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Review
. 2019 Mar;34(3):365-378.
doi: 10.1007/s00467-017-3849-3. Epub 2018 Mar 22.

HIF stabilizers in the management of renal anemia: from bench to bedside to pediatrics

Dalvir Kular  1 , Iain C Macdougall  2
Affiliations
Review

HIF stabilizers in the management of renal anemia: from bench to bedside to pediatrics

Dalvir Kular et al. Pediatr Nephrol. 2019 Mar.

Abstract

Anemia is a common complication of chronic kidney disease (CKD) in adult and pediatric patients. It has traditionally been treated with erythropoietin therapy and iron supplementation, with great success. With the discovery of the major transcription factor hypoxia inducible factor (HIF) for the erythropoietin gene in 1992, molecules were created that inhibit the HIF prolyl-hydroxylase enzyme. This new class of drug-called HIF stabilizers, or HIF prolyl-hydroxylase inhibitors-prevents the proteasomal degradation of HIF-α, thereby inducing upregulation of the erythropoietin gene. This new strategy for treating CKD anemia is already in phase III clinical trials in adults, and the potential advantages of this therapy are that it is orally active (thereby avoiding injections), and patients are exposed to lower circulating levels of erythropoietin. The long-term safety of this strategy, however, requires elucidation in these trials, particularly since there are many other hypoxia-sensitive genes, notably, angiogenic factors such as vascular endothelial growth factors (VEGF), as well as glycolytic enzymes. As with all new therapies, it is only once a positive benefit: risk profile has been ascertained in adults that the treatment will translate across into pediatrics. Specific issues in the pediatric CKD population are discussed in this review.

Keywords: Anemia; Chronic kidney disease; HIF prolyl-hydroxylase inhibitor; HIF stabilizer.

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Conflict of interest statement

Iain Macdougall has received consultancy fees, speaker fees, and research support from a number of manufacturers of HIF stabilizers, including FibroGen, Astellas, GlaxoSmithKline, Akebia, and Bayer. Dalvir Kular reports no conflict of interest.

Figures

Fig. 1
Fig. 1
Regulation of hypoxia inducible factor (HIF) activity. HIF-PH hypoxia inducible factor prolyl-hydroxylase, HIF-α hypoxia inducible factor alpha, HIF-β hypoxia inducible factor beta, HRE hypoxia response element, O2 oxygen, OH hydroxyl group, VHL von Hippel-Lindau, EPO erythropoietin gene
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