Hepcidin and Cardiovascular Events in CKD With and Without Dialysis

Introduction Hepcidin's prognostic role in patients with anemia and chronic kidney disease (CKD), regardless of dialysis requirement, remains unclear. Methods This was a post-hoc analysis of ASCEND-ND and ASCEND-D, two phase 3 trials assessing daprodustat's efficacy and safety compared with conventional erythropoiesis-stimulating agents (ESAs). Patients were divided according to quartiles (Q1–4) of baseline hepcidin levels. Results In ASCEND-ND and ASCEND-D, baseline hepcidin values were available for 3,807 and 2,881 patients (medians, 106 ng/mL and 176 ng/mL), respectively. Higher baseline hepcidin levels were associated with female sex, lower hemoglobin levels, higher transferrin saturation, higher ferritin levels, and higher C-reactive protein levels in both trials. In non-dialysis patients, Kaplan–Meier curves for major cardiovascular events (MACE) demonstrated that Q2 exhibited the lowest incidence, followed by Q1 and Q3, with Q4 having the highest. This association persisted after risk factor adjustment (P for non-linearity, 0.032). In dialysis patients, Kaplan–Meier curves for MACE demonstrated no association between baseline hepcidin quartiles and MACE, remaining consistent following adjustment for confounding factors. Temporal changes in hepcidin levels were not independently associated with MACE risk. Daprodustat's treatment effects were not modified by baseline hepcidin levels in either trial. Conclusions In non-dialysis patients with CKD, a non-linear relationship was observed between baseline hepcidin levels and MACE, whereas no association was found in dialysis patients. Baseline hepcidin levels did not modify the treatment effect of daprodustat compared with ESAs, irrespective of dialysis status, suggesting limited utility of hepcidin for guiding treatment selection.