Chronic Kidney Disease: Manifestations and Pathogenesis
Chronic kidney disease is characterized by a decrease in glomerular filtration rate (GFR) and histologic evidence of a reduction in nephron population. The clinical course is typically one of a progressive and unrelenting loss of nephron function, ultimately leading to end-stage renal disease (ESRD). However, the time between the initial onset of disease and ultimate development of ESRD may vary considerably, not only between different diseases but also in different patients with similar disease processes.
Assessment of Function in Chronic Kidney Disease
Assessment of GFR continues to be the most useful quantitative index of kidney function. Exogenous and endogenous markers have been used for the measurement of GFR. An ideal filtration marker should be freely filtered across the glomerular capillary wall and excreted only by glomerular filtration (1). Inulin fulfills all the criteria for an ideal filtration marker, and its renal clearance has been considered as a standard measure of GFR. However, renal clearance of inulin requires precise regulation of an intravenous infusion of inulin to achieve a steady-state plasma inulin concentration and several timed urine collection with complete emptying of the bladder. Because of the inconvenience, it is only performed in research settings. Renal 125I-iothalamate or 51Cr-EDTA clearance after subcutaneous injection and timed urine collection also has been used as an alternative method (2,3).
van Slyke et al. introduced the concept of clearance in 1929 in their description of urea clearance. Blood urea nitrogen (BUN), however, is a less reliable indicator of kidney function, because factors other than the GFR—including protein intake, state of hydration, antianabolic agents (tetracycline and corticosteroids), blood in the bowel, fever, and infection—all can cause changes in BUN in the absence of changes in kidney function. In contrast, the blood level of creatinine, produced endogenously by the hydrolysis of phosphocreatine, provides a reasonable index of kidney function. Approximately 1 mg of creatinine is produced daily by the metabolism of 20 g of muscle (4). In addition, about 20% of urinary creatinine is derived from the ingestion of meat. Small quantities of creatinine are secreted by the renal tubules so that the creatinine clearance slightly overestimates true glomerular filtration. As a result, the 24-hour endogenous creatinine clearance generally exceeds inulin clearance, and this difference increases in patients with advanced chronic kidney disease and proteinuria. For clinical purposes, creatinine clearance is a simple and reliable method of estimating GFR and thus the degree of impairment of kidney function. Creatinine clearance (Ccr) can be estimated from serum creatinine (SrCr) determinations alone using the Cockcroft and Gault equation (5):
This equation corrects for the major factors that affect GFR, that is, age, sex, and weight. The normal creatinine clearance established by this method is 140 + 27 mL/minute for men and 112 ± 20 mL/minute for women.
A more accurate method to estimate GFR from serum creatinine was recommended by the Modification of Diet in Renal Diseases (MDRD) study (6) which included 1,628 patients with diverse characteristics and causes of chronic kidney disease. The equation derived from this study, as shown in the following, predicts GFR by serum creatinine concentration (Pcr), demographic characteristics (age, gender, and ethnicity) as well as other serum measurements (serum urea nitrogen [SUN] and albumin [Alb]):
This equation has less variability and is more accurate than other commonly used equations. Besides, it could be easily implemented and there is no need for 24-hour urine collections. It, however, is not very accurate with GFR values of 60 mL/minute or above. The MDRD study equation appears to be able to provide drug dosage adjustments similar to the Cockcroft and Gault equation. The new CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) (6) equation improves performance and risk prediction compared to the MDRD study equation in patients with a GFR of mL/minute or above. Current cystatin C-based equations (6) are not accurate in all populations, even in those with reduced muscle mass or chronic illness, where cystatin C would be expected to outperform creatinine. Estimated GFR, on the basis of prediction equations, reporting has led to a greater number of referrals to nephrologists, but the increased numbers do not appear to be excessive or burdensome.
The serum creatinine concentration doubles for every 50% reduction in GFR. For example, if a patient has a GFR of 100 mL/min/1.73 m2 with a serum creatinine of 1 mg/dL, when the GFR falls to 50 mL/min/1.73 m2 serum creatinine increases to 2 mg/dL. With a further fall in function to 25 mL/min/1.73 m2, serum creatinine again doubles and is 4 mg/dL. As can be seen in Figure 11-1, changes in serum creatinine become a very sensitive method of estimating further impairment in kidney function when there is already extensive kidney damage. A plot of the reciprocal of the serum creatinine against time yields a straight line in many patients with chronic kidney disease. The linear decline in the reciprocal serum creatinine value with time is consistent with a linear loss of glomerular filtration. A change in the slope may indicate the superimposition of some additional factor that accelerates renal functional loss, such as volume depletion or a nephrotoxic agent if the slope is increased. Conversely, a decrease in the slope represents slowing of the rate of decline in function. Irrespective of the underlying kidney disease, progression to ESRD is a common event once the serum creatinine exceeds 1.5 to 2.0 mg/dL. However, the rate of progression to ESRD occurs at a variable rate. When a patient is first seen with chronic kidney disease, it is most important to document the degree of renal impairment and attempt to determine if potentially reversible factors have contributed to the severity of kidney function decline.
Incidence and Prevalence of Chronic Kidney Disease
Chronic kidney disease is defined as the presence of kidney damage or GFR <60 mL/min/1.73 m2 for 3 months or longer, irrespective of cause (6). Chronic kidney disease was divided into stages of severity (Table 11-1). The staging of chronic kidney disease is useful because it endorses a model in which primary physicians and specialists share responsibility for the care of patients with kidney disease. This classification also offers a common language for patients and the practitioners involved in the treatment of chronic kidney disease patients. For each stage of chronic kidney disease, the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) provides recommendations for a clinical action plan (Table 11-1) (7,8). Importantly, the staging system is based on estimated GFR and not only on the measurement of serum creatinine. The gradual decline of kidney function in patients with chronic kidney disease is initially asymptomatic. The earliest stages of chronic kidney disease are characterized by an apparent preservation of renal function of remaining nephrons. The basal GFR may be normal or even elevated because of hyperfiltration. Measurement of GFR after imposed stresses, such as after a high-protein meal, may reveal the absence of normal renal reserve. A diminution of renal reserve happens when GFR is reduced to 25% of normal. The patient usually has no symptoms, azotemia is present, and the serum creatinine is increased. As GFR falls to <25% of normal, an increasing number and severity of uremic clinical manifestations and biochemical abnormalities supervene. The magnitude of the population with chronic kidney disease is just beginning to be appreciated. Jones et al. (7) analyzed serum creatinine data from the Third National Health and Nutritional Survey (NHANES III), gathered between 1988 and 1994. Among men, the proportion of the population that had serum creatinine levels ≥1.5 mg/dL, ≥1.7 mg/dL, and ≥2.0 mg/dL were 4.98%, 1.87%, and 0.64%, respectively. Among women, the comparable figures were 1.55%, 0.73%, and 0.33%, respectively. On the basis of the population demography, the authors estimated that 6.2 million Americans have serum creatinine levels ≥1.5 mg/dL, 2.5 million have levels of ≥1.7 mg/dL, and 0.8 million have levels of ≥2.0 mg/dL. It is unclear as to what proportion of patients with abnormal serum creatinine progress to ESRD; however, there is increasing evidence that these patients develop irreversible but preventable complications of chronic kidney disease during this phase of renal insufficiency. More recently it was noticed that the prevalence of chronic kidney disease increased from 10.0% in 1988 to 1994 to 13.1% in 1999 to 2004, of the U.S. population. This increase was partly explained by the increasing prevalence of diabetes and hypertension (8).
GFR (mL/min/1.73 m3)
Estimated No of U.S. adults in 2000
At increased risk
≥60 (with chronic kidney disease risk factors)
Screening: chronic kidney disease risk reduction
Kidney damage with normal or increased GFR
Diagnosis and treatment; treatment of comorbid conditions; slowing progression; CVD risk reduction
Kidney damage with slightly decreased GFR
Moderately decreased GFR
Evaluating and treating complications
Severely decreased GFR
Preparation for kidney replacement therapy
GFR, glomerular filtration rate; CVD, cardiovascular disease.
The term “ESRD” is used for patients who are on renal replacement therapy (dialysis or transplantation) in order to avoid life-threatening uremia. The incidence of ESRD shows marked geographic variation as determined by the population base with regard to age, race, and sex. The reported incidence of ESRD in the United States in 2013 was 360 per million population (9). The prevalent rate of ESRD, adjusted for age, gender, and race, rose to reach 2,000 per million population in 2013. A similar increase in prevalence is occurring in most other industrialized countries as well; the reason for this increase in frequency of ESRD is unclear. In the United States, the distribution of patients reported by race most recently shows that 54.7% were white, 38.3% were African American, with the remaining 5.3% Asian/Pacific islanders and Native Americans. Overall, 10.3% of the patients are Hispanic. In the U.S. population, it is clear that chronic kidney disease is more prevalent in the African American and Native American populations than in the white population.
Although life for chronic kidney disease patients can be sustained by chronic dialysis and kidney transplantation, neither form of therapy is totally satisfactory. The current yearly mortality rate in the U.S. dialysis population is over 20%. Results with renal transplantation have improved considerably with the advent of improved immunosuppressive therapy (9). The adjusted and averaged 1-year graft survival was over 90% for living related donors and ˜85% for cadaveric donor transplants (10,11). With improved transplant outcomes, growth in the number of patients wanting or needing a transplant has outpaced the supply of available organs. Although kidney transplant has become the preferred method of treatment for many ESRD patients, fewer than 20% of patients entering ESRD programs receive kidney transplantation because of age, associated disease, anatomic abnormalities of the urinary tract, the presence of preformed cytotoxic antibodies, or lack of availability of a suitable donor.
The rehabilitation rate of patients on chronic dialysis has been disappointing, and the cost of this treatment has been of increasing concern. Driven predominantly by recent growth in the ESRD patient population, total Medicare expenditures for the ESRD program alone have been increased steadily from $5 billion in 1991 to $30 billion in 2013 (9). Because of the cost as well as the morbidity and mortality associated with ESRD, every attempt should be made to preserve kidney function as long as possible, ideally preventing any further progression of the underlying renal disease.
Causes of Chronic Kidney Disease
The cause of kidney disease should be established, if possible, because some conditions may result in partial or full functional recovery if corrected. The major causes of chronic kidney disease found in patients entering the ESRD program are shown in Figure 11-2.
Diabetes mellitus has become the most common cause of chronic kidney disease. It is estimated that 40% of patients who have type 1 diabetes mellitus for more than 20 years will develop kidney disease. Although the incidence of ESRD in patients with type 2 diabetes may be less than that found in type 1 diabetes, because of the larger number of patients with type 2 diabetes it is a more frequent cause of ESRD than type 1 diabetes (36.5% vs. 7.2%) (11). Of note, in the United States at least 80% of diabetic patients with ESRD are type 2 diabetic (9).
Glomerulonephritis represents the third most common cause of ESRD. The most common glomerular diseases are focal segmental glomerulosclerosis (FSGS) and membranoproliferative and lupus glomerulonephritis. However, it should be noted that the majority of glomerular diseases are unclassified. It is possible that this disease accounts for a relatively large fraction of unclassified glomerular diseases because immunoglobulin A (IgA) nephropathy is the most common glomerular disease responsible for ESRD in most other developed countries.
Hypertension is the second leading reported cause of ESRD. A 15-year follow-up study of 361,659 men with hypertension found that 924 developed ESRD (12). This represented an incidence of 17.12 per 100,000 person-years. The relative risk for development of ESRD for diastolic blood pressure >120 mm Hg versus <70 mm Hg was 30.9. For systolic blood pressure >200 mm Hg versus <120 mm Hg, the relative risk was 48.2. Across the entire range, blood pressure represented an independent risk factor for kidney disease progression. The relative risk for African Americans was 1.99 (12). This increased risk could not be explained by difference in levels of systolic or diastolic pressures or other known risk factors. In general, ESRD secondary to hypertension occurs in African American patients with a long history of uncontrolled hypertension or almost any patient with a history of malignant or accelerated hypertension (13–15). Although the incidence of chronic kidney disease from hypertension can be markedly attenuated by treatment of accelerated or malignant hypertension (13,16), adequate chronic treatment of milder hypertensive states, especially in the African American population, may not prevent progression of kidney disease (12,14).
Other less common vascular causes of chronic kidney disease are atheroembolic disease and bilateral renal artery stenosis. Atheroembolic disease should be suspected in any individual who develops progressive decrease in kidney function following a vascular diagnostic procedure or surgery. In contrast to other vascular renal disease, atheroembolic disease may include high-grade proteinuria, eosinophiluria, and decreased serum complement. Diagnosis of atheroembolic disease largely depends on renal biopsy in which the cholesterol clefts are observed. There is no specific treatment for atheroembolic disease. Bilateral renal artery stenosis, as a cause of ischemic nephropathy, is suggested by a further reversible reduction in renal function precipitated by converting enzyme inhibitors.
Arteriography usually is required for the diagnosis of renal artery stenosis. As of this time, there is no consistent evidence that kidney function can predictably be improved in patients with bilateral renal artery stenosis by either angioplasty or surgical correction of the lesions. Uncontrolled studies, however, have suggested that these procedures can improve kidney function in some instances.
Interstitial nephritis is a descriptive term implying fibrosis and an inflammatory response in the interstitium of the kidney. The glomeruli are involved only secondarily as a result of the fibrosis and vascular changes. Because of the potential reversibility or prevention of this group of renal diseases, it is important to differentiate interstitial nephritis from glomerulonephritis.
A number of clinical and biochemical features, listed in Table 11-2, tend to separate these two forms of renal disease. Characteristically, patients with interstitial nephritis complain of polyuria and nocturia. Their urine volume is unusually large (3 to 5 L/day) because the kidney’s ability to concentrate urine is lost early in the course of kidney disease. The diluting capability in interstitial nephritis is maintained even late in the course of kidney disease; thus, the urine osmolality and specific gravity may be low when determined on a random collection of urine.
A feature of advanced glomerular diseases is high-grade proteinuria, which usually is in excess of 2.5 g/day. Even with advanced interstitial nephritis, the 24-hour urinary protein excretion is usually <1 to 2 g. Furthermore, the urinary protein may be predominantly an α2– or β-globulin instead of albumin. In interstitial nephritis, serum uric acid is commonly elevated, and in one type of interstitial nephritis—lead nephropathy—clinical gout has been recognized in ˜50% of the patients (17,18). The urinary sediment in interstitial nephritis may be totally unremarkable, or there may be a few white blood cells (WBCs) and hyaline casts. Renal salt wasting appears to be more common in patients with interstitial nephritis than in other forms of kidney disease, and salt supplementation sometimes must be given to maintain extracellular fluid (ECF) volume. Finally, hypertension is less common in interstitial nephritis and anemia may be disproportionately more severe for the degree of compromised kidney function than in chronic glomerulonephritis.
As is apparent in Table 11-3, a variety of drugs and toxins can be the etiologic agent responsible for causing interstitial nephritis. In general, with the exception of analgesics, drugs cause an acute interstitial nephritis that is reversible when the drugs are discontinued. The severity and chronicity of other forms of interstitial nephritis are largely related to the amount and duration of exposure to the various nephrotoxins. Interstitial nephritis accounts for 3% of the patients in this country being treated for ESRD. In this group, currently analgesic nephropathy accounts for 0.8% of patients being treated for ESRD. Analgesic nephropathy used to account for up to 20% of ESRD in several countries (19). However, following the removal from the market of analgesics containing the combination of aspirin and phenacetin, the incidence of this disease has markedly decreased worldwide. The typical patient with this disease is a depressed, middle-aged woman who gives a history of years of daily ingestion of analgesics containing caffeine, aspirin, and phenacetin. Usually, the total consumption of analgesics amounts to several kilograms. Patients frequently complain of headaches, backache, or other types of chronic pain and state that the analgesics are consumed to relieve this pain. There is evidence that sometimes the headaches may result from the caffeine or phenacetin ingestion, or both. The headaches may disappear if the patient can be persuaded to discontinue the analgesics. The patient commonly presents with recurrent urinary tract infections, gross hematuria, or symptoms of uremia. However, because papillary necrosis is common, acute kidney injury, and ureteral colic may develop as a result of the passing of necrotic papillae down one or both ureters. In this disease, the kidney has a remarkable capacity to recover even after what would appear to be a terminal state of ESRD (20). With conservative treatment and discontinuation of the analgesics, the patient can achieve significant improvement in kidney function and have a relatively good, long-term survival. Many times, however, it is very difficult to convince the patient to break a long habit of drug abuse.
Numerous cells and red blood cell casts
Few cells and casts
Normal until late
Moderate severity until late
Disproportionately severe for degree of renal failure
Penicillin and homologs
Nonsteroidal antiinflammatory drugs
Associated with small bowel disease
Anesthetic agents: methoxyflurane
Uric acid and oxalate nephropathy and cystinosis represent <0.1% each of the ESRD population (11). Chronic kidney disease is uncommon in patients with primary gout, and when it does occur, it is slowly progressive and only becomes clinically important late in life (20). However, in some hematologic disorders, particularly in association with the use of chemotherapeutic agents, there may be marked overproduction of uric acid, which may cause acute kidney injury caused by deposition of urate crystals in the tubules.
Another compound capable of inducing a severe interstitial nephritis is oxalate. Besides ethylene glycol intoxication (21), increased urinary excretion of oxalate can occur in association with genetic disorders as well as with a number of acquired conditions. Two enzymatic defects have been described that can result in the accumulation of glyoxylic acid and hyperoxaluria. In the first type, urinary excretion of oxalic acid, glyoxylic acid, and glycolic acid is increased as a result of deficiency of 2-oxoglutarate-glyoxylate carboligase (22). In the second defect, urinary excretion of glycolic acid is normal, but the excretion of L-glyceric acid and oxalate is increased. This condition owes to a deficiency of D-glyceric dehydrogenase (22). Both diseases are characterized by nephrolithiasis, nephrocalcinosis, and ESRD, with few patients living beyond the age of 40 years.
Recently, a number of acquired forms of hyperoxaluria and kidney disease have been described. Methoxyflurane anesthesia can cause hyperoxaluria and azotemia (23). In addition, it has been recognized that patients with distal small bowel disease may have hyperoxaluria (24). In this group of patients, calcium oxalate stones are common; however, marked oxalate deposition occasionally may occur in the kidney, resulting in interstitial nephritis and loss of kidney function. The mechanism responsible for hyperoxaluria has been shown to be a consequence of increased absorption of dietary oxalate (24). It is felt that this results from calcium and possibly magnesium (which normally binds oxalate in the gut, rendering it insoluble and nonabsorbable) being bound to fatty acids in steatorrheic states, allowing the oxalate to be absorbed. Similarly, this condition has been treated successfully by giving supplemental calcium. Furthermore, cholestyramine also has been shown to be effective in decreasing oxalate absorption from the bowel and thus in decreasing urinary excretion of this compound (24).
All other causes of interstitial nephritis are even less prevalent. Conditions that cause hypercalcemia, hypercalciuria, or both can lead to the deposition of calcium in the kidney, with a resulting interstitial nephritis. Radiographic evidence of nephrocalcinosis is frequently a late finding and even then may be observed only by using the technique of nephrotomography. Thus, radiographic evidence of nephrocalcinosis cannot be relied on to establish the diagnosis even when kidney function is severely impaired. In this condition, if the underlying cause responsible for the disturbance of calcium metabolism such as primary hyperparathyroidism, sarcoid, or milk–alkali syndrome is corrected or treated, further progression of kidney disease can be either slowed or prevented (25,26).
A final group of agents that can produce a chronic interstitial nephritis are some of the heavy metals, including copper, lead, cadmium, and uranium. Lead nephropathy is common in Queensland, Australia (18), and has been reported in some areas of the United States in patients who have consumed moonshine whiskey (27). Lead nephropathy may occur more commonly than previously suspected in this country. Batuman et al. (28) have suggested that patients having the combination of interstitial nephritis and gout should be suspected of having lead nephropathy. This supposition was supported by the finding that ethylenediaminetetraacetic acid (EDTA) mobilized significantly greater amounts of lead in patients with kidney disease and gout than in patients with either gout or chronic kidney disease alone. Cadmium intoxication also can lead to an interstitial nephritis and renal tubular dysfunction. Characteristically, patients present with aminoaciduria, glycosuria, phosphaturia, and severe osteomalacia (29). As a result of industrial contamination with the element, chronic cadmium intoxication is especially prevalent in the people living along the Jinzū River in Japan (29). In Wilson disease, copper is deposited in the proximal tubule cells and may cause a variety of renal functional abnormalities, including Fanconi syndrome, proteinuria, and hematuria; however, it does not appear to progress to ESRD.
Evidence suggests that, in the adult, chronic urinary tract infection without obstruction rarely, if ever, leads to ESRD. However, there are some exceptions in which renal bacterial infections can lead to chronic kidney disease if untreated; among them are tuberculosis, multiple renal abscesses, and bacterial infections associated with papillary necrosis.
Because a number of patients with interstitial nephritis have a potentially preventable or reversible form of kidney disease, a careful history should be obtained relating to medications, small bowel disease, and possible environmental exposure to some toxin. In addition, serum and urinary uric acid and calcium should be determined. In selected cases, urinary oxalate excretion should be measured and heavy metal screens performed. The normal values to be used for these screening procedures are given in Table 11-4.
Reflux nephropathy is the second most common kidney disease in children (30). According to the European Dialysis and Transplantation Association, it accounts for 30% of advanced kidney disease in children <16 years. The infant kidney is especially susceptible to intrarenal reflux. Most evidence would suggest that scarring usually occurs by 2 years of age (31) and that new scarring is unusual after age 5 (31–33). Increasing evidence suggests that severe congenital kidney damage already may be present at birth (31). This may represent a disorder in kidney embryogenesis as a result of an abnormal development of the ureteral bud. Recent evidence also suggests that this condition may have a heritable basis with contribution from several genetic foci. Prognosis is largely determined by the extent to which the kidney is scarred and contracted when the patient is initially seen. It has been shown also that the severity of the reflux can be correlated with the degree of kidney damage and that surgical correction of reflux is associated with eradication of upper urinary tract infection and improvement in renal growth and function. However, a recent study in children suggests that surgical correction of reflux offers no advantage over good medical management (33). Although there are no control trials in adults regarding surgical correction of reflux, most studies suggest that it does not influence the course of kidney disease.
Cadmium, mercury, and uranium
aFollowing 1 g of ethylenediaminetetraacetic acid.
HEREDITARY RENAL DISEASE
Approximately 5% to 8% of patients with chronic kidney disease have an hereditary etiology such as autosomal dominant polycystic kidney disease (ADPKD), Alport syndrome, Fabry disease, congenital nephrotic syndrome, medullary cystic disease, cystinosis, or familial amyloidosis. This is another group of kidney diseases for which specific treatment is not available (34). Through genetic counseling, however, a number of these diseases are potentially preventable. Therefore, the physician has an obligation to advise potential parents of the risk of having children with kidney disease and to determine when possible which family members are at risk or have diagnosable kidney disease. In ADPKD, which is inherited as an autosomal dominant disorder with complete penetrance, a DNA probe has localized the majority of cases (>90%) to a mutation in the short arm of human chromosome 16 (PKD1). This technique has been used to diagnose the disease in utero in a 9-week fetus (35). A mutation of chromosome 4 (PKD2) accounts for ˜10% of patients with the disease. The genes for PKD1 and PKD2 have been identified. PKD1 encodes polycystin. An abnormality in polycystin may impair cell–cell and cell–matrix interactions, leading to abnormal epithelial cell differentiation and various phenotypic expressions (36,37). The PKD2 gene encodes for a channel protein. Mutation of the same leads to decrease cellular calcium with increased cyclic AMP that has been known to contribute to cyst formation.
The potential success of genetic counseling for hereditary diseases is demonstrated by a study carried out at the genetic clinic at the Hospital for Sick Children in London. Approximately two-thirds of the families who were informed that the chances were >10% that their children would develop hereditary disease decided to have no more children, whereas three-fourths of families informed that the chances were ≤10% elected to have more children (36).
Risk Factors for Development of End-Stage Renal Disease
The four important risk factors for the development of ESRD are race, age, sex, and family history.
RACE AND ETHNICITY
Male African Americans aged 25 to 44 years are 20 times more likely to develop kidney disease secondary to hypertension than white men (15,38). African Americans also have a very high incidence of idiopathic FSGS as well as that associated with intravenous drug use and acquired immunodeficiency syndrome (AIDS) (9,39). The attack rate of FSGS in African American men with AIDS is ˜10 times as great as in white men. In fact, FSGS is the most common cause of kidney disease in young adult African American men. African Americans also have a fourfold greater risk than whites of developing ESRD from type 2 diabetes (11). In contrast, two diseases, ADPKD and especially IgA nephropathy, occur with considerably less frequency in the African American than in the white population. In Native Americans, diabetes accounts for almost twice as much ESRD (68.2%) as found in the white or African American population. Hispanics also have a high frequency of diabetic ESRD, with some reports as high as 60% (9).
Since 2000, the adjusted incident rate of ESRD has increased by 11.0% for patients ≥75 years, while the rate for those age 20 to 44 years has grown by 6.1% (9). The incidence of diabetic kidney disease also increases dramatically with age. However, in contrast to the total causes of chronic kidney disease, which continue to increase with advanced age, over 66% of diabetic ESRD occurs before 64 years of age. Before age 40, FSGS, lupus erythematosus, Henoch–Schönlein purpura, AIDS-related nephropathy, and congenital and hereditary disease (e.g., renal agenesis, obstructive nephropathy, Alport syndrome, and reflux nephropathy) are most commonly seen. In the age group 40 to 55 years, ADPKD, membranous glomerulonephritis, membranoproliferative glomerulonephritis, and hemolytic uremic syndrome are seen with increasing frequency. Goodpasture syndrome, interstitial nephritis, analgesic nephropathy, amyloidosis, multiple myeloma, and Wegener granulomatosis are the most common diseases in the age group >55 years.
Sex is an additional risk factor for the development and progression of certain types of kidney disease. Overall, the incidence of ESRD is greater in males than in females (9). However, there are certain causes of ESRD that occur more frequently in females, such as lupus erythematosus, scleroderma, and hemolytic uremic syndrome/thrombotic thrombocytopenia purpura.
Genetic factors also are important in predisposing individuals to developing ESRD. Patients with diabetes who have a family history of essential hypertension and abnormal lithium–sodium countertransport are at greater risk of developing chronic kidney disease (40,41). Both candidate locus and genome-wide strategies have been used to target genes that contribute to the risks for development of these orders. Similarly, there are numerous types of hereditary renal disease such as Alport syndrome and ADPKD, plus a variety of less common and largely recessive or sex-linked hereditary diseases such as Fabry disease, tuberous sclerosis, medullary cystic disease, sickle cell disease, familial Mediterranean fever, type 1 glycogen storage disease, cystinosis, oxalate nephropathy, and infantile PKD (42–44).
Individual variability in the rate of progression to ESRD is a characteristic feature among patients with either inherited or acquired causes of kidney diseases. A number of genetic foci that contribute to the progression of chronic kidney disease have been identified. Most extensively studied has been an insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene. Studies in a variety of disorders have revealed an important contribution of this locus in the progressive deterioration of kidney function. The two different alleles defined by this polymorphism of the ACE gene are associated with corresponding differences in the endogenous activity of the encoded enzyme. The homozygous deletion/deletion (D/D) variant is associated with the highest expression of endogenous activity and a greater risk of progression to ESRD. This group of patients with the DD polymorphism of the ACE gene may also be more likely to have an antiproteinuric response to ACE inhibitors (45–47).
Symptomatology of Chronic Uremia
Early in chronic kidney disease, when the GFR is >25 mL/min/1.73 m2 (i.e., ˜25% of normal), the majority of patients have few symptoms, and the biochemical abnormalities are equally unremarkable. Although a rise in serum uric acid has been reported to occur early in kidney disease, the increment usually is <1 mg/dL (18). Therefore, with the exception of some patients with interstitial nephritis, secondary gout is uncommon in ESRD. Proteinuria is common at this stage and the nephrotic syndrome may be present in some glomerular diseases. In association with high-grade proteinuria, the patient may also lose antithrombin III, with resulting antithrombin III deficiency, a hypercoagulable state, and a predisposition to thromboembolic complications (48). The third major finding in the early stage of kidney disease is hypertension. If the hypertension is not treated, arteriolar nephrosclerosis as well as focal glomerulosclerosis may develop and accelerate the loss of kidney function. Because it is extremely difficult to determine whether the progressive loss of kidney function is a consequence of the underlying kidney disease or the hypertensive state, it is imperative that blood pressure be well controlled.
FLUID AND ELECTROLYTE DISTURBANCES
Disturbances of fluid and electrolytes may occur as the GFR falls below 25 mL/min/1.73 m2. The interesting aspect is that on a normal diet, even with a GFR of 3 to 5 mL/min/1.73 m2, there may be only minimal disturbances of plasma electrolytes and the body water content. This is a result of the fact that as GFR falls there is increased fractional clearance of electrolytes, as well as water. This has been termed “the magnification phenomenon” by Bricker et al. (49). This implies that the diseased kidney continues to be under the control of a variety of biologic systems that regulate the excretion of the various electrolytes, and the excretory response per nephron evoked by these systems varies inversely with the number of surviving nephrons. Because of this, the individual with advanced chronic kidney disease is able to excrete the elements and waste products obtained from a normal dietary intake, maintaining reasonable water and electrolyte balance.
However, the range over which the individual can maintain balance is limited with advanced chronic kidney disease. Because of the impaired capacity to dilute or concentrate urine, the patient will develop increasing dehydration and hypernatremia if water intake is restricted; and the degree of azotemia may increase secondary to further impaired excretion of nitrogenous waste products. Conversely, hyponatremia may occur if water intake is excessive.
When placed on a low-sodium diet, the majority of patients with advanced chronic kidney disease are unable to reduce urinary sodium excretion to the level of their sodium intake, or it takes three to four times longer to do so than in a normal person. In a few patients, usually with medullary cystic disease, ADPKD, or interstitial nephritis, an excess sodium intake may be necessary to maintain sodium balance (50). A rare patient may require as much as 10 to 20 g of salt supplementation daily to maintain ECF volume and maximum kidney function. In general, such severe renal salt wasting is very infrequent and occurs in the presence of far-advanced kidney disease.
Hyperkalemia rarely occurs in patients who have a GFR >25 mL/min/1.73 m2 in the absence of an endogenous or exogenous potassium load. Potassium balance is maintained in the majority of patients by a combination of increased tubular secretion of potassium, which is mediated in part by aldosterone (51,52) and the increased fecal potassium loss (51,52). Because these mechanisms must work to the maximum in advanced kidney disease, there are several circumstances in which hyperkalemia may develop. Competitive inhibition of aldosterone with spironolactone, or inhibitors of distal potassium secretion (e.g., amiloride or triamterene) may induce severe hyperkalemia. A second cause of hyperkalemia is an increased intake of potassium; and third is acute acidosis that caused intracellular potassium to be released into the extracellular pool. A rough clinical estimate of the effect of acidosis on serum potassium concentration is as follows: for every decrease of 0.1 pH unit, serum potassium increases by ˜0.6 mEq/L. β-Blockers, nonsteroidal antiinflammatory drugs (NSAIDs), ACE inhibitors, and angiotensin receptor blockers (ARBs) also may interfere with the renin–angiotensin system and lead to hyperkalemia.
Schambelan et al. (53) described an additional cause for the spontaneous occurrence of hyperkalemia in patients with kidney disease. Although all their patients had hyperkalemia in association with chronic kidney disease, the degree of kidney function impairment often was not severe. The majority of their patients had either diabetes mellitus or interstitial nephritis (53). The highlight of the findings in these patients was diminished plasma levels of renin and aldosterone. Studies suggest that the hyperkalemia is a result of hypoaldosteronism, which is attributable to hyporeninemia. The diminished plasma renin activity may in turn result from an autonomic neuropathy or sclerosis of the juxtaglomerular apparatus in the diabetic patients. Sickle cell disease, kidney transplantation, and lupus nephritis also have been associated with hyperkalemia, probably secondary to diminished tubular secretory capacity. Another cause of hyperkalemia occurs in some patients with chronic obstructive uropathy (54). These individuals appear to have a tubular resistance to aldosterone in contrast to the hyporeninemic–hypoaldosterone patients. Thus, these conditions should be considered when hyperkalemia is noted in patients with chronic kidney disease and other causes have been excluded.
Hypokalemia also may occur in patients with chronic kidney disease. A number of factors may be responsible for this finding, including poor dietary intake of potassium, diarrhea, diuretic therapy, metabolic alkalosis with secondary hyperaldosteronism, or specific renal tubular defects such as those found in association with type 1 renal tubular acidosis (RTA) and Fanconi syndrome (type 2 RTA).
Total body burdens of other elements, although not totally corrected by the diseased kidney, are corrected to the extent that the remaining alterations are associated with few, if any, clinical symptomatology until ESRD has occurred. The fractional clearance of phosphorus, magnesium, and calcium all increase as GFR progressively falls. As a result, plasma magnesium and phosphorus are not elevated until GFR falls below 25 mL/min/1.73 m2 (55). Even then, plasma values rarely increase >1 to 2 mg/dL until GFR falls below 5 mL/min/1.73 m2. The serum magnesium concentration may be slightly elevated when the patient is ingesting a normal magnesium intake. Magnesium-containing antacids and laxatives should be avoided because such patients have difficulty in excreting large magnesium loads (56).
Although fractional clearance of calcium is increased in kidney disease, absolute excretion is actually decreased. In contrast to other elemental disturbances, there may be major consequences as a result of the altered calcium metabolism associated with the uremic state. Parathyroid hormone (PTH) levels are found to significantly increase when GFR falls to 45% of normal, and 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) levels fall when GFR is 70% to 80% of normal. Hypocalcemia also is a common finding in patients with advanced kidney disease. Hypocalcemia probably results from a combination of factors including low 1,25(OH)2D3 with decreased gastrointestinal absorption of calcium, hyperphosphatemia, and bone resistance to the calcemic effect of PTH.
Acidosis is a common disturbance at a more advanced stage of chronic kidney disease. Normally, the kidneys are responsible for excreting 60 to 70 mEq of hydrogen ions daily. Although the urine can be acidified normally in a majority of patients with chronic kidney disease (57), these patients have a reduced ability to produce ammonia. With advanced kidney disease, total daily acid excretion is usually reduced to 30 to 40 mEq; thus, throughout the remainder of their course of chronic kidney disease, many patients may be in a positive hydrogen ion balance of 20 to 40 mEq/day. The retained hydrogen ions probably are buffered by bone salts, although this has not yet been unequivocally proven. On occasion, hyperchloremic RTA with a normal anion gap may occur in the early stage of kidney disease. With more advanced chronic kidney disease, the plasma chloride concentration becomes normal, and a fairly large anion gap may develop. In most patients with chronic kidney disease, the metabolic acidosis is mild, and the pH rarely is <7.35. As with other abnormalities in chronic kidney disease, primary symptomatic manifestations of acid–base disturbances occur when the patient receives an excessive endogenous or exogenous acid load or loses excessive alkali (e.g., diarrhea).
The final stage of chronic kidney disease occurs when the GFR falls below 10 mL/min/1.73 m2. The deranged metabolic functions present at this stage of kidney disease are responsible for the striking clinical features of uremia.
The prevalence of anemia increases with progression of kidney disease and 90% of patients with a GFR <25 mL/min/1.73 m2 have anemia defined as a hemoglobin <12 g/dL (58). The anemia of chronic kidney disease has been felt to result from a combination of factors, including reduced erythropoietin (EPO) activity, circulating factors that appear to inhibit the bone marrow response to EPO, and shortened erythrocyte life span. Red blood cell (RBC) survival is decreased from 120 to 80 days in chronic kidney disease patients. Both metabolic and mechanical factors contribute to this short life span of RBC. Almost all patients with chronic kidney disease have much lower baseline EPO levels than those of normal subjects at the same degrees of anemia. Patients with ADPKD are the exception and usually have higher EPO levels with less severe anemia. EPO, a glycosylated, 165 amino acid protein produced by renal peritubular capillary endothelial cells, acts on erythroid progenitor cells in the bone marrow. With the recent availability of recombinant EPO, it appears that the major cause of anemia has been a failure of EPO production by the diseased kidney, because uremic patients typically respond so well to exogenously administered EPO (58).
Low hemoglobin levels have been associated with increased left ventricular hypertrophy and cardiovascular outcomes in patients with kidney disease. Therefore, several studies have evaluated whether treatment of anemia results in improved outcomes in chronic kidney disease patients. The United States Normal Hematocrit Trial (59) of chronic hemodialysis patients with cardiac disease randomly assigned patients to a target hematocrit of 42% or 30%. The primary outcome was time to death or nonfatal myocardial infarction (MI). The study was stopped early as the group assigned to the higher hematocrit had an increased risk of mortality that was trending toward statistical significance and a higher rate of adverse vascular access events due to thrombosis. In the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) (60) trial, 1,432 patients with moderate and advanced chronic kidney disease and a hemoglobin <11 g/dL were randomized to achieve a target hemoglobin of either 11.3 or 13.5 g/dL. The CHOIR trial was also terminated early as a significantly higher number of cardiovascular events was observed in the higher hemoglobin group. Of note, patients in the higher hemoglobin group did not reach the target of 13.5 g/dL; they only reached a mean hemoglobin concentration of 12.6 g/dL and despite randomization, the higher hemoglobin group had more cardiac comorbidities, which could have contributed to the adverse outcomes observed in these patients. Similarly, the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) (60) trial randomly assigned 603 patients with moderate and advanced chronic kidney disease and anemia to achieve a target hemoglobin of normal (13–15 g/dL) or low normal (10.5–11.5 g/dL). After 3 years of follow-up, both groups had a similar risk of achieving the primary end point (composite of cardiovascular events) and the higher hemoglobin group had increased quality of life and general health. Treatment of anemia did not have any effect on left ventricular hypertrophy, as the left ventricular mass index remained unchanged in both groups.
The optimal hemoglobin level remains controversial and the current K/DOQI recommendations are not to exceed a hemoglobin level of 12 g/dL in chronic kidney disease patients (60). The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) (60), which enrolled more patients than the CHOIR and CREATE trials combined, demonstrated similar results. The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke (60).
Disturbances in the coagulation system also occur with an advanced stage of chronic kidney disease. Approximately 20% of uremic patients have a modest degree of thrombocytopenia, but it is rare to find a platelet count of <50,000. Severe thrombocytopenia may occur in patients with the hemolytic uremic syndrome as a consequence of disseminated intravascular coagulation. However, this is not a common cause of chronic kidney disease in adults. Platelet factor 3 is reduced and platelet aggregation is decreased (61) in advanced kidney disease. This results in prolongation of the Ivy bleeding time and poor clot retraction. However, platelet function is caused by multiple factors such as the retention of uremic toxins, nitric oxide, anemia, and hyperparathyroidism. The importance of uremic toxins is suggested by the beneficial effect of acute dialysis on platelet dysfunction. How uremic toxins might interfere with platelet function is not completely understood. In vitro studies suggest that a dialyzable factor might interfere with the binding of fibrinogen. Uremia-induced changes in nitric oxide production also may contribute to inhibition of platelet aggregation. Treatment of the uremic state with dialysis improves platelet function in the majority of patients, suggesting some dialyzable factor is responsible for this abnormality. It is of interest that D-deaminoarginine vasopressin (dDAVP) improves bleeding time without affecting platelet abnormalities (62). This suggests that an abnormality in factor VIII or von Willebrand factor may play a role in the pathogenesis of the bleeding abnormality in the uremic state (62). Anemia also contributes to the abnormal bleeding time present in uremic patients. A higher hematocrit causes the platelets to skim at the endothelial surface, which is optimal for platelet–endothelium interaction. Such skimming does not occur with hematocrits <25% to 30%.
Another complication noted with some frequency in patients with far-advanced chronic kidney disease is involvement of the serous membranes as manifested by pericarditis and pleuritis. The involved membrane is markedly thickened, extremely vascular, and infiltrated with plasma cells and histiocytes (63). Both pleural and pericardial friction rubs may be heard. When pleural and pericardial effusions are present, they are uniformly hemorrhagic and usually contain fewer than 10,000 WBCs/mm2. Pericardiocentesis, as well as thoracentesis, is occasionally necessary to relieve clinical symptoms. However, if the uremic state is not improved with treatment of reversible factors or hemodialysis, recurrent effusions are common. Rarely, constrictive pericarditis may follow healing of acute uremic pericarditis.
Chronic ascites also may be a manifestation of uremic serositis and advanced kidney disease. This complication arises primarily in patients who have had previous abdominal surgery or peritoneal dialysis. The ascitic fluid is an exudate with the ascitic fluid albumin/plasma albumin concentration ratio of >0.5. Although fluid overload may worsen uremic ascites, fluid removal frequently is not a successful mode of treatment. Renal transplantation or several consecutive days of intensive dialysis has been useful in treating uremic ascites.
Most patients with far-advanced kidney disease have gastrointestinal symptoms that are a major part of their clinical picture (64). Specifically, nausea, vomiting, and anorexia are extremely common. Uremic stomatitis, characterized by dry mucous membranes and multiple, bright-red, small, ulcerative lesions, may occur with advanced uremia. Poor dental hygiene appears to contribute to the development of uremic stomatitis. Because saliva in uremic patients has an increased urea content, it has been suggested that the stomatitis results from high levels of ammonium, which is formed by bacteria ureases from the high levels of salivary urea. Inflammation of salivary glands (e.g., parotitis) also may occur in uremic patients and is usually associated with stomatitis. The salivary glands may become markedly swollen in chronic kidney disease, but characteristically they are not tender or indurated, as might be seen in inflammatory parotitis.
Pancreatic involvement also has been found on postmortem examination in patients who have died from uremia. Typically, on histologic examination of the pancreas, there is dilatation of the acini, flattening of the epithelial cells, and inspissation of the intraacinar secretions. Clinical symptoms of pancreatitis also may occur. It was felt previously that uremia alone, as a result of chronic loss of kidney function and thus the inability to excrete amylase, could significantly elevate the serum amylase concentration, but this has been shown not to be the case (65). Rather, when a high elevation of serum amylase concentration is found in patients with chronic kidney disease, pancreatitis should be considered strongly. In acute kidney injury, however, serum amylase elevations are common but are rarely over twice normal in the absence of clinical evidence of pancreatitis (65). Other findings in the gastrointestinal tract in advanced uremia include erosive gastritis and uremic colitis characterized by submucosal hemorrhages and small mucosal ulcerations. With the exception of anorexia, nausea, and vomiting, the majority of other gastrointestinal complications of uremia are rarely seen in patients with kidney disease now that treatment with dialysis and renal transplantation is possible and initiated relatively early.
The neuromuscular disturbances occurring in patients with advanced kidney disease were some of the earliest clinical symptoms described in uremia (66). The initial symptoms are mild and consist of emotional lability, insomnia, and a lack of facility in abstract thinking. If the uremic state is allowed to progress, more striking changes are noted, consisting of increased deep tendon reflexes, clonus, asterixis, and stupor, which progress to coma, convulsions, and death.
Uremic neuropathy is another major and potentially disabling complication of chronic kidney disease. The earliest feature is the restless legs syndrome, in which the patient has a tendency to avoid inactivity of the lower extremities because of a sensation of numbness. This syndrome is followed by a sensory neuropathy characterized by paresthesia and hypalgesia, especially of the feet. In the most severe cases, a motor neuropathy also may occur. Typically, there is symmetrical involvement of the lower extremities, which is more severe distally and usually is manifested initially by bilateral footdrop (66). Uremic neuropathy occasionally can progress rapidly to a state of total quadriplegia. Histologically, the damage in the peripheral nerve occurs in the distal portion of the medullated fibers and involves a loss of myelin. For unknown reasons, the motor neuropathy is much more common in males than in females.
SKELETAL ABNORMALITIES (RENAL OSTEODYSTROPHY)
Other major causes of disability in chronic kidney disease, especially in children, are abnormalities in the skeletal system (Table 11-5). Growth is markedly retarded in children with kidney disease. The reasons are not well understood, but there is evidence that dialysis, especially chronic cyclic peritoneal dialysis, improves the growth rate. A high caloric and protein intake also may be helpful. Even with these measures, however, children on dialysis rarely grow normally. The use of corticosteroids after kidney transplantation also is associated with growth retardation. Recombinant human growth hormone has been used with considerable success to increase height velocity in uremic children and those who have received transplants (67).
Can be increased
Normal or increased
DFO stimulation test
Normal (adynamic) Elevated delta (aluminum OM)
Usually asymptomatic unless very severe disease
Asymptomatic (dynamic) Symptomatic (aluminum OM)
DFO, deferoxamine; OM, osteomalacia.