Serum Erythroferrone Levels Associate with Mortality and Cardiovascular Events in Hemodialysis and in CKD Patients: A Two Cohorts Study

Erythroferrone (ERFE) is a hepcidin inhibitor whose synthesis is stimulated by erythropoietin, which increases iron absorption and mobilization. We studied the association between serum ERFE and mortality and non-fatal cardiovascular (CV) events in a cohort of 1123 hemodialysis patients and in a cohort of 745 stage 1-5 chronic kidney disease (CKD) patients. Erythroferrone was measured by a validated enzyme-linked immunosorbent assay (ELISA). In the hemodialysis cohort, serum ERFE associated directly with erythropoiesis stimulating agents (ESA) dose (p < 0.001) and inversely with serum iron and ferritin (p < 0.001). Erythroferrone associated with the combined outcome in an analysis adjusting for traditional risk factors, factors peculiar to end-stage kidney disease, serum ferritin, inflammation, and nutritional status (HR, hazard ratio, (5 ng/mL increase: 1.04, 95% confidence interval, CI: 1.01-1.08, p = 0.005). Furthermore, treatment with ESA modified the relationship between ERFE and the combined end-point in adjusted analyses (p for the effect modification = 0.018). Similarly, in CKD patients there was a linear increase in the risk for the same outcome in adjusted analyses (HR (2 ng/mL increase): 1.04, 95% CI: 1.0-1.07, p = 0.015). Serum ERFE is associated with mortality and CV events in CKD and in HD patients, and treatment by ESA amplifies the risk for this combined end-point in HD patients.