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Chronic Kidney Disease

Updated: Aug 01, 2019
Author: Pradeep Arora, MD; Chief Editor: Vecihi Batuman, MD, FASN more...

OVERVIEW

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 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 patients with diabetes mellitus who
experienced AKI in multiple hospitalizations. [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. Pediatric CKD 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 with 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 DNAJC16 and 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
m², 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
m², 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 viable renal mass shrinks and 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-microglobulin–associated 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).

CKD–mineral 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 m².
Increased phosphate concentration also affects 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 its onset
before the initiation of dialysis has been reported in some cases. The pathogenesis of
adynamic bone disease is not well defined, but possible contributing factors include the
following:

• High calcium load

• Use of vitamin D sterols
• Increasing age
• Previous corticosteroid therapy
• Peritoneal dialysis
• 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.