Dyslipidemia
Dyslipidemia is a major risk factor for 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. 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 interferes with uptake of triglyceride-rich, apolipoproteinB-containing lipoproteins by the liver and in peripheral tissue, yielding increased circulation of these atherogenic lipoproteins. Hypercholesterolemia in nephrotic syndrome is thought to be due to 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 . Studies also suggest that hyperparathyroidism and the accumulation of calcium in pancreatic islet cells likely contribute to dyslipidemia of CKD as well.
Clinical trials in the general population have demonstrated that coronary heart disease mortality decreases proportional to LDL-cholesterol level reduction. Evidence for benefit of statins in reducing cardiovascular risk (i.e., 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. 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 9,000 patients with CKD and 3,000 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 non-fatal myocardial infarction or cardiac death, non-fatal or fatal stroke, or an arterial revascularization procedure.
A relationship between total cholesterol levels and coronary heart disease (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 1,167 stage 5 kidney disease patients. Hypercholesterolemia (total cholesterol levels >200) 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.