A Review on Vadadustat: Hope in Treatment of Anemia Patients Having Chronic Kidney Disease

Abstract

Vadadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, may offer an oral alternative to injectable erythropoiesis-stimulating agents (ESAs) to treat anemia in patients undergoing peritoneal dialysis. Current standard of care for anemia linked to chronic kidney disease (CKD) is the use of ESAs. Targeting the HIFs-the basic elements of RBC production-presents an oral alternative to the standard ESAs. Due to their low oxygen environment, HIF transcription factors are, by nature, constitutively activated at high altitude, which enhances iron mobilization and boosts production of endogenous erythropoietin (EPO). While clinical trials have demonstrated safety and efficacy for vadadustat, whether it will promote cancer is still a topic under investigation. In fact, research has suggested that activation of HIFs promotes tumor growth due to stimulation of angiogenesis through vascular endothelial growth factor (VEGF). The HIF system includes two subunits, α and β. Under low-oxygen conditions, the HIF-1α subunit accumulates and translocates to the cell nucleus, where it binds to HIF-β to form the heterodimer HIF-1αβ. This complex initiates the expression of sensitive hypoxic genes, including the EPO gene, whose production is increased under such conditions. Three isoforms of the HIF-α subunit exist: HIF-1α, HIF-2α, and HIF-3α, all of which can dimerize with HIF-β and activate the transcription of other genes besides EPO. In the intestine, duodenal cytochrome b (DCYTB) reduces ferric iron (Fe3+) to ferrous iron (Fe2+), which is then taken into enterocytes by the divalent metal transporter-1 (DMT1). HIF-2 controls both DCYTB and DMT1. Iron is exported from cells by ferroportin (FPN), and this export is repressed by hepcidin but stimulated by HIF. In blood, iron is transported in a complex with transferrin (TF) to the liver, RES cells, bone marrow, and other tissues. The increased erythropoietic activity in the marrow leads to the production of growth differentiation factor 15 (GDF15) and erythroferrone, which are known to inhibit hepcidin in liver cells. The inflammatory cytokine relates with increased hepcidin production in the liver, whose action is mediated by decreased ferroportin expression on the cell surface and lower blood iron levels. Vadadustat has HIF stabilized for the promotion of the secretion of EPO but does not seem to have an effect on the production of VEGF. It is also reported that increased activity of HIF results in an antitumor effect. Results from clinical trials support the use of vadadustat without genotoxicity, facilitating the treatment of anemia in patients with chronic kidney disease.