Updates on Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in the Treatment of Renal Anemia

Abstract

Background: Anemia is a common complication of chronic kidney disease. The hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) is a new class of oral drugs for the treatment of renal anemia.

Summary: Clinical trials have consistently shown that HIF-PHIs can effectively increase hemoglobin in both the dialysis population and the nondialysis population. The effects of HIF-PHIs in treating renal anemia include promoting endogenous erythropoietin production and facilitating iron mobilization. Several studies suggest that the erythropoiesis effect of roxadustat is less affected by inflammation. Careful monitoring of thromboembolic events and tumor before and during HIF-PHI treatment is necessary.

Key messages: HIF-PHIs are effective in correcting renal anemia. The long-term safety of HIF-PHIs needs to be further studied.

Keywords: Anemia; Chronic kidney disease; Hypoxia-inducible factor; Iron.

Fig. 1

Prolyl hydroxylase domain (PHD) is a therapeutic target for CKD anemia. In normoxic conditions, HIFα is hydroxylated on proline residues by PHD. Prolyl-hydroxylated HIFα is recognized and ubiquitylated by the von Hippel-Lindau (VHL) complex. Polyubiquitylated HIFα is then degraded by the proteasomal degradation system. In hypoxic conditions or during HIF-PHI treatment, HIFα translocates to the nucleus and forms a heterodimer with HIFβ. The heterodimer binds to hypoxia-response elements and induces the transcription of oxygen-regulated genes, including genes associated with erythropoiesis, angiogenesis, glycolysis, etc.

Fig. 2

Effect of HIF on iron absorption and mobilization. In the intestine, Fe³⁺ is reduced to Fe²⁺ by duodenal cytochrome b reductase 1 (DCYTB), and then Fe²⁺ enters intestinal cells via divalent metal transporter 1 (DMT1). Intracellular Fe²⁺ exits cells through ferroportin (FPN), and then Fe³⁺ is used for erythropoiesis. Dmt1, Dcytb, Fpn, transferrin, and transferrin receptor have been demonstrated to be target genes of HIF. Stabilizing HIF is associated with reduced levels of hepcidin. Hepcidin suppression increases FPN, which enhances iron absorption and utilization.