Dysfunctional High-Density Lipoprotein in Patients on Chronic Hemodialysis

被引:170
作者
Yamamoto, Suguru [1 ]
Yancey, Patricia G. [2 ]
Ikizler, Alp [2 ]
Jerome, W. Gray [3 ]
Kaseda, Ryohei [1 ]
Cox, Brian [4 ]
Bian, Aihua [5 ]
Shintani, Ayumi [5 ]
Fogo, Agnes B. [1 ,2 ,3 ]
Linton, MacRae F. [2 ,6 ]
Fazio, Sergio [2 ,3 ]
Kon, Valentina [1 ]
机构
[1] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA
[3] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA
[4] Vanderbilt Univ, Med Ctr, Dept Microbiol & Immunol, Nashville, TN USA
[5] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN USA
[6] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA
关键词
atherosclerosis; kidney; lipoprotein; statin; CHRONIC KIDNEY-DISEASE; APOLIPOPROTEIN-A-I; CORONARY-HEART-DISEASE; CHOLESTEROL EFFLUX; RISK-FACTORS; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS RISK; RENAL PROTECTION; LDL CHOLESTEROL; MORTALITY RISK;
D O I
10.1016/j.jacc.2012.09.013
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 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 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. (J Am Coll Cardiol 2012;60:2372-9) (C) 2012 by the American College of Cardiology Foundation
引用
收藏
页码:2372 / 2379
页数:8
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