Levels of the erythropoietin-responsive hormone erythroferrone in mice and humans with chronic kidney disease

Hanudel, Mark R.; Rappaport, Maxime; Chua, Kristine J.; Gabayan, Victoria; Qiao, Bo; Jung, Grace; Salusky, Isidro B.; Ganz, Tomas; Nemeth, Elizabeta

doi:10.3324/haematol.2017.181743

Cited by 43 publications

(40 citation statements)

References 14 publications

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“…We have to emphasize however that the level of hepcidin in these rHU‐EPO free patients did not reach values below the normal range. This suggests an ongoing ‘failure’ of EPO and Erythroferrone (ERFE) repressor induced hepcidin suppression, as this was shown to be very highly increased in HD patients . Whether ERFE levels are modulated in rHU‐EPO free patients remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Functional erythropoietin‐hepcidin axis in recombinant human erythropoietin independent haemodialysis patients

et al. 2019

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Section: Discussionmentioning

confidence: 99%

Functional erythropoietin‐hepcidin axis in recombinant human erythropoietin independent haemodialysis patients

et al. 2019

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“…Erythroferron, hypoxia inducible factors (HIFs), and platelet derived growth factor BB are all signaling peptides induced by hypoxia and were found to impact directly or via modulation of hepcidin on iron availability for erythropoiesis [91,92,93]. The biomarkers of hypoxia thus hold promise to better identify subjects suffering from AI/ID and to predict the erythroid response in patients with AI with and without ID, once commercially available ELISAs are available [94,95,96]. Of importance, none of these tests is currently standardized, which is a necessity to make them a reliable routine biomarker for the evaluation of iron status.…”

Section: Diagnosismentioning

confidence: 99%

Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases

2018

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Inflammation, being a hallmark of many chronic diseases, including cancer, inflammatory bowel disease, rheumatoid arthritis, and chronic kidney disease, negatively affects iron homeostasis, leading to iron retention in macrophages of the mononuclear phagocyte system. Functional iron deficiency is the consequence, leading to anemia of inflammation (AI). Iron deficiency, regardless of anemia, has a detrimental impact on quality of life so that treatment is warranted. Therapeutic strategies include (1) resolution of the underlying disease, (2) iron supplementation, and (3) iron redistribution strategies. Deeper insights into the pathophysiology of AI has led to the development of new therapeutics targeting inflammatory cytokines and the introduction of new iron formulations. Moreover, the discovery that the hormone, hepcidin, plays a key regulatory role in AI has stimulated the development of several therapeutic approaches targeting the function of this peptide. Hence, inflammation-driven hepcidin elevation causes iron retention in cells and tissues. Besides pathophysiological concepts and diagnostic approaches for AI, this review discusses current guidelines for iron replacement therapies with special emphasis on benefits, limitations, and unresolved questions concerning oral versus parenteral iron supplementation in chronic inflammatory diseases. Furthermore, the review explores how therapies aiming at curing the disease underlying AI can also affect anemia and discusses emerging hepcidin antagonizing drugs, which are currently under preclinical or clinical investigation.

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“…In this study, ERFE emerged as a coherent direct risk factor of death and CV complications in two separate CKD cohorts. Erythroferrone is strongly related in an inverse fashion to hepcidin in HD patients [13], which is per sé a direct correlate of CV events in HD patients [11]. Therefore, our observation that ERFE is directly associated with the combined outcome is prima facie counterintuitive with this finding.…”

Section: Discussionmentioning

confidence: 71%

“…In the second study by Hanudel et al [13], serum ERFE levels, measured by the recent assay by Ganz et al [20], were similar in 51 CKD and 161 healthy control subjects (6.1 (2.6–15.0) ng/mL and 7.8 (4.7–13.2) ng/mL, respectively) but twice lower than in 97 HD patients (15.7 (7.9–32.5) ng/mL). In the present study, including 1123 HD patients and 745 CKD patients, we measured serum ERFE by a kit based on Ganz assay and found that ERFE was much higher in HD patients than in CKD patients but, on average, ERFE levels in our patients were lower than in the corresponding patients’ groups in Hanudel study [13].…”

Section: Discussionmentioning

confidence: 99%

“…Biomarkers of iron metabolism like serum ferritin and hepcidin have been independently associated with the risk of death [9,10] and cardiovascular (CV) events [11] in this population. Information on ERFE in CKD is limited to just two studies [12,13], and in both studies circulating ERFE showed a dose-response relationship with the amount of erythropoiesis stimulating agents (ESA) administered, which is in line with experimental knowledge in animal models [3]. 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.…”

Section: Introductionmentioning

confidence: 99%

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

Spoto

Kakkar

et al. 2019

JCM

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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.

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Levels of the erythropoietin-responsive hormone erythroferrone in mice and humans with chronic kidney disease

Cited by 43 publications

References 14 publications

Functional erythropoietin‐hepcidin axis in recombinant human erythropoietin independent haemodialysis patients

Functional erythropoietin‐hepcidin axis in recombinant human erythropoietin independent haemodialysis patients

Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases

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

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