HDL Cholesterol Efflux Predicts Graft Failure in Renal Transplant Recipients

Abstract

High-density lipoprotein (HDL) particles are involved in the protection against cardiovascular disease by promoting cholesterol efflux, in which accumulated cholesterol is removed from macrophage foam cells. We investigated whether HDL cholesterol efflux capacity is associated with cardiovascular mortality, all-cause mortality, and graft failure in a cohort of renal transplant recipients (n=495, median follow-up 7.0 years). Cholesterol efflux capacity at baseline was quantified using incubation of human macrophage foam cells with apolipoprotein B-depleted plasma. Baseline efflux capacity was not different in deceased patients and survivors (P=0.60 or P=0.50 for cardiovascular or all-cause mortality, respectively), whereas recipients developing graft failure had lower efflux capacity than those with functioning grafts (P,0.001). Kaplan-Meier analysis demonstrated a lower risk for graft failure (P=0.004) but not cardiovascular (P=0.30) or all-cause mortality (P=0.31) with increasing gender-stratified tertiles of efflux capacity. Cox regression analyses adjusted for age and gender showed that efflux capacity was not associated with cardiovascular mortality (hazard ratio [HR], 0.89; 95% confidence interval [95% CI], 0.67 to 1.19; P=0.43). Furthermore, the association between efflux capacity and all-cause mortality (HR, .79; 95% CI, 0.63 to 0.98; P=0.031) disappeared after further adjustment for potential confounders. However, efflux capacity at baseline significantly predicted graft failure (HR, 0.43; 95% CI, 0.29 to 0.64; P,0.001) independent of apolipoprotein A-I, HDL cholesterol, or creatinine clearance. In conclusion, this prospective study shows that cholesterol efflux capacity from macrophage foam cells is not associated with cardiovascular or all-cause mortality but is a strong predictor of graft failure independent of plasma HDL cholesterol levels in renal transplant recipients.

HDL

“…12 This is important, because it is currently not clear which particular functionality or panel of functionalities is physiologically relevant or whether a particular beneficial or detrimental metric of HDL function actually predicts a hard clinical end point. Thus, although it is likely that other HDL functionalities are impaired in recipients of renal transplants, the results reported by Annema et al 10 emphasize that HDL's CEC strongly predicts the clinical end point of graft loss. What are the possible reasons for this association?…”

“…9 Although renal transplantation improves long-term survival of patients with ESRD on dialysis, renal transplantation is associated with an accelerated form of atherosclerosis. 9 In this issue of JASN, Annema et al 10 address the interesting possibility that CEC can predict adverse cardiovascular and renal events in recipients of renal transplants. This prospective study examined whether CEC at baseline is associated with future cardiovascular mortality, all-cause mortality, and graft failure.…”

“…Interestingly, however, the association between CEC and all-cause mortality reported in this study became significant after adjustment for recipient age and sex, although the association was lost with additional adjustment for ApoAI, HDL-C, and creatinine clearance. 10 The total number of subjects studied was relatively small, and only cardiovascular mortality and total mortality were examined compared with the analyses of incident cardiovascular events in some of the studies above. Larger prospective trials with well defined cardiovascular end points would be required to further clarify the relationship between efflux capacity and other measures of HDL function with cardiovascular events and mortality after renal transplantation.…”

“…Some 2,5 used J774 mouse macrophage cells that were not loaded with cholesterol but were labeled with 3 H-cholesterol and stimulated with cAMP to induce the cholesterol transporter ATP-binding cassette transporter A1, whereas others 4 used a fluorescence-based assay. In the study by Annema et al, 10 THP-1 human monocytes were loaded with acetylated LDL and efflux capacity of HDL. Therefore, it is likely that differences in the assays yield different information regarding HDL function, and this may underlie some apparent differences in outcome results.…”

“…Annema et al 10 point to parallelism between atherosclerosis and the transplant vasculopathy that leads to chronic transplant dysfunction and ultimately, graft failure. Annema et al 10 suggest that impaired capacity of HDL to remove cholesterol from macrophages as well as other parenchymal cells, such as endothelial cells, promotes the vasculopathy, whereas improving HDL functionality may have the potential to lessen intragraft atherosclerosis and preserve kidney function.…”