Altered HDL proteome predicts incident CVD in chronic kidney disease patients

Patients with chronic kidney disease (CKD) are at high risk for CVD. However, traditional lipid risk factors, including low HDL levels, cannot completely explain the increased risk. Altered HDL proteome is linked with both CVD and CKD, but the role of HDL proteins in incident CVD events in patients with CKD is unknown. In this prospective case-control study, we used targeted proteomics to quantify 31 HDL proteins in 92 subjects (46 incident new CVD and 46 one-to-one matched controls) at various stages of CKD. We tested associations of HDL proteins with incident CVD using matched logistic regression analysis. In the model fully adjusted for clinical confounders, lipid levels, C-reactive protein, and proteinuria, no significant associations were found for HDL-C, but we observed inverse associations between levels of HDL proteins paraoxonase/arylesterase 1 (PON1), paraoxonase/arylesterase 3 (PON3), and LCAT and incident CVD. Odds ratios (per 1 SD) were 0.38 (0.18–0.97, P = 0.042), 0.42 (0.20–0.92, P = 0.031), and 0.30 (0.11–0.83, P = 0.020) for PON1, PON3, and LCAT, respectively. Apolipoprotein A-IV remained associated with incident CVD in CKD patients in models adjusted for clinical confounders and lipid levels but lost significance with the addition of C-reactive protein and proteinuria to the model. In conclusion, levels of four HDL proteins, PON1, PON3, LCAT, and apolipoprotein A-IV, were found to be inversely associated with incident CVD events in CKD patients. Our observations indicate that HDLs' protein cargo, but not HDL-C levels, can serve as a marker—and perhaps mediator—for elevated CVD risk in CKD patients.