Amelioration of chronic kidney disease-associated anemia by vadadustat in mice is not dependent on erythroferrone

Vadadustat is an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor that increases endogenous erythropoietin production and has been shown to decrease hepcidin levels, ameliorate iron restriction, and increase hemoglobin concentrations in anemic patients with chronic kidney disease (CKD). In studies of physiological responses to other erythropoietic stimuli, erythropoietin induced erythroblast secretion of erythroferrone (ERFE), which acts on the liver to suppress hepcidin production and mobilize iron for erythropoiesis. We therefore investigated whether vadadustat effects on erythropoiesis and iron metabolism are dependent on ERFE. Wild type and ERFE knockout mice with and without CKD were treated with vadadustat or vehicle. In both wild type and ERFE knockout CKD models, vadadustat was similarly effective, as evidenced by normalized hemoglobin concentrations, increased expression of duodenal iron transporters, lower serum hepcidin levels, and decreased tissue iron concentrations. This is consistent with ERFE-independent increased iron mobilization. Vadadustat treatment also lowered serum urea nitrogen and creatinine concentrations and decreased expression of kidney fibrosis markers. Lastly, vadadustat affected fibroblast growth factor 23 (FGF23) profiles: in non-CKD mice, vadadustat increased plasma total FGF23 out of proportion to intact FGF23, consistent with the known effects of hypoxia-inducible factor-1α and erythropoietin on FGF23 production and metabolism. However, in the mice with CKD, vadadustat markedly decreased both total and intact FGF23, effects likely contributed to by the reduced loss of kidney function. Thus, in this CKD model, vadadustat ameliorated anemia independently of ERFE, improved kidney parameters, and decreased FGF23. How vadadustat affects CKD progression in humans warrants future studies. Vadadustat is an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor that increases endogenous erythropoietin production and has been shown to decrease hepcidin levels, ameliorate iron restriction, and increase hemoglobin concentrations in anemic patients with chronic kidney disease (CKD). In studies of physiological responses to other erythropoietic stimuli, erythropoietin induced erythroblast secretion of erythroferrone (ERFE), which acts on the liver to suppress hepcidin production and mobilize iron for erythropoiesis. We therefore investigated whether vadadustat effects on erythropoiesis and iron metabolism are dependent on ERFE. Wild type and ERFE knockout mice with and without CKD were treated with vadadustat or vehicle. In both wild type and ERFE knockout CKD models, vadadustat was similarly effective, as evidenced by normalized hemoglobin concentrations, increased expression of duodenal iron transporters, lower serum hepcidin levels, and decreased tissue iron concentrations. This is consistent with ERFE-independent increased iron mobilization. Vadadustat treatment also lowered serum urea nitrogen and creatinine concentrations and decreased expression of kidney fibrosis markers. Lastly, vadadustat affected fibroblast growth factor 23 (FGF23) profiles: in non-CKD mice, vadadustat increased plasma total FGF23 out of proportion to intact FGF23, consistent with the known effects of hypoxia-inducible factor-1α and erythropoietin on FGF23 production and metabolism. However, in the mice with CKD, vadadustat markedly decreased both total and intact FGF23, effects likely contributed to by the reduced loss of kidney function. Thus, in this CKD model, vadadustat ameliorated anemia independently of ERFE, improved kidney parameters, and decreased FGF23. How vadadustat affects CKD progression in humans warrants future studies. Novel roles of HIF-PHIs in chronic kidney disease: the link between iron metabolism, kidney function, and FGF23Kidney InternationalVol. 100Issue 1PreviewHanudel et al. investigated the effects of hypoxia-inducible factor–prolyl hydroxylase domain inhibitors (HIF-PHIs) on iron metabolism in a chronic kidney disease (CKD) mouse model and showed that vadadustat, an HIF-PHI, exerted beneficial effects on anemia and iron disorders independently of erythroferrone. Vadadustat also inhibited the progression of CKD and the CKD-associated increase of plasma fibroblast growth factor 23 in CKD mice. This study provides new insights into the action of HIF-PIHs in CKD. Full-Text PDF In this issueKidney InternationalVol. 100Issue 1PreviewWu et al. examined the role of annexin A1 in diabetic kidney disease. Based on the known activities of annexin 1, they postulated that it may be an endogenous regulator of inflammation that could positively affect the diabetic kidney. The team demonstrated that annexin A1 is found in abundance in the glomeruli and tubulointerstitium of diabetic patients. Using a mouse model of diabetes, the investigators showed that if annexin 1 is knocked out, diabetic kidney disease worsens, and if annexin 1 is overexpressed, diabetic kidney disease is attenuated. Full-Text PDF Hypoxia-inducible factor prolyl hydroxylase inhibitor, C-terminal fibroblast growth factor 23 fragments, and hepcidinKidney InternationalVol. 100Issue 3PreviewWith great interest, I read the impressive new findings by Hanudel et al. recently published in Kidney International showing that erythroferrone-mediated suppression of hepcidin is not essential for the beneficial effects of vadadustat, as hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), on anemia in chronic kidney disease.1 In the discussion section, the authors meticulously listed several alternative pathways that may function as the predominant mechanism linking HIF-PHI and hepcidin suppression. Full-Text PDF The author replies:Kidney InternationalVol. 100Issue 3PreviewI appreciate the insightful letter from Dr. Eisenga regarding potential interactions among vadadustat—a hypoxia-inducible factor prolyl hydroxylase inhibitor in development for the treatment of chronic kidney disease (CKD) anemia, C-terminal fibroblast growth factor 23 (FGF23), and hepcidin.1 As Dr. Eisenga astutely points out, in our murine models, vadadustat treatment resulted in an increase in the percentage of circulating FGF23 that was fragmented (C-terminal FGF23). In both of our non-CKD and CKD cohorts (including both wild-type and erythroferrone knockout genotypes), vadadustat treatment significantly increased the circulating percentage of C-terminal FGF23 by an average of 16%. Full-Text PDF