Chronic Kidney Disease

CHRONIC RENAL FAILURE - Karl Skorecki, Jacob Green*, Barry M. Brenner

NOTE

*Deceased

MECHANISMS OF CHRONIC RENAL FAILURE

DEFINITIONS

Chronic renal disease (CRD) is a pathophysiologic process with multiple etiologies, resulting in the inexorable attrition of nephron number and function and frequently leading to end-stage renal disease (ESRD). In turn, ESRD represents a clinical state or condition in which there has been an irreversible loss of endogenous renal function, of a degree sufficient to render the patient permanently dependent upon renal replacement therapy (dialysis or transplantation) in order to avoid life-threatening uremia. Uremia is the clinical and laboratory syndrome, reflecting dysfunction of all organ systems as a result of untreated or undertreated acute or chronic renal failure. Given the capacity of the kidneys to regain function following acute injury (Chap. 260), the vast majority (>90%) of patients with ESRD have reached this state as a result of CRD.

PATHOPHYSIOLOGY OF CRD (SEE ALSO CHAP. 259)

The pathophysiology of CRD1 involves initiating mechanisms specific to the underlying etiology as well as a set of progressive mechanisms that are a common consequence following long-term reduction of renal mass, irrespective of etiology. Such reduction of renal mass causes structural and functional hypertrophy of surviving nephrons. This compensatory hypertrophy is mediated by vasoactive molecules, cytokines, and growth factors and is due initially to adaptive hyperfiltration, in turn mediated by increases in glomerular capillary pressure and flow. Eventually, these short-term adaptations prove maladaptive, in that they predispose to sclerosis of the remaining viable nephron population. Increased intrarenal activity of the renin-angiotensin axis appears to contribute both to the initial adaptive hyperfiltration and to the subsequent maladaptive hypertrophy and sclerosis.

The definition of CRD1 requires that the pathophysiologic process described above last more than 3 months. A recently widely accepted international classification divides CRD into a number of stages (Table 261-1) defined by clinical estimation of the glomerular filtration rate (GFR). These stages help guide clinical diagnostic and management approaches. First, it is important to identify factors that increase the risk for CRD, even in individuals with normal GFR. Such factors include family history of heritable renal disease, hypertension, diabetes, autoimmune disease, older age, past episode of acute renal failure, and current evidence of kidney damage with normal or even increased GFR. Such evidence of kidney damage in the face of normal or increased GFR places affected individuals into stage 1 CRD and includes proteinuria, abnormal urinary sediment, or urinary tract structural abnormalities (e.g., vesicoureteric reflux) evident on imaging studies. Even at this stage, when baseline GFR is normal, there is often a characteristic loss of renal reserve. This early stage is particularly well documented in diabetic nephropathy. Further stages in the pathogenesis of CRD are characterized by a progressive decline in estimated GFR with mild, moderate, and severe stages defined at GFR levels (mL/min per 1.73 m2) of 60 to 89, 30 to 59, and 15 to 29, respectively. At a GFR < 15 mL/min per 1.73 m2, renal replacement therapy may be indicated if uremia is present. For purposes of staging CRD, current guidelines recommend estimating GFR using one of the two equations shown in Table 261-2, based on measured plasma creatinine concentration, age, gender, and ethnic origin. The normal annual mean decline in GFR with age beginning at age 20 to 30 years is 1 mL/min per 1.73 m2, reaching a mean value in males of 70 at age 70. GFR is slightly lower in women than men. By the time plasma creatinine concentration is even mildly elevated, substantial chronic nephron injury has already occurred.

Albuminuria serves as a key adjunctive tool for monitoring nephron injury and response to therapy in many forms of CRD1. Current guidelines recommend use of albumin-specific dipstick measurement or quantitation by measurement of albumin-to-creatinine ratio in a spot first morning urine sample. Persistence of >17 mg albumin per gram of creatinine in adult males and 25 mg albumin per gram of creatinine in adult females usually signifies chronic renal damage, irrespective of GFR2, and can be followed in monitoring natural history and response to therapy, especially in CRD consequent to diabetes, hypertension, or glomerulonephritis. Further considerations in the overall clinical approach to proteinuria are provided in Chap. 40.

During stages 1 and 2 CRD1, patients often remain free of symptoms, other than those that might accompany the underlying etiologic process causing renal disease. As the decline in GFR2 progresses to stages 3 and 4 (GFR < 60 mL/min per 1.73 m2), clinical and laboratory complications of CRD become progressively more prominent. Virtually all organ systems are affected, but the most evident complications include anemia and loss of energy; decreasing appetite and disturbances in nutritional status; abnormalities in calcium and phosphorus metabolism accompanied by metabolic bone disease; and abnormalities in sodium, water, potassium, and acid-base homeostasis. When GFR falls to <15 mL/min per 1.73 m2, patients usually experience a severe disturbance in their activities of daily living, sense of well-being, nutritional status, and water and electrolyte homeostasis, eventuating in an overtly uremic state wherein continued survival without renal replacement therapy becomes impossible.

ETIOLOGY AND EPIDEMIOLOGY

It has been estimated that at least 6% of the adult U.S. population have chronic renal damage with a GFR2 > 60 mL/min per 1.73 m2 (stages 1 and 2 CRD1) and hence are at imminent risk of a progressive further decline in GFR. An additional ~4.5% of the U.S. population are in stages 3 and 4 CRD. Diabetic and hypertensive nephropathy are the leading underlying etiologies of both CRD and ESRD3. Hypertension is a particularly common cause and consequence of CRD in the elderly, in whom chronic renal ischemia due to renovascular disease may be an underrecognized additional contribution to the pathophysiologic process. It should be noted that cardiovascular mortality precludes most patients with CRD from reaching the stage of ESRD. Identification of CRD as a major risk factor for cardiovascular morbidity and mortality, and the expectation of effective interventions to diminish premature cardiovascular mortality, and increasing longevity overall, will increase the cohort of patients reaching ESRD.

Although the clinical manifestations of the declining GFR2 per se dominate the clinical presentation in all forms of CRD1, in many cases the underlying etiology can be presumed from associated additional clinical information (Table 261-3).

GENETIC CONSIDERATIONS
Disorders with clear-cut monogenic inheritance comprise a small but important component among the etiologies of CRD1. Among these, autosomal dominant polycystic kidney disease is the most common on a world-wide basis (Chap. 265). Alport’s hereditary nephritis (Chap. 264) is a less common cause of both benign hematuria without progression to CRD and more severe nephron injury with progression to ESRD4, and it most often displays an X-linked pattern of inheritance. Several genetic loci have been identified that encode important components of the glomerular podocyte-associated filtration barrier, and mutations in these genes cause inherited forms of focal segmental glomerular sclerosis with glucocorticoid nonresponsive nephrotic syndrome and progression to ESRD. Nephronopthisis, medullary cystic kidney disease, and Fabry’s disease are among other rare causes of progressive CRD with monogenic inheritance based on well-characterized genetic loci. In contrast, the two most common etiologies of CRD, diabetes mellitus (both types 1 and 2) and essential hypertension, display complex polygenic patterns of inheritance.

The striking interindividual variability in the rate of progression to ESRD5 has an important heritable component, and a number of genetic loci that contribute to the progression of CRD1 have been identified. Most extensively studied has been an insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene. The homozygous deletion (D/D) variant is associated with the highest expression of endogenous ACE activity and a greater risk of CRD progression. This finding leads to the prediction that ACE inhibitor therapy might be most effective in patients who are homozygous for the "at-risk" allele. Similar conclusions have been reached with respect to genes encoding other components of the renin-angiotensin axis. More recent studies of genetic association with renal failure progression have focused on a region of human chromosome 10, homologous to a well-characterized rodent renal failure susceptibility gene (Rf1).

PATHOPHYSIOLOGY AND BIOCHEMISTRY OF UREMIA

Azotemia refers to the retention of nitrogenous waste products as renal insufficiency develops. Uremia refers to the more advanced stages of progressive renal insufficiency when the complex, multiorgan system derangements become clinically manifest.

Although not the major cause of overt uremic toxicity, urea may contribute to some of the clinical abnormalities, including anorexia, malaise, vomiting, and headache. Additional categories of nitrogenous excretory products include guanido compounds, urates and hippurates, end products of nucleic acid metabolism, polyamines, myoinositol, phenols, benzoates, and indoles, among others. Nitrogenous compounds with a molecular mass of 500 to 12,000 Da (so-called middle molecules) are also retained in CRD1 and similarly are believed to contribute to morbidity and mortality in uremic subjects. However, uremia involves more than renal excretory failure alone. A host of metabolic and endocrine functions normally subserved by the kidney are also impaired, resulting in anemia; malnutrition; impaired metabolism of carbohydrates, fats, and proteins; defective utilization of energy; and metabolic bone disease. Furthermore, plasma levels of many polypeptide hormones, including parathyroid hormone (PTH), insulin, glucagon, luteinizing hormone, and prolactin, rise with renal failure, not only because of impaired renal catabolism but also because of enhanced endocrine secretion, occurring as a secondary consequence of primary excretory or synthetic renal dysfynction. On the other hand, the renal production of erythropoietin (EPO) and 1,25-dihydroxycholecalciferol is impaired. Thus, the pathophysiology of the uremic syndrome can be divided into two sets of abnormalities: (1) those consequent to the accumulation of products of protein metabolism; and (2) those consequent to the loss of other renal functions, such as fluid and electrolyte homeostasis and hormonal abnormalities.

CLINICAL AND LABORATORY MANIFESTATIONS OF CHRONIC RENAL FAILURE AND UREMIA

Uremia leads to disturbances in the function of every organ system. Chronic dialysis (Chap. 262) reduces the incidence and severity of these disturbances, so that, where modern medicine is practiced, the overt and florid manifestations of uremia have largely disappeared. Unfortunately, as indicated in Table 261-4, even optimal dialysis therapy is not a panacea, because some disturbances resulting from impaired renal function fail to respond fully, while others continue to progress.

FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS (SEE ALSO CHAPS. 41, 42, AND 259)

Sodium and Water Homeostasis In most patients with stable CRD1, the total body contents of Na+ and H2O are increased modestly, although this may not be clinically apparent. The underlying etiologic disease process may itself disrupt glomerulotubular balance and promote Na+ retention (e.g., glomerulonephitis), or excessive Na+ ingestion may lead to cumulative positive Na+ balance and attendant extracellular fluid volume (ECFV) expansion. Such ECFV expansion contributes to hypertension, which in turn accelerates further the progression of nephron injury. As long as water intake does not exceed the capacity for free water clearance, the ECFV expansion will be isotonic and the patient will remain normonatremic. Hyponatremia is an uncommon complication in predialysis patients, and water restriction is only necessary when hyponatremia is documented. Weight gain usually associated with volume expansion may be offset in patients with CRD by concomitant loss of lean body mass. In the CRD patient who is not yet on dialysis but has clear evidence of ECFV expansion, administration of loop diuretics coupled with restriction of salt intake are the mainstays of therapy. It should be noted that resistance to loop diuretics in renal failure often mandates use of higher doses than those usually used when GFR2 is well preserved. The combination of loop diuretics with metalozone, which inhibits the Na+Cl- cotransporter of the distal convoluted tubule, can sometimes overcome diuretic resistance. When the GFR falls to <5 to 10 mL/min per 1.73 m2, even high doses of combination diuretics are ineffective. ECFV expansion under these circumstances usually means that dialysis is indicated.

Patients with CRD1 also have impaired renal mechanisms for conserving Na+ and H2O (Chap. 259). When an extrarenal cause for fluid loss is present (e.g., vomiting, diarrhea, sweating, fever), these patients are prone to volume depletion. Depletion of ECFV6 may compromise residual renal function with resulting signs and symptoms of overt uremia. Because of impaired renal Na+ and H2O conservation, the usual indices of prerenal azotemia (oliguria, high urine osmolality, low urinary Na+ concentration, and low fractional excretion of Na+) are not useful. Cautious volume repletion, usually with normal saline, returns ECFV to normal and usually restores renal function to prior levels.

Potassium Homeostasis (See also Chap. 41) In CRD1, the decline in GFR2 is not necessarily accompanied by a concomitant and proportionate decline in urinary K+ excretion. In addition, K+ excretion in the gastrointestinal tract is augmented in patients with CRD. However, hyperkalemia may be precipitated in a number of clinical situations, including constipation, augmented dietary intake, protein catabolism, hemolysis, hemorrhage, transfusion of stored red blood cells, metabolic acidosis, and following the exposure to a variety of medications that inhibit K+ entry into cells or K+ secretion in the distal nephron. Most commonly encountered medications in this regard are beta blockers, ACE7 inhibitors and angiotensin receptor blockers, K+-sparing diuretics (amiloride, triamterene, spironolactone), and nonsteroidal anti-inflammatory drugs (NSAIDs). In addition, certain etiologies of CRD may be associated with earlier and more severe disruption of K+ secretory mechanisms in the distal nephron, relative to the reduction in GFR. Most important are conditions associated with hyporeninemic hypoaldosteronism (e.g., diabetic nephropathy and certain forms of distal renal tubular acidosis; Chaps. 264 and 265).

Hypokalemia is uncommon in CRD1 and usually reflects markedly reduced dietary K+ intake, in association with excessive diuretic therapy or gastrointestinal losses. Hypokalemia occurs as a result of primary renal K+ wasting in association with other solute transport abnormalities, as in Fanconi’s syndrome, renal tubular acidosis, or other forms of hereditary or acquired tubulointerstitial diseases. However, even under these circumstances, as GFR2 declines, the tendency to hypokalemia diminishes and hyperkalemia may supervene. Accordingly, K+ supplementation and K+-sparing diuretics should generally be avoided as GFR declines.

Metabolic Acidosis (See also Chap. 42) Acidosis is a common disturbance during the advanced stages of CRD1. Although in a majority of patients with CRD the urine can be acidified normally, these patients have a reduced ability to produce ammonia. Hyperkalemia further depresses urinary ammonium excretion. The combination of hyperkalemia and hyperchloremic metabolic acidosis (known as type IV renal tubular acidosis, or hyporeninemic hypoaldosteronism) is most characteristically seen in patients with diabetes or in those with predominantly tubulointerstitial disease. Treatment of the hyperkalemia frequently improves the acidosis as well.

With advancing renal failure, total urinary net daily acid excretion is usually limited to 30 to 40 mmol, and an anion gap of ~20 mmol/L with a reciprocal fall in plasma [HCO3-] may develop. In most patients, the metabolic acidosis is mild; the pH is rarely <7.35 and can usually be corrected by treating the patient with 20 to 30 mmol of NaHCO3 or sodium citrate daily. However, the concomitant Na+ load mandates careful attention to volume status and the potential need for diuretic agents. Also, citrate enhances aluminum absorption in the large bowel, and citrate-containing agents should be avoided if aluminum-containing drugs are also administered. Severe symptomatic manifestations of acid-base imbalance may occur when the patient is challenged with an excessive endogenous or exogenous acid load or loses excessive alkali (e.g., with diarrhea).

TREATMENT
Adjustments in dietary intake and use of loop diuretics, occasionally in combination with metalozone, may be needed to maintain salt and hence extracellular fluid volume balance. In contrast, overzealous salt restriction and diuretic use may cause hypovolemia and precipitate a further decline in GFR2. Occasional patients with salt-wasting states need to be given sodium-rich diets or sodium supplements. Water restriction is indicated only if there is a demonstrated propensity to hyponatremia. Intractable ECFV8 expansion, despite dietary restriction and diuretic use, indicates the need to initiate renal replacement therapy. Hyperkalemia often responds to dietary restriction of potassium, avoidance of potassium-containing or -retaining medications, and to the use of diuretics if they are also indicated for management of sodium balance. Many salt substitutes contain potassium instead of sodium, and patients with CRD1 seeking to avoid sodium should be cautioned accordingly as part of their dietary counseling. Potassium-binding resins taken with cathartics can promote gastrointestinal potassium losses and thus are useful as temporizing measures in the treatment or avoidance of hyperkalemia in CRD patients. However, the need for such treatment over a prolonged period, in the absence of other reversible causes of hyperkalemia, usually signifies the need to initiate renal replacement therapy.

BONE DISEASE AND DISORDERS OF CALCIUM AND PHOSPHATE METABOLISM (FIG. 261-1; SEE ALSO CHAPS. 331 AND 332)

The major disorders of bone disease in CRD1 can be classified into those associated with high bone turnover and high PTH9 levels (including osteitis fibrosa, the hallmark lesion of secondary hyperparathyroidism) and low bone turnover with low or normal PTH levels (osteomalacia and adynamic bone disease).

The pathophysiology of bone disease due to secondary hyperparathyroidism is related to abnormal mineral metabolism. (1) Decreased GFR2 leads to reduced inorganic phosphate (PO43-) excretion and consequent PO43- retention, (2) retained PO43- has a direct stimulatory effect on PTH9 synthesis and on cellular mass of the parathyroid glands, (3) retained PO43- also indirectly causes excessive production and secretion of PTH through lowering of ionized Ca2+ and by suppression of calcitriol (1,25-dihydroxycholecalciferol) production, and (4) reduced calcitriol production in CRD1 results both from decreased synthesis due to reduced kidney mass and from hyperphosphatemia. Low calcitriol levels, in turn, lead to hyperparathyroidism via both direct and indirect mechanisms. Calcitriol is known to have a direct suppressive effect on PTH transcription (i.e., a genomic effect), and therefore reduced calcitriol in CRD causes elevated levels of PTH. In addition, reduced calcitriol leads to impaired Ca2+ absorption from the gastrointestinal tract, thereby leading to hypocalcemia, which then increases PTH secretion and production. Taken together, hyperphosphatemia, hypocalcemia, and reduced calcitriol synthesis all promote the production of PTH and the proliferation of parathyroid cells, resulting in secondary hyperparathyroidism.

In addition to excessive release of PTH9 from individual parathyroid cells, the mass of parathyroid cells increases progressively with CRD1. Excessive parathyroid gland cellular mass may assume one of the following patterns: (1) diffuse hyperplasia (polyclonal), (2) nodular growth (monoclonal) within diffuse hyperplastic tissue, or (3) diffuse monoclonal hyperplasia ("adenoma" or tertiary autonomous hyperparathyroidism). Patients with monoclonal ("autonomous") hyperplasia are especially prone to develop hypercalcemia following successful kidney transplantation, often necessitating parathyroidectomy. High PTH levels stimulate osteoblasts and result in high bone turnover, which leads to osteitis fibrosa cystica. The latter is characterized by irregularly woven abnormal osteoid, fibrosis, and cyst formation, which result in decreased cortical bone and bone strength and an increased risk of fracture.

Low-turnover bone disease can be classified into two categories — osteomalalcia and adynamic bone disease. Both lesions are characterized by a reduced number of osteoclasts and osteoblasts and decreased activity of the latter. In osteomalacia there is an accumulation of unmineralized bone matrix, or increased osteoid volume, which may be caused by vitamin D deficiency, excess aluminum deposition, or metabolic acidosis. Adynamic bone disease is now recognized to be as prevalent as the hyperparathyroid bone lesion in patients with CRD1 and ESRD10, and is especially common among diabetic patients. Adynamic bone disease is characterized by reduced bone volume and mineralization and may result in part from excessive suppression of PTH9 production with calcitriol treatment or, currently less common, from aluminium exposure.

Irrespective of the cause for skeletal abnormalities in CRD1, bone disease can lead to pain, increased incidence of fractures, and severe incapacity. Bone fractures complicate both the high- and low-turnover types of bone disease, and it is now appreciated that patients with adynamic bone may be more predisposed to fractures than those with osteitis fibrosa cystica. In the latter disorder, however, a PTH9-associated proximal myopathy often coexists, giving rise to gait abnormalities and impaired ambulation.

Other Complications of Abnormal Calcium-Phosphate Product Metabolism In addition to abnormalities in bone metabolism, abnormal calcium-phosphate product metabolism may lead to calciphylaxis, i.e., extraosseous ("metastatic") calcification of soft tissue and blood vessels. Electron beam computed tomography in patients with CRD1 has revealed highly elevated coronary calcification scores, which likely represent a major factor in the predisposition to occlusive coronary vascular disease in the CRD and ESRD11 populations. The pathogenesis remains unclear, but hyperphosphatemia, hypercalcemia, elevated calcium-phosphate product, and increased PTH9 levels are all thought to contribute to this process. Calciphylaxis represents a severe and systemic form of vascular and soft tissue calcium-phosphate product deposition associated with skin and soft tissue necrosis, which can lead to extremity loss.

TREATMENT
Secondary hyperparathyroidism and osteitis fibrosa are best prevented and treated by reducing the plasma PO43- concentration through the use of a phosphate-restricted diet as well as oral phosphate-binding agents. Calcium carbonate and calcium acetate are useful phosphate-binding agents. Sevelamer, a nonabsorbable, non-calcium-containing polymer has been recently added to the phosphate-lowering armamentarium. It has an advantage over the calcium-based phosphate chelating agents in that it does not predispose CRD1 patients to hypercalcemia and attenuates calcium deposition in the coronary arteries and aorta.

Daily oral calcitriol, or intermittent oral or intravenous pulses, appears to exert a direct suppressive effect on PTH9 secretion, in addition to the indirect effect mediated through raising plasma Ca2+ concentration. The use of calcitriol and calcium preparations in the predialysis population must take into account potential effects of increased PO43- and Ca2+ on the rate of progression of CRD1. The recommended target plasma PO43- concentration is approximately 1.4 mmol/L (4.5 mg/dL), with a corresponding plasma Ca2+ concentration of approximately 2.5 mmol/L (10 mg/dL) in an attempt to suppress parathyroid hyperplasia, thus avoiding or reversing osteitis fibrosa cystica, osteomalacia, and myopathy. It is particularly important to maintain the calcium-phosphate product in the normal range to avoid metastatic calcification. Recognition of the role of the extracellular calcium-sensing receptor has led to the development of calcimimetic agents that enhance the sensitivity to Ca2+-suppressive effects on PTH secretion. The first-generation calcimimetic agent tested produced a dose-dependent reduction in PTH and plasma Ca2+ concentration, and subsequent formulations with improved pharmacokinetic profiles show great promise as effective and safe treatments for secondary hyperparathyroidism. However, since adynamic bone disease is often a consequence of overzealous treatment of secondary hyperparathyroidism, suppression of PTH levels to <120 pg/mL in CRD patients may not be desirable.

The incidence of aluminum-induced osteomalacia has been greatly reduced with the recognition of aluminum as the principal culprit. Therapy for this disorder is based on the complete cessation of the use of aluminum combined with the use of a chelating agent such as deferoxamine.

Management of metabolic acidosis should aim to maintain a nearly normal level of plasma bicarbonate with the administration of calcium acetate or calcium carbonate, with the addition of sodium bicarbonate (limited by considerations of sodium load) if necessary. Excessive administration of alkali should be avoided to minimize risk of urinary precipitation of Ca2+ phosphate.

CARDIOVASCULAR ABNORMALITIES

Cardiovascular disease is the leading cause of morbidity and mortality in patients with CRD1 at all stages. Estimates of the increase in cardiovascular disease risk attributable to CRD range from 10- to 200-fold, depending on the stage of CRD, other risk factors, and comorbid conditions. Between 30 and 45% of patients reaching ESRD12 already have advanced cardiovascular complications. Thus the management of patients with CRD should emphasize prevention of cardiovascular complications as well as measures aimed at alleviating the progression and complications of CRD itself.

Ischemic Cardiovascular Disease CRD1 at all stages constitutes a major risk factor for ischemic cardiovascular disease, including occlusive coronary heart, cerebrovascular, and peripheral vascular diseases. Increased prevalence of coronary heart disease in CRD derives from both traditional ("classic") and CRD-related ("nontraditional") risk factors. The former include hypertension (see below), hypervolemia, dyslipidemia, sympathetic overactivitiy, and hyperhomocysteinemia. The CRD-related risks include anemia, hyperphosphatemia, hyperparathyroidism, and a state of "microinflammation" that can be found at all stages of CRD but is undoubtedly aggravated by dialysis. The inflammatory state elicits a rise in acute-phase reactants such as interleukin 6 and C-reactive protein, which contribute to the coronary occlusive process and are predictors of cardiovascular disease risk. Other abnormalities augment myocardial ischemia. These include reduced myocardial tolerance to ischemia due to left ventricular hypertrophy (see below) and microvascular disease. Also, coronary reserve, defined as the increase in coronary blood flow in response to greater demand, is attenuated. Nitric oxide is an important mediator for vascular dilatation. Its availability in CRD is decreased because of increased concentrations of asymmetric dimethyl-l-arginine, even at early stages of CRD, and also because nitric oxide is scavenged by reactive oxygen species. In addition, coronary arteriolar hypertrophy/hyperplasia limits vasodilatory capacity.

Congestive Heart Failure (See also Chap. 216) Abnormal cardiac function secondary to myocardial ischemic disease and/or left ventricular hypertrophy, together with salt and water retention in uremia, often result in congestive heart failure and/or pulmonary edema. A unique form of pulmonary congestion and edema may occur even in the absence of volume overload and is associated with normal or mildly elevated intracardiac and pulmonary capillary wedge pressures. This entity, characterized radiologically by peripheral vascular congestion giving rise to a "butterfly wing" distribution, is due to increased permeability of alveolar capillary membranes. This "low-pressure" pulmonary edema as well as cardiopulmonary abnormalities associated with circulatory overload usually respond promptly to vigorous dialysis.

Hypertension and Left Ventricular Hypertrophy (See also Chap. 230) Hypertension is the most common complication of CRD1 and ESRD13. It may develop early during the course of CRD and is associated with adverse outcomes — in particular, more rapid loss of renal function and development of cardiovascular disease. Numerous epidemiologic studies and clinical trials have shown a relationship between the level of blood pressure and rate of progression of diabetic and non-diabetic kidney disease (see below).

Administration of EPO14 (p. 1658) may raise blood pressure and increase the requirement for antihypertensive drugs in CRD1 patients. Left ventricular hypertrophy and dilated cardiomyopathy are among the most ominous risk factors for excess cardiovascular morbidity and mortality in patients with CRD and ESRD15 and are thought to be related primarily to prolonged hypertension and ECFV16 overload. In addition, anemia and the surgical placement of an arteriovenous anastomosis for future or ongoing dialysis access may generate a high cardiac output state and pulmonary hypertension, which also intensify the burden placed on the left ventricle. Absence of hypertension may signify the presence of a salt-wasting form of renal disease (e.g., medullary cystic disease, chronic tubulointerstitial disease, or papillary necrosis), ongoing antihypertensive therapy, volume-depletion due to gastrointestinal causes or diuretic therapy, or reduced cardiac index.

Since volume overload is the major cause of hypertension in uremia, the normotensive state can often be restored by appropriate (not overzealous) use of salt restriction and natriuretic drugs or ultrafiltration in the dialysis setting. Nevertheless, because of hyperreninemia and other disturbances in renal vasoconstrictors and vasodilators, some patients remain hypertensive despite rigorous salt and water restriction and ultrafiltration. Rarely, such patients may develop accelerated or malignant hypertension. Intravenous labetolol, or more recently approved agents such as fenoldopam or urapidil, together with control of ECFV17 generally control such hypertension. Enalaprilat or other ACE18 inhibitors may also be considered, but in the face of bilateral renovascular disease they have the potential to further reduce GFR2 abruptly.

TREATMENT
Management of Hypertension (See also Chap. 230) There are two overall goals: to slow the progression of CRD1 itself and to prevent the extrarenal complications of hypertension, such as cardiovascular disease and stroke. In all patients with CRD, blood pressure should be controlled to at least the level established in the guidelines of the Sixth Joint National Commission on Hypertension Detection Education and Follow-up Program (130/80 to 85 mmHg). In CRD patients with diabetes or proteinuria >1 g per 24 h, blood pressure should be further reduced to 125/75 mmHg. Volume control with salt restriction and diuretics is the mainstay of therapy. When volume management is not sufficient, the choice of antihypertensive agent is similar to that in the general population, with the added consideration of cardioprotective benefit provided by ACE19 inhibition, or angiotensin receptor blockade. The choice of antihypertensive agents may come from all the major classes, with careful consideration of comorbid conditions. However, powerful direct-acting vasodilators, such as hydralazine or minoxidil, may perpetuate the tendency to cardiac hypertrophy, despite the lowering of blood pressure. Therefore, prolonged use of such agents should be reserved for those very rare patients in whom severe refractory hypertension persists, despite adequate volume reduction and compliance with all other classes of antihypertensives.

Management of Cardiovascular Disease Hypertension, hyperhomocysteinemia, and lipid abnormalities promote atherosclerosis but are potentially treatable complications of CRD1. Ongoing or prior nephrotic syndrome is also associated with hyperlipidemia and hypercoagulability, which increase the risk of occlusive vascular disease. Since diabetes mellitus and hypertension are themselves the two most frequent etiologies of CRD, it is not surprising that cardiovascular disease is the most frequent cause of death in ESRD20 patients. Therefore, accepted life-style changes and therapeutic measures for cardiac risk reduction (Chap. 225) are especially important in this group of patients. Hyperhomocysteinemia may respond to vitamin therapy, which includes folate supplementation to between 1 and 5 mg/d. Hyperlipidemia in patients with CRD and ESRD should be managed aggressively according to the guidelines of the National Cholesterol Education Program (Chap. 335). If dietary measures are inadequate, the preferred lipid-lowering medications are gemfibrozil and an HMG-CoA reductase inhibitor. However, caution should be exercised in combining these two classes of agents because of an increased risk of myositis and rhabdomyolysis in CRD and ESRD patients.

Pericarditis (See also Chap. 222) With the advent of early initiation of renal replacement therapy, pericarditis is now observed more often in underdialyzed patients than in predialysis CRD1 patients. Pericardial pain with respiratory accentuation, accompanied by a friction rub, are the hallmarks of uremic pericarditis. The finding of a multicomponent friction rub strongly supports the diagnosis. Classic electrocardiographic abnormalities include PR-interval depression and diffuse ST-segment elevation. Pericarditis may be accompanied by the accumulation of pericardial fluid that is readily detected by echocardiography and that sometimes leads to cardiac tamponade. Pericardial fluid in uremic pericarditis is more often hemorrhagic than in viral pericarditis.

TREATMENT
Uremic pericarditis is an absolute indication for initiation of dialysis or for intensification of the dialysis prescription in those already on dialysis. Because of the propensity to hemorrhagic pericardial fluid, heparin-free dialysis is indicated. Pericardiectomy should be considered only if more conservative measures fail. Nonuremic causes of pericarditis and pericardial effusion include viral, malignant, and tuberculous pericarditis and pericarditis associated with myocardial infarction; these are also more frequent in patients with ESRD21 and should be managed according to the dictates of the underlying disease process.

HEMATOLOGIC ABNORMALITIES

Anemia A normocytic, normochromic anemia attributable to CRD1 is observed beginning at stage 3 CRD and is almost universal at stage 4. If untreated, the anemia of CRD is associated with a number of physiologic abnormalities, including decreased tissue oxygen delivery and utilization, increased cardiac output, cardiac enlargement, ventricular hypertrophy, angina, congestive heart failure, decreased cognition and mental acuity, altered menstrual cycles, and impaired host defense against infection. In addition, anemia may play a role in growth retardation in children with CRD. The primary cause of anemia in patients with CRD is insufficient production of EPO22 by the diseased kidneys. Additional factors include iron and folate deficiency, severe hyperparathyroidism, acute and chronic inflammation, aluminum toxicity, shortened red cell survival, and associated comorbid conditions such as hemoglobinopathies. These potential contributing factors should be considered and addressed, especially in EPO-resistant patients.

TREATMENT
The anemia of CRD1 is due to several factors including chronic blood loss, hemolysis, marrow suppression by retained uremic factors and reduced renal production of EPO23. The availability of recombinant human EPO, epoetin alfa, has made possible one of the most significant advances in the care of renal patients since the introduction of dialysis and transplantation. More recently, a novel erythropoiesis-stimulating protein has been introduced for the treatment of anemia in CRD patients. This protein, darbopoetin alfa, is a hyperglycosylated analogue of recombinant human EPO that possesses greater biologic activity and prolonged half-life. Thus, dose intervals can be extended and still effectively correct renal anemia in both predialysis and dialysis patients. Guidelines for using epoetin and darbopoetin alfa for the management of anemia of CRD are provided in Table 261-5.

The iron status of the patient with CRD1 must be assessed, and adequate iron stores should be available before treatment with EPO24 is initiated. Iron supplementation is usually essential to ensure an adequate response to EPO in patients with CRD, because the demands for iron by the erythroid marrow frequently exceed the amount of iron that is immediately available for erythropoiesis (as measured by percent transferrin saturation) as well as iron stores (as measured by serum ferritin). In most cases, intravenous iron is required to achieve and/or maintain adequate iron. However, excessive iron therapy may be associated with a number of complications, including hemosiderosis, accelerated atherosclerosis, increased susceptibility to infection, and possibly an increased propensity to the emergence of malignancies. In addition to iron, an adequate supply of the other major substrates and cofactors for erythrocyte production must be assured, especially vitamin B12 and folate. Anemia resistant to recommended doses of EPO in the face of adequate availability of iron and vitamin factors often suggests inadequate dialysis; uncontrolled hyperparathyroidism; aluminum toxicity; chronic blood loss or hemolysis; associated hemoglobinopathy, malnutrition, chronic infection, multiple myeloma, or another malignancy. Blood transfusions may contribute to suppression of erythropoiesis in CRD; because they increase the risk of hepatitis, hemosiderosis, and transplant sensitization, they should be avoided unless the anemia fails to respond to erythropoietin and the patient is symptomatic.

Abnormal Hemostasis This is common in CRD1 and is associated with prolongation of bleeding time, decreased activity of platelet factor III, abnormal platelet aggregation and adhesiveness, and impaired prothrombin consumption. Clinical manifestations include an increased tendency to abnormal bleeding and bruising; bleeding from surgical wounds; and spontaneous bleeding into the gastrointestinal tract, pericardial sac, or intracranial vault (in the form of subdural hematoma or intracerebral hemorrhage). Notwithstanding these abnormalities in hemostasis, CRD patients have a greater susceptibility to thromboembolic complications, particularly if their underlying disease was characterized by a nephrotic presentation.

TREATMENT
Abnormal bleeding times and coagulopathy in patients with renal failure may be reversed with desmopressin, cryoprecipitate, conjugated estrogens, and blood transfusions, as well as EPO25. On the other hand, patients with CRD1 should also be viewed as being at greater risk for thromboembolic complications and receive appropriate anticoagulant prophylaxis when indicated. Avoidance or dose adjustment of certain anticoagulants, such as fractionated low-molecular-weight heparin, is necessary in CRD patients.

NEUROMUSCULAR ABNORMALITIES

Central, peripheral, and autonomic neuropathy, as well as abnormalities in muscle composition and function, are all common complications in CRD1. Retained nitrogenous metabolites and middle molecules as well as PTH9 all contribute to the pathophysiology of neuromuscular abnormalities. Subtle clinical manifestations of uremic neuromuscular disease usually become evident beginning at stage 3 CRD. Early manifestations of central nervous system complications include mild disturbances in memory and concentration and sleep disturbance. Neuromuscular irritability, including hiccups, cramps, and fasciculations/twitching of muscles, becomes evident at later stages. Asterixis, myoclonus, and chorea are common in terminal uremia, which may also be associated with seizures and coma.

Peripheral neuropathy usually becomes clinically evident when the patient has been at stage 4 CRD1 for >6 months, although electrophysiologic and histologic evidence of peripheral neuropathy occurs earlier. Initially, sensory nerves are involved more than motor nerves, lower extremities more than upper, and distal portions of the extremities more than proximal. The "restless legs syndrome" is characterized by ill-defined sensations of discomfort in the legs and feet requiring frequent leg movement. If dialysis is not instituted soon after onset of sensory abnormalities, motor involvement follows, including muscle weakness and loss of deep tendon reflexes. Accordingly, evidence of peripheral neuropathy is a firm indication for renal replacement therapy. Some of the central nervous system and neuromuscular complications of advanced uremia resolve with dialysis, although nonspecific electroencephalographic abnormalities may persist. Successful transplantation may reverse residual peripheral neuropathy.

GASTROINTESTINAL AND NUTRITIONAL ABNORMALITIES

Uremic fetor, a uriniferous odor to the breath, derives from the breakdown of urea to ammonia in saliva and is often associated with an unpleasant metallic taste sensation. Gastritis, peptic disease, and mucosal ulcerations at any level of the gastrointestinal tract occur in uremic patients and can lead to abdominal pain, nausea, vomiting, and blood loss. Other gastrointestinal complications of CRD1 include an increased incidence of diverticulosis, particularly in patients with polycystic kidney disease, and an increased incidence of pancreatitis. In addition, central nervous system effects of uremia contribute to anorexia, hiccups, nausea, and vomiting. Protein restriction is useful in diminishing nausea and vomiting late in the course of renal failure. However, protein restriction should not be implemented in patients with signs of protein-energy malnutrition, which is a consequence of low protein and caloric intake, resistance to anabolic actions of insulin and other hormones and growth factors, disturbed dietary protein utilization, proinflammatory cytokine activation, and metabolic acidosis. Assessment for protein-energy malnutrition should begin at stage 3 CRD (GFR2< 60 mL/min per 1.73 m2). A number of indices are useful in this assessment and include dietary history, edema-free body weight, measurement of urinary protein nitrogen appearance, and plasma markers, of which albumin is the most useful. Guidelines for calorie and protein intake in patients with CRD are provided below (p. 1661).

ENDOCRINE-METABOLIC DISTURBANCES

Disturbances in parathyroid function have already been considered (p. 1656).

Glucose metabolism is impaired in CRD1, as evidenced by a slowing of the rate at which blood glucose levels decline after a glucose load. Fasting blood glucose is usually normal or only slightly elevated, and the mild glucose intolerance related to uremia per se, when present, does not require specific therapy. Because the kidney contributes significantly to insulin removal from the circulation, plasma levels of insulin are slightly to moderately elevated in most uremic subjects, both in the fasting and postprandial states. However, the response to insulin and glucose utilization is impaired in CRD. Many hypoglycemic drugs require dose reduction in renal failure, and some, such as metformin, are contraindicated when the GFR2 has diminished by more than approximately 25 to 50%.

In women, estrogen levels are low, and amenorrhea and inability to carry pregnancies to term are common manifestations of uremia. When the GFR2 has declined by ~30%, pregnancy may hasten the progression of CRD1. In men with CRD, including those receiving chronic dialysis, impotence, oligospermia, and germinal cell dysplasia are common, as are reduced plasma testosterone levels. Like growth, sexual maturation is often impaired in adolescent children with CRD, even among those treated with chronic dialysis. Many of these abnormalities improve or reverse with successful renal transplantation.

DERMATOLOGIC ABNORMALITIES

The skin may show evidence of anemia (pallor), defective hemostasis (ecchymoses and hematomas), calcium-phosphate deposition and secondary hyperparathyroidism (pruritus, excoriations), and deposition of pigmented metabolites or urochromes (yellow discoloration) or urea itself (uremic frost). Although many of these cutaneous abnormalities improve with dialysis, uremic pruritus often remains a problem. The first lines of management are to rule out unrelated skin disorders and to control PO43-concentration with avoidance of an elevated calcium-phosphate product. Occasionally, pruritus remains refractory to these measures and to other nonspecific systemic and topical therapies. Skin necrosis can occur as part of the calciphylaxis syndrome, which also includes subcutaneous, vascular, joint, and visceral calcification in patients with poorly controlled calcium-phosphate product.

EVALUATION AND MANAGEMENT OF PATIENTS WITH CRD

INITIAL APPROACH

History and Physical Examination Complaints referred to the kidneys themselves are often conspicuously absent in CRD1, and this often surprises patients and is a cause of skepticism and denial. Of special importance in establishing the etiology of CRD are a history of hypertension; diabetes; systemic infectious, inflammatory, or metabolic diseases; exposure to drugs and toxins; and a family history of renal and urologic disease. Drugs of particular importance include analgesics (usage frequently underestimated or denied by the patient), NSAIDs26, gold, penicillamine, antimicrobials, lithium, and ACE27 inhibitors. In evaluating the uremic syndrome, questions about appetite, diet, nausea, vomiting, hiccupping, shortness of breath, edema, weight change, muscle cramps, pruritus, mental acuity, and activities of daily living are especially helpful.

On physical examination, particular attention should be paid to blood pressure, fundoscopy, precordial examination, examination of the abdomen for bruits and palpable renal masses, examination for edema, and neurologic examination for the presence of asterixis, muscle weakness, and neuropathy. In addition the evaluation of prostate size in men, and potential pelvic masses in women should be undertaken.

Laboratory Investigations These should also focus on a search for clues to an underlying disease process and its continued activity. Therefore, if the history and physical examination warrant, immunologic tests for systemic lupus erythematosus and vasculitis might be considered. Serum and urinary protein electrophoresis should be undertaken in all patients >40 years with unexplained CRD1 and anemia, to rule out paraproteinemia. Other tests to determine the stage and chronicity of the disease, including complications of the uremic syndrome, include serial measurements of plasma creatinine and estimation of GFR2, urea, electrolytes (including HCO3-, Ca2+, and PO43-), and alkaline phosphatase to assess metabolic bone disease as well as hemoglobin. Urinalysis may be helpful in assessing the presence of ongoing activity of the underlying inflammatory or proteinuric disease process and, when indicated, should be supplemented by a 24-h urine collection for protein excretion. The latter is particularly helpful in guiding management strategies aimed at ameliorating the progression of CRD. The presence of broad casts on examination of the urinary sediment is a nonspecific finding seen with all underlying etiologies and reflects chronic tubulointerstitial scarring and tubular atrophy with widened tubule diameter, usually signifying an advanced stage of CRD.

Imaging Studies The most useful imaging study is renal ultrasonography. An ultrasound examination of the kidneys can verify the presence of two symmetric kidneys, provide an estimate of kidney size, and rule out renal masses and obstructive uropathy. The documentation of symmetric small kidneys supports the diagnosis of progressive CRD1 with an irreversible component of scarring. Normal kidney size suggests the possibility of an acute rather than chronic process. However, polycystic kidney disease, amyloidosis, diabetes, and HIV-associated renal disease (Chap. 173) may lead to CRD with normal kidney size. Documentation of asymmetric kidney size suggests either a unilateral developmental abnormality or chronic renovascular disease. In the latter case, a vascular imaging procedure, such as duplex doppler sonography of the renal arteries, radionuclide scintigraphy, or magnetic resonance angiography should be strongly considered if the possibility of revascularization is feasible. A spiral computed tomographic scan without contrast may be useful in assessing kidney stone activity. Voiding cystourethrography to rule out reflux may be indicated in some patients with a history of enuresis or with a family history of reflux. However, in most cases by the time CRD is established, reflux has resolved, and even if present, its repair does not stabilize renal function. In any case, imaging studies should avoid exposure to intravenous radiocontrast dye where possible because of its nephrotoxicity.

Renal Biopsy This procedure should be reserved for patients with near-normal kidney size, in whom a clear-cut diagnosis cannot be made by less invasive means and when the possibility of a reversible underlying disease process remains tenable, such that clarification of the underlying etiology may alter management. The extent of tubulointerstitial scarring on kidney biopsy generally provides the most reliable pathologic correlate indicating prognosis for continued deterioration toward ESRD28. Contraindications to renal biopsy include bilateral small kidneys, polycystic kidney disease, uncontrolled hypertension, urinary tract or perinephric infection, bleeding diathesis, respiratory distress, and morbid obesity. Ultrasound-guided percutaneous biopsy is the favored approach, but surgical approaches, including laparoscopic biopsy, may be considered in special circumstances such as biopsy of a solitary kidney.

ESTABLISHING THE DIAGNOSIS AND ETIOLOGY OF CRD

The most important initial step in the evaluation of a patient presenting de novo with biochemical or clinical evidence of renal failure is to distinguish newly diagnosed CRD1 from acute renal failure. Availability of past medical records documenting serial measurements of the plasma urea and/or creatinine concentrations can be of great help in this regard. In the absence of such information, some of the laboratory tests and imaging studies outlined above can be useful. In particular, a urinary sediment that is inactive or reveals proteinuria and broad casts; the demonstration of evidence of chronic metabolic bone disease with hyperphosphatemia, hypocalcemia, elevated PTH9 levels, and radiologic bone disease; normocytic and normochromic anemia; and the finding of bilaterally reduced kidney size (< 8.5 cm) by imaging studies, strongly favor a long-standing process consistent with CRD. However, these findings do not rule out the superimposition of an acute and reversible exacerbating factor that may have accelerated the decline in GFR2 (see below).

In the early stages of CRD1 it is often possible to establish the underlying etiology. Integration of a particular constellation of clinical, laboratory, and imaging findings based on the approach noted above strongly supports a particular presumed underlying etiologic disease process. For example, in a patient with insulin-dependent type 1 diabetes mellitus of 15 to 20 years duration, diabetic retinopathy, and nephrotic-range albuminuria without hematuria, the diagnosis of diabetic nephropathy is likely. The diagnosis of chronic hypertensive nephrosclerosis requires a history of long-standing hypertension, in the absence of evidence for another renal disease process, and hence it is usually a diagnosis of exclusion. Usually proteinura is mild to moderate (< 3 g/d) and the urine sediment inactive. It should be noted that in many cases of presumed hypertensive nephrosclerosis, renovascular disease not only may be the cause of hypertension but also may cause ischemic renal damage. In this regard, bilateral renovascular ischemic disease may be a greatly underdiagnosed cause of CRD. This is of therapeutic significance from two points of view: (1) documentation of ischemic renal disease secondary to occlusive vascular disease may prompt revascularization therapy in some subgroups of patients, with occasional stabilization and improvement in renal function; (2) renovascular ischemic disease is a contraindication to ACE29 inhibitor therapy in most cases. Analgesic-associated chronic tubulointerstitial nephropathy is also an underdiagnosed cause of CRD. Imaging studies, including computed tomography, often reveal pathognomonic features such as papillary calcification and necrosis. Under such circumstances, cessation of analgesic exposure may dramatically stabilize renal function.

In the absence of an etiologically suggestive clinical constellation, renal biopsy may be the only recourse to establish etiology in early CRD1. However, in advanced stages of CRD, definitively establishing an underlying etiology becomes less feasible and is also of less therapeutic significance.

TREATMENT
Specific treatments aimed at selected underlying etiologies of CRD1 are provided in the respective chapters describing these disease states. The optimal time for such therapy is usually well before there has been a measurable decline in baseline GFR2 and usually well before CRD is established. It is of benefit to follow and plot the rate of decline in GFR in all patients. Any acceleration in the rate of decline should prompt a search for superimposed acute processes that may lead to an acute and reversible decline in GFR in patients with CRD. These include superimposed volume depletion, accelerated and uncontrolled hypertension, urinary tract infection, superimposed obstructive uropathy (e.g., due to stone disease, papillary necrosis), nephrotoxic effect of medications (e.g., NSAIDs30) and radiocontrast agents, and reactivation or flare of the original underlying etiologic disease process.

SLOWING THE PROGRESSION OF CRD While there is great interindividual variation in the rate of decline of GFR2 in patients with CRD1, a series of therapeutic interventions should be pursued that aim to stabilize the GFR or reduce the annual rate of decline.

Protein Restriction (Table 261-6) A major goal of protein restriction in CRD1, beyond ameliorating the complications of uremia, is to slow the rate of nephron injury. This concept is based on clinical and experimental evidence demonstrating the role of protein-mediated hyperfiltration in progressive nephron injury. The effectiveness of protein restriction in slowing the progression of CRD has been shown in controlled clinical trials in patients with both diabetic and nondiabetic renal disease.

Protein restriction should be carried out in the context of an overall dietary program that optimizes nutritional status and avoids malnutrition, especially as patients near dialysis or transplantation. Metabolic and nutritional studies indicate that protein requirements for patients with CRD1 are similar to those for normal adults and are in the range of 0.6 g/kg per day. However, there is a particular requirement in patients with CRD that the composition of dietary protein be higher in essential amino acids, and that this be combined with an overall energy supply sufficient to mitigate a catabolic state. Energy requirements in the range of 35 kcal/kg per day are recommended. Fortunately, even patients with advanced CRD (GFR2 ~ 10 to 15 mL/min per 1.73 m2) are able to activate the same adaptive responses to dietary protein restriction as healthy individuals, i.e., a postprandial suppression of whole-body protein degradation and a marked inhibition of amino acid oxidation. These compensatory responses to dietary protein restriction and nutritional indices are sustained during long-term therapy.

Reducing Intraglomerular Hypertension and Proteinuria (See also p. 1657) In addition to reduction of cardiovascular disease risk, antihypertensive therapy in patients with CRD1 also aims to slow the progression of nephron injury, by ameliorating intraglomerular hypertension and hypertrophy. Progressive renal injury in CRD appears to be most closely related to the height of intraglomerular pressure and/or the extent of glomerular hypertrophy. Control of hypertension is as at least as important as dietary protein restriction in slowing the progression of CRD. Furthermore, the target for pharmacologic therapy is highly dependent on the level of proteinuria. Indeed, proteinuria is now considered a risk factor for both progressive nephron injury as well cardiovascular disease. Elevated blood pressure increases proteinuria due to the transmission to the glomeruli of the elevated systemic pressure. Conversely, the renoprotective effect of antihypertensive medications is evident through the curtailment of proteinuria. Thus, the more effective a given treatment is in lowering proteinuria, the greater the subsequent impact on protection from GFR2 decline. This is the basis for the treatment guideline establishing 125/75 mmHg as the target blood pressure value in proteinuric CRD patients.

Owing to their unique effect on the glomerular microcirculation (i.e., dilatation of the efferent arteriole), which is related to inhibition of the renin-angiotensin system, ACE31 inhibitors and angiotensin receptor blockers are now clearly established as effective, antiproteinuric agents. Several multicenter studies have shown that these drugs are effective in slowing the progression of renal failure in patients with both diabetic and nondiabetic renal failure. The slowing in the progression of renal failure by these drugs is strongly related to their proteinuria-lowering effect. In the absence of a significant antiproteinuric response, combined treatment with both an ACE inhibitor and angiotensin receptor blocker can be tried. Contraindications to or adverse effects of the use of these classes of agents (e.g., intractable cough, anaphylaxis, hyperkalemia not controlled by dietary restriction) may prompt the choice of calcium channel blockers as a second-line therapeutic approach. Among the calcium channel blockers, diltiazem and verapamil may exhibit superior antiproteinuric and renal protective effects. Available clinical studies have indicated that calcium antagonists as a group do not adversely affect renal function in patients with nondiabetic renal insufficiency, and also indicate that they may be more effective in preventing or ameliorating progressive renal injury than some other classes of antihypertensive drugs in this group of patients. Thus, it appears that at least two different categories of responses may exist: one in which progression is strongly associated with systemic and intraglomerular hypertension and with proteinuria (e.g., diabetic nephropathy, glomerular diseases) and in which ACE inhibitors and angiotensin receptor blockers are likely to be the first choice; and the second in which proteinuria is mild or absent (e.g., adult polycystic kidney disease), probably with a less prominent role for intraglomerular hypertension, and which might respond as well to calcium entry blockers.

SLOWING DIABETIC RENAL DISEASE (SEE ALSO CHAP. 323) Diabetic nephropathy is now the leading cause of CRD1 eventuating in ESRD32 in many parts of the world. Furthermore, the prognosis of diabetic patients on chronic renal replacement therapy is very poor, owing to accelerated cardiovascular disease. Therefore, it is particularly compelling to search for strategies whose aim is to prevent or slow the progression of this complication of diabetes mellitus.

Glucose Control Although tight glycemic control reduces the risk of kidney disease in patients with type 1 diabetes, there has been prolonged controversy over whether the same is true in patients with type 2 diabetes. The results of recent controlled prospective studies provide incontrovertible evidence that in type 2 diabetes mellitus the risk of the development and progression of albuminuria and CRD1 can also be substantially reduced by improving glycemic control. The United Kingdom Prospective Diabetes Study showed that the way in which glycemic control was achieved, whether by insulin or oral antihyperglycemic agents such as sulfonylureas or metformin, was far less important than success in achieving control. Achieving a target hemoglobin A1C level of <7.2%, as compared to >9%, is associated with an approximately 50% reduction in the occurrence of indices of progressive nephropathy. As a result of these findings, recommendations for glucose control aim to achieve plasma values for preprandial glucose in the range of 90 to 130 mg/dL, and for average bedtime glucose of 110 to 150 mg/dL and hemoglobin A1C< 7%. Reduction in GFR2 mandates dose adjustment of many antihyperglycemic agents, and in particular the discontinuation of metformin when the plasma creatinine is >133 umol/L (1.5 mg/dL).

Control of Blood Pressure and Proteinuria Hypertension or an abnormal circadian blood pressure profile is found in 80% of type 2 diabetic patients at the time of diagnosis. Both of these findings correlate with the presence of albuminuria and are powerful predictors of cardiovascular and renal events. The onset of microalbuminuria precedes the decline in GFR2 in diabetic patients and heralds renal as well as cardiovascular complications. Therefore, microalbuminuria testing is recommended in all diabetic patients at least annually, and more frequently to follow therapeutic interventions. Antihypertensive treatment reduces albuminuria and diminishes the risk of progression of albuminuria even in normotensive patients with diabetes. There is now compelling evidence that ACE33 inhibitors and angiotensin receptor blockers have specific renoprotective properties in diabetic patients with microalbuminuria or overt proteinuria. These salutary effects are almost certainly mediated by reducing intraglomerular pressure and inhibition of transforming growth factor ß-mediated sclerosing pathways.

MANAGING OTHER COMPLICATIONS OF CHRONIC RENAL FAILURE Impending Uremic Symptomatology Temporary relief of symptoms and signs of impending uremia, such as anorexia, nausea, vomiting, asterixis, lassitude, and other central nervous system manifestations, may be achieved with protein restriction. However, this must be associated with careful monitoring of nutritional status, so as to avoid protein-energy malnutrition, evidence of which serves as a clear-cut indication for initiation of renal replacement therapy.

Medication Dose Adjustment (See also Chap. 3) Although the loading dose of most drugs is not affected by CRD1, maintenance doses of many drugs need to be adjusted. For those drugs in which >70% excretion is by a nonrenal (e.g., hepatic or intestinal) route, dosage adjustment may not be needed. Some drugs that should be entirely avoided include meperidine, metformin, and other oral hypoglycemics with a renal route of elimination. Commonly used medications that require either a reduction in dosage or changes in interval include allopurinol, many antibiotics, several antihypertensives, and antiarrhythmics. For a comprehensive detailed and authoritative listing of the recommended dose adjustment for most of the commonly used medications, the reader is referred to the American College of Physicians’ handbook "Drug Prescribing in Renal Failure" (see www.acponline.org). In addition to dose adjustment requirements, many drugs have nephrotoxicity as a prominent side effect, to which patients with CRD are more susceptible. Of particular notoriety in this regard are NSAIDs34, because of their widespread availability and usage. These drugs aggravate the tendency to sodium retention, hypertension, hyperkalemia, and hyponatremia and further reduce GFR2 in patients with CRD. In this regard, there is no advantage to more selective inhibitors of cyclooxygenase-2.

Preparation for Renal Replacement Therapy (See also Chaps. 262 and 263) Over the past 40 years, renal replacement therapy using dialysis and transplantation has prolonged the lives of hundreds of thousands of patients with ESRD35. Renal replacement therapy should not be initiated when the patient is totally asymptomatic; however, dialysis and/or transplantation should be started sufficiently early to prevent serious complications of the uremic state. Clear indications for initiation of renal replacement therapy include pericarditis, progressive neuropathy attributable to uremia, encephalopathy, muscle irritability, anorexia and nausea that are not ameliorated by reasonable protein restriction, evidence of protein-energy malnutrition, and fluid and electrolyte abnormalities that are refractory to conservative measures. The latter include volume overload unresponsive to diuretic therapy, hyperkalemia unresponsive to dietary potassium restriction, and progressive metabolic acidosis that cannot be managed with alkali therapy. Clinical clues indicating the imminent development of uremic complications are a history of hiccupping, intractable pruritus, morning nausea and vomiting, muscle twitching and cramps, and the presence of asterixis on physical examination. In addition, the patient whose follow-up and compliance with conservative management are questionable should be considered for earlier initiation of renal replacement therapy, lest potentially life-threatening uremic complications or electrolyte disturbances supervene.

Since there is considerable interindividual variability in the severity of uremic symptoms and renal function, it is ill-advised to assign a certain "usual" level of blood urea nitrogen, serum creatinine, or GFR2 to the need to start dialysis. Nevertheless, in the United States, the Health Care Financing Administration has assigned levels of serum creatinine and creatinine clearance to qualify for reimbursement from Medicare for patients receiving dialysis. Serum creatinine must be =700 umol/L (=8.0 mg/dL) and the creatinine clearance must be =10 mL/min. Recent controlled studies have failed to show a survival advantage for early initiation of renal replacement therapy prior to onset of clinical indications.

Patient Education and Adjustment Social, psychological, and physical preparation for the transition to renal replacement therapy and choice of the optimal initial modality is best accomplished with a gradual approach involving a multidisciplinary team. While conservative measures are being carried out in patients with CRD1, it is important to prepare them with an intensive educational program, explaining the likelihood and timing of initiation of renal replacement therapy and the various forms of therapy available. The more knowledgable patients are concerning hemodialysis, peritoneal dialysis, and transplantation, the easier and more appropriate will be their decisions at a later time. Exploration of social service support resources is of great importance. In those who may perform home dialysis or undergo transplantation, early education of family members for selection and preparation as a home dialysis helper or a related donor for transplantation should occur long before the onset of symptomatic renal failure.

Selection of patients to be treated with various modalities of dialysis or transplantation is a matter of some debate, with considerable variation in different parts of the world. In general, in the United States and some other countries, nearly all patients who have reached ESRD36 are accepted for dialysis if they or their families desire prolongation of life, irrespective of age.

Only kidney transplantation (Chap. 263) offers the potential for nearly complete rehabilitation. This is because dialysis techniques replace only 10 to 15% of normal kidney function at the level of small-solute removal and are even less efficient at the removal of larger solutes. Generally, kidney transplantation follows a prior period of dialysis treatment. All patients in whom an acute reversible component of renal failure has not been completely excluded should be supported with dialysis first, at least for some period of time, to allow for possible return of renal function before consideration of transplantation. Recovery of endogenous renal function in patients treated with dialysis for >6 months is a rare occurrence. For patients approaching ESRD37 in whom a reversible component has been excluded, and who have a good antigenic match with a willing donor, consideration should be given to preemptive or primary transplantation without intervening dialysis.