Abstract
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.
Highlights
Iron plays a crucial role in several fundamental biological processes such as oxygen transport, cellular respiration, and metabolic reactions [1]
This hormone is encoded by the FAM132B gene— renamed ERFE gene—and coincides with a protein expressed in the skeletal muscle, called myonectin (CTRP15) [4]
With this background in mind, we studied the relationship between serum ERFE, mortality, and CV events in a cohort of predialysis patients with chronic kidney disease (CKD) of various severities and in a separate cohort of end-stage kidney disease (ESKD) patients maintained on chronic hemodialysis (HD)
Summary
Iron plays a crucial role in several fundamental biological processes such as oxygen transport, cellular respiration, and metabolic reactions [1]. In 2014, a new iron metabolism regulating factor synthesized in erythroblasts in response to erythropoietin—erythroferrone (ERFE)—was identified [3] This hormone is encoded by the FAM132B gene— renamed ERFE gene—and coincides with a protein expressed in the skeletal muscle, called myonectin (CTRP15) [4]. Because of the peculiar combination of risk factors underlying anemia [14] and the risk for CV events [15,16] in CKD, studying the relationship between ERFE, mortality, and CV disease is a relevant issue that has never been investigated in this population. Because of the physiological relationship between serum ERFE and EPO levels, a second pre-specified goal of this study was to test whether the relationship of ERFE with mortality and non-fatal CV events is modified by the dose of ESA in these patients
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