cardiovascular morbidity and mortality and is common among patients with CKD. Lipid profiles vary widely in these patients, reflecting the level of kidney function and the degree of proteinuria [43]. In general, the prevalence of hyperlipidemia increases as renal function declines, with the degree of hypertriglyceridemia and elevation of LDL cholesterol being proportional to the severity of renal impairment. Several factors contribute to the development dyslipidemia associated with chronic renal impairment. Patients with CKD have a reduction in the activity of lipoprotein lipase and hepatic triglyceride lipase. This 336 THOMAS et al interferes with uptake of triglyceride-rich, apolipoprotein B–containing lipoproteins by the liver and in peripheral tissue, yielding increased circulation of these atherogenic lipoproteins. Hypercholesterolemia in nephrotic syndrome is thought to be a result of increased production and decreased catabolism of lipoproteins. The degree of lipoprotein abnormality is roughly proportional to the amount of proteinuria and inversely proportional to serum albumin levels. However, infusions of albumin or dextran both normalize lipoprotein concentrations, suggesting that oncotic pressure changes rather than hypoalbuminemia signals increased lipoprotein synthesis by the liver. Additional data supporting this hypothesis is derived from in vitro experiments demonstrating direct stimulation of increased hepatic apolipoprotein-B gene transcription in cells exposed to reduced oncotic pressure [44]. Studies also suggest that hyperparathyroidism and the accumulation of calcium in pancreatic islet cells likely contribute to dyslipidemia of CKD as well [45]. Fig. 1. Interplay of processes secondary to chronic kidney disease leading to cardiovascular disease and death. Red arrows: Pathogenetic pathways; black arrow: feedback loop; kidney disease worsened by heart failure. CHRONIC KIDNEY DISEASE AND ITS COMPLICATIONS 337 Clinical trials in the general population have demonstrated that CHD mortality decreases proportional to LDL-cholesterol level reduction. Evidence for benefit of statins in reducing cardiovascular risk (ie, composite outcomes) in CKD patients is less definitive. Recently, the largest clinical trial of statins in patients with stage 5 CKD (4D trial) was conducted in Germany. In this study, atorvastatin did not to reduce death from fatal stroke, nonfatal myocardial infarction, or nonfatal stroke in 200 patients with diabetes and stage 5 CKD [46]. The results of the Study of Heart and Renal Protection (SHARP) will be available in 2008 and should provide further insight into the role of cholesterol-lowering therapy in reducing cardiovascular events in kidney disease patients. SHARP is a prospective, randomized trial in which 9000 patients with CKD and 3000 dialysis patients without coronary artery disease have been enrolled to assess the effects of lowering LDL-cholesterol with the combination of simvastatin and ezetimibe, with the primary outcome measure being the time to a first ‘‘major vascular event’’ defined as nonfatal myocardial infarction or cardiac death, nonfatal or fatal stroke, or an arterial revascularization procedure. A relationship between total cholesterol levels and CHD mortality as the primary outcome also has not been clearly established. In fact, several observational studies of stage 5 kidney disease patients suggest that lower total cholesterol levels are associated with higher mortality rate. For example, in a recent 10-year prospective study, the importance of total cholesterol levels on mortality was evaluated in 1167 stage 5 kidney disease patients [47]. Hypercholesterolemia (total cholesterol levels O200) was associated with increased all-cause mortality rate. Further studies are needed to evaluate whether low cholesterol identifies a subgroup of more severely ill patients or whether inflammation and/or malnutrition were confounding variables in these studies. A complete fasting lipid profile with assessment of total, LDL and HDL cholesterol, and triglyceride levels should be included in the evaluation of patients with CKD and hyperlipidemia. Individuals with elevated cholesterol or other forms of hyperlipidemia should undergo evaluation for secondary dyslipidemias before initiation of lipid-lowering therapy [48]. K/DOQI guidelines recommend that all stages of CKD be considered a CHD-risk equivalent. Thus, patients with CKD are viewed as being in the highest risk group for CHD and LDL-cholesterol levels should be lowered below 100 mg/dL (2.6 mmol/L). CKD patients may achieve LDL goals via implementation of lifestyle modification (dietary modification with dietitian consultation, increased physical activity, moderate alcohol intake, and smoking cessation). All adults with CKD should be evaluated for lipid abnormalities. In CKD patients with nephrotic syndrome, the primary goal is to induce remission of the disease [49]. When this is not possible, any reduction in urinary protein excretion will be beneficial. In addition, nephrotic patients with elevated lipid levels should be treated with a lipid-lowering diet, which may aid in reducing total cholesterol and LDL cholesterol levels. 338 THOMAS et al Specific K/DOQI guidelines on the management of hyperlipidemia include the following: 1. For patients with LDL cholesterol levels between 100 and 129 mg/dL (2.57 to