Renal Changes With Aging and End-Stage Renal Disease

Renal Changes With Aging and End-Stage Renal Disease

Xin J. (Joseph) Zhou

Andrew Z. Fenves

Nosratola D. Vaziri

Ramesh Saxena

The growth in the proportion of older adults is unmatched in the history of humankind. Improvements in prevention and medical treatment of diseases have led to increased life expectancies all over the world, resulting in an absolute increase in the numbers of the elderly. In addition, the lower population growth rates in the developed world have led to a relative increase in the elderly, leading to an inversion of the population pyramid. By 2030, there will be 72 million adults aged 65 years and older in United States accounting for approximately 20% of the US population (1). Aging is accompanied by a higher rate of morbidity, with a consequent impact on economic and human resources. Compared to younger individuals, it costs three to five times to provide health care for an American older than 65 years and treatment for this population accounts for 66% of the U.S. healthcare budget (1). It is well known that advancing age per se is associated with deterioration of renal function. The presence of diverse chronic diseases in older individuals could accelerate the age-related decline in renal function. Thus, the prevalence of chronic kidney disease (CKD) is greatest in the elderly, and the older population has the fastestgrowing segment of end-stage renal disease (ESRD) (2).

Mirroring the elderly populace, the world population has lately experienced an exponential growth of ESRD requiring renal replacement therapy (RRT). The 2013 United States Renal Data System (USRDS) report showed more than 50% increase in the prevalent dialysis population between 2000 and 2011 (2). There were 615,899 ESRD patients in 2011, and with an annual growth of 3.2%, the ESRD population is projected to grow to more than 700,000 dialysis patients by 2020 (2). While ESRD comprises only 1% of total Medicare population, it consumes 8.1 % of the Medicare budget and $49.27 billion in total spending (2). With extensive efforts made to prevent or slow progression of renal disease, there has been a recent reduction of the overall ESRD incidence (2). Nevertheless, the incidence of ESRD continues to grow particularly among elderly patients. Since 2000, there has been a 7.1% growth in the incidence rate of ESRD in patients over 75 years of age. Moreover, as of 2011, the incidence rate was four times higher in patients over 65 years of age compared to the overall incidence rate of ESRD in the US population (2). Furthermore, the total number of elderly patients 65 years and older with ESRD has increased by
68%, since 2000 (2). Currently, one in four patients starting dialysis in the United States is over the age of 75 years (2). An increase in the prevalence of associated comorbidities such as diabetes and hypertension as well as improved survival from cardiovascular (CV) disease may explain the increase in ESRD incidence among the elderly. This increase in the numbers of ESRD patients has obvious social and economic dimensions that are even more pronounced in the case of older patients (2,3).

ESRD is the terminal phase of CKD caused by a progressive deterioration of kidney function to the point of requiring RRT. The Kidney Disease Outcomes Quality Initiative (K/DOQI) defines CKD as kidney damage or glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 for 3 months or more, irrespective of cause (4). By this definition, 11% of the United States adult population (more than 20 million individuals) has been estimated to have CKD (5). CKD is subclassified into five stages according to the level of GFR (Table 28.1) (6). Individuals with stage 5 CKD (GFR less than 15 mL/min/1.73 m2) that require dialysis are termed ESRD patients. It has been recently observed that the lifetime risk of ESRD at the age of 40 is significantly higher in patients with reduced kidney function (eGFR 44 to 59 mL/min/1.73 m2) compared with individuals with normal kidney function (7). ESRD is sometimes diagnosed when patients undergo renal biopsy for unexplained renal failure. The recognition that a final point has been reached in a disease process allows patients to be placed on dialysis and to avoid unneeded diagnostic or therapeutic measures. In addition, the specific disease that has lead to the renal failure can often be identified. When patients have been supported by dialysis for several years, the original renal disease may be obscured by the advanced degree of tissue changes. But even among these cases, the cause can often be assigned to at least one of five major categories of disease (hypertension, diabetes, glomerulonephritis, interstitial nephritis, or ischemic nephropathy). It also may be possible to discriminate specific forms of glomerulonephritis and interstitial nephritis. It is important to realize that, while structural and functional changes of the kidney occur ubiquitously with aging, there is no specific disease confined only to the geriatric population. In general, the types of renal diseases seen in the elderly are similar to those encountered in the general population, although certain disorders such as diabetes and hypertension may have an increased prevalence and accelerate the development of CKD in this population (Table 28.2) (8,9). Therefore, the approach
to the interpretation of renal biopsies in the elderly is similar to that of the general population. However, given the high prevalence of type 2 diabetes mellitus and hypertension in the elderly, these two disorders should be ruled out before ascribing any morphologic changes to aging.

TABLE 28.1 Stages of chronic kidney disease



GFR (mL/min/1.73 m2)


Kidney damage with normal or elevated GFR



Kidney damage with mildly decreased GFR



Moderately decreased GFR



Severely decreased GFR



Chronic kidney failure

<15 or dialysis

Adapted from Kidney Disease Outcome Quality Initiative (K/DOQI). Part 4. Definition and classification of stages of chronic kidney disease. Am J Kidney Dis 2002;39(Suppl):S46-S75.

TABLE 28.2 Diseases that commonly affect the aging kidney

Systemic diseases


Diabetes mellitus




Myeloma cast nephropathy


Light-chain deposition disease


Glomerular diseases

Membranous GN

Mesangial proliferative GN (including IgA nephropathy)

Pauci-immune crescentic GN

Anti-GBM disease

Minimal change disease

Focal segmental glomerulosclerosis

Acute renal failure

Hypovolemic and cardiovascular shock

Septic shock

Nephrotoxic injury

Nonsteroidal anti-inflammatory agents

Antibiotics (penicillins, cephalosporins, sulfonamides, rifampin, ciprofloxacin)

Diuretics (furosemide, potassium-sparing diuretics)

Contrast media

Cancer chemotherapy




Interstitial nephritis

Urinary tract infection

Renal stones

Obstructive uropathy

Benign causes

Nodular hyperplasia of prostate

Neurogenic bladder

Renal stones

Obstructive pyelonephritis/papillary necrosis

Urethral stricture

Malignant causes

Prostate cancer

Bladder cancer

Pelvic tumors

Colonic tumors

Retroperitoneal tumors

Renal tumors



Simple renal cysts

GN, glomerulonephritis; GBM, glomerular basement membrane Adapted from Zhou XJ, Rakheja D, Yu XQ, et al. The Aging Kidney. Kidney Int 2008;74:710-720.


Clinical Features

Patients with CKD most often present with nonspecific complaints or are asymptomatic and are referred to a nephrologist because of abnormal blood or urinary findings (10). In symptomatic patients with CKD, often symptoms have been present for months or years (4). Urinary symptoms suggesting CKD include difficulty with urination, history of urinary tract infections, passage of kidney stones, dysuria, and nocturia.

A common early sign of uremic encephalopathy is sleep disturbance. Typically, patients have difficulty falling asleep, awaken during the night, and again have difficulty falling asleep, with subsequent early morning awakening accompanied by daytime sleeping. Subsequent loss of short-term memory, difficulty concentrating, and episodes of confusion can occur.

Another early sign of CKD is dependent edema that presents first as ankle or periorbital edema. Uremic patients frequently develop congestive heart failure, in which case dependent edema becomes increasingly severe and may progress to anasarca. The skin of uremic patients has a sallow, yellow appearance because it is pigmented with carotene. When blood urea levels are greatly elevated, urea is secreted through the skin where it can dry into a white uremic frost. The patient’s breath has a uriniferous odor because of urea being metabolized to ammonia by mouth bacteria. In terminal stages, uremic patients become delirious and lapse into coma before death. Because of the nearly universal access to RRT, cases of fully developed uremia are rare. Nevertheless, ESRD patients have a high prevalence of nonrenal comorbid disease. With prolonged survival on dialysis, pathologic changes occur in virtually all systems of the body.

Cardiovascular System

CKD is an independent risk factor for CV disease and all-cause mortality. Observational studies indicate that rates of both stroke and myocardial infarction are higher in patients with CKD before the development of ESRD. For example, Go et al. (11) reported on the risk of all-cause mortality and CV hospitalizations among 1.2 million participants in the Northern California Kaiser Permanente health care system. They found a graded increase in mortality and CV hospitalizations as estimated GFR declined. This association was independent of traditional CV risk factors such as age, blood pressure, diabetes, hypercholesterolemia, and proteinuria and suggests that CKD may be an independent risk factor for coronary heart disease (11).

CKD markedly increases the risk of CV death from cardiac events and stroke (2). The mortality risk in CKD patients with CVD is 10- to 30-fold higher than that in normal, age-matched populations. Median survival after an acute myocardial infarction in patients undergoing dialysis is less than 18 months, even in the thrombolytic era. Hypertensive patients with elevated serum creatinine are at higher risk of myocardial infarction and stroke, and diabetic patients with proteinuria are at greater risk for fatal myocardial infarction and stroke (2). Prevalence of left ventricular hypertrophy (LVH) and congestive heart failure is strikingly elevated in patients with CKD stages 2 through 5, including those undergoing dialysis (12). Morbidity and mortality for congestive heart failure and coronary heart disease are also excessive in CKD. Moreover, presence of coronary artery disease increases the risk of progression to ESRD in CKD patients. McClellan et al. (13) observed that patients hospitalized for myocardial infarction or congestive heart failure who also had CKD had a high rate of progression to ESRD in a 12-month period following the cardiovascular event. Current clinical practice guidelines target the treatment of the risk factors of hypertension, hyperlipidemia, and tobacco use not only for the prevention of CV disease but also to retard the progression of CKD (6).

Cardiomyopathies of End-Stage Renal Disease

The cardiomyopathies of ESRD are classified into dilated or hypertrophic cardiomyopathy (14). Dilated cardiomyopathy is characterized by enlargement of the chamber of the left ventricle but without an increase in the thickness of the left ventricular free wall or interventricular septum. It is clinically associated with impaired systolic function and a low left ventricular ejection fraction. Dilated cardiomyopathy precedes dialysis in 16% of ESRD patients and develops in another 15% during the course of dialytic therapy (14). Dilated cardiomyopathy seems to occur most frequently in hypertensive patients who have hyperparathyroidism and high-turnover bone disease. It is suggested that an excessive entry of calcium into myocardial cells limits their capacity to hypertrophy in response to elevated blood pressure. To compensate for the increased workload, the heart is forced to dilate to maintain cardiac output.

Hypertrophic cardiomyopathy is characterized by LVH. Concentric LVH is the most common form of hypertrophic cardiomyopathy in the patient with ESRD and consists of an increased thickness of both the interventricular septum and left ventricular free wall. Eccentric hypertrophy and asymmetric septal hypertrophy do occur but are less common. LVH affects up to 70% of patients during intermediate stages of CKD and approaching 90% of patients with ESRD (15,16). Using magnetic resonance imaging, Patel et al. (17) observed 63.8% prevalence of LVH among 246 HD patients. Independent predictors of LVH were predialysis blood pressure and diastolic LV volume (suggesting volume overload) and the calcium phosphorus product but not anemia. LVH among these patients was associated with LV systolic and diastolic dysfunction. The study suggests the role of preload and afterload in causing LVH and confirms some of the previous studies done with the echocardiograms in HD patients that noted a similar prevalence of LVH (15,16,17). However, LVH has been seen in some patients whose blood pressure appears to be adequately controlled, and the regression of LVH after transplantation suggests that other CKD-specific risk factors are involved (16). To this end, recent studies have shown that circulating concentrations of FGF23 were markedly elevated in patients with advanced CKD and the elevated FGF23 was independently associated with greater left ventricular mass and greater prevalence of
LVH (18,19,20). FGF23 functions as an endocrine hormone that regulates phosphorus homeostasis through binding to the FGF receptor (FGFR) and Klotho (its coreceptor) in the kidney and parathyroid glands (21). The authors demonstrated that FGF23 directly induces pathologic hypertrophy of isolated rat cardiomyocytes and that mice develop LVH after intraventricular or intravenous injection of FGF23. In addition, FGFR blocker attenuates the severity of LVH in 5/6 nephrectomized rats without affecting blood pressure (18). Thus, chronically elevated FGF23 levels may contribute directly to high rates of LVH and mortality in individuals with CKD. Recent studies have also demonstrated the possible role of activation of the mammalian target of rapamycin (mTOR) pathway in LVH. To this end, LVH associated with uremia can be mitigated or even reversed by rapamycin administration in a mouse model of chronic renal failure. LVH also can be modulated by microRNAs, which regulate cardiac growth by degradation of mRNA or inhibition of translocation. The histone acetylation/deacetylation pathway can also modulate the development of LVH (22). Acetylation relaxes chromatin structure and allows access of transcription factors, whereas deacetylation produces opposite effects.

Atherosclerotic Coronary Artery Disease

Atherosclerotic CV disease is the principal cause of morbidity and mortality in ESRD patients. This largely reflects the prevalence of hypertension and diabetes mellitus in this population and the severity of the atherosclerotic vascular disease that is part of the natural history of these diseases. Nevertheless, severe atherosclerosis can be seen at an unusually young age. In addition, oxidative stress, inflammation, and HDL deficiency and dysfunction contribute to the pathogenesis of accelerated atherosclerosis and CV disease in the ESRD population (23,24). In a retrospective analysis of transplantation candidates with no active symptoms of coronary artery disease (CAD), noninvasive imaging revealed abnormalities suggestive of ischemia in 30.7% of patients and coronary angiography showed obstructive disease in 54.1% of the same cohort (25). Braun et al. (26) measured cardiac and coronary artery calcification by electronbeam computed tomography to assess coronary artery disease in 49 chronic hemodialysis (HD) patients aged 39 to 74 years. The results were compared with 102 age-matched nondialysis patients with known coronary artery disease who had undergone coronary angiography. A 2.5- to 5-fold higher coronary artery calcification score was found in the dialysis patients, and the scores significantly increased when the patients were reexamined after 1 year.

The high CV mortality in patients with CKD is closely associated with vascular calcification (27). The severity of calcification in atherosclerotic plaques can be related to plaque size (28). Although calcification can be found in small plaques, it is most pronounced in larger, complicated plaques having a necrotic lipid core and varying amounts of inflammation (29). Calcification also occurs along the media of coronary arteries as Mönckeberg medial calcific sclerosis, in which there is little intimal thickening or luminal narrowing (30). The bone matrix proteins osteopontin, osteocalcin, and osteoblastic differentiation factor (Cbfa1) are expressed in areas of medial and plaque calcification. The presence of these locally produced bone matrix-stimulating factors indicates that metastatic calcification is an active, cell-mediated process similar to osteogenesis rather than a passive deposition of minerals (31,32). Moe et al. (32,33) and Chen et al. (31) have suggested that chronic uremia may up-regulate the local deposition of bone matrix proteins and promote atherosclerotic plaque growth.

Hypertension, dyslipidemia, diabetes, and elevated plasma phosphate, homocysteine, and osteoprotegerin levels are risk factors for vascular calcification (34). Defects in endogenous anticalcification factors may also play a role (35). In a recent study, Hu et al. showed that CKD is associated with Klotho deficiency, which contributes to soft tissue calcification (36). By enhancing phosphaturia, preserving glomerular filtration, and directly inhibiting phosphate uptake by vascular smooth muscle, Klotho can mitigate vascular calcification in CKD.

Sudden cardiac death is the single most common cause of death in ESRD patients and accounts for one quarter to one third of all deaths (2). In an analysis of outcomes of 102 cardiac arrests in HD units in the Seattle area, it was observed that ventricular fibrillation (65%) and pulseless electrical activity (23%) were the two most common reasons of cardiac arrests in HD patients. More than one third of patients died in the dialysis unit, only approximately one quarter were discharged alive from the hospital, and only 15% were alive at 1 year (37). The possible risk factors for sudden death in dialysis patients include hyper-/hypokalemia and hypervolemia, LVH and heart failure, myocardial fibrosis, QT dispersion, sympathetic overactivity, hyperphosphatemia, and possibly sleep apnea (38). Unlike nondialysis patients, underlying ischemic heart disease is not an important contributor to sudden cardiac death in the dialysis population (39). It is unknown whether preventing or treating any of the aforesaid risk factors will reduce the incidence of sudden death in dialysis patients.

Valvular Calcification

The cardiac valves of ESRD patients are frequently abnormal. Valvular calcification is closely related to coexisting atherosclerotic coronary artery disease, and the extent of valvular calcification has been found to predict CV mortality (26,40,41,42). The mitral valve is calcified in 10% to 59% and the aortic valve in 28% to 55% of dialysis patients. The calcification most severely affects the annulus (Figs. 28.1 and 28.2). Although involvement of the aortic valve cusps and mitral leaflets can produce clinically significant stenosis, this is not common, and the relationship between valvular calcification and cardiac death is primarily owing to the close association of valvular calcification with coronary artery disease (26,42). Calcification of the mitral valve can cause heart block or other arrhythmias when the calcification of the annulus extends into the adjacent ventricular wall. Oxalosis is sometimes found in the hearts of ESRD patients as a result of the secondary oxalosis of advanced CKD. It can extensively involve the coronary arteries or be deposited in the AV node and conducting bundles.

Calcemic Uremic Arteriopathy

Calcemic uremic arteriopathy (CUA) or calciphylaxis is an uncommon clinical condition that occurs in some patients with long-standing ESRD. Calcification of arterioles in the dermis and subcutaneous tissues produces painful red skin nodules that frequently undergo ischemic necrosis and ulceration (Fig. 28.3) and is most commonly found on the thighs, buttocks, and abdomen. When the hands or feet are affected, there may be gangrene of the fingers or toes. Involvement of the mesenteric
artery has also been reported. Histologically, the skin shows medial calcification and intimal fibrosis of arterioles and small arteries. The intimal fibrosis may be occlusive or accompanied by thrombosis, and coagulative necrosis is found in the dermis and subcutaneous tissue. Ulceration frequently develops, and a necrotizing panniculitis is sometimes seen that is often complicated by septicemia. Studies have reported incidences ranging from 1% to 4% in chronic HD patients. A case-control study of 67 Japanese patients with CUA identified warfarin therapy, low serum albumin level, elevated plasma glucose level, and increased serum calcium level at the time of diagnosis to be significantly associated with CUA (43). However, no significant associations were found with female sex, vitamin D analog therapy, serum phosphate level, adjusted calcium-phosphate products, or serum alkaline-phosphatase level. This study suggests that in high-risk patients with poor control of blood sugar and calcium levels, warfarin therapy should be undertaken only with great caution. Treatment of CUA is unsatisfactory. Therapeutic strategies include removing medications thought to contribute to calciphylaxis (calcium-based phosphate binders, active vitamin D analogs, and warfarin) as well as aggressive wound management and antibiotic therapy, supplemented by intensified HD, intravenous sodium thiosulfate, and attempted oxygen therapy including hyperbaric oxygen (44). Bisphosphonates or cinacalcet may also be helpful in selected patients (45). There are no randomized control trials, and most of the literature is anecdotal, and results are variable (46).

FIGURE 28.1 Nodular calcification of the annulus and base of the mitral valve in a 55-year-old hemodialysis patient.

FIGURE 28.2 Thrombosis over a calcified plaque of the left anterior descending coronary artery in the hemodialysis patient with the mitral valve calcification shown in Figure 28.1. Note the fissuring of the plaque over the necrotic and calcified core. (H&E, ×400.)

FIGURE 28.3 Calcemic uremic arteriopathy. An arteriole in the dermis of a painful skin nodule on the lower leg of a hemodialysis patient is calcified. (H&E, ×400.)


Uremia appears to increase the permeability of small blood vessels and allows a fibrinous exudate to leak across the pericardium leading to uremic pericarditis (47,48). The gross examination of the heart shows easily broken bands of fibrin producing the classical bread and butter appearance (Fig. 28.4). The histopathology of uremic pericarditis reveals a fibrinous exudate accompanied by sparse inflammatory cells covering the visceral and parietal surfaces of the pericardium.

A fibrinous pericarditis can also be seen in acute renal failure and occasionally in adequately dialyzed patients. When it occurs 1 month or more after beginning dialysis, it is diagnosed as dialysis-associated pericarditis (47,48). It is generally held that dialysis-associated pericarditis and uremic
pericarditis represent the same pathologic condition. It is often seen when dialysis patients become infected or when they are under increased metabolic stress, such as following surgery. In most cases, dialysis-associated pericarditis clears after treatment schedules are intensified (47,48). In long-standing pericarditis, the fibrinous exudate is organized into fibrous tissue that produces a constrictive pericarditis, which is usually a complication of ESRD, but has also been described with acute renal failure following a single episode of pericarditis. Typically, uremic or dialysis-associated pericarditis is associated with pleuritic chest pain and, if a significant amount of fluid accumulates, with cardiac tamponade (47,48). Hemorrhage can occur into the pericardium and is an additional cause of cardiac tamponade in the uremic patient.

FIGURE 28.4 Dialysis-associated pericarditis from an autopsy of a 58-year-old diabetic hemodialysis patient who died of septicemia. The heart is coated with a fibrinous exudate.


The cardiomyopathy of ESRD frequently decompensates into congestive heart failure as a result of anemia, fluid retention, and hypertension. Congestive heart failure is one of the most common causes of death among ESRD patients. Patients develop pulmonary edema when the passive accumulation of blood within the pulmonary vasculature causes alveolar intracapillary hydrostatic pressure to exceed oncotic pressure. Grossly, the lungs involved by pulmonary edema are heavy, and their sectioned surfaces are covered by frothy, blood-tinged fluid. Microscopically, alveolar capillaries are distended with blood. The perivascular interstitium and interlobular septa are edematous, and lymphatics are dilated. Alveoli become filled with amorphous, slightly eosinophilic edema fluid that can contain a few red blood cells. If patients have been in congestive heart failure for several days, some hyaline membrane formation may be present (49,50).

In advanced uremia, proteinaceous fluid sometimes leaks into the alveoli, producing what has been referred to as uremic pneumonitis, which is a form of pulmonary edema caused by injury to and increased permeability of the alveolar capillaries (49,50,51). It has been suggested that IL-6 is a direct mediator of uremia-induced increase in vascular permeability (52). Grossly, the lungs have a stiff, rubbery consistency, and the sectioned surfaces have a dark, reddish color. Histologically, the earliest stage reveals a hemorrhagic fibrinous fluid filling the alveoli with hyaline membranes being formed along alveolar walls and alveolar ducts. If the process does not resolve, fibrin in the alveolar fluid and hyaline membranes is organized into whorls of fibrous tissue referred to as Masson bodies (50).

When ESRD is complicated by metastatic calcification, it is usually found in the lung. The calcification may be focal or diffuse and tends to affect the upper lobes most severely. Both lungs can be involved. Metastatic pulmonary calcification is usually clinically asymptomatic, and the pattern of deposition may be so delicate that it will not be detected by routine chest radiographs. Nevertheless, if the calcification is extensive, it can lead to respiratory failure. Grossly, the involved areas of lung have a firm but brittle consistency and a fine net-like appearance that exaggerates the outlines of open alveoli. The areas are gray to pale yellow in color and typically contrast sharply with the adjacent normal or congested lung. They are gritty to the touch. Histologically, linear calcifications outline basement membranes within the alveolar septae. Calcifications also are seen along the elastica of arteries, veins, bronchi, and bronchioles and in fibrotic nodules within the lung parenchyma (50).

Beta-2-Microglobulin Amyloidosis

Beta-2-microglobulin is the light chain of class I HLA molecules, which enters the bloodstream when HLA molecules are degraded and shed from the surfaces of cell membranes. Beta-2-microglobulin accumulates in the plasma of ESRD patients and is deposited as insoluble amyloid fibrils in the articular surfaces of bone, in periarticular connective tissue (Fig. 28.5), and in
nerve sheaths in as many as 80% of HD patients after 10 years of treatment (53). It causes carpal tunnel syndrome and a destructive arthropathy of medium- and large-sized joints, mainly of the shoulders and knees (53,54). Dialysis-associated amyloid tumors of breast and ovary, nodular skin masses particularly of the buttocks and shoulder area, and nodules of the tongue are additionally described (55,56,57,58). Beta-2-microglobulin amyloid was found in the hearts of 7 of 18 HD patients who had been dialyzed for more than 10 years (59). Amyloid was present in the endocardium and myocardium of the left atrium. In the left ventricle, it was localized to the walls of blood vessels and around areas of calcification of the mitral valve. Rarely, amyloid deposits can occur in the intestinal wall (60,61).

FIGURE 28.5 Beta-2-microglobulin-related amyloidosis in the synovium from the right hand of a 54-year-old long-term hemodialysis patient who had a several-week history of interphalangeal joint pain and swelling. Nodular deposits of amorphous hyalin material are seen in the synovial connective tissue. (H&E, ×200.)

Beta-2-microglobulin amyloid is found within bone of 19% of HD patients after 10 years of treatment (62). These bone deposits are responsible for cysts that develop in the carpal bones, femur, and femoral head and possibly for the unusually high prevalence of pathologic femoral neck fractures in HD patients (Figs. 28.6 and 28.7). Onishi et al. (62) observed that 62% of patients had femoral neck fractures when periosteal amyloid deposits were found in posterior iliac crest bone biopsies. Only 4% of a control group of HD patients having biopsies who did not show periosteal amyloid had femoral neck fractures.

Beta-2-microglobulin amyloid shows Congo red-positive staining and apple-green birefringence under polarized light. By electron microscopy, it is composed of fine fibrils 8 to 10 nm in diameter having a curvilinear structure that is thought to be characteristic of beta-2-microglobulin (Fig. 28.8) (62). Since beta-2-microglobulin is cleared to some extent through the peritoneum and PD patients often have more residual renal function, amyloidosis does not seem to be as prevalent with CAPD as it is with HD (53). The addition of beta-2-microglobulin adsorption columns in tandem with HD reduces the radiolucency of bone cysts in the wrist joints and improves clinical symptoms associated with dialysis-related amyloidosis (63). A successful renal transplantation often results in marked symptomatic improvement and may arrest the growth of the cysts (64).

FIGURE 28.6 Beta-2 microglobulin-related amyloidosis of the femoral head removed from a 37-year-old long-term hemodialysis patient who had a femoral neck fracture. A necrotic cyst surrounded by a rim of solid white material is present beneath the insertion of the ligamentum teres.

FIGURE 28.7 Histologic section from the solid area surrounding the femoral head cyst shown in Figure 28.6. Amyloid is present in the walls of blood vessels and in the interstitium. (Congo red, ×100.)

Gastrointestinal Tract and Pancreas

Terminal uremia is accompanied by edema, inflammation, mucosal erosions, and ulcerations of the entire gastrointestinal tract. Gastrointestinal bleeding is a common clinical problem
among dialysis patients and most frequently originates in a hemorrhagic gastritis (65). Many dialysis patients have a mild gastritis, duodenitis, or peptic ulcer disease in which Helicobacter pylori can sometimes be found; although, these findings may not be any more common than in the general population (66).

FIGURE 28.8 Electron microscopic photomicrograph of the synovial tissue shown in Figure 28.5. Curvilinear fibrils characteristic of beta-2-microglobulin amyloidosis are demonstrated. (×18,000.)

Colonic bleeding can originate from cecal ulcers, stercoral ulcers, angiodysplasia, diverticulosis, or ischemic colitis (65,67). Multiple shallow ulcers attributed to uremia may be found in the cecum and ascending colon. Constipation and fecal impaction, resulting from the use of oral phosphate binders as well as other medications, produce stercoral ulcers in the transverse and rectosigmoid colon. Angiodysplasia consisting of clusters of abnormally dilated mucosal and submucosal blood vessels is found primarily in the cecum and ascending colon. Angiodysplasia is more prevalent in dialysis patients than in the general population, and in some series, it is the most frequent cause of gastrointestinal hemorrhage among ESRD patients (65,67,68). Diverticulosis, diverticulitis, pericolic abscesses, and colonic perforation may be more common in autosomal dominant polycystic kidney disease (ADPKD) than with other categories of renal disease (69).

The severe atherosclerosis of diabetes and hypertension places ESRD patients at high risk for ischemic colitis and intestinal infarction (67). HD patients with beta-2-microglobulin amyloidosis may have amyloid deposited in the connective tissue and small blood vessels of the mucosa and submucosa of the GI tract (60). The gastrointestinal amyloid is usually an incidental finding, but massive involvement of the muscularis propria of the colon has been identified as a cause of bleeding and intestinal infarction (61).

Systemic inflammation is a constant feature and a major mediator of CV disease and numerous other complications in the ESRD population. Systemic inflammation is associated with and, in part, mediated by endotoxemia, which is invariably present in ESRD patients in the absence of clinically detectable infection (70). Until recently, little attention had been paid to the role of gastrointestinal tract and its microbial flora in the pathogenesis of the CKD-associated inflammation. However, recent studies have demonstrated marked disintegration of the gastric, small intestinal and colonic epithelial tight junction (71) and extensive alteration of the composition of colonic bacterial flora in humans and animals with advanced chronic renal failure (72). More recent in vitro studies have revealed the role of urea and its conversion to ammonia by microbial flora as a major cause of the uremia-induced disintegration of colonic epithelial tight junction and barrier dysfunction (73). Discovery of the disruption of gastrointestinal epithelial tight junction complex has helped to elucidate the underlying mechanism of endotoxemia and contribution of the intestinal tract to the local and systemic inflammation in ESRD (70). In addition, via the disruption of the normal symbiotic relationship, the ESRD-associated profound changes in the composition and function of the intestinal microbial flora can contribute to local and systemic inflammation and uremic toxicity. In fact, recent studies have documented the role of colonic bacteria as the primary source of several well-known proinflammatory/prooxidant uremic toxins as well as many asyet unidentified retained compounds in ESRD patients (74).

Patients dying of uremia may develop an acute pancreatitis in which pancreatic ductules and acini are dilated and contain inspissated eosinophilic material (75). The dilated acini become disrupted and surrounded by an acute inflammatory reaction. Pancreatitis is also seen in patients who are well maintained on long-term peritoneal and hemodialysis (76). The pancreas may show focal or generalized fibrosis. Sometimes, fibrosis may be the sequela of episodes of acute pancreatitis, but it has also been related to hyperphosphatemia and to ischemic atrophy secondary to the marked arteriolosclerosis that is often found in the small pancreatic arteries (75). Nephrogenic or dialysis-associated ascites occurs in a small proportion of HD patients (77). Some of these patients had been previously treated by peritoneal dialysis (PD), and histologic studies of the peritoneum have shown fibrosis and chronic inflammation.

Hematopoietic System

Anemia is a highly prevalent complication in CKD patients. Contributing factors include erythropoietin (EPO) deficiency, frequently coexistent iron deficiency, and shortened erythrocyte life span. In addition to common causes of iron deficiency that occur in the general population, CKD and more so ESRD patients are at further risk because of impaired gastrointestinal iron absorption, blood loss during the HD, and enhanced incorporation of iron stores into hemoglobin by erythropoietinstimulating agents (ESAs) (78). A shortened red blood cell life span also contributes to the anemia of CKD. This is reflected in peripheral blood smears that show numerous poikilocytes resulting from extrinsic factors that fragment or metabolically alter the erythrocyte. The anemia of CKD is usually normocytic and normochromic. Since red blood cell production and iron utilization are low, bone marrow examinations of patients with the typical anemia of CKD show normal to increased amounts of iron. Gastrointestinal bleeding and poor dietary intake, however, can lead to iron deficiency and a microcytic hypochromic anemia. Aluminum toxicity causes a microcytic hypochromic anemia in which adequate iron stores are present (79). Correction of anemia provides relief from many of the debilitating symptoms of ESRD (80). These include improvement in sleep, cognitive function, and exercise tolerance. The response to EPO is poor in some ESRD patients, and they require high doses of EPO to raise their hemoglobin levels. There are disease differences in EPO requirements. Patients with IgA nephropathy and polycystic kidney disease have lower requirements than other patients, and patients with hypertension appear to need higher doses than diabetics. The differences may be partly explained by underlying inflammatory conditions or infections. Patients with ESRD owing to SLE, vasculitis, and AIDS require relatively high doses, and EPO resistance is more common in African American patients. The hypertrophic cardiomyopathy of ESRD has been observed to regress after EPO therapy, and hemodynamic improvement has been seen with dilated cardiomyopathy (81). However, administration of high doses of EPO to achieve hemoglobin levels ≥12 g/dL has been shown to increase morbidity and mortality in patients with ESRD and CKD patients not requiring dialysis. These adverse effects are primarily due to the nonerythropoietic actions of high doses of EPO and intravenous iron preparations (78,82). Hemorrhage into skin, mucous membranes, and gastrointestinal tract is a common problem in the patient with ESRD. The bleeding tendency is attributed to platelet dysfunction. Platelets are normal in number but appear unable to adequately adhere to damaged blood vessels
and form hemostatic plugs (83). The ESRD-associated platelet dysfunction is in part due to impaired calcium signaling, which is ameliorated by EPO therapy (84). In addition, EPO administration increases platelet production and can potentially cause thrombosis in ESRD patients (85).

Chronic Hepatitis and Hepatic Iron Overload

Hepatitis C virus is the most common cause of chronic liver disease in ESRD. In December 2002, all US chronic HD centers were surveyed regarding selected patient care practices and dialysis-associated diseases. Routine testing for antibody to hepatitis C virus (anti-HCV) was performed on patients at 64% of centers; anti-HCV was found in 7.8% of patients (86). The prevalence of seropositivity is related to the number of transfusions that the patients have received. Liver biopsies have demonstrated chronic liver disease in 50% to 100% of anti-HCV-positive patients (87). Martin et al. (87) found mild or moderate necroinflammatory changes in all of 28 anti-HCV-positive patients who had liver biopsies while being referred for transplantation. Fibrosis was seen in 79%, and 3 of the 28 (11%) had cirrhosis. Hepatitis C infection does not seem to change mortality rates of dialysis patients (88). The other common liver abnormality in the ESRD population is iron overload, which was due to frequent use of blood transfusion in the preerythropoietin era and is caused by excessive use of intravenous iron preparations in recent years (89).

Central Nervous System

Central nervous system disorders in ESRD have been defined clinically as uremic encephalopathy, dialysis disequilibrium syndromes, and dialysis dementia (50,90). The clinical manifestations of uremic encephalopathy are lethargy, confusion, obtundation, and coma (90). The signs and symptoms can evolve rapidly in patients with acute renal failure and are less often seen in patients who slowly progress to chronic renal failure. If patients have been severely hypertensive, the brain at autopsy may show fibrinoid necrosis of small arteries and provide evidence of a hypertensive encephalopathy. Otherwise, the brain may reveal only nonspecific changes of cerebral edema, or if patients have been dehydrated, the brain may be dry and reduced in size. The dialysis disequilibrium syndrome is rarely seen in current nephrology practice. The clinical symptoms are caused by elevated intracranial pressure such as nausea, vomiting, tremor, muscle cramps, dizziness, and blurred vision (90). Dialysis dementia is caused by the chronic toxicity of aluminum absorbed from oral phosphate binders or dialysate water. Aluminum exposure is now closely controlled, and dialysis dementia has virtually disappeared as a clinical syndrome (90).

Secondary Parathyroid Hyperplasia

In early-stage CKD, plasma fibroblastic growth factor 23 (FGF23), a bone-derived phosphaturic hormone, is increased to maintain neutral phosphate balance through down-regulation of sodium-phosphate cotransporters and suppression of renal production of 1,25(OH)2D (or calcitriol) by inhibiting 1-alpha-hydroxylase and stimulating 24-hydroxylase (91). Calcitriol normally acts through the vitamin D receptor to inhibit parathyroid hormone (PTH) transcription and growth of parathyroid cells. Via loss of this inhibitory activity, low serum levels of calcitriol directly contribute to the increased secretion of PTH and promote parathyroid hyperplasia. In addition, low calcitriol reduces the intestinal absorption of calcium and further contributes to secondary parathyroid hyperplasia. In ESRD, dietary phosphate overwhelms the compensatory mechanisms of elevated FGF23, resulting in overt hyperphosphatemia. Hyperphosphatemia together with decreased 1,25(OH)2D and resulting hypocalcemia contributes to further stimulation of PTH secretion and parathyroid cell proliferation (91).

Grossly, all four parathyroid glands and any accessory glands are enlarged in cases of secondary hyperplasia, although there can be considerable variation in the size of each gland. Single-gland weights can range from less than 100 mg to more than 2 g (normal combined gland weight is 50 to 300 mg). The enlargement may be diffuse or nodular. Histologically, the hyperplasia is composed of a mixture of chief cells and oxyphil cells with chief cells usually predominating (Fig. 28.9). In cases of refractory secondary hyperparathyroidism, clonal chromosomal changes have been detected in the parathyroid glands of 61% of dialysis patients (92). The most common abnormality was a deletion of 1p that was found in 71% of the glands having chromosomal abnormalities. A deletion of 1p is the most common cytogenetic abnormality found in parathyroid adenomas, and the recurring clonality of the deletion in secondary hyperplasia suggests a neoplastic process and the involvement of a tumor suppressor gene (92).

CKD-Mineral Bone Disorder and Renal Osteodystrophy

CKD-mineral bone disorder is defined as a systemic condition of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: (a) abnormalities of calcium, phosphorus, PTH, and vitamin D metabolism; (b) abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and (c) vascular or other soft tissue calcification (93). The term renal osteodystrophy is used exclusively to define alterations in bone morphology associated with CKD, which can be further assessed by histomorphometry (93).
It encompasses the following disorders: osteitis fibrosa cystica, osteomalacia, mixed patterns of osteitis fibrosa and osteomalacia, and adynamic bone disease (94). Osteitis fibrosa cystica is caused by secondary hyperparathyroidism. It is characterized by a high rate of bone formation and resorption and is referred to as high-turnover bone disease. PTH activates bone remodeling by stimulating marrow stromal cells to proliferate and differentiate into osteoblasts and fibroblasts (94). PTH also promotes proliferation of osteoclasts either directly or through cytokines and growth factors produced by marrow stromal cells and osteoblasts (95). The most important of these locally produced factors appear to be macrophage colony-stimulating factor, IL-6, osteoprotegerin, and receptor activator of NF-κB ligand (RANKL).

FIGURE 28.9 Secondary parathyroid hyperplasia in a 47-year-old chronic hemodialysis patient. Nodules of oxyphil cells are separated by chief cells in a parathyroid gland that weighed 1.12 g. (H&E, ×40.)

The bones then undergo a continuing process of resorption and deposition that is not under the normal control of local mechanical strain. The cortex of long bones becomes more porous, and the trabecular bone of the medulla becomes thicker as a result of an increase in unmineralized woven bone or osteoid. Histologically, bone biopsies show an increased number of trabeculae composed of lamellar, mineralized bone of irregular shape and thickness lined by increased amounts of osteoid (94) (Fig. 28.10). Osteoblasts are prominently clustered along the osteoid. Trabeculae are surrounded by fibrous tissue and are scalloped by osteoclasts within the Howship lacunae (Fig. 28.11). Unconnected trabecular islands can be seen within the medullary fibrous tissue emphasizing the lack of organization to the remodeling. The bones are susceptible to spontaneous fractures and, in advanced cases, develop medullary cysts and become markedly deformed.

Osteomalacia is a low-turnover bone disease and, in most cases, is the result of aluminum toxicity (50,94). Osteomalacia softens the bones that can then become deformed and fracture with mild mechanical stress. Bone biopsies show normal numbers of abnormally thickened trabeculae (50,94). The trabeculae consist of a core of irregularly thickened and thinned lamellar bone surrounded by a markedly widened zone of osteoid (Fig. 28.12). Osteoblasts and osteoclasts are reduced below the number found in normal bone and are sparsely seen in histologic sections. Mixed bone disease shows a background of osteomalacia with foci of osteitis fibrosa in which there is increased osteoblastic and osteoclastic activity (50,94). Histochemical stains such as alizarin red react stoichiometrically with aluminum. Aluminum bone disease can be diagnosed when a biopsy shows osteomalacia or normal to thinned bone, a low rate of bone turnover, and aluminum histochemical staining over 25% or more of the trabecular surfaces (96) (Fig. 28.13).

FIGURE 28.10 Osteitis fibrosa in a 27-year-old hemodialysis patient with secondary hyperparathyroidism. Fibrous tissue surrounds irregularly shaped trabeculae with numerous multinucleated osteoclasts. Undecalcified section. (H&E, ×100.)

FIGURE 28.11 Higher magnification of Figure 28.10. Irregularly shaped trabeculae with a widened zone of unmineralized osteoid are lined on the lower edge by osteoblasts (arrow). Osteoclasts are identified in the Howship lacunae in the center. Undecalcified section. (H&E, ×200.)

FIGURE 28.12 Osteomalacia in a long-term hemodialysis patient with low-turnover bone disease. There is a marked excess of pinkstaining osteoid and no osteoblastic or osteoclastic activity. The mineralized parts of the trabeculae are stained black. Undecalcified section. (von Kossa, ×100.)

FIGURE 28.13 Iliac crest bone biopsy stained for aluminum. Osteomalacia is diagnosed by the wide osteoid seams, represented by the pale-staining areas outside the mineralized bone (arrows). The aluminum histochemical reaction product is the red line at the interface between mineralized bone and osteoid. Undecalcified section. (Alizarin red, ×200.)

Adynamic bone disease is also a low-turnover state (50,94). The underlying mechanism is oversuppression of PTH. It also can be caused by aluminum overload (97). Patients with adynamic bone disease have bone pain of uncertain cause. In some patients, pain may be the result of microfractures of trabecular bone. In cases of aluminum overload, bone pain can sometimes be rapidly relieved by treatment with deferoxamine. Bone biopsies of adynamic bone disease show normal to decreased numbers of normal-appearing or thinned trabeculae composed of lamellar bone with reduced numbers of osteocytes (94,96,97). The trabeculae show little or no osteoid and few osteoblasts or osteoclasts.

The principal therapeutic approaches for CKD bone and mineral disease include control of hyperphosphatemia/phosphate retention with phosphate binders, administration of vitamin D sterols to suppress PTH, calcimimetic therapy in selected cases of secondary hyperparathyroidism, and parathyroidectomy in refractory cases. All of these measures need to be conducted with attention to the calcium burden since such therapeutic maneuvers can increase the risk of calcium overload with accompanying soft tissue and vascular calcification particularly when using calcium containing phosphorus binders (calcium carbonate and calcium acetate) and vitamin D sterols. Hence, vitamin D administration is not recommended if serum calcium, corrected for albumin, is greater than 9.5 mg/dL or serum phosphorus is more than 4.5 mg/dL (98). Consequently, novel therapeutic strategies are being developed that utilize calcium-free phosphorus binders (lanthanum carbonate and sevelamer carbonate/chloride) and calcimimetic agents (cinacalcet) to reduce serum phosphorus and suppress PTH without increasing calcium burden (99).

Hypertension in End-Stage Renal Disease

Ninety percent of patients with CKD experience hypertension (defined as a BP of greater than 130/80 mm Hg) during the course of the disease. Uncontrolled hypertension accelerates the rate of progression regardless of the cause of renal failure. Clinical trials and epidemiologic studies indicate that hypertension is a major risk factor for progressive kidney disease. Evaluation of subjects screened in a multiple risk factor intervention trial who were monitored over a 16-year period showed that (a) higher blood pressure was a strong and independent risk factor for the development of ESRD and (b) the relative risk for ESRD increased with rising systolic blood pressure independent of diastolic blood pressure. In patients with type 2 diabetes mellitus, there is almost a linear relationship between increase in mean arterial blood pressure and yearly decrease in GFR. Analysis of the National Health and Nutrition Evaluation Survey (NHANES) III data suggests that adequate blood pressure control is achieved in only 11% of patients with hypercreatininemia (serum creatinine greater than 1.5 mg/dL) (100). Analysis of the NHANES IV indicates that only 37% of hypertensive patients with CKD have blood pressure controlled to a level of less than 130/80 mm Hg. Risk factors for uncontrolled hypertension included age older than 65, black race, and presence of albuminuria (101). In general, older people with hypertension are unaware of their blood pressure elevation, and the majority of those who are aware have poor control rates. CKD prevalence is higher in older age groups, in which systolic hypertension is very common (2). The importance and potential benefit of blood pressure control in renal outcome cannot be overemphasized.


Renal Hemodynamics

Several studies conducted in elderly individuals without significant renal disease have demonstrated that renal blood flow (RBF) decreases with advancing age. Total RBF was well maintained through approximately the fourth decade and, progressively, declined by approximately 10% per decade thereafter (102). In a study of 207 healthy kidney donors, Hollenberg et al. (103) demonstrated an explicit and progressive reduction in mean blood flow per unit kidney mass with advancing age, suggesting that the decrease in RBF does not simply reflect the decline in the renal mass with aging. The fall in renal perfusion with aging is most profound in the cortex, with relative sparing of flow to the medulla. This redistribution of blood flow from the cortex to medulla may explain the slight increase in filtration fraction observed in the elderly population. The precise mechanisms of reduced RBF with aging are incompletely understood. Aging is associated with changes in vascular tone, which is determined by the balance between vasoconstrictors and vasodilators. In aging, there is an attenuated responsiveness to vasodilators such as nitric oxide (NO), endothelial-derived hyperpolarizing factor (EDHF), and prostacyclin and enhanced responsiveness to vasoconstrictors such as angiotensin II (Ang II) (104). This may result in enhanced vasoconstrictive responses in aging that can potentially cause renal damage and ultimately a fall in GFR. Although the renin-angiotensin system (RAS) is suppressed in aging, the intrarenal RAS may be relatively spared. In particular, aging-associated oxidative stress can reduce NO availability by inactivation of NO, inhibition of NO synthase (NOS) via depletion of NOS cofactor tetrahydrobiopterin, uncoupling of endothelial NOS,
accumulation of the endogenous NOS inhibitor asymmetric dimethylarginine, and limiting uptake of the NOS substrate L-arginine by endothelial cells via down-regulation of cationic amino acid transporter-1 (105).

Elastic arteries undergo two distinct aging-related physical changes, namely dilation and stiffness due to fatigue and fracture of the medial elastin with little aging change in distal muscular arteries (106,107). Thus, dilation and stiffening are most marked in the proximal aorta and its major branches, namely the brachiocephalic, carotid, and subclavian arteries. Increased arterial stiffening results in an increase in pulse wave velocity (PWV), which is the speed with which pulse wave travels along the artery (108). A typical value is 5 m/s in a 20-year-old and 12 m/s in an 80-year-old person representing a 2.5-fold increase in 60 years (109). The elastic properties of the aorta in the young serve to partially store blood volume and pressure during systole and release them during diastole via the recoiling process. This phenomenon helps to protect the vital organs by sustaining blood flow during diastole and blunting the damaging effects of high-pressure waves during systole. In addition, the microcirculation, which comprises small arteries, arterioles, and capillaries and constitutes the greatest resistance to blood flow, participates in transforming pulsatile flow to steady flow by reflecting the pulsations that enter from the larger arteries. With aortic stiffening and consequent increase in aortic PWV, transmission of flow pulsations downstream into various organs, principally the brain and kidney, can damage the microvessels (110,111). The lesions comprise damage to medial smooth muscle and endothelium (not attributable to atherosclerosis) and, in their chronic form, are described as “lipohyalinosis” (112). The renal afferent arterioles and glomeruli are exposed to the same high pulsatile microvascular stress and strain as in the brain. Recent studies have shown that independent of conventional brachial systolic and diastolic pressure values, measures of arterial stiffness are closely related to outcomes attributable to microvascular damage to vital organs, particularly the brain and kidney. Furthermore, measures of large artery stiffness are closely related to the effects of microvascular changes in the kidney, including albuminuria (110,111).

Glomerular Filtration Rate

The GFR gradually increases after birth approaching adult levels by the end of the second decade. It remains stable until age of 30 to 40 years and then usually declines linearly at an average rate of about 8 mL/min/decade, a phenomenon that can be partially explained by age-associated glomerulopenia (8,113,114). Thus, inulin clearance, an excellent measure of the GFR, is about 20 mL/min at birth and gradually rises to around 120 mL/min by the age of 30 years. It is a generally accepted dogma that the GFR declines with increasing age after the age of about 30 years, when it starts dropping at an average rate of 1 mL/min/yr, resulting in an inulin clearance of 65 mL/min at the age of 90 years (114). However, in the Baltimore longitudinal study of aging among 254 “normal” subjects, although the mean decline in creatinine clearance was 0.75 mL/min/yr, 36% of the subjects showed no aging-related decrease in creatinine clearance, and a few of these actually showed an increase in their creatinine clearance (115). Creatinine clearance, of course, is influenced by the nutritional status, protein intake, and muscle mass and is, therefore, an inferior method of estimating GFR in the elderly. Healthy elderly subjects with daily ingestion of more than 1 g of protein per kilogram body weight had a creatinine clearance of 90 to 100 mL/min/1.73 m2, while those with diets poorer in protein had lower creatinine clearances (116). In addition, the creatinine production gradually declines with age, in proportion with the decreasing muscle mass and body weight. Therefore, the urinary creatinine output also shows a corresponding decline. This is the reason why the plasma creatinine does not rise with increasing age, despite the aging-related reduction in the creatinine clearance (117). Thus, a modestly elevated plasma creatinine is often of greater significance in the elderly than in a younger patient.

Since one third of elderly individuals show no change in GFR (115), factors other than aging may be responsible for the apparent reduction in renal function. For instance, an increase in blood pressure (still within the normotensive range) is associated with accelerated age-related loss of renal function. The use of creatinine clearance in a timed urinary collection is commonly used to estimate GFR. Inulin and iothalamate clearances are very accurate measurements of GFR but are clinically cumbersome to perform (118). To obviate the need for a timed urine collection, various equations have been developed and are increasingly used to estimate GFR. In adults, creatinine clearance is often estimated by the Cockcroft-Gault (CG) equation and GFR by the Modification of Diet in Renal Disease (MDRD) formula (119,120).

Cockcroft-Gault formula:

MDRD formula:

It is important to point out that the CG equation estimates GFR in mL/min, while the MDRD formula expresses GFR in mL/min/1.73 m2. However, neither MDRD nor CG equation was developed for elderly individuals, and reduced reliability would be expected when used in this population. The MDRD equation generally yielded higher estimates of GFR than the CG equation (121). A new creatinine-based equation was developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). It reported a more accurate estimation of GFR than the MDRD equation, particularly at higher levels of estimated GFR (eGFR) (122). However, the performance of the serum creatinine-based estimating equations remains insufficiently evaluated in older patients, in whom there may be a high prevalence of chronic disease associated with alterations in muscle mass and diet, resulting in overestimation of measured GFR and underestimation of severity of CKD. Recently, cystatin C, a filtration marker that is less related to muscle mass than creatinine, is found to have a particular advantage in the estimation of GFR in the elderly population (123). In a study involving 11,909 patients, risk of death, CV events, and kidney failure were compared in patients with GFR less than 60 mL/min/1.73 m2 (CKD) to those with GFR greater than 60 mL/min/1.73 m2 estimated by creatinine and cystatin C measurements. The survey showed that cystatin
C-based estimates were better predictors of adverse outcomes among adults with CKD, suggesting that cystatin C may be useful in identifying patients with CKD who have higher risks of complications (124).

Tubular Function

Renal Concentrating and Diluting Ability

The Baltimore longitudinal study of aging evaluated urine concentrating ability in healthy people aged between 20 and 79 years by assessing maximum urine osmolality, minimal urine flow rate over a period of 12 hours, and ability to concentrate solutes (or reabsorb sodium and urea). Compared to younger age groups, individuals aged 60 to 79 years had approximately 20% reduction in maximal urine osmolality, a 100% increase in minimal urine flow rate, and a 50% decrease in the ability to conserve solutes (125). These changes could not be explained by the reduction in GFR. No significant differences in ADH levels have been observed between the elderly and the younger cohorts suggesting that the defect is likely due to ADH resistance as opposed to ADH deficiency (126). A decrease in the abundance of aquaporin and urea transporter proteins, as observed with aging in the kidneys of animals, likely accounts for the reduced urinary concentrating capacity in the elderly. Experimental studies suggest that the abundance of aquaporins 2 and 3 is reduced by 80% and 50%, respectively, in the aged rats’ renal medullary collecting ducts (127,128). Besides the decrease in aquaporin 2, there is impairment of its phosphorylation, which may interfere with trafficking and insertion of aquaporin 2 in the apical membrane of the collecting duct. Together, these defects diminish the urine-concentrating ability by decreasing water reabsorption in the collecting ducts. In addition, aging results in decreased abundance of the major urea transporters (UT-A1 and A2) in the inner medullary collecting duct (127,128,129) and reduced NaCl transporter NKCC2/BSC1 in the thick ascending limb of the loop of Henle (128,130). These changes can reduce urine concentrating ability in the elderly by limiting urea and sodium reabsorption and, hence, inner medullary osmolality.

Although much less data are available on renal diluting capacity, existing studies suggest a mild impairment of renal diluting ability in the elderly due to reduced GFR. There is no evidence for impaired function of the diluting segment or altered suppressibility of vasopressin in the pathogenesis of this disorder. Reduced renal diluting capacity renders the older individuals more susceptible to the development of dilutional hyponatremia in the setting of excess water load; stress situations such as surgery, fever, acute illness; or administration of drugs such as diuretics or those that enhance vasopressin production and action. These events may act alone or in concert to impair the renal diluting ability and render the elderly patients susceptible to water intoxication.

Fluid and Electrolyte Balance

Age has no effect on basal plasma electrolyte concentrations or the ability to maintain normal extracellular fluid volume. However, structural changes in the elderly kidney have an impact on the adaptive mechanisms responsible for maintaining homeostasis of extracellular fluid volume and composition. In the elderly, the capacity to conserve sodium in response to reduced sodium intake is impaired (131). The exact mechanism is not known, but reduction in the number of functioning nephrons with increased sodium load per each remaining nephron as well as reduced aldosterone secretion in response to sodium depletion are plausible explanations. Nevertheless, inability to conserve sodium may predispose the elderly to hemodynamic instability in the setting of sodium loss. This, along with other structural and functional changes, makes older patients more prone to develop acute kidney injury (132). In addition to impaired sodium conservation, the elderly are also prone to volume expansion when challenged with a sodium load, which is due to a diminished capacity of renal sodium excretion (133). Additionally, the elderly seem to have more sodium excretion at nighttime compared to daytime, suggesting an impaired circadian variation (134). Impaired pressure natriuresis and altered response to Ang II are apparent mechanisms involved (135). Elderly subjects also show abnormalities in renal potassium and calcium handling, which are discussed in the next section.

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Jun 21, 2016 | Posted by in UROLOGY | Comments Off on Renal Changes With Aging and End-Stage Renal Disease
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