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End-stage renal disease (ESRD) is associated with accelerated atherosclerosis and premature death from cardiovascular disease. These events are driven by oxidative stress inflammation and lipid disorders. ESRD-induced lipid abnormalities primarily stem from dysregulation of high-density lipoprotein (HDL) and triglyceride-rich lipoprotein metabolism and oxidative modification of lipoproteins. In this context, production and plasma concentration of Apo-I and Apo-II are reduced, HDL maturation is impaired, HDL composition is altered, HDL anti-oxidant and anti-inflammatory functions are depressed, clearance of triglyceride-rich lipoproteins and their atherogenic remnants is impaired, their composition is altered, and their plasma concentration is elevated in ESRD. The associated defect in HDL maturation is largely caused by acquired lecithin-cholesterol acyltransferase (LCAT) deficiency while its triglyceride enrichment is due to hepatic lipase deficiency. Hyper-triglyceridemia, abnormal composition, and impaired clearance of triglyceride-rich lipoproteins and their remnants are mediated by down-regulation of lipoprotein lipase, hepatic lipase, VLDL receptor, and LDL receptor-related protein (LRP), relative reduction of ApoC-II/ApoC-III ratio, upregulation of acyl-CoA cholesterol acyltransferase (ACAT) and elevated plasma level of cholesterol ester-poor pre-beta HDL. Impaired clearance and accumulation of oxidation- prone VLDL and chylomicron remnants and abnormal LDL composition in the face of oxidative stress and inflammation favors their uptake by macrophages and resident cells in the artery wall. The effect of heightened influx of lipids is compounded by impaired HDL-mediated reverse cholesterol transport leading to foam cell formation which is the central event in atherosclerosis plaque formation and subsequent plaque rupture, thrombosis and tissue damage.
End-stage renal disease (ESRD) is associated with accelerated atherosclerosis and a high incidence of cardiovascular morbidity and mortality . A number of factors contribute to atherosclerosis and cardiovascular disease in ESRD population. Chief among them are oxidative stress, inflammation, hypertension, endothelial dysfunction, insulin resistance, vascular calcification and dyslipidemia [2–9]. The ESRD-induced dyslipidemia is characterized by hyper-triglyceridemia, elevated level of very low density lipoprotein (VLDL), high plasma concentration of lipoprotein remnants, accumulation of oxidized lipids and lipoproteins, low plasma HDL cholesterol concentration and impaired HDL maturation and function . Serum cholesterol and LDL cholesterol values are frequently within or below the normal limits in hemodialysis-treated ESRD patients but are commonly increased in those maintained on peritoneal dialysis modalities. Finally, in ESRD patients low density lipoprotein (LDL) consists of highly atherogenic small-dense particles which contains abnormal levels of residual triglycerides [10, 11].
The ESRD-associated changes of plasma lipid pattern can be significantly altered by dialysis modality, lipid-altering drugs (e.g. statins, fibrates, sevelamer, calcineurin inhibitors, steroids and rapamycin), pre-existing genetic disorders of lipid metabolism, malnutrition and inflammation among other factors. For example, use of the phosphate binding resin, sevelamer, lowers plasma cholesterol by acting as a bile acid sequestrant. Moreover, inflammation, which is a common feature of ESRD, can reduce serum total cholesterol and HDL cholesterol levels. In contrast, chronic peritoneal dialysis which results in substantial losses of proteins in the peritoneal fluid effluent, can cause significant elevation of serum total cholesterol and LDL [10, 11] by simulating nephrotic syndrome[12,13].
This article is intended to provide a brief overview of the mechanisms responsible for dysregulation of lipid metabolism in chronic renal failure.
In the artery wall, oxidized or otherwise modified lipoproteins are engulfed by macrophages and resident cells via scavenger receptors, a process that can lead to foam cell formation and atherosclerosis. HDL plays a major role in mitigating this process by limiting lipid/lipoprotein oxidation and by retrieving surplus cholesterol from vascular tissue for disposal in the liver, a process commonly known as reverse cholesterol transport (figure 1) . In addition, HDL plays a major role in metabolism of triglyceride-richlipoproteins by serving as an ApoC and ApoE donor to the nascent chylomicrons and VLDL, a process which is vital in metabolism of these triglyceride-rich lipoproteins . Moreover, HDL serves as a potent endogenous inhibitor of inflammation, platelet adhesion, and lipid/lipoprotein oxidation .
HDL-mediated removal of surplus lipids from tissue macrophages and resident cells requires attachment of nascent HDL to ATP binding cassette transporter type 1 (ABCA1) or binding of mature HDL to ABCG-1 on the cell membrane [17–19]. Binding of the nascent HDL to ABCA1 triggers active transfer of phospholipids and free cholesterol from adjacent caveolae to the surface of HDL . In addition, HDL binding to ABCG-1 leads to further cholesterol enrichment and maturation of HDL . Free cholesterol reaching the surface of HDL is rapidly esterified by LCAT and sequestered in the core of HDL, allowing maximal uptake of cholesterol by HDL. This process is critical for HDL maturation and efficient HDL-mediated reverse cholesterol transport. Once loaded with cholesterol ester, HDL detaches from ABCA-1/ABCG-1 transporters and travels to the liver. In the liver, HDL forms a reversible bond with the HDL docking receptor, SRB-1, which facilitates simultaneous unloading of its cholesterol ester content, as well as hydrolysis and extraction of its fatty acid cargo by hepatic lipase. This is followed by detachment of the unloaded HDL from SRB-1 and its return to the blood stream for recycling . In addition to SRB1, liver contains an endocytic HDL receptor, beta chain of ATP synthase, which binds and internalizes HDL for degradation .
Several factors contribute to reduction of HDL cholesterol and increased proportion of lipid-poor pre-beta HDL, impaired maturation of cholesterol ester-poor to cholesterol ester -rich HDL, and elevated triglyceride content of HDL in this population. The essential steps in HDL metabolism and impact of chronic renal failure or ESRD thereon are briefly described below:
As noted earlier, ESRD results in hyper-triglyceridemia, elevation of VLDL, impaired VLDL and chylomicron clearance as well as increased plasma concentration of IDL and chylomicron remnants and prolonged post-prandial lipemia [8,10,42–45]. This is associated with a relative increase in plasma ApoC-III (a potent inhibitor of lipoprotein lipase) and relative decline in ApoC-II, which is the activator of lipoprotein lipase [8,10,42]. Several factors contribute to hyper-triglyceridemia, elevation of VLDL and accumulation of VLDL and chylomicron remnants in ESRD population. The essential steps in triglyceride and triglyceride-rich lipoprotein metabolism and impact of chronic renal failure or ESRD thereon are briefly described below:
As mentioned earlier, serum cholesterol and LDL cholesterol concentrations are usually within or below the normal range in hemodialysis-treated ESRD patients but are commonly elevated in individuals maintained on peritoneal dialysis. Moreover, LDL in ESRD patients consists of small and dense particles which contain abnormal levels of residual triglycerides [10, 11]. The critical steps in cholesterol and LDL metabolism and impact of chronic renal failure or ESRD thereon are briefly described below:
The constellation of oxidative stress, inflammation and lipid disorders which are nearly constant features of ESRD is largely responsible for accelerated atherosclerosis and premature death from cardiovascular vascular disease in this population. Impaired clearance and accumulation of oxidation- prone VLDL and chylomicron remnants and abnormal LDL composition in the face of oxidative stress and inflammation favors their uptake by macrophages and resident cells in the artery wall. The effect of heightened influx of lipids is compounded by impaired HDL-mediated reverse cholesterol transport leading to foam cell formation which is the central event in atherosclerosis plaque formation and subsequent plaque rupture, thrombosis and tissue damage. In addition to their impact on plasma lipid profile and atherogenesis, impaired clearance of triglyceride-rich lipoproteins in ESRD has major implication on energy metabolism. This is because impaired lipoprotein lipase activity and VLDL receptor deficiency can limit the availability of lipid fuel for energy production in skeletal muscle and thereby exercise capacity. Similarly, these deficiencies can limit the storage of energy in adipose tissue and contribute to the wasting syndrome.
Since plasma cholesterol is usually normal or reduced in hemodialysis patients, use of cholesterol lowering agents appears to be of little value except in the minority of patients with hyper-cholesterolemia. This supposition is supported by clinical trials of HMG-CoA reductase inhibitors which have yielded negative results in the ESRD populations [62,63]. Instead, the logical treatment should ideally include strategies aim at alleviating inflammation and oxidative stress, enhancing clearance of VLDL, IDL and chylomicron and their remnant as well as restoring HDL metabolism and function. It should be noted that the ideal tools to readily achieve these objectives remain elusive at this time. None the less dietary modifications, increased physical activity, longer and/or more frequent dialysis treatments, use of ultra-pure dialysates, biocompatible dialyzers, and fistulas instead of catheters or A-V grafts, and refraining from overzealous use of intravenous iron preparations and erythropoiesis stimulating agents represent important steps in the right direction
This study was in part supported by the NIH grant, 5 U54 RR0119234;
The author thanks Dr Zhenmin Ni for his assistance with preparation of the figures