Erythropoietin and a hypoxia‐inducible factor prolyl hydroxylase inhibitor (HIF‐PHDi) lowers FGF23 in a model of chronic kidney disease (CKD). Issue 11 (31st May 2020)

• Record Type: Journal Article
• Authors: Noonan, Megan L.; Clinkenbeard, Erica L.; Ni, Pu; Swallow, Elizabeth A.; Tippen, Samantha P.; Agoro, Rafiou; Allen, Matthew R.; White, Kenneth E.
• Is Part Of: Physiological reports. Volume 8:Issue 11(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-05-31
• Subjects: CKD -- EPO -- FGF‐23 -- HIF‐PHDi -- phosphate; Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.14434
• Languages: English
• ISSNs: 2051-817X

Abstract

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. Abstract : Iron‐deficiency anemia is a potent stimulator of the phosphaturic hormone FGF23, and anemia, elevated FGF23, and serum phosphate are all significant risk factors for chronic kidney disease (CKD) patient death; however, the contribution of anemia to circulating FGF23 in CKD is not understood. We found that a CKD mouse model treated with EPO or a HIF‐PHDi to restore proper iron utilization had a 70% reduction of circulating iFGF23, normalization of vitamin D metabolic enzymes, and no exacerbation of hyperphosphatemia. In summary, our work demonstrated that the major portion of elevated iFGF23 in CKD is likely due to the associated anemia/iron deficiency, is therapeutically responsive to the control of iron utilization, and may thus provide modifiable patient benefit for mineral handling during CKD.