AI Article Synopsis

  • - Vadadustat is a new drug that boosts erythropoietin production, helps combat anemia in chronic kidney disease (CKD) patients, and lowers hepcidin levels, which improves iron availability for red blood cell production.
  • - Research using both wild type and ERFE knockout mice showed that treatment with vadadustat improved hemoglobin levels and iron metabolism similarly in both types, indicating its effectiveness does not rely on erythroferrone (ERFE).
  • - Vadadustat also positively impacted kidney function, reducing harmful substances in the blood and affecting FGF23 levels differently in CKD and non-CKD mice, suggesting it may help manage CKD progression in humans, but further studies are needed

Article Abstract

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.

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Source
http://dx.doi.org/10.1016/j.kint.2021.03.019DOI Listing

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