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

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.

Decreased Hemoglobin Concentration and Iron Metabolism Disorder in Periodontitis: Systematic Review and Meta-Analysis

“…Despite many efforts made to tackle this burden, it retains a high prevalence around the world. Generally, anemia of inflammation (AI), a hallmark of chronic and persistent inflammatory diseases with prolonged immune activation (Weiss et al, 2019), is characterized by the insufficient production of erythropoietin (EPO) and decreased response of erythroid progenitors to EPO (Spoto et al, 2019). In addition, AI inhibits the release of iron from the body stores and alters the iron status after being stimulated by hepcidin (Schumann and Solomons, 2017).…”

Iron and Chronic Kidney Disease: Still a Challenge

“…However, ERFE concentrations and actions are not well-characterized in CKD patients. As yet, information on ERFE in CKD is scarce and, in fact, limited to three studies, which yield slightly inconsistent results (27)(28)(29). All of them confirmed positive correlations between serum ERFE levels and serum EPO, as well as ESA dose, while the relationships between ERFE and biomarkers of iron metabolism have not been clearly demonstrated (27)(28)(29).…”

“…As yet, information on ERFE in CKD is scarce and, in fact, limited to three studies, which yield slightly inconsistent results (27)(28)(29). All of them confirmed positive correlations between serum ERFE levels and serum EPO, as well as ESA dose, while the relationships between ERFE and biomarkers of iron metabolism have not been clearly demonstrated (27)(28)(29). In the Honda et al study of hemodialysis (HD) patients treated with long-acting ESAs (darbepoetin-α or continuous EPO receptor activator), levels of ERFE increased shortly after ESA injection, FIGURE 5 | The regulation of hepcidin expression by iron and inflammation.…”

Perspectives for the therapy of anemia of chronic diseases

“…ERFE is a physiological regulator of hepcidin, which is synthesized and secreted by erythroblasts in the bone marrow and other tissues in response to EPO. ERFE inhibits hepcidin transcription by an unknown mechanism that involves BMP6 pathway and probably some known membrane receptors [30,31]. ERFE antagonists and agonists, and also other substances involved in the BMP6 signaling pathway, may prove useful in the prevention and treatment of iron disorders.…”

“…However, a recently published study suggested a correlation between increased ERFE levels and death/cardiovascular events in hemodialysis patients with CKD, which is further enhanced by the administration of ESA [30]. Therefore, the potential use of ERFE in anemia requires further research and careful determination of patient groups who may benefit from such a therapy.…”