Dysfunctional high-density lipoprotein in patients on chronic hemodialysis

Suguru Yamamoto, Patricia G. Yancey, T. Alp Ikizler, W. Gray Jerome, Ryohei Kaseda, Brian Cox, Aihua Bian, Ayumi Shintani, Agnes B. Fogo, MacRae F. Linton, Sergio Fazio, Valentina Kon

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2372-2379
Number of pages8
JournalJournal of the American College of Cardiology
Volume60
Issue number23
DOIs
StatePublished - Dec 11 2012
Externally publishedYes

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HDL Lipoproteins
Renal Dialysis
Chronic Kidney Failure
Cholesterol
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Macrophages
Cardiovascular Diseases
Tissue Extracts
Interleukin-1beta
Chronic Renal Insufficiency
C-Reactive Protein
Dialysis
Interleukin-6
Therapeutics
Tumor Necrosis Factor-alpha
Cytokines
Inflammation
Kidney

Keywords

  • atherosclerosis
  • kidney
  • lipoprotein
  • statin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Yamamoto, S., Yancey, P. G., Ikizler, T. A., Jerome, W. G., Kaseda, R., Cox, B., ... Kon, V. (2012). Dysfunctional high-density lipoprotein in patients on chronic hemodialysis. Journal of the American College of Cardiology, 60(23), 2372-2379. https://doi.org/10.1016/j.jacc.2012.09.013

Dysfunctional high-density lipoprotein in patients on chronic hemodialysis. / Yamamoto, Suguru; Yancey, Patricia G.; Ikizler, T. Alp; Jerome, W. Gray; Kaseda, Ryohei; Cox, Brian; Bian, Aihua; Shintani, Ayumi; Fogo, Agnes B.; Linton, MacRae F.; Fazio, Sergio; Kon, Valentina.

In: Journal of the American College of Cardiology, Vol. 60, No. 23, 11.12.2012, p. 2372-2379.

Research output: Contribution to journalArticle

Yamamoto, S, Yancey, PG, Ikizler, TA, Jerome, WG, Kaseda, R, Cox, B, Bian, A, Shintani, A, Fogo, AB, Linton, MF, Fazio, S & Kon, V 2012, 'Dysfunctional high-density lipoprotein in patients on chronic hemodialysis', Journal of the American College of Cardiology, vol. 60, no. 23, pp. 2372-2379. https://doi.org/10.1016/j.jacc.2012.09.013
Yamamoto, Suguru ; Yancey, Patricia G. ; Ikizler, T. Alp ; Jerome, W. Gray ; Kaseda, Ryohei ; Cox, Brian ; Bian, Aihua ; Shintani, Ayumi ; Fogo, Agnes B. ; Linton, MacRae F. ; Fazio, Sergio ; Kon, Valentina. / Dysfunctional high-density lipoprotein in patients on chronic hemodialysis. In: Journal of the American College of Cardiology. 2012 ; Vol. 60, No. 23. pp. 2372-2379.
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abstract = "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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AU - Cox, Brian

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