Abstract Background/ Introduction Chronic kidney disease (CKD) is a progressive condition that, in its advanced stages, necessitates dialysis. Patients undergoing dialysis are characterized by various comorbidities, including anemia and chronic inflammation, both of which are strongly associated with major adverse cardiovascular events (MACE). Hepcidin is overexpressed in patients with CKD due to reduced renal clearance and chronic inflammation, leading to impaired intestinal iron absorption and anemia. However, the prognostic role of hepcidin in patients with CKD remains unclear. Furthermore, it remains unknown whether the prognostic impact of daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor that reduces hepcidin levels in patients with CKD, can be modified by baseline hepcidin levels. Purpose This study aimed to clarify (A) the prognostic values of hepcidin level, and (B) the association between baseline hepcidin levels and daprodustat treatment effects in patients undergoing dialysis. Methods This is a post-hoc analysis of the Anemia Studies in Chronic Kidney Disease: Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor Daprodustat–Dialysis (ASCEND-D) trial, which is a randomized, open-label, phase 3 trial to test the efficacy and safety of daprodustat compared with conventional erythropoiesis-stimulating agents (ESAs). Patients undergoing dialysis were included. The primary endpoint was defined as MACE, including death from any cause, non-fatal myocardial infarction, and non-fatal stroke. Results Baseline hepcidin values were available for a total of 2,881 patients undergoing dialysis, with a median level of 176 ng/mL (interquartile range, 109–255). Higher hepcidin levels at baseline were associated with more female, higher body mass index, higher C-reactive protein levels, higher ferritin levels, and higher transferrin saturation at baseline. Hepcidin levels were lower in the daprodustat group compared to the ESA group at 4 weeks after treatment (P 0.001), and remained lower at 52 weeks (P 0.001). Kaplan-Meier curves showed no difference in the incidence of the primary endpoint across quartiles of baseline hepcidin levels (Log-rank P = 0.78). Additionally, no difference was observed in the incidence of the primary endpoint across quartiles of percentage changes in hepcidin levels from baseline to 4 weeks (Log-rank P = 0.31), or from baseline to 52 weeks (Log-rank P = 0.97). The prognostic impact of treatment (daprodustat vs. ESA) was not interacted by baseline hepcidin levels (P for interaction = 0.675). Furthermore, analyses for the secondary outcomes, including death alone, heart failure composite outcome, and thrombus composite outcome, yielded consistent results. Conclusions In patients undergoing dialysis, neither baseline hepcidin levels nor their temporal changes were associated with subsequent MACE, and baseline hepcidin levels did not modify the prognostic effect of daprodustat.
Fujimoto et al. (Sat,) studied this question.