Wu PH, Glerup RI, Svensson MHS, Eriksson N, Christensen JH, Linde T, Ljunggren Ö, Fellström B
Nephrol Dial Transplant - (-) - [2021-06-04; online 2021-06-04]
Disturbances in bone mineral metabolism are associated with increased mortality and cardiovascular events (CVEs). However, the association between bone-associated protein biomarkers, mortality, and CVEs independent of cytokine activation remains unknown. This study aimed to investigate bone-associated protein biomarkers, and the association with inflammatory cytokines, and cardiovascular outcomes. This prospective study enrolled hemodialysis (HD) patients in Denmark between December 2010 and March 2011. Using a proximity extension proteomics assay, nine bone-associated proteins were examined: cathepsin D (CTSD), cathepsin L1 (CTSL1), dickkopf-related protein 1 (Dkk-1), fibroblast growth factor 23 (FGF-23), leptin, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-Β ligand (RANKL), TNF-related apoptosis-inducing ligand (TRAIL), and TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2). The importance of the bone-associated protein markers was evaluated by a random forest algorithm (RF). The association between bone-associated proteins with all-cause death, cardiovascular death, and CVEs was analyzed in multivariable Cox models adjusted for age, gender, comorbidities, laboratory data, and dialysis duration. We enrolled 331 patients (63.7% men; mean [SD] age, 65 [14.6] years) in a prospective cohort study with five years follow-up. When adjusting for confounders, CTSL1 remained associated with all-cause death, and four biomarkers were associated with CVE. However, the association between bone markers and the outcomes was attenuated after adjusting for inflammatory proteins, and just OPG remained associated with CVE in the adjusted model. Evaluating the importance of bone markers by RF, OPG was the most important marker related to CVEs. OPG also improved the prediction of CVE when added clinical information alone in integrated discrimination improvement and net reclassification improvement analyses. OPG, a well-known bone biomarker, was associated with CVEs independent of cytokine activity. In contrast, the association between CVEs and the remaining three bone-associated proteins (TRAIL-R2, CTSD, and CTSL1) was affected by cytokine inflammation activity.