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3853 Erythroferrone Overexpression Mitigates Anemia and Improves Kidney Function in a Mouse Model of CKD

Program: Oral and Poster Abstracts
Session: 102. Iron Homeostasis and Biology: Poster III
Hematology Disease Topics & Pathways:
Research, Translational Research
Monday, December 9, 2024, 6:00 PM-8:00 PM

Brian Czaya, PhD1*, Elizabeta Nemeth, PhD2 and Tomas Ganz, MD, PhD2

1Center for iron disorders, David Geffen School of Medicine At UCLA, Los Angeles, CA
2Center for Iron Disorders, University of California, Los Angeles, Los Angeles, CA

Chronic kidney disease (CKD) affects over 800 million people worldwide, most of whom develop anemia caused by relative erythropoietin deficiency, increased levels of the iron-regulatory hormone hepcidin, as well as absolute and functional iron deficiency.

Erythropoietin-stimulating agents (ESAs) and iron supplementation ameliorate anemia in CKD but patients often become hyporesponsive to ESAs. Increasing ESA doses may heighten risks of thrombosis and cardiovascular mortality, highlighting the need for alternative strategies.

Erythroferrone (ERFE) is an erythroid suppressor of hepcidin, facilitating iron mobilization for erythropoiesis. In CKD, diminished marrow erythroblasts contribute to decreased ERFE production, likely further increasing hepcidin.

To explore the potential therapeutic use of ERFE in CKD, we tested the impact of augmented ERFE on systemic iron homeostasis and kidney function. Transgenic mice with erythroid overexpression of ERFE (ERFE-Tg) had similar iron stores to WT mice at weaning but became iron overloaded as they aged. To prevent early iron overload, we placed ERFE-Tg on 4ppm diet at weaning. 8-week-old male ERFE-Tg and wild-type (WT) mice were then fed 0.2% adenine-rich diet containing 100 ppm Fe for 8 weeks to induce CKD.

At 16 weeks, both WT and ERFE-Tg mice developed CKD and anemia but ERFE-Tg had higher hemoglobin, MCV and serum iron, as well as lower liver hepcidin mRNA/liver iron content ratio, indicating effective suppression of hepcidin by ERFE. Furthermore, kidney function (BUN and serum creatinine) was less impaired in ERFE-Tg. Thus, ERFE overexpression in adenine-induced nephropathy improves CKD-associated anemia and renal dysfunction, suggesting that ERFE has therapeutic potential in CKD.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH