours. The goal is to keep the blood pressure less than 130/80 mmHg.

E. Nephron adaptation in chronic renal failure

As renal failure progresses, the number of functioning nephrons is reduced. In order to maintain
homeostasis, there must be adaptive changes in the handling of solutes and water since each nephron must
handle a proportionately greater load. We will now consider adaptive changes that are observed with
respect to sodium, potassium, hydrogen ion, and water handling in chronic renal failure.
Figure 4
1. Sodium balance
Steady State GFR and
Fractional Sodium Excretion
Slatopolsky et al., J. Clin. Invest. 47: 521, 1968 As GFR declines, sodium excretion remains
24 relatively constant, thus maintaining an extracellular
Fractional Sodium Excretion

fluid volume that remains close to normal. In order for

16 sodium balance to be maintained, the remaining
functioning nephrons must proportionately increase
(%)

8 sodium excretion. Studies measuring fractional

excretion of sodium in a population of patients with a
wide range of renal insufficiency have documented this
25 50 75 100 adaptation, demonstrating a gradual increase in the
GFR
(% of normal) fractional excretion of sodium as GFR declines (Figure
4).

The mechanisms responsible for increasing the fractional excretion of sodium as GFR declines are
not entirely clear, but recent work has demonstrated increased levels of atrial natriuretic peptide.
Micropuncture studies have shown that most of the increased sodium excretion occurs in the distal tubule.
Although zero sodium balance may be maintained in the absence of a significant change in sodium intake,
the ability of the nephron to increase sodium excretion when challenged with a large sodium load is
impaired in chronic renal failure.
 In the later stages of chronic renal failure, there is transient net sodium retention leading to
expansion of the extracellular fluid volume. Renal perfusion is consequently increased resulting in
decreased proximal sodium reabsorption and a pressure natriuresis. Although the ECF volume may expand
in the later stages of renal insufficiency, edema is not a consistent finding as the increase in the interstitial
space is often less the 2-3 liters required to result in edema formation. Patients with nephrotic syndrome,
however, will uniformly develop edema due to the increased renal sodium avidity associated with this
syndrome.

2. Potassium balance

As GFR declines, there is a progressive increase in the fractional excretion of potassium to

maintain the serum potassium in the normal range. It is only when the GFR falls to about 10% normal that
the serum potassium rises. Early in the course of chronic renal failure, transient elevations in the serum and
intracellular potassium result in increased secretion of potassium in the cortical collecting duct. Increased
aldosterone may play some role in this adaptation, but can not account for all of the observed increase in
potassium excretion. Increased activity of the Na-K-ATPase on the basolateral surface of principle cells in
the cortical collecting duct has been demonstrated in advanced chronic renal insufficiency, thus facilitating
increased potassium excretion per nephron.

Figure 5 3. Urinary Concentration and Dilution in Chronic

Urinary Concentrating Capacity in Renal Failure
Chronic Renal Failure
Dorhout-Mees, EJ: Br. Med. J. 1: 1159, 1959. As GFR declines, there is an impair-ment in
1200 both urinary concentration (figure 5) and dilution due
Maximal Urine Concentration

to limited renal mass. A higher solute load is imposed

900 on each nephron, and there is insufficient tubular
surface area to maintain medullary interstitial
(mOsm)

600 hypertonicity. The osmolarity of the urine is close to

that of plasma (isosthenuria). Since solute intake
300 remains unchanged, the obligate urine volume will
increase. Patients will often complain of polyuria and
nocturia due to the limited ability to concentrate urine.
25 50 75 100 Limited urinary diluting capacity results in decreased
GFR free water clearance and hypoosmolality when water
(% of normal) intake exceeds excretion and losses.

4. Acid-base Homeostasis

Metabolic acidosis predictably develops as renal failure progresses. Early in the course of chronic
renal failure, hydrogen balance is maintained by increased synthesis of ammonia per nephron. Eventually,
the total ammonia synthesis decreases as the decline in nephron mass exceeds the increase in ammonia
synthesis per functioning nephron, and a metabolic acidosis ensues.

Figure 6 F. Calcium-phosphorus metabolism in

Hyperparathyroid Related Bone Disease chronic renal failure

As renal mass decreases, the excretion

Pi Ca2+ + of phosphorus decreases resulting in a rise in
the serum phosphorus. This results in a
transient decrease in the serum calcium. At the
Acidosis Impaired
Absorption same time, calcium absorption is also impaired
PTH

Renal Mass +

1-alpha-hydroxylase
1-alpha- hydroxylase

25(OH)D3 1,25(OH)2D3 Osteitis Fibrosa

Cystica
resulting in a fall in the serum calcium. The latter results from a deficiency in 1,25-dihydroxy-vitamin D.
Recall that 1-alpha-hydroxylase is localized to the kidney, and its activity will decrease as result of both a
decrease in renal mass as well as a consequence of the acidosis of chronic renal failure.

Both hypocalcemia and hyperphosphatemia lead to increased parathyroid hormone synthesis or

secondary hyperparathyroidism. Although this leads to restoration of the serum calcium to the normal
range, it does so at the expense of increased bone turnover. Because 1,25-hydroxy-vitamin D acts as an
inhibitor of parathyroid synthesis, the relative deficiency of active vitamin D in chronic renal failure also
leads to increased parathyroid hormone synthesis. These alterations are summarized in figure 6.

Persistent untreated hyperparathyroidism leads to a distinct form of bone disease characterized by

increased bone turnover and fibrosis termed osteitis fibrosa cystica. Once established, this bone disorder is
essentially irreversible. Prevention, therefore, remains the best therapeutic strategy. The objective of
therapy is first to minimize the hypocalcemia and hyperphosphatemia. Calcium supplements are given
with meals to act as phosphate binders. Patients should see a dietician once the GFR declines to less than
30 ml/min to receive dietary counseling to achieve adequate dietary phosphorus restriction. Finally, the
active vitamin D analogue calcitriol is administered to facilitate calcium absorption and to suppress
parathyroid hormone synthesis. Care should be taken to avoid increasing the calcium phosphorus product
(Serum Ca {mg/dl} X Serum Phos {mg/dl}) to greater than 65. Elevations of this product above this range
will result in metastatic calcification and has been shown to be associated with excess mortality.

G. Anemia of Chronic Renal Failure

Erythropoietin is synthesized in the kidney and is essential for normal hematopoiesis. When the
GFR declines to the 30 ml/min range, a normocytic, normochromic anemia develops. In 1990,
recombinant human erythropoietin became available for the care of patients with ESRD and chronic renal
failure. Previously, it was not unusual for patients on dialysis to have hematocrits in the 16-18% range.
Today we have the capacity to maintain hematocrits in the 33-36% range. This has markedly improved the
overall sense of well being and quality of life for patients on dialysis. More recently, erythropoietin use has
increased in patients in the pre-ESRD stage.

T able 5
Sym ptom s of the U rem ic Syn drom e
II. The Uremic Syndrome

E arly L ate Literally, uremia translates to “urine in the

• L oss of appetite
• A ltered taste sensation
• L ack of energy
• P oor concentration
• P ruritus
• W eight loss
• C om a blood.” It refers to the clinical syndrome associated a
• Intractable vom iting marked reduction in GFR (<10-15 ml/min). Symptoms
• P aresthesias are non-specific and range from vague fatigue to full-
blown coma (Table 5).
 Table 6
Clinical Features of Uremia

Early Late Early in the course of uremia patients will

• Expanded ECF • Pericarditis complain of lassitude, altered taste and subtle cognitive
• Hypertension • Peripheral neuropathy
changes. Because dialysis is generally initiated early in the
• Anemia • Asterixis
• Bone disease • Acidosis
course of uremia, it is now rare to see the end stage findings
• Poor growth • Hyperkalemia of uremia which may include coma as well as marked
• Infertility • GI bleeding metabolic perturbations including severe acidosis and
• Amenorrhea • Hyperpigmentation hyperkalemia (Table 6).
• Hyperlipidemia

The pathogenesis of the syndrome remains unexplained. The toxins responsible for the clinical
symptoms have yet to be identified, but it believed that the uremic toxins are relatively small molecules
with molecular weights less than 300 daltons. Indirect evidence for this derives from the fact that the
syndrome resolves with dialysis, and molecules in this molecular weight range are removed by the dialysis
procedure. The blood urea nitrogen (BUN) level remains the most helpful surrogate marker of uremia,
although there is a wide range of levels wherein the syndrome develops in individual patients. In general, a
BUN level of 100 mg/dl has served as a level at which dialysis is initiated in patients with acute renal
failure, but clinical judgement remains the most important factor in determining when dialysis should be
initiated.

Table 7
Examples of Suspected Uremic Toxins
Interestingly, studies in which normal
Substance Molecular Weight volunteers are infused with urea have demonstrated none
Urea 60 of the characteristic features of the syndrome, even when
BUN levels are increased to 200 mg/dl. It is now
Creatinine 113
believed that the syndrome results from the
Methylguanidine 175
accumulation of a number of small molecules (Table 7).
Guanidinosuccinic acid 175
Phenolic acids 100-300
Dimethyamine 46