HDL in CKD-The Devil Is in the Detail

Abstract

The picture of HDL cholesterol (HDL-C) as the "good" cholesterol has eroded. This is even more surprising because there exists strong evidence that HDL-C is associated with cardiovascular disease (CVD) in the general population as well as in patients with impairment of kidney function and/or progression of CKD. However, drugs that dramatically increase HDL-C have mostly failed to decrease CVD events. Furthermore, genetic studies took the same line, as genetic variants that have a pronounced influence on HDL-C concentrations did not show an association with cardiovascular risk. For many, this was not surprising, given that an HDL particle is highly complex and carries >80 proteins and several hundred lipid species. Simply measuring cholesterol might not reflect the variety of biologic effects of heterogeneous HDL particles. Therefore, functional studies and the involvement of HDL components in the reverse cholesterol transport, including the cholesterol efflux capacity, have become a further focus of study during recent years. As also observed for other aspects, CKD populations behave differently compared with non-CKD populations. Although clear disturbances have been observed for the "functionality" of HDL particles in patients with CKD, this did not necessarily translate into clear-cut associations with outcomes.

Keywords: cardiovascular disease; cholesterol transport; high-density lipoprotein; lipids; progression of chronic renal failure; reverse.

Figure 1.

Schematic illustration of the major normal lipoprotein metabolic pathways. Blue arrows refer to points of action of the respective enzymes in blue. ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; ApoA-I, apolipoprotein A-I; ApoA-IV, apolipoprotein A-IV; CE, cholesterol ester; CETP, cholesteryl ester transfer protein; FFA, free fatty acid; HTGL, hepatic triglyceride lipase; IDL, intermediate-density lipoprotein; LCAT, lecithin–cholesterol acyltransferase; LDL-R, LDL receptor; LPL, lipoprotein lipase; LRP, LDL-R–related protein; SR-B1, scavenger receptor B1; TG, triglyceride; VLDL, very low-density lipoprotein; VSMC, vascular smooth muscle cells. Reprinted and adapted from reference , with permission.

Figure 2.

Schematic illustration of a Mendelian randomization approach of HDL-C influencing genetic variants and outcomes of interest. Let us assume there exists a large number of genes that influence HDL-C concentrations (e.g., genes 1–89). For each gene, we know genetic variants that decrease and others that increase HDL-C, and others that are neutral. For each gene, it is determined randomly at the time of conception which of the two alleles from the father (F) and which of the two alleles from the mother (M) are transmitted to the offspring. Because many genes influence HDL-C concentrations, it is finally a question of whether an offspring has a preponderance of HDL-C–lowering alleles to which they are is exposed for their lifetime. If there is a causal effect of HDL-C concentrations on outcomes such as CVD or kidney function, one would expect that there will be also a preponderance of the HDL-C concentration-decreasing alleles in the patient groups with the outcome of interest compared with groups without that outcome. Usually, a large number of patients and controls have to be investigated to get reliable results.

Figure 3.

Schematic overview on the study design, main findings, and interpretation of the results derived from two genome-wide association studies on HDL-C and eGFR. For explanation, see Genetic Observations on HDL-C and CKD. Reprinted from reference , with permission.

Figure 4.

Principle of cholesterol efflux capacity assays. Macrophage cell lines are enriched with labeled cholesterol and stimulated with cAMP to induce cholesterol transporters. Then a cholesterol acceptor, such as apoB-depleted serum of the patient under investigation, is added to the medium. After incubation the efflux of labeled cholesterol from the cells to the medium is quantified and reflects the cholesterol transport mediated by ABCA1, ABCG1, SR-B1, and aqueous diffusion.