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Published on: October 12, 2017
Dysfunctional high-density lipoprotein in patients on chronic hemodialysis
Suguru Yamamoto1, Patricia G Yancey, T Alp Ikizler
1Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Insights
High-density lipoprotein (HDL) from patients with end-stage renal disease on dialysis (ESRD-HD) is less effective at removing cholesterol, contributing to cardiovascular disease. This impaired HDL function may explain statin resistance in ESRD-HD patients.
Area of Science:
- Cardiovascular Science
- Nephrology
- Lipid Metabolism
Background:
- Cardiovascular disease (CVD) is highly prevalent in chronic kidney disease patients, particularly those with end-stage renal disease on dialysis (ESRD-HD).
- Standard CVD risk factors do not fully explain this risk, and ESRD-HD patients often show resistance to statin therapy.
- High-density lipoprotein (HDL) plays a crucial role in preventing atherosclerosis by removing cholesterol from tissues and reducing inflammation.
Purpose of the Study:
- To investigate the functional capacity of high-density lipoprotein (HDL) in individuals undergoing chronic hemodialysis.
- To assess whether HDL dysfunction contributes to the elevated cardiovascular risk observed in end-stage renal disease on dialysis (ESRD-HD) patients.
Main Methods:
- Assessed cellular cholesterol efflux from macrophages exposed to HDL from ESRD-HD patients and control subjects.
- Evaluated the inflammatory response of macrophages treated with HDL from ESRD-HD patients and controls.
- Investigated the impact of activating cellular cholesterol transporters on efflux capacity.
Main Results:
- HDL from ESRD-HD patients exhibited significantly impaired cholesterol acceptor function compared to control HDL (6.9% vs. 14.9% efflux).
- This efflux impairment persisted in ESRD-HD patients with diabetes compared to diabetic patients without renal disease.
- HDL from ESRD-HD patients showed reduced anti-atherogenic properties, including decreased antichemotactic ability and increased pro-inflammatory cytokine release from macrophages.
Conclusions:
- Dysfunctional HDL, specifically its reduced capacity for cholesterol efflux, is a significant factor driving excess cardiovascular disease in patients on chronic hemodialysis.
- The impaired HDL function may elucidate the limited efficacy of statin therapy in reducing cardiovascular events in this population.
- Cellular cholesterol transporters represent a promising therapeutic target for mitigating cardiovascular risk in ESRD-HD patients.
Objectives:
This study examined the functionality of high-density lipoprotein (HDL) in individuals with end-stage renal disease on dialysis (ESRD-HD).
Background:
The high rate of cardiovascular disease (CVD) in chronic kidney disease is not explained by standard risk factors, especially in patients with ESRD-HD who appear resistant to benefits of statin therapy. HDL is antiatherogenic because it extracts tissue cholesterol and reduces inflammation.
Methods:
Cellular cholesterol efflux and inflammatory response were assessed in macrophages exposed to HDL of patients with ESRD-HD or controls.
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% to 10.2%) versus control (median 14.9%; IQR: 9.8% to 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% to 12.9%) versus control (median 13.6%; IQR: 11.0% to 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 antichemotactic 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 while maintaining impaired cholesterol acceptor function. Interestingly, impaired HDL-mediated efflux did not correlate with circulating C-reactive protein levels or cellular inflammatory response.
Conclusions:
These findings suggest that 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.
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