Abstract: PO0291
Amelioration of CKD-Associated Anemia by Vadadustat in Mice Is Not Dependent on Erythroferrone
Session Information
- Anemia and Iron Management
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Anemia and Iron Metabolism
- 200 Anemia and Iron Metabolism
Authors
- Hanudel, Mark R., University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
- Wong, Shirley, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
- Jung, Grace, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
- Qiao, Bo, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
- Gabayan, Victoria Rivka, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
- Ganz, Tomas, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
Background
Vadadustat is an investigational hypoxia inducible factor prolyl hydroxylase inhibitor that increases endogenous erythropoietin (EPO) production, and has been shown to decrease hepcidin levels, improve iron status, and increase hemoglobin concentrations in anemic chronic kidney disease (CKD) patients. Increased EPO induces erythroblast secretion of erythroferrone (ERFE), which acts on the liver to suppress serum hepcidin production. To determine whether vadadustat mechanisms of action are dependent on ERFE, we treated wild type (WT) and ERFE knockout (EKO) mice, with and without adenine diet-induced CKD, with vadadustat.
Methods
6-week-old male C57BL/6 WT and EKO mice were placed on 8-week diets that did or did not contain 0.2% adenine. For the last 3 weeks of the diets, the mice were treated with vadadustat (75 mg/kg/day via oral gavage) or vehicle solution. Mice were euthanized at 14 weeks of age (n=8 mice per group).
Results
Unlike the WT mice, EKO mice had undetectable spleen Erfe mRNA, minimal marrow Erfe mRNA, and no increase in ERFE mRNA or protein in response to vadadustat. However, in both WT and EKO CKD models, vadadustat normalized hemoglobin concentrations (Fig 1a), increased expression of duodenal iron transporters, tended to lower serum hepcidin, and decreased tissue iron concentrations (consistent with increased iron mobilization), suggesting ERFE-independent pro-erythropoietic effects. Vadadustat treatment was also associated with improved kidney function (Fig 1b) and decreased expression of renal fibrosis markers. Lastly, vadadustat affected FGF23 profiles: In non-CKD mice, vadadustat increased plasma total FGF23 out of proportion to intact FGF23, consistent with the known effects of HIF1α and EPO on FGF23 production and metabolism. However, in the CKD mice, vadadustat markedly decreased both total and intact FGF23 (Fig 1c), effects likely contributed to by improved kidney function.
Conclusion
Vadadustat ameliorates CKD-associated anemia independently of ERFE, and also improves kidney function and lowers FGF23 in this CKD model. How vadadustat affects CKD progression in humans may warrant future studies.
Funding
- Commercial Support –