Lower Apo A-I and Lower HDL-C Levels Are Associated With Higher Intermediate CD14 ++ CD16 + Monocyte Counts That Predict Cardiovascular Events in Chronic Kidney Disease

Abstract

Objective— Patients with chronic kidney disease (CKD) display impaired cholesterol efflux capacity and elevated CD14 ++ CD16 + monocyte counts. In mice, dysfunctional cholesterol efflux causes monocytosis. It is unknown whether cholesterol efflux capacity and monocyte subsets are associated in CKD. Approach and Results— In 438 patients with CKD, mediators of cholesterol efflux capacity (high-density lipoprotein cholesterol/apolipoprotein A-I) and monocyte subsets were analyzed as predictors of cardiovascular events. Monocyte subset-specific intracellular lipid content, CD36, CD68, and ABCA1 were measured in a subgroup. Experimentally, we analyzed subset-specific cholesterol efflux capacity and response to oxidized low-density lipoprotein cholesterol stimulation in CKD. Epidemiologically, both low Apo-I and low high-density lipoprotein cholesterol were associated with high CD14 ++ CD16 + monocyte counts in linear regression analyses (apolipoprotein A-I: β=−0.171; P <0.001; high-density lipoprotein cholesterol: β=−0.138; P =0.005), but not with counts of other monocyte subsets. In contrast to apolipoprotein A-I or high-density lipoprotein cholesterol, higher CD14 ++ CD16 + monocyte counts independently predicted cardiovascular events (hazard ratio per increase of 1 cell/μL: 1.011 [1.003–1.020]; P =0.007). Experimentally, CD14 ++ CD16 + monocytes demonstrated preferential lipid accumulation, high CD36, CD68, and low ABCA1 expression and, consequently, displayed low cholesterol efflux capacity, avid oxidized low-density lipoprotein cholesterol uptake, and potent intracellular interleukin-6, interleukin-1β, and tumor necrosis factor-α production. Conclusions— Taken together, mediators of cholesterol efflux are associated with CD14 ++ CD16 + monocyte counts, which independently predict adverse outcome in CKD.