Dyslipidemia in Chronic Kidney Disease: An Approach to Pathogenesis and Treatment

The incidence and prevalence of chronic kidney disease (CKD) are increasing worldwide and are associated with poor outcomes. According to the 1999–2004 National Health and Nutrition Examination Survey (NHANES), the prevalence of CKD among the USA population is 15.3% 1. Although there is still some controversy whether CKD represents an independent causal risk factor for incident cardiovascular disease (CVD), accumulating evidence over the last decade marks out CVD as the major cause of mortality in patients with mild to moderate CKD and end-stage renal disease (ESRD) 2, 3. It becomes apparent that the severity of CKD along with CVD severity in any population makes a ‘devastated’ combination for both patients and healthcare systems. Approximately 50% of patients with ESRD die from a cardiovascular event 4, which indicates a cardiovascular mortality that is 30 times higher in dialysis patients and 500 times higher in 25- to 34-year-old ESRD patients than in individuals from the general population of the same age and race 2, 4. Premature CVD extends from mild to moderate stages of CKD. A pooled analysis of four community-based studies showed that moderate renal insufficiency carries a 19% excess risk of cardiovascular complications 5. In a retrospective cohort study only a tiny minority of patients (0.5–1%) with mild to moderate CKD developed ESRD over a 5-year follow-up, while as many as 19 and 24% of these patients with mild and moderate renal insufficiency, respectively, died mostly of cardiovascular complications in the same period 6.In the general population as much as 75% of the excess risk of coronary heart disease could be explained by traditional Framingham risk factors 7. However, use of traditional risk factors underestimates the CVD risk in patients with CKD 8, while the Framingham predictive instrument demonstrates poor overall accuracy in predicting cardiac events in patients with mild to moderate CKD 9. Moreover, traditional CVD risk factors were found often to relate to outcome in ESRD dialysis patients in an opposite direction, a phenomenon termed ‘reverse epidemiology’ 10. The introduction of uremia-related, non-traditional CVD risk factors and evaluation of their corresponding biomarkers were thought to enhance the clinical ability to predict cardiovascular events in patients with all stages of CKD. However, studies investigating the usefulness of current CVD biomarkers have concluded that they only add moderately to traditional risk factors for risk assessment of individuals both with almost normal renal function 11 as well as with mild to moderate CKD 12, 13.Dyslipidemia has been established as a well-known traditional risk factor for CVD in the general population and large-scale observational studies have shown that total and low-density lipoprotein (LDL)-cholesterol values are two of the most important independent predictors of cardiovascular morbidity and mortality 14. Also, it is well known that patients with impaired renal function exhibit significant alterations in lipoprotein metabolism, which in their most advanced form may result in the development of severe dyslipidemia. In this review studies on the pathogenesis of renal dyslipidemia and the results of drug therapy are discussed.The process of exogenous and endogenous pathways of lipid metabolism is a complicated phenomenon in both normal and abnormal conditions. A schematic presentation of both pathways is shown in figure 1.Although lipid abnormalities were originally considered as complications of ESRD, these changes can be present in early stages of CKD and may actively participate in the pathogenesis of serious complications such as atherosclerotic vascular disease. Although the nature of dyslipidemia can be significantly influenced by several intrinsic (nephrotic range proteinuria, concomitant diseases such as diabetes mellitus, hereditary disorders of lipid metabolism) or exogenous (epoietin administration, drugs such as steroids, calcineurin inhibitors, etc.) factors, the most common quantitative lipid abnormalities in predialysis CKD patients are hypertriglyceridemia, increased concentrations of triglyceride-rich lipoprotein remnants, reduced high-density lipoprotein (HDL)-cholesterol levels as well as increased concentrations of lipoprotein(a) (Lp(a)) 15. Notably, total and LDL-cholesterol levels are usually within normal limits or slightly reduced in these individuals (table 1) 16.Hypertriglyceridemia represents an early feature of renal failure. Indeed, previous studies have shown that patients with impaired renal function exhibit increased concentrations of triglycerides even though serum creatinine levels are within normal limits 17, 18. In addition, individuals with renal insufficiency usually display abnormal increases in serum triglyceride levels after a fat meal (postprandial lipemia) 19. Experimental studies revealed that the accumulation of triglyceride-rich lipoproteins (very-low-density lipoprotein (VLDL), chylomicrons and their remnants) in individuals with predialysis CKD is mainly due to their decreased catabolism 20. The downregulation of the expression of several genes 21,22,23 along with the changes in the composition of lipoprotein particles 24 and the direct inhibitory effect of various uremic ‘toxins’ on the enzymes involved in lipid metabolism 25, represent the most important pathophysiological mechanisms underlying the development of hypertriglyceridemia in renal failure. Interestingly, it has been proposed that secondary hyperparathyroidism may also contribute to the impaired catabolism of triglyceride-rich lipoproteins 26, 27 and that parathyroidectomy or the administration of the calcium channel blocker verapamil 28 may partially ameliorate the hypertriglyceridemia of CKD. It is well known that impaired insulin sensitivity represents an early feature of CKD 17,18,19. Thus, it could be hypothesized that the insulin resistance-driven overproduction of VLDL may significantly contribute to the development of hypertriglyceridemia in CKD patients. However, the role of the increased hepatic production of triglyceride-rich lipoproteins in the pathogenesis of renal dyslipidemia remains a subject of debate 20.Epidemiological studies have shown that HDL-cholesterol levels are inversely related to the future cardiovascular risk 29. HDL particles possess multiple antiatherogenic activities including reverse cholesterol transport (transport of surplus cholesterol from the arterial wall to the liver for excretion) as well as antioxidative, anti-inflammatory and antithrombotic functions, which are attributed to HDL-associated apolipoproteins (mainly apolipoprotein AI) and enzymes (paraoxonase-1, platelet-activating factor acetylhydrolase and lecithin-cholesterol acyltransferase (LCAT)) 30. A schematic presentation of the normal reverse cholesterol transport pathway is shown in figure 2. Studies in patients or laboratory animals with predialysis renal failure consistently reveal decreased concentrations of HDL-cholesterol compared to individuals with normal renal function 31, 32. Several mechanisms, working in concert, may underlie this reduction in HDL-cholesterol levels, which is usually indicative of impaired reverse cholesterol transport. Thus, uremic patients usually exhibit decreased levels of apolipoproteins AI and AII (the main protein constituents of HDL) 32, diminished activity of LCAT (the enzyme responsible for the esterification of free cholesterol in HDL particles) 22, 33 as well as increased activity of cholesteryl ester transfer protein 34 that facilitates the transfer of cholesterol esters from HDL to triglyceride-rich lipoproteins thus reducing the serum concentrations of HDL-cholesterol. In addition to their reduced efficiency as cholesterol acceptors, HDL particles from individuals with renal failure may also possess impaired antioxidative and anti-inflammatory function. This impairment can, at least in part, be attributed to the reduction in the activities of HDL-associated enzymes 35, 36.Lp(a) represents an LDL-like particle distinguished from LDL by the presence of apolipoprotein(a) (apo(a)), which is attached to the apolipoprotein B-100 molecule through disulfide linkage 37. Apo(a) is highly homologous to the plasma protease zymogen plasminogen and thus it has been suggested that may by 37. 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However, studies have the efficiency and the of these in patients with chronic kidney there is a of evidence their on the cardiovascular risk in this studies are to the role of these drugs in the of dyslipidemia in individuals with represents an of CKD. in lipoprotein metabolism (mainly accumulation of or partially apolipoprotein particles as well as reduced concentrations of are even at the early stages of CKD and usually a that the in renal function. several intrinsic kidney or exogenous of renal factors can the expression of these the of the pathophysiological mechanisms that underlie their development is of studies that dyslipidemia in these patients may actively participate in the pathogenesis of CVD as well as in the of renal function. 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