Pathophysiology

A normal kidney contains approximately 1 million nephrons, each of which

contributes to the total glomerular filtration rate (GFR). In the face of renal
injury (regardless of the etiology), the kidney has an innate ability to maintain
GFR, despite progressive destruction of nephrons, as the remaining healthy
nephrons manifest hyperfiltration and compensatory hypertrophy. This
nephron adaptability allows for continued normal clearance of plasma solutes.
Plasma levels of substances such as urea and creatinine start to show
measurable increases only after total GFR has decreased to 50%.
The plasma creatinine value will approximately double with a 50% reduction in
GFR. For example, a rise in plasma creatinine from a baseline value of 0.6
mg/dL to 1.2 mg/dL in a patient, although still within the adult reference range,
actually represents a loss of 50% of functioning nephron mass.
The hyperfiltration and hypertrophy of residual nephrons, although beneficial
for the reasons noted, has been hypothesized to represent a major cause of
progressive renal dysfunction. The increased glomerular capillary pressure
may damage the capillaries, leading initially to secondary focal and segmental
glomerulosclerosis (FSGS) and eventually to global glomerulosclerosis. This
hypothesis is supported by studies of five-sixths nephrectomized rats, which
develop lesions identical to those observed in humans with chronic kidney
disease (CKD).
Factors other than the underlying disease process and glomerular
hypertension that may cause progressive renal injury include the following:
Systemic hypertension
Nephrotoxins (eg, nonsteroidal anti-inflammatory drugs [NSAIDs],
intravenous contrast media)
Decreased perfusion (eg, from severe dehydration or episodes of shock)
Proteinuria (in addition to being a marker of CKD)
Hyperlipidemia
Hyperphosphatemia with calcium phosphate deposition
Smoking
Uncontrolled diabetes
Thaker et al found a strong association between episodes of acute kidney
injury (AKI) and cumulative risk for the development of advanced CKD in
multiple hospitalized patients with diabetes mellitus. [6] Any AKI versus no AKI
was a risk factor for stage 4 CKD, and each additional AKI episode doubled
that risk. [6]
Findings from the Atherosclerosis Risk in Communities (ARIC) Study, a
prospective observational cohort, suggest that inflammation and hemostasis
are antecedent pathways for CKD. [7] This study used data from 1787 cases of
CKD that developed between 1987 and 2004.
Childhood renal function and CKD in children
In children, the GFR increases with age and is calculated with specific
equations that are different than those for adults. Adjusted for body surface
area, the GFR reaches adult levels by age 2-3 years.
Aspects of pediatric kidney function and the measure of creatinine are
informative not only for children but also for adults. For example, it is
important to realize that creatinine is derived from muscle and, therefore, that
children and smaller individuals have lower creatinine levels independent of
the GFR. Consequently, laboratory reports that do not supply appropriate
pediatric normal ranges are misleading. The same is true for individuals who
have low muscle mass for other reasons, such as malnutrition, cachexia, or
amputation.
Another important note for childhood CKD is that physicians caring for
children must be aware of normal blood pressure levels by age, sex, and
height. Prompt recognition of hypertension at any age is important, because it
may be caused by primary renal disease.
Fortunately, CKD during childhood is rare and is usually the result of
congenital defects, such as posterior urethral valves or dysplastic kidney
malformations. Another common cause is FSGS. Genetic kidney diseases are
also frequently manifested in childhood CKD. Advances in pediatric
nephrology have enabled great leaps in survival for pediatric CKD and end-
stage renal disease (ESRD), including for children who need dialysis or
transplantation.
Aging and renal function
The biologic process of aging initiates various structural and functional
changes within the kidney. [8, 9] Renal mass progressively declines with
advancing age, and glomerulosclerosis leads to a decrease in renal weight.
Histologic examination is notable for a decrease in glomerular number of as
much as 30-50% by age 70 years. The GFR peaks during the third decade of
life at approximately 120 mL/min/1.73 m2; it then undergoes an annual mean
decline of approximately 1 mL/min/y/1.73 m2, reaching a mean value of 70
mL/min/1.73 m2 at age 70 years.
Ischemic obsolescence of cortical glomeruli is predominant, with relative
sparing of the renal medulla. Juxtamedullary glomeruli see a shunting of blood
from afferent to efferent arterioles, resulting in redistribution of blood flow
favoring the renal medulla. These anatomic and functional changes in renal
vasculature appear to contribute to an age-related decrease in renal blood
flow.
Renal hemodynamic measurements in aged humans and animals suggest
that altered functional response of the renal vasculature may be an underlying
factor in diminished renal blood flow and increased filtration noted with
progressive renal aging. The vasodilatory response is blunted in the elderly
when compared to younger patients.
However, the vasoconstrictor response to intrarenal angiotensin is identical in
young and older human subjects. A blunted vasodilatory capacity with
appropriate vasoconstrictor response may indicate that the aged kidney is in a
state of vasodilatation to compensate for the underlying sclerotic damage.
Given the histologic evidence for nephronal senescence with age, a decline in
the GFR is expected. However, a wide variation in the rate of GFR decline is
reported because of measurement methods, race, gender, genetic variance,
and other risk factors for renal dysfunction.
Genetics
Most cases of CKD are acquired rather than inherited, although CKD in a child
is more likely to have a genetic or inherited cause. Well-described genetic
syndromes associated with CKD include autosomal dominant polycystic
kidney disease(ADPKD) and Alport syndrome. Other examples of specific
single-gene or few-gene mutations associated with CKD include Dent
disease, nephronophthisis, and atypical hemolytic uremic syndrome (HUS).
APOL1 gene
More recently, researchers have begun to identify genetic contributions to
increased risk for development or progression of CKD. Friedman et al found
that more than 3 million black persons with genetic variants in both copies of
apolipoprotein L1 (APOL1) are at higher risk for hypertension-attributable
ESRD and FSGS. In contrast, black individuals without the risk genotype and
European Americans appear to have similar risk for developing nondiabetic
CKD. [10]
FGF-23 gene
Circulating levels of the phosphate-regulating hormone fibroblast growth factor
23 (FGF-23) are affected by variants in the FGF23 gene. Isakova et al
reported that elevated FGF-23 levels are an independent risk factor for ESRD
in patients who have fairly well-preserved kidney function (stages 2-4) and for
mortality across the scope of CKD. [11]
Single-nucleotide polymorphisms
A review of 16 single-nucleotide polymorphisms (SNPs) that had been
associated with variation in GFR found that development of albuminuria was
associated mostly with an SNP in the SHROOM3 gene. [12] Even accounting
for this variant, however, there is evidence that some unknown genetic variant
influences the development of albuminuria in CKD. This study also suggests a
separate genetic influence on development of albuminuria versus reduction in
GFR. [12]
A genome-wide association study (GWAS) that included over 130,000
patients found 6 SNPs associated with reduced GFR, located in or
near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. [13] The SNP
in SLC47A1 was associated with decreased GFR in nondiabetic individuals,
whereas SNPs located in the DNAJC16and CDK12 genes were associated
with decreased GFR in individuals younger than 65 years. [13]
Immune-system and RAS genes
A number of genes have been associated with the development of ESRD.
Many of these genes involve aspects of the immune system
(eg, CCR3, IL1RN, IL4). [14]
Unsurprisingly, polymorphisms in genes involving the renin-angiotensin
system (RAS) have also been implicated in predisposition to CKD. One study
found that patients with CKD were significantly more likely to have the
A2350G polymorphism in the ACE gene, which encodes the angiotensin-
converting enzyme (ACE). [15] They were also more likely to have the C573T
polymorphism in the AGTR1 gene, which encodes the angiotensin II type 1
receptor. [15]
Hyperkalemia
The ability to maintain potassium excretion at near-normal levels is generally
maintained in CKD, as long as aldosterone secretion and distal flow are
maintained. Another defense against potassium retention in patients with CKD
is increased potassium excretion in the gastrointestinal tract, which also is
under control of aldosterone.
Hyperkalemia usually does not develop until the GFR falls to less than 20-25
mL/min/1.73 m, at which point the kidneys have decreased ability to excrete
potassium. Hyperkalemia can be observed sooner in patients who ingest a
potassium-rich diet or have low serum aldosterone levels. Common sources
of low aldosterone levels are diabetes mellitus and the use of ACE inhibitors,
NSAIDs, or beta-blockers.
Hyperkalemia in CKD can be aggravated by an extracellular shift of
potassium, such as occurs in the setting of acidemia or from lack of insulin.
Hypokalemia
Hypokalemia is uncommon but can develop in patients with very poor intake
of potassium, gastrointestinal or urinary loss of potassium, or diarrhea or in
patients who use diuretics.
Metabolic acidosis
Metabolic acidosis often is a mixture of normal anion gap and increased anion
gap; the latter is observed generally with stage 5 CKD but with the anion gap
generally not higher than 20 mEq/L. In CKD, the kidneys are unable to
produce enough ammonia in the proximal tubules to excrete the endogenous
acid into the urine in the form of ammonium. In stage 5 CKD, accumulation of
phosphates, sulfates, and other organic anions are the cause of the increase
in anion gap.
Metabolic acidosis has been shown to have deleterious effects on protein
balance, leading to the following:
Negative nitrogen balance
Increased protein degradation
Increased essential amino acid oxidation
Reduced albumin synthesis
Lack of adaptation to a low-protein diet
Hence, metabolic acidosis is associated with protein-energy malnutrition, loss
of lean body mass, and muscle weakness. The mechanism for reducing
protein may include effects on adenosine triphosphate (ATP)dependent
ubiquitin proteasomes and increased activity of branched-chain keto acid
dehydrogenases.
Metabolic acidosis also leads to an increase in fibrosis and rapid progression
of kidney disease, by causing an increase in ammoniagenesis to enhance
hydrogen excretion.
In addition, metabolic acidosis is a factor in the development of renal
osteodystrophy, because bone acts as a buffer for excess acid, with resultant
loss of mineral. Acidosis may interfere with vitamin D metabolism, and
patients who are persistently more acidotic are more likely to have
osteomalacia or low-turnover bone disease.
Salt- and water-handling abnormalities
Salt and water handling by the kidney is altered in CKD. Extracellular volume
expansion and total-body volume overload results from failure of sodium and
free-water excretion. This generally becomes clinically manifested when the
GFR falls to less than 10-15 mL/min/1.73 m, when compensatory
mechanisms have become exhausted.
As kidney function declines further, sodium retention and extracellular volume
expansion lead to peripheral edema and, not uncommonly, pulmonary edema
and hypertension. At a higher GFR, excess sodium and water intake could
result in a similar picture if the ingested amounts of sodium and water exceed
the available potential for compensatory excretion.
Tubulointerstitial renal diseases represent the minority of cases of CKD.
However, it is important to note that such diseases often cause fluid loss
rather than overload. Thus, despite moderate or severe reductions in GFR,
tubulointerstitial renal diseases may manifest first as polyuria and volume
depletion, with inability to concentrate the urine. These symptoms may be
subtle and require close attention to be recognized. Volume overload occurs
only when GFR reduction becomes very severe.
Anemia
Normochromic normocytic anemia principally develops from decreased renal
synthesis of erythropoietin, the hormone responsible for bone marrow
stimulation for red blood cell (RBC) production. The anemia starts early in the
course of the disease and becomes more severe as, with the shrinking
availability of viable renal mass, the GFR progressively decreases.
Using data from the National Health and Nutrition Examination Survey
(NHANES), Stauffer and Fan found that anemia was twice as prevalent in
people with CKD (15.4%) as in the general population (7.6%). The prevalence
of anemia increased with stage of CKD, from 8.4% at stage 1 to 53.4% at
stage 5. [16]
No reticulocyte response occurs. RBC survival is decreased, and bleeding
tendency is increased from the uremia-induced platelet dysfunction. Other
causes of anemia in CKD include the following:
Chronic blood loss: Uremia-induced platelet dysfunction enhances
bleeding tendency
Secondary hyperparathyroidism
Inflammation
Nutritional deficiency
Accumulation of inhibitors of erythropoiesis

Bone disease
Renal bone disease is a common complication of CKD. It results in skeletal
complications (eg, abnormality of bone turnover, mineralization, linear growth)
and extraskeletal complications (eg, vascular or soft-tissue calcification).
Different types of bone disease occur with CKD, as follows:
High-turnover bone disease from high parathyroid hormone (PTH) levels
Low-turnover bone disease (adynamic bone disease)
Defective mineralization (osteomalacia)
Mixed disease
Beta-2-microglobulinassociated bone disease
Bone disease in children is similar but occurs during growth. Therefore,
children with CKD are at risk for short stature, bone curvature, and poor
mineralization (renal rickets is the equivalent term for adult osteomalacia).
CKDmineral and bone disorder (CKD-MBD) involves biochemical
abnormalities related to bone metabolism. CKD-MBD may result from
alteration in levels of serum phosphorus, PTH, vitamin D, and alkaline
phosphatase.
Secondary hyperparathyroidism develops in CKD because of the following
factors:
Hyperphosphatemia
Hypocalcemia
Decreased renal synthesis of 1,25-dihydroxycholecalciferol (1,25-
dihydroxyvitamin D, or calcitriol)
Intrinsic alteration in the parathyroid glands, which gives rise to increased
PTH secretion and increased parathyroid growth
Skeletal resistance to PTH
Calcium and calcitriol are primary feedback inhibitors; hyperphosphatemia is a
stimulus to PTH synthesis and secretion.
Hyperphosphatemia and hypocalcemia
Phosphate retention begins in early CKD; when the GFR falls, less phosphate
is filtered and excreted, but because of increased PTH secretion, which
increases renal excretion, serum levels do not rise initially. As the GFR falls
toward CKD stages 4-5, hyperphosphatemia develops from the inability of the
kidneys to excrete the excess dietary intake.
Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-
hydroxyvitamin D to calcitriol, so serum calcitriol levels are low when the GFR
is less than 30 mL/min/1.73 m. Increased phosphate concentration also
effects PTH concentration by its direct effect on the parathyroid glands
(posttranscriptional effect).
Hypocalcemia develops primarily from decreased intestinal calcium
absorption because of low plasma calcitriol levels. It also possibly results from
increased calcium-phosphate binding, caused by elevated serum phosphate
levels.
Increased PTH secretion
Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all
been demonstrated to independently trigger PTH synthesis and secretion. As
these stimuli persist in CKD, particularly in the more advanced stages, PTH
secretion becomes maladaptive, and the parathyroid glands, which initially
hypertrophy, become hyperplastic. The persistently elevated PTH levels
exacerbate hyperphosphatemia from bone resorption of phosphate.
Skeletal manifestations
If serum levels of PTH remain elevated, a high bone turnover lesion, known
as osteitis fibrosa, develops. This is one of several bone lesions, which as a
group are commonly known as renal osteodystrophy and which develop in
patients with severe CKD. Osteitis fibrosa is common in patients with ESRD.
The prevalence of adynamic bone disease in the United States has increased,
and it has been described before the initiation of dialysis in some cases. The
pathogenesis of adynamic bone disease is not well defined, but several
factors may contribute, including high calcium load, use of vitamin D sterols,
increasing age, previous corticosteroid therapy, peritoneal dialysis, and
increased level of N-terminally truncated PTH fragments.
Low-turnover osteomalacia in the setting of CKD is associated with aluminum
accumulation. It is markedly less common than high-turnover bone disease.
Another form of bone disease is dialysis-related amyloidosis, which is now
uncommon in the era of improved dialysis membranes. This condition occurs
from beta-2-microglobulin accumulation in patients who have required chronic
dialysis for at least 8-10 years. It manifests with cysts at the ends of long
bones.