Impaired Delivery of Cholesterol Effluxed From Macrophages to Hepatocytes by Serum From CKD Patients May Underlie Increased Cardiovascular Disease Risk

Graham T Gipson; Salvatore Carbone; Jing Wang; Dave L Dixon; Ion S Jovin; Daniel E Carl; Todd W Gehr; Shobha Ghosh

doi:10.1016/j.ekir.2019.11.003

Impaired Delivery of Cholesterol Effluxed From Macrophages to Hepatocytes by Serum From CKD Patients May Underlie Increased Cardiovascular Disease Risk

Kidney Int Rep. 2019 Nov 9;5(2):199-210. doi: 10.1016/j.ekir.2019.11.003. eCollection 2020 Feb.

Authors

Graham T Gipson¹, Salvatore Carbone¹, Jing Wang¹, Dave L Dixon², Ion S Jovin³, Daniel E Carl¹, Todd W Gehr¹, Shobha Ghosh^{1

3}

Affiliations

¹ Department of Internal Medicine, Virginia Commonwealth University (VCU) School of Medicine, Richmond, Virginia, USA.
² Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University (VCU) School of Pharmacy, Richmond, Virginia, USA.
³ Hunter Holmes McGuire Veterans Affairs Medical Center (VAMC), Richmond, Virginia, USA.

Abstract

Introduction: Although chronic kidney disease (CKD) is associated with increased risk for coronary artery disease (CAD), the underlying mechanisms are not completely defined. In the present study, we tested the hypothesis that flux of cholesterol from macrophage foam cells to liver is impaired in subjects with CKD.

Methods: Consecutive healthy patients, patients with at least 1 CAD risk factor, patients with established CAD, and patients with CKD stages G3 to G5 (n ≥ 15/group) were recruited prospectively. The ability of total patient serum without any modifications to (i) facilitate efflux of cholesterol from human THP1-macrophage foam cells under physiological conditions (cholesterol efflux capacity [CEC]) and (ii) to deliver this effluxed cholesterol to primary hepatocytes with physiological expression of high-density lipoprotein (HDL) receptor SR-BI (capacity to deliver cholesterol to hepatocytes [CDCH]) was evaluated.

Results: Although healthy patients, patients with at least 1 CAD risk factor, and patients with established CAD all showed similar CEC, patients with CKD showed significantly higher CEC. CDCH was significantly lower in all groups compared with the healthy patients; however, when corrected for higher CEC, CDCH in patients with CKD was significantly lower than in patients with CAD. CDCH correlated with age, body mass index, metabolic parameters, inflammatory markers, and kidney function markers (estimated glomerular filtration rate [eGFR], serum creatinine, and serum cystatin C).

Conclusions: These results suggest that aberrations in delivery of cholesterol effluxed from macrophage foam cells to liver for final elimination or the last step of reverse cholesterol transport, may underlie the increased risk of CAD in patients with CKD.

Keywords: cardiovascular disease risk; chronic kidney disease; delivery of cholesterol to the liver; reverse cholesterol transport; serum cholesterol efflux capacity.