Patients with renal impairment experience a disproportionately large burden of cardiovascular morbidity and mortality, largely the result of accelerated atherogenesis, a hallmark characteristic of significant renal dysfunction (1,2). This elevated risk extends across the entire spectrum of renal insufficiency, with the magnitude of risk correlating with the degree of renal impairment (3). Among patients with end-stage renal failure, cardiac mortality accounts for approximately half of all deaths, and of these, over 50% occur as a result of acute myocardial infarction, with an incidence three to five times higher than in the general population (4). Also contributing to symptomatic myocardial ischemia is small vessel disease, reduced capillary density, volume overload, and altered myocyte bioenergetics. Several factors underlie this increased risk, including a greater prevalence and consequence of traditional coronary risk factors such as diabetes, lipid abnormalities, and hypertension (5,6).

Cardiac failure is observed in approximately 35% to 40% of the renal dialysis population (6). Among dialysis patients, concentric left ventricular (LV) hypertrophy is evident in 42%, eccentric LV hypertrophy in 23%, and systolic dysfunction in 16% of patients (7,8). In addition, high-output states associated with atrioventricular (AV) fistulas, salt and water overload, and anemia lead to ventricular overload and LV hypertrophy. Chronic ischemia and increased myocardial oxygen demand, hyperparathyroidism, uremia, and malnutrition all contribute to cardiomyocyte loss, fibrosis, and systolic dysfunction (9,10,11,12).

This chapter focuses on the effect of the numerous metabolic derangements associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD), including secondary hyperparathyroidism, vitamin D deficiency, phosphorus, calcium, and lipid abnormalities. These disturbances may be causal in changes of cardiac structure and function responsible for the high cardiovascular morbidity and mortality within this population. Diagnosis and treatment of cardiac disease in this unique population is also discussed, along with a description of the cardiovascular effects of renal replacement therapies modalities.

Even a modest decline in renal function are now recognized as a potent and common risk factor for adverse short- and long-term outcome among patients with coronary artery disease (3). Not surprisingly, given the prevalence of advanced age, diabetes, and hypertension, moderate renal impairment (creatinine clearance <60 mL/min) is evident in up to one quarter of patients enrolled in acute coronary syndrome (ACS), cardiac failure, and coronary revascularization clinical trials and an even greater proportion of registry patients. As a risk factor for ischemic and bleeding events among cardiac patients, this degree of renal dysfunction has been associated with a two- to fourfold increased in adverse outcome, including late mortality (13,14,15,16). Other emerging measures of renal function associated with increased cardiovascular risk include microalbuminuria, the urinary albumin:creatinine ratio, and the serum blood urea nitrogen (BUN) level, although the incremental clinical value of these clinical markers requires further clarification (17,18,19). Recently, a relationship between cystatin C, a renal marker independent of age and gender, and late mortality has also been demonstrated (20).

Long-term morbidity and mortality from cardiac disease among patients with significant renal impairment remains high. Mortality is observed at a rate of approximately 1% per year among patients with renal insufficiency not treated with dialysis. Following renal transplantation, annual mortality of 0.54% or about twofold greater than the general population is documented. Among patients receiving renal replacement therapy, cardiac mortality accounts for over 40% of all deaths with an annual cardiovascular mortality 10- to 30-fold higher than the general population. The annual incidence of myocardial
infarction among hemodialysis patients is 8%, with a similar annual incidence of developing pulmonary edema or requirement for extra hemofiltration. Salient data from the 34,189-patient U.S. registry of long-term dialysis demonstrates that myocardial infarction was associated with a 59% 1-year, 73% 2-year, and 90% 5-year mortality (21). LV function remains an important determinant of survival. Among patients starting dialysis therapy, systolic dysfunction portends a median survival of approximately 3 years; outcomes for those with LV dilation or concentric LV hypertrophy are slightly better. The development of new-onset cardiac failure when on hemodialysis therapy is associated with a median survival of 18 months (8).

Abnormal lipid metabolism is common in patients with CKD and ESRD (36). Abnormalities include those that are demonstrated among patients with nephrotic syndrome as well as the seemingly paradoxical relationship between lipid and outcomes among patients with ESRD.

The two most common lipid abnormalities in the nephrotic syndrome are hypercholesterolemia and hypertriglyceridemia potentially through a reduction in plasma oncotic pressure (36,37). For reasons that are not clear, hepatic synthesis of lipoproteins containing apolipoprotein B and cholesterol increases. Raising the plasma oncotic pressure with albumin or dextran produces a rapid reduction in lipid levels in nephrotic patients. New techniques suggest that diminished catabolism, rather than increased hepatic protein synthesis, is primarily responsible for hypercholesterolemia in patients with the nephrotic syndrome (38). Impaired metabolism is primarily responsible for the elevated triglyceride levels. The delipidation cascade, in which very-low-density lipoproteins are converted to intermediate-density lipoproteins and then to LDL by lipoprotein lipases is slowed in the nephrotic syndrome (39).

Interventional trials in patients with nephrotic syndrome have not been performed; however, patients with persistent, long-standing hyperlipidemia are at increased risk for atherosclerotic disease (40). Among nephrotic patients without diabetes mellitus, the relative risk of death from coronary artery disease may be as high as 5.5-fold (41). Although optimal treatment for patients with long-standing, persistent nephrotic syndrome is uncertain, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers may be a potential adjunctive therapy (42). The reduction in proteinuria seen with these agents may be associated with a 10% to 20% decline in the plasma levels of total and LDL cholesterol and lipoprotein (a) (43,44).

Among patients with CKD not specifically related to nephrotic syndrome and ESRD, lipid abnormalities are common. Although the primary finding is hypertriglyceridemia, malnutrition must be considered in the evaluation of patients with normal or low total cholesterol concentrations (45). Triglyceride levels can be elevated because of diminished clearance related to both an alteration in the composition of circulating triglycerides (which become enriched with apolipoprotein C-III) and reduction in the activity of lipoprotein lipase and hepatic triglyceride lipase (46,47). Lipoprotein lipase activity may be reduced owing to PTH secretion or retention of a circulating lipase inhibitor (48). Other alterations in lipids include a decline in high-density lipoprotein cholesterol and an elevation in lipoprotein(a) (49,50,51). This may be accentuated among patients on peritoneal dialysis related presumably to absorption of glucose from the dialysate solution. Therapeutic interventions for the hypertriglyceridemia include fibric acids; however, no long-term benefit of drug therapy with these agents has been demonstrated. The increased risk of rhabdomyolysis among patients with renal disease must be noted.

With regard to cholesterol-lowering and statin therapy, three trials address the long-term effects among patients with either CKD or ESRD. The Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) randomized patients with microalbuminuria and creatinine clearance of less than 60% of the normal age-adjusted value to receive fosinopril versus placebo and pravastatin versus placebo evaluating the effect of both medications on a primary outcome of cardiovascular mortality and hospitalization for cardiovascular morbidity (52). Subjects treated with fosinopril showed a 40% lower incidence of the primary end point (hazard ratio [HR] = 0.60, P = .01), subjects treated with pravastatin did not show similar significant reduction (HR = 0.87, P = .65). Among patients with type 2 diabetes mellitus and ESRD, the Die Deutsche Diabetes Dialyse (4D) trial randomized subjects to receive 20 mg/d of atorvastatin or placebo and followed patients for the primary end point of cardiovascular death, nonfatal myocardial infarction, or stroke (53). Although there was no significant difference in outcomes among treatment groups with respect to the primary composite endpoint (relative risk [RR], 0.92; 95% confidence interval [CI], 0.77 to 1.10; P = .37), differences between treatment groups existed when each event was analyzed separately. Fatal stroke was more likely among those receiving atorvastatin (RR = 2.03, P = .04), and all cardiac events were less likely among patients receiving the drug (RR = 0.82, P = .03). Last, among patients with CKD, the ongoing trial Study of Heart and Renal Protection (SHARP) will assess the effects of cholesterol-lowering therapy with a combination of simvastatin and the cholesterol absorption inhibitor ezetimide on nonfatal myocardial infarction or cardiac death, nonfatal or fatal stroke, or revascularization.

Current Kidney Disease Outcomes Quality Initiative guidelines that do not yet incorporate the results of these two negative trials recommend a goal LDL cholesterol of less than 100 mg/dL (<2.6 mmol/L) in patients with CKD using dietary modification, exercise, weight loss, and drug therapy to include statins. As the results of the SHARP study become available and additional interpretation of the results from both PREVEND IT and the 4D trial take place, a reevaluation of current lipid lowering guidelines may be required.