Overexpression of the Iron Regulatory Hormone Erythroferrone Mitigates Anemia and Enhances Kidney Function in a Mouse Model of CKD

Background: Most CKD patients develop anemia because of combined effects of relative erythropoietin deficiency, iron restriction caused by increased levels of the iron-regulatory hormone hepcidin, as well as absolute iron deficiency. Erythropoietin-stimulating agents (ESAs) and iron supplementation mitigate anemia in CKD, but patients often become hyporesponsive to the treatment, requiring higher doses of these drugs. Increasing ESA doses may heighten risks of thrombosis and cardiovascular mortality, highlighting the need for alternative strategies. Erythroferrone (ERFE) is a hormone produced by erythroblasts in response to EPO, and functions as a physiological suppressor of hepcidin to facilitate iron mobilization for erythropoiesis. In CKD, diminished marrow erythroblasts and inadequate EPO concentrations contribute to decreased ERFE production, likely further increasing hepcidin. Exploring the potential therapeutic use of ERFE in CKD, we tested the impact of augmented ERFE on systemic iron homeostasis, hypoxia, inflammation, and kidney function. Methods: Transgenic mice with erythroid overexpression of ERFE (ERFE-Tg) have similar iron stores to wild-type littermates (WT) at weaning but become iron-overloaded as they age. To prevent early iron overload prior to CKD, we placed ERFE-Tg at weaning on low iron (4 ppm) diet for 4 weeks. WT mice were fed iron-replete diet. At 8 weeks of age, male ERFE-Tg and WT were then fed identical 0.2% adenine-rich diet containing 100 ppm iron for 8 weeks to induce CKD. Results: At 16 weeks, both WT and ERFE-Tg developed CKD and anemia, but ERFE-Tg had higher hemoglobin, MCV and serum iron, as well as a lower ratio of serum hepcidin to liver iron content, indicating effective suppression of hepcidin by ERFE even in the setting of CKD. Systemic hypoxia as reflected by serum VEGF levels was also reduced in ERFE-Tg, indicating improved tissue oxygenation. Furthermore, although systemic and kidney inflammation (TNFa, IL1b, IL6) were similar between WT and ERFE-Tg, kidney function (BUN and serum creatinine) was less impaired in ERFE-Tg. Conclusion: Our study demonstrates that despite chronic inflammation, ERFE overexpression in adenine-induced nephropathy improves CKD-associated anemia, hypoxia and kidney function. These data indicate that therapeutic augmentation of ERFE could provide multiple benefits in CKD. Funding: NIDDK Support