Residual Cardiovascular Risk in Chronic Kidney Disease: Role of High-density Lipoprotein

Abstract

Although reducing low-density lipoprotein-cholesterol (LDL-C) levels with lipid-lowering agents (statins) decreases cardiovascular disease (CVD) risk, a substantial residual risk (up to 70% of baseline) remains after treatment in most patient populations. High-density lipoprotein (HDL) is a potential contributor to residual risk, and low HDL-cholesterol (HDL-C) is an established risk factor for CVD. However, in contrast to conventional lipid-lowering therapies, recent studies show that pharmacologic increases in HDL-C levels do not bring about clinical benefits. These observations have given rise to the concept of dysfunctional HDL where increases in serum HDL-C may not be beneficial because HDL loss of function is not corrected by or even intensified by the therapy. Chronic kidney disease (CKD) increases CVD risk, and patients whose CKD progresses to end-stage renal disease (ESRD) requiring dialysis are at the highest CVD risk of any patient type studied. The ESRD population is also unique in its lack of significant benefit from standard lipid-lowering interventions. Recent studies indicate that HDL-C levels do not predict CVD in the CKD population. Moreover, CKD profoundly alters metabolism and composition of HDL particles and impairs their protective effects on functions such as cellular cholesterol efflux, endothelial protection, and control of inflammation and oxidation. Thus, CKD-induced perturbations in HDL may contribute to the excess CVD in CKD patients. Understanding the mechanisms of vascular protection in renal disease can present new therapeutic targets for intervention in this population.

Keywords: Cardiovascular disease; Cholesterol efflux; Chronic kidney disease; HDL; Residual cardiovascular risk; Statins.

Figure 1

Relative risk reduction and residual cardiovascular risk in the general population and patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD) on maintenance dialysis. (A color figure can be found in the online version of this article.)

Figure 2

The kidney and high-density lipoprotein (HDL) metabolism. (A) Under normal conditions, ApoA-I and small HDL3 cross the glomerular filtration barrier and are taken up by the cubilin-megalin complex to undergo catabolism, be reabsorbed and brought back into the circulation, or be lost in the urine. (B) In proteinuric conditions, greater quantity of ApoA-I, HDL3 as well as larger HDL particles such as HDL2 cross the glomerular filtration barrier. (C) In CKD, as GFR falls, fewer HDL particles can be filtered and reduced HDL-C may reflect increased catabolism in the liver. (A color figure can be found in the online version of this article.)