Lipid Disorders and Their Relevance to Outcomes in Chronic Kidney Disease

Cardiovascular disease is the major cause of death in patients with chronic kidney disease (CKD). Cardiovascular disease and many other complications of CKD are mediated by oxidative stress, inflammation, and dyslipidemia. This review provides a concise overview of the nature and mechanisms of CKD-induced lipid disorders and their adverse consequences. Lipid abnormalities in end-stage renal disease are characterized by: (a) reduced serum apoA-1 and high-density lipoprotein (HDL) concentrations, impaired HDL maturation and defective HDL antioxidant, anti-inflammatory and reverse cholesterol transport properties; (b) impaired clearance of very low-density lipoprotein and chylomicrons by the muscle and adipose tissue and of their remnants by the liver leading to hypertriglyceridemia, accumulation of intermediate-density lipoprotein and chylomicron remnants, and (c) oxidative modification of LDL and lipoprotein remnants favored by their structural abnormalities, oxidative stress, and impaired HDL antioxidant activity. Together these abnormalities result in: (a) uptake of oxidized LDL and remnant particles by macrophages and resident cells in the arPublished online: January 10, 2011 N.D. Vaziri, MD, MACP University of California, Irvine Medical Center Division of Nephrology and Hypertension The City Tower, 4th f loor, Orange CA 92868 (USA) Tel. +1 714 456 5142, Fax +1 714 456 6034, E-Mail ndvaziri @ uci.edu © 2011 S. Karger AG, Basel 0253–5068/11/0313–0189$38.00/0 Accessible online at: www.karger.com/bpu D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 8 :3 5: 21 P M Vaziri /Norris Blood Purif 2011;31:189–196 190 of lipid metabolism and their contribution to the pathogenesis of atherosclerosis, inflammation, oxidative stress, impaired exercise capacity and wasting syndrome. Effects of CKD on Lipid Profile The plasma lipid profile frequently evolves during the course of progression of CKD. For instance, patients with mild to moderate CKD, especially those with significant proteinuria, commonly exhibit hypercholesterolemia and elevated low-density lipoprotein (LDL) levels [7] . However, serum total cholesterol and LDL cholesterol concentrations are usually normal or reduced in patients with end-stage renal disease (ESRD) maintained on hemodialysis. Serum triglycerides and very low-density lipoprotein (VLDL) levels are elevated, and clearance of VLDL and chylomicrons and their atherogenic remnants is impaired in patients with advanced CKD or ESRD. This is accompanied by presence of small dense LDL and accumulation of oxidized LDL, intermediate-density lipoprotein (IDL) and chylomicron remnants [7–10] . The other major CKDinduced lipid disorder is significant reduction in serum apoA-1 and high-density lipoprotein (HDL) cholesterol concentration, impaired HDL maturation and defective HDL antioxidant, anti-inflammatory and reverse cholesterol transport (RCT) capacities [7, 8, 11–13] . In ESRD patients, the dialysis modality can significantly affect lipid profile. For instance, unlike hemodialysis patients, peritoneal dialysis patients frequently have elevated serum total cholesterol and LDL cholesterol levels simulating the lipid profile seen in nephrotic syndrome [7, 9, 10] . This phenomenon appears to be due to the losses of proteins in the peritoneal fluid effluent mimicking heavy proteinuria in functionally anephric person [14, 15] . In addition to dialysis modality, plasma lipid profile can be influenced by concomitant genetic disorders of lipid metabolism, severity of inflammation, malnutrition and lipid-altering drugs such as statins, fibrates, steroids, rapamycin, calcineurin inhibitors and sevelamer among others. In this context, binding and sequestration of bile acids by the phosphate-binding resin sevelamer can significantly reduce serum cholesterol level. The prevailing oxidative stress and inflammation which are constant feature of CKD [2, 3] result in activation of endothelial cells, upregulation of adhesion molecules, expression of chemotactic factors leading to adhesion and infiltration of monocytes and their transformation to macrophages in the artery wall [16] . Simultaneously oxidative stress promotes oxidation of LDL, remnant particles and phospholipids and their uptake by macrophages in the artery wall. This, in turn, results in formation of foam cells, which is a critical step in development and progression of atherosclerosis. The underlying mechanisms responsible for the CKD-induced lipid disorders are briefly described below. HDL Metabolism and Function in CKD Physiologic Functions of HDL As illustrated in figure 1 , normal HDL protects against atherosclerosis by several mechanisms [17–19] : (a) inhibition and reversal of lipid and lipoprotein oxidation via HDL’s constituent antioxidant enzymes paraoxonase and glutathione peroxidase; (b) removal and disposal of oxidized fatty acids via apoA1 and lecithin:cholesterol acyltransferase (LCAT); (c) suppression of inflammation via uptake and disposal of endotoxin and oxidized phospholipids by apoA1 and conversion of ox-LDL by paraoxonase; (d) retrieval of surplus cholesterol and phospholipids from vascular and other tissues for disposal in the liver, a phenomenon which is commonly known as RCT; (e) antithrombotic action via platelet-activating factor acetylhydrolase, which is a potent platelet inhibitor; (f) contribution to metabolism of VLDL and chylomicrons and limiting formation of their atherogenic remnants by donating ApoC and ApoE to the nascent chylomicrons and VLDL, a process which is essential for metabolism and clearance of these lipoproteins [20] , and (g) contribution to cholesterol enrichment and triglyceride depletion of IDL and its maturation to LDL via cholesteryl ester transfer protein (CETP)-mediated exchange of cholesterol ester for triglycerides. This process is referred to as indirect RCT as it employs LDL to dispose a portion of HDL’s cholesterol cargo in the liver via LDL receptor. This phenomenon is important in conversion of oxidationprone atherogenic IDL to cholesterol-rich LDL which can be readily removed by the liver. Iatrogenic disruption of this process may have been responsible for paradoxical increase in adverse cardiovascular outcomes despite dramatic rise in HDL cholesterol which resulted in early termination of clinical trials of a CETP inhibitor [21] . RCT is mediated by binding of HDL to ATP-binding cassette transporter type A1 (ABCA1) and ABCG1 (the gate keepers of cholesterol efflux) on the cell membrane [19, 22] . Binding to the ABCA1 transporter initiates active transfer of free cholesterol and phospholipids to the surface of the lipid-poor discoid HDL [19] , wherein free D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 8 :3 5: 21 P M Dyslipidemia of CKD Blood Purif 2011;31:189–196 191 cholesterol is rapidly esterified by LCAT and transferred to the core of HDL. LCAT-mediated esterification of cholesterol is essential for maximal uptake of cholesterol by HDL. Binding of the mature HDL to ABCG-1 transporter causes further cholesterol enrichment of HDL [22] . In addition to the energy-dependent cholesterol uptake via these transporters, a small but significant amount of cellular free cholesterol is passively delivered to the circulating HDL via albumin which plays a partial role in RCT [23] . Once loaded with cholesterol ester, HDL travels to the liver where it binds to the HDL docking receptor, SRB-1. Binding to SRB-1 accommodates release of cholesterol ester content of HDL in the liver and hydrolysis of its triglyceride and phospholipid contents by hepatic lipase. After unloading its lipid cargo, HDL is released from the liver to repeat the cycle [24] . Unlike SRB1, the endocytic HDL receptor ( -chain of ATP synthase) mediates uptake and degradation apoA-1 and lipid-poor HDL particles in the liver [25] . HDL Abnormalities in CKD Serum apoA-1 and HDL cholesterol concentrations are reduced, HDL triglyceride content is elevated, HDL maturation is impaired, proportion of lipid-poor pre-HDL is increased and antioxidant, anti-inflammatory and RCT capacity of HDL are greatly reduced in patients with advanced CKD [7, 8, 13, 26] . Advanced CKD is associated with marked reduction in serum concentrations of apoAI (the main protein constituent of HDL) and apoA-II [7, 11, 26] . The CKD-induced apoA-1 deficiency contributes LCAT*