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HYPERLIPIDEMIA 1.

Pathophysiology Decreased clearance of trigyceride-rich lipoproteins due to inhibition of lipoprotein lipase and triglyceride lipase Other factors such as peripheral insulin resistance, carnitine deficiency, and hyperthyroidism may contribute to lipid abnormalities In nephrotic syndrome, decreased effective plasma albumin circulation results in increased lipoprotein synthesis to maintain plasma oncotic pressure Symptoms In nephrotic syndrome, there are elevations of plasma total and low-density lipoprotein (LDL) cholesterol with variable changes in high-density lipoprotein (HDL) cholesterol In chronic renal failure patients without nephrotic syndrome, there is hyperlipidemia with hypertriglyceridemia

2. Therapy for Chronic Renal Failure-Induced Hyperlipidemia Note that patients with chronic renal failure (both predialysis and end stage renal disease) are at increased risk from cardiovascular mortality Hyperlipidemia may contribute to the progression of renal disease, and consequently antihyperlipidemic therapy may contribute to slowing progression of renal disease a) Lifestyle modifications Weight reduction Alcohol restriction Increase exercise Dietary restriction of carbohydrate, cholesterol, and an increase in polyunsaturated to saturated fat ratio

b) Pharmacotherapy Nephrotic Syndrome Bile acid sequesterants and fibric acid derivatives have marginal benefit However, HMG-CoA reductase inhibitors (lovastatin, simvastatin) reduced LDL cholesterol by 30-41% and triglycerides by 5.5-29% and increased HDL cholesterol by 8-31% within 4-8 weeks Patients respond satisfactorily to low initial doses of HMG-CoA reductase inhibitors with doses being titrated up every 4 weeks as necessary Combined drug therapy has not been studied but HMG-CoA reductase inhibitors + bile acid sequestrants, nicotinic acid or gemfibrozil may be useful Note that there is potential for myopathy and rhabdomyolysis with acute renal failure, especially when used with cyclosporine, gemfibrozil or niacin ACE inhibitors can reduce proteinuria and produce slight improvements in total and LDL cholesterol

End-Stage Renal Disease Drug therapy usually reserved for trigylceride levels greater than 11.3 mmol/L (1000 mg/dl) to prevent pancreatitis Clofibrate and gemfibrozil have documented effectiveness Fenofibrate (micro-ionized) demonstrated to be safe and effective in lowering triglycerides and LDL, and raising HDL in patients with chronic renal insufficiency Clofibrate causes increased creatine kinase (CK), myositis and myalgias in patients with renal failure Gemfibrozil is the drug of choice since its half-life is not altered in renal failure however it can increase CK levels in dialysis patients Recommend micro-ionized fenofibrate (200 mg) if increase in triglycerides is greater than increase in LDL, atorvastatin if other abnormalities of lipid profile. Patients with higher risk factors for CAD should be started with HMG-CoA reductase inhibitor 3. Clinical Pearls Reduce hyperlipidemia in chronic renal failure patients to prevent possible progression of renal disease Reduce hypertriglyceridemia in chronic renal failure patients to prevent possible pancreatitis Reduce dyslipidemia to prevent progression of cardiovascular disease/atherosclerosis Hyperlipidemia: Useful References
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Cesar A, Brosius III F. Pharmacologic management of adult idiopathic nephrotic syndrome. Clinical Pharmacy 1993; Vol 12. DAmico G, Gentile MG. Treatment of hyperlipidemia in human renal disease. Miner Electrolyte Metab 1993;196-204. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 1993;269:3015-23. Keane WF, St. Peter J, Kasiske BL. Is the aggressive management of hyperlipidemia in nephrotic syndrome mandatory? Kidney Int 1992;(suppl 38):S134-41. Levin A, Duncan L, Djurdjev O, Shapiro RJ, Frolich J, Belanger A, Dumas R, Ross S. A randomized placebo-controlled double-blind trial of lipid lowering strategies in patients with renal insufficiency: diet modification with or without fenofibrate. Clin Nephrol, 1999, in press.