Erythropoietin and a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHDi) lowers FGF23 in a model of chronic kidney disease (CKD).

Megan L. Noonan,Rafiou Agoro,Elizabeth A. Swallow,Kenneth E. White,Erica L. Clinkenbeard,Pu Ni,Matthew R. Allen,Samantha P. Tippen

doi:10.14814/phy2.14434

Abstract

Iron‐deficiency anemia is a potent stimulator of the phosphaturic hormone Fibroblast growth factor‐23 (FGF23). Anemia, elevated FGF23, and elevated serum phosphate are significant mortality risk factors for patients with chronic kidney disease (CKD). However, the contribution of anemia to overall circulating FGF23 levels in CKD is not understood. Our goal was to investigate the normalization of iron handling in a CKD model using the erythropoiesis stimulating agents (ESAs) Erythropoietin (EPO) and the hypoxia‐inducible factor prolyl hydroxylase inhibitor (HIF‐PHDi) FG‐4592, on the production of, and outcomes associated with, changes in bioactive, intact FGF23 (“iFGF23”). Our hypothesis was that rescuing the prevailing anemia in a model of CKD would reduce circulating FGF23. Wild‐type mice were fed an adenine‐containing diet to induce CKD, then injected with EPO or FG‐4592. The mice with CKD were anemic, and EPO improved red blood cell indices, whereas FG‐4592 increased serum EPO and bone marrow erythroferrone (Erfe), and decreased liver ferritin, bone morphogenic protein‐6 (Bmp‐6), and hepcidin mRNAs. In the mice with CKD, iFGF23 was markedly elevated in control mice but was attenuated by >70% after delivery of either ESA, with no changes in serum phosphate. ESA treatment also reduced renal fibrosis markers, as well as increased Cyp27b1 and reduced Cyp24a1 mRNA expression. Thus, improvement of iron utilization in a CKD model using EPO and a HIF‐PHDi significantly reduced iFGF23, demonstrating that anemia is a primary driver of FGF23, and that management of iron utilization in patients with CKD may translate to modifiable outcomes in mineral metabolism.

Highlights

Chronic kidney disease (CKD) is the most prevalent form of combined phosphate and iron handling defects
The marked increase in Fibroblast growth factor-23 (FGF23) during CKD goes beyond phosphate, as it was demonstrated in a mouse model of autosomal dominant hypophosphatemic rickets (ADHR) that intact FGF23 (iFGF23) was elevated during iron-deficiency anemia in the genetic background of an Fgf23 stabilizing mutation (Farrow et al, 2011)
The primary use of the erythropoiesis stimulating agents (ESAs) EPO and HIF-PHDi is to treat the anemia of CKD

Summary

Introduction

Chronic kidney disease (CKD) is the most prevalent form of combined phosphate and iron handling defects. The marked increase in FGF23 during CKD goes beyond phosphate, as it was demonstrated in a mouse model of autosomal dominant hypophosphatemic rickets (ADHR) that iFGF23 was elevated during iron-deficiency anemia in the genetic background of an Fgf stabilizing mutation (Farrow et al, 2011). It was shown in non-dialysis patients with CKD that circulating FGF23 is associated with anemia (Nam et al, 2018). These findings suggest that there is crosstalk between phosphate and iron homeostasis via FGF23, a critical relationship since elevated FGF23 is associated with a > 6-fold increased odds for CKD patient death (Isakova, Xie, et al, 2011)

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