Dysfunctional High-Density Lipoprotein in Patients on Chronic Hemodialysis

Study Questions:

What is the functionality of high-density lipoprotein (HDL) particles in individuals with end-stage renal disease on dialysis (ESRD-HD)?

Methods:

Cellular cholesterol efflux and inflammatory response were assessed in macrophages exposed to HDL of 29 patients with ESRD-HD and 28 controls. Demographic and clinical factors were compared, and the correlation between efflux and mRNA expression of inflammatory parameters (high-sensitivity C-reactive protein [hsCRP], interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha) was assessed with the Spearman rank correlation test. The adjusted difference in efflux between patients with ESRD-HD and controls was assessed using multivariable linear regression models with adjustment for age, sex, race, body mass index, diabetes, statin usage, hsCRP, total cholesterol, triglycerides, HDL, low-density lipoprotein, cardiovascular disease (CVD), and angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker usage.

Results:

HDL from patients with ESRD-HD was dramatically less effective than normal HDL in accepting cholesterol from macrophages (median 6.9%; interquartile range [IQR], 1.4-10.2) versus control (median 14.9%; IQR, 9.8-17.8; p < 0.001). The profound efflux impairment was also seen in patients with ESRD-HD and diabetes compared with patients with diabetes without renal disease (median 8.1%; IQR, 3.3-12.9) versus control (median 13.6%; IQR, 11.0-15.9; p = 0.009). In vitro activation of cellular cholesterol transporters increased cholesterol efflux to both normal and uremic HDL. HDL of patients with ESRD-HD had reduced anti-chemotactic ability and increased macrophage cytokine response (tumor necrosis factor-alpha, interleukin-6, and interleukin-1-beta). HDL of patients with ESRD-HD on statin therapy had reduced inflammatory response, but impaired cholesterol acceptor function. Impaired HDL-mediated efflux did not correlate with circulating CRP levels or cellular inflammatory response.

Conclusions:

An abnormal HDL capacity to mediate cholesterol efflux is a key driver of excess CVD in patients on chronic hemodialysis, and may explain why statins have limited effect to decrease CV events. The findings also suggest cellular cholesterol transporters as potential therapeutic targets to decrease CV risk in this population.

Perspective:

Dysfunctional HDL particles have a lack of or reduced ability to promote reverse cholesterol transport, have pro- rather than anti-inflammatory effects, and may be pro-thrombotic. The inability of statins to reduce CV event rates in ESRD has been demonstrated in several trials. HDL dysfunction is likely an important contributor to the very high CV event rates in ESRD, but may not explain the failure of statins.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Cytokines, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoproteins, Cholesterol, Renal Dialysis, Renal Insufficiency, C-Reactive Protein, Body Mass Index, Cardiology, Cardiovascular Diseases, Triglycerides, Diabetes Mellitus


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