Chronic Kidney Disease 

Chronic kidney disease (CKD) is a worldwide public health problem. It is recognized as a common condition that is associated with an increased risk of cardiovascular disease and chronic renal failure (CRF). In the United States, there is a rising incidence and prevalence of kidney failure, with poor outcomes and high cost (see Epidemiology).

The Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) defines chronic kidney disease as either kidney damage or a decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m² for 3 or more months. Whatever the underlying etiology, the destruction of renal mass with irreversible sclerosis and loss of nephrons leads to a progressive decline in GFR. The different stages of chronic kidney disease form a continuum in time.

In 2002, K/DOQI published its classification of the stages of chronic kidney disease, as follows:

• Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m²)
• Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m²)
• Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m²)
• Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m²)
• Stage 5: Kidney failure (GFR < 15 mL/min/1.73 m² or dialysis)

In stage 1 and stage 2 chronic kidney disease, GFR alone does not clinch the diagnosis. Other markers of kidney damage, including abnormalities in the composition of blood or urine or abnormalities on imaging studies, should also be present in establishing a diagnosis of stage 1 and stage 2 chronic kidney disease.

The K/DOQI definition and classification of chronic kidney disease allow better communication among physicians and facilitate intervention at the different stages.

Patients with chronic kidney disease stages 1-3 are generally asymptomatic; clinically manifestations typically appear in stages 4-5 (see Clinical). Early diagnosis and treatment of the underlying cause and/or institution of secondary preventive measures is imperative in patients with chronic kidney disease. These may delay, or possibly halt, progression. The medical care of patients with chronic kidney disease (see Treatment) should focus on the following:

• Delaying or halting the progression of chronic k idney disease
• Treating the pathologic manifestations of chronic kidney disease
• Timely planning for long-term renal replacement therapy

Approximately 1 million nephrons are present in each kidney, each contributing to the total 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, by hyperfiltration and compensatory hypertrophy of the remaining healthy nephrons.

This nephron adaptability allows for continued normal clearance of plasma solutes. Plasma levels of substances such as urea and creatinine start to show significant increases only after total GFR has decreased to 50%, when the renal reserve has been exhausted.

The plasma creatinine value will approximately double with a 50% reduction in GFR. 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 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. This is believed to occur because of increased glomerular capillary pressure, which damages the capillaries and leads initially to secondary focal and segmental glomerulosclerosis and eventually to global glomerulosclerosis. This hypothesis has been based on studies of five-sixths nephrectomized rats, which develop lesions identical to those observed in humans with chronic kidney disease.

Factors other than the underlying disease process and glomerular hypertension that may cause progressive renal injury include the following:

• Systemic hypertension
• Acute insults from nephrotoxins or decreased perfusion
• Proteinuria
• Increased renal ammoniagenesis with interstitial injury
• Hyperlipidemia
• Hyperphosphatemia with calcium phosphate deposition
• Decreased levels of nitrous oxide
• Smoking
• Uncontrolled diabetes

Hyperkalemia

The ability to maintain potassium (K) excretion at near-normal levels is generally maintained in chronic kidney disease as long as both aldosterone secretion and distal flow are maintained. Another defense against potassium retention in patients with chronic kidney disease is increased potassium excretion in the GI tract, which also is under control of aldosterone.

Therefore, hyperkalemia usually develops when the GFR falls to less than 20-25 mL/min because of the decreased ability of the kidneys to excrete potassium. It can be observed sooner in patients who ingest a potassium-rich diet or if serum aldosterone levels are low, such as in type IV renal tubular acidosis commonly observed in people with diabetes or with use of angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs).

Hyperkalemia in chronic kidney disease can be aggravated by an extracellular shift of potassium, such as that occurs in the setting of acidemia or from lack of insulin. Hypokalemia is uncommon but can develop among patients with very poor intake of potassium, gastrointestinal or urinary loss of potassium, diarrhea, or diuretic use.

Metabolic acidosis

Metabolic acidosis often is a mixture of normal anion gap and increased anion gap; the latter is observed generally with chronic kidney disease stage 5 but with the anion gap generally not higher than 20 mEq/L. In chronic kidney disease, 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 chronic kidney disease stage 5, 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 causes an increase in ammoniagenesis to help excrete more hydrogen. However, this leads to an increase in fibrosis and rapid progression of kidney disease.

Metabolic acidosis is a factor in the development of renal osteodystrophy, as 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 chronic kidney disease. Extracellular volume expansion and total-body volume overload results from failure of sodium and free water excretion. This generally becomes clinically manifest when the GFR falls to less than 10-15 mL/min, 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.

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. It starts early in the course of disease and becomes more severe as the GFR progressively decreases with the availability of less viable renal mass.

No reticulocyte response occurs. RBC survival is decreased, and tendency of bleeding is increased from the uremia-induced platelet dysfunction. Other causes of anemia in chronic kidney disease include the following:

• Chronic blood loss
• Secondary hyperparathyroidism
• Inflammation
• Nutritional deficiency
• Accumulation of inhibitors of erythropoiesis

Bone disease

Renal bone disease is a common complication of chronic kidney disease. It results in both 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 chronic kidney disease, as follows:

• High-turnover bone disease due to high parathyroid hormone (PTH) levels
• Low-turnover bone disease (adynamic bone disease)
• Defective mineralization (osteomalacia)
• Mixed disease
• Beta-2-microglobulin associated bone disease

Chronic kidney disease–mineral and bone disorder (CKD-MBD) involves biochemical abnormalities, (ie, serum phosphorus, PTH, vitamin D levels, and alkaline phosphatase) related to bone metabolism.

Secondary hyperparathyroidism develops in chronic kidney disease 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 gland, which give rises to increased PTH secretion as well as increased parathyroid growth
• Skeletal resistance to PTH

Calcium and calcitriol are primary feedback inhibitors; hyperphosphatemia is a stimulus to PTH synthesis and secretion.

Phosphate retention begins in early chronic kidney disease; when the GFR falls, less phosphate is filtered and excreted, but serum levels do not rise initially because of increased PTH secretion, which increases renal excretion. As the GFR falls toward chronic kidney disease 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. Increased phosphate concentration also effects PTH concentration by its direct effect on parathyroid gland (posttranscriptional effect).

Hypocalcemia develops primarily from decreased intestinal calcium absorption because of low plasma calcitriol levels and possibly from calcium binding to elevated serum levels of phosphate.

Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all been demonstrated to independently trigger PTH synthesis and secretion. As these stimuli persist in chronic kidney disease, 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.

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. These lesions develop in patients with severe chronic kidney disease and are common in those 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 chronic kidney disease is associated with aluminum accumulation. It is markedly less common than high-turnover bone disease.

Dialysis-related amyloidosis from beta-2-microglobulin accumulation in patients who have required chronic dialysis for at least 8-10 years is another form of bone disease. It manifests with cysts at the ends of long bones.

Causes of chronic kidney disease include the following:

• Diabetic kidney disease
• Hypertension
• Vascular disease
• Glomerular disease (primary or secondary)
• Tubulointerstitial disease
• Urinary tract obstruction

Vascular diseases that can cause chronic kidney disease include the following:

• Renal artery stenosis
• Cytoplasmic pattern antineutrophil cytoplasmic antibody (C-ANCA)–positive and perinuclear pattern antineutrophil cytoplasmic antibody (P-ANCA)–positive vasculitides
• Antineutrophil cytoplasmic antibody (ANCA)–negative vasculitides
• Atheroemboli
• Hypertensive nephrosclerosis
• Renal vein thrombosis
• Unrecovered acute kidney injury

Primary glomerular diseases include the following:

• Membranous nephropathy
• Immunoglobulin A (IgA) nephropathy
• Focal and segmental glomerulosclerosis (FSGS)
• Minimal change disease
• Membranoproliferative glomerulonephritis

Rapidly progressive (crescentic) glomerulonephritis Secondary causes of glomerular disease include the following:

• Diabetes mellitus
• Systemic lupus erythematosus
• Rheumatoid arthritis
• Mixed connective tissue disease
• Scleroderma
• Goodpasture syndrome
• Wegener granulomatosis
• Mixed cryoglobulinemia
• Postinfectious glomerulonephritis
• Endocarditis
• Hepatitis B and C
• Syphilis
• Human immunodeficiency virus (HIV)
• Parasitic infection
• Heroin use
• Gold
• Penicillamine
• Amyloidosis
• Light chain deposition disease
• Neoplasia
• Thrombotic thrombocytopenic purpura (TTP)
• Hemolytic-uremic syndrome (HUS)
• Henoch-Schönlein purpura
• Alport syndrome
• Reflux nephropathy

Causes of tubulointerstitial disease include the following:

• Drugs (eg, sulfa, allopurinol)
• Infection (viral, bacterial, parasitic)
• Sjögren syndrome
• Chronic hypokalemia
• Chronic hypercalcemia
• Sarcoidosis
• Multiple myeloma cast nephropathy
• Heavy metals
• Radiation nephritis
• Polycystic kidneys
• Cystinosis

Urinary tract obstruction may result from any of the following:

• Urolithiasis
• Benign prostatic hypertrophy
• Tumors
• Retroperitoneal fibrosis
• Urethral stricture
• Neurogenic bladder

Findings from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective observational cohort, suggest that inflammation and hemostasis are antecedent pathways for chronic kidney disease.^[1] This study used data from 1787 cases of chronic kidney disease that developed between 1987 and 2004.

Thaker et al found that aside from other major risk factors of progression, a strong association between acute kidney injury (AKI) and a cumulative risk for the development of advanced chronic kidney disease was seen in multiply hospitalized patients with diabetes mellitus.^[2]

After adjustments for various factors, such as demographics, smoking, blood pressure, diabetes, lipid levels, prior myocardial infarction (MI), antihypertensive use, and alcohol use, the above study revealed that the risk for chronic kidney disease rose with increasing quartiles of white blood cell (WBC) count, fibrinogen, von Willebrand factor, and factor VIIIc. The investigators found a strong inverse association between serum albumin level and chronic kidney disease risk.

In the United States, there is a rising incidence and prevalence of kidney failure, with poor outcomes and high cost. Kidney disease is the ninth leading cause of death in the United States.

The Third National Health and Examination Survey (NHANES III) estimated that the prevalence of chronic kidney disease in adults in the United States was 11% (19.2 million): 3.3% (5.9 million) had stage 1, 3% (5.3 million) had stage 2, 4.3% (7.6 million) had stage 3, 0.2% (400,000) had stage 4, and 0.2% (300,000) had stage 5.

The prevalence of chronic kidney disease stages 1-4 increased from 10% in 1988-1994 to 13.1% in 1999-2004. This increase is partially explained by the increase in the prevalence of diabetes and hypertension, the two most common causes of chronic kidney disease. Data from the United States Renal Data System (USRDS) indicated that the prevalence of chronic renal failure increased 104% between the years 1990-2001.

According to the Third National Health and Nutrition Examination Survey, it was estimated that 6.2 million people (ie, 3% of the total US population) older than 12 years had a serum creatinine value above 1.5 mg/dL; 8 million people had a GFR of less than 60 mL/min, the majority of them being in the Medicare senior population (5.9 million people).

Therefore, for the first time, the US Surgeon General’s latest 10-year national objectives for improving the health of all Americans, Healthy People 2020, contains a chapter focused on chronic kidney disease. For 2020, Healthy People lays out 14 goals and strategies to reduce the incidence, morbidity, mortality, and health costs of chronic kidney disease in the United States. Reducing renal failure will require additional public health efforts, including effective preventive strategies and early detection and treatment of chronic kidney disease.

Because of the nonuniform definition of kidney disease prior to publication of the K/DOQI classification in 2002, among other factors, most patients with earlier stages of chronic kidney disease have not been recognized or adequately treated.

The incidence rates of end-stage renal disease (ESRD) have increased steadily internationally since 1989. The United States has the highest incident rate of ESRD, followed by Japan. Japan has the highest prevalence per million population, with the United States taking second place.

Racial demographics

Chronic kidney disease affects all races, but, in the United States, a significantly higher incidence of ESRD exists in blacks than in whites; the incidence rate for blacks is nearly 4 times that for whites.

Choi et al found that rates of ESRD among black patients exceeded those among white patients at all levels of baseline estimated GFR (eGFR).^[3] Risk of ESRD among black patients was highest at an eGFR of 45-59 mL/min/1.73 m² (hazard ratio, 3.08), as was the risk of mortality (hazard ratio, 1.32).

Schold et al found that among black kidney transplant recipients graft loss and acute rejection rates are higher than whites, especially among younger patients.^[4] Hicks et al looked at the connection between African Americans with the sickle cell trait and their increased risk for kidney disease; the study found that sickle cell trait is not associated with diabetic or nondiabetic ESRD in a large sample of African Americans.^[5]

Sex- and age-related demographics

In NHANES III, the distribution of estimated GFRs for the chronic kidney disease stages was similar in both sexes. Nonetheless, the USRDS 2004 Annual Data Report reveals that the incident rate of ESRD cases is higher for males, with 409 per million population in 2002 compared with 276 for females.

Chronic kidney disease is found in persons of all ages. Nonetheless, in the United States, the highest incidence rate of ESRD occurs in patients older than 65 years. As per NHANES III data, the prevalence of chronic kidney disease was 37.8% among patients older than 70 years. A study of Israeli youth revealed that patients aged 16-25 years with persistent asymptomatic isolated microscopic hematuria had an increased risk of treated ESRD for 22 years; however, the absolute risk and incidence was slight.^[6]

Besides diabetes mellitus and hypertension, age is an independent major predictor of chronic kidney disease. The geriatric population is the most rapidly growing kidney failure (chronic kidney disease stage 5) population in the United States.

The biologic process of aging initiates various structural and functional changes within the kidney. Renal mass progressively declines with advancing age. 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 shows 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 the afferent to efferent arterioles, resulting in redistribution of blood flow favoring the renal medulla. These anatomical and functional changes in renal vasculature appear to contribute to an age-related decrease in renal blood flow.

Renal hemodynamic measurements in aged human 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 both 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 decline in the GFR is reported because of measurement methods, race, gender, genetic variance, and other risk factors for renal dysfunction.

Patients with chronic kidney disease generally progress to ESRD. The rate of progression depends on the underlying diagnosis, on the successful implementation of secondary preventive measures, and on the individual patient. Timely initiation of chronic renal replacement therapy is imperative to prevent the uremic complications of chronic kidney disease that can lead to significant morbidity and death.

Tangri et al developed and validated a model that uses routine laboratory results to predict progression from chronic kidney disease (stages 3-5) to kidney failure. The study showed that lower estimated GFR, higher albuminuria, younger age, and male sex pointed to a faster progression of kidney failure. Also, a lower serum albumin, calcium, and bicarbonate, and a higher serum phosphate can predict an elevated risk of kidney failure.^[7]

In the United States, the general hemodialysis and peritoneal dialysis populations have 2 hospital admissions per patient per year; patients who have a renal transplant have an average of 1 hospital admission per year. Additionally, patients with ESRD who undergo renal transplantation survive longer than those on chronic dialysis.

The mortality rates associated with hemodialysis are striking and indicate that the life expectancy of patients entering into hemodialysis is markedly shortened. In 2003, over 69,000 dialysis patients enrolled in the ESRD program died (annual adjusted mortality rate of 210.7 per 1000 patient-years at risk for the dialysis population, which represents a 14% decrease since peaking at 244.5 per 1000 patient-years in 1988).

The highest mortality rate is within the first 6 months of initiating dialysis. Mortality then tends to improve over the next 6 months, before increasing gradually over the next 4 years. The 5-year survival rate for a patient undergoing chronic dialysis in the United States is approximately 35%, and approximately 25% in patients with diabetes.

A study by Sens found that the risk of mortality was elevated in patients with end-stage renal disease and congestive heart failure who received peritoneal dialysis compared with those who received hemodialysis.^[8]

At every age, patients with ESRD on dialysis have significantly increased mortality when compared with nondialysis patients and individuals without kidney disease. At age 60 years, a healthy person can expect to live for more than 20 years, whereas the life expectancy of a 60-year-old patient starting hemodialysis is closer to 4 years. Among patients with ESRD aged 65 years and older, mortality rates are 6 times higher than in the general population.^[9]

The most common cause of sudden death in patients with ESRD is hyperkalemia, which often follows missed dialysis or dietary indiscretion. The most common cause of death overall in the dialysis population is cardiovascular disease; cardiovascular mortality is 10-20 times higher in dialysis patients than in the normal population.

The morbidity and mortality of dialysis patients is much higher in the United States compared with most other countries, which is probably a consequence of selection bias. Due to liberal criteria for receiving government-funded dialysis in the US and rationing (both medical and economic) in most other countries, US patients receiving dialysis are on the average older and sicker than those in other countries.

In the NHANES III prevalence study, hypoalbuminemia (a marker of protein-energy malnutrition and a powerful predictive marker of mortality in dialysis patients as well as in the general population) was independently associated with low bicarbonate as well as the inflammatory marker C-reactive protein. A study by Raphael et al suggests that higher serum bicarbonate levels are associated with better survival and renal outcomes in African Americans.^[10]

Friedman et al found that more than 3 million African Americans with genetic variants in both copies of apolipoprotein L1 (APOL1) are at higher risk for hypertension-attributable ESRD and focal segmental glomerulosclerosis. In contrast, African Americans without the risk genotype and European Americans appear to have similar risk for developing nondiabetic chronic kidney disease.^[11]

An elevated level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) has been linked with mortality in patients with ESRD. Isakova et al reported that elevated FGF-23 is also an independent risk factor for end-stage renal disease in patients who have fairly preserved kidney function (stages 2-4) and for mortality across the scope of chronic kidney disease.^[12]

Reproductive issues

Female patients with advanced chronic kidney disease commonly develop menstrual irregularities; women with ESRD are typically amenorrheic and infertile.

Pregnancy in chronic kidney disease can be associated with accelerated renal decline. In advanced chronic kidney disease and ESRD, pregnancy is associated with markedly decreased fetal survival.

Patients with chronic kidney disease should be educated about the following:

• Importance of compliance with secondary preventive measures
• Natural disease progression
• Prescribed medications (highlighting their potential benefits and adverse effects)
• Avoidance of nephrotoxins
• Diet
• Renal replacement modalities, including peritoneal dialysis, hemodialysis, and transplantation
• Permanent vascular access options for hemodialysis