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Review
. 2022 Oct 31;9(1):1-11.
doi: 10.1159/000527835. eCollection 2023 Jan.

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

Jing Li  1 , Volker H Haase  2   3   4 , Chuan-Ming Hao  1
Affiliations
Review

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

Jing Li et al. Kidney Dis (Basel). .

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.

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Conflict of interest statement

Chuan-Ming Hao received honoraria from FibroGen for speaking engagements and advisory board participation related to physician education. The other authors do not disclose any conflicts of interest. Volker H. Haase is a scientific advisor and has received honoraria from Akebia Therapeutics. Volker H. Haase is supported by the Krick-Brooks Chair in Nephrology.

Figures

Fig. 1
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
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.
See this image and copyright information in PMC

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