Associations among Erythroferrone and Biomarkers of Erythropoiesis and Iron Metabolism, and Treatment with Long-Term Erythropoiesis-Stimulating Agents in Patients on Hemodialysis

Abstract

BackgroundWe aimed to identify associations between erythroferrone (ERFE), a regulator of hepcidin 25, and biomarkers of erythropoiesis and iron metabolism. We also aimed to determine the effects of erythropoiesis-stimulating agents (ESA), continuous erythropoietin receptor activator (CERA) and darbepoetin-α (DA) on ERFE production in patients on hemodialysis (HD).MethodsBlood samples were obtained from 59 patients before HD sessions on day 0 (baseline). Twenty patients who were injected with either CERA (N = 10) or DA (N = 10) at the end of the dialysis week (day 0), who had ferritin ≥ 100 ng/mL and/or transferrin saturation ≥ 20%, and hemoglobin > 9 g/dL were selected from among the 59 patients. Blood was sampled serially before HD sessions on days 3, 5, 7 from patients on DA and on the same days plus day 14 from those on CERA.ResultsLevels of ERFE correlated inversely with those of hepcidin 25 and ferritin, and positively with those of soluble transferrin receptor. The hepcidin 25: ERFE ratio and hepcidin 25 levels positively correlated with ferritin levels. Levels of ERFE significantly increased from day 3 of treatment with DA and CERA and decreased by days 7 and 14, respectively. Erythropoiesis-stimulating agents concomitantly decreased levels of hepcidin 25 as those of ERFE increased.ConclusionWe identified a novel association between ESA and ERFE in patients on HD. Both DA and CERA increased levels of ERFE that regulated hepcidin 25 and led to iron mobilization from body stores during erythropoiesis.

EPO and hepcidin plasma concentrations in blood donors and β‐thalassemia intermedia are not related to commercially tested plasma ERFE concentrations

“…The absence of a correlation between ERFE and hepcidin plasma levels in our study differs from a previous report on associations between both analytes that were observed using the same FAM132B ELISA in a study among hemodialysed patients 3. However, our observations on lack of correlations of ERFE plasma levels and plasma hepcidin and EPO levels are in agreement with those obtained in a study among patients with chronic mountain sickness (as defined by excessive erythrocytosis, hemoglobin ≥ 21 g/dL, and hypoxemia with no other medical explanation), who underwent isovolemic venesection of 500 mL on four consecutive days (days 1‐4) 6.…”

“…Correlations were found between levels of ERFE and hepcidin, ferritin, and soluble transferrin receptor (sTfR) 3. In the present study we aim to validate this kit by measurement of ERFE in β‐thalassemia intermedia patients and in healthy blood donors before and after blood donation and to correlate findings with other markers of erythropoiesis and iron metabolism.…”

“…Recently, associations between ERFE and biomarkers of erythropoiesis and iron metabolism have been evaluated for the first time in patients with chronic kidney disease on hemodialysis exploiting a commercially available sandwich ELISA kit for the quantification of ERFE (FAM132B) in human serum samples 3. Correlations were found between levels of ERFE and hepcidin, ferritin, and soluble transferrin receptor (sTfR) 3.…”

Anaemia of Chronic Kidney Disease: What We Know Now

“…Honda et al examined the association between ERFE and biomarkers of iron metabolism in haemodialysis patients and found that levels of ERFE were inversely correlated with levels of hepcidin and ferritin and positively correlated with soluble transferrin receptor. They also showed that the use of ESAs increased the levels of ERFE that regulated hepcidin and led to iron mobilisation from body stores during erythropoiesis (30). Additional studies of this pathway and its potential effects in CKD are warranted.…”

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

“…It is likely that increased erythroblasts in the dyserythropoietic bone marrow secrete a factor that inhibits hepcidin expression. In mice, erythroferrone (FAM132b), a tumor necrosis factor superfamily molecule, was shown to be expressed by erythroblasts and suppress hepcidin expression [54][55][56][57][58].…”