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.

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.