Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Jul;26(4):253-266.
doi: 10.1053/j.ackd.2019.04.004.

Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience

Neil S Sanghani  1 , Volker H Haase  2
Affiliations
Review

Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience

Neil S Sanghani et al. Adv Chronic Kidney Dis. 2019 Jul.

Abstract

Prolyl hydroxylase domain oxygen sensors are dioxygenases that regulate the activity of hypoxia-inducible factor (HIF), which controls renal and hepatic erythropoietin production and coordinates erythropoiesis with iron metabolism. Small molecule inhibitors of prolyl hydroxylase domain dioxygenases (HIF-PHI [prolyl hydroxylase inhibitor]) stimulate the production of endogenous erythropoietin and improve iron metabolism resulting in efficacious anemia management in patients with CKD. Three oral HIF-PHIs-daprodustat, roxadustat, and vadadustat-have now advanced to global phase III clinical development culminating in the recent licensing of roxadustat for oral anemia therapy in China. Here, we survey current clinical experience with HIF-PHIs, discuss potential therapeutic advantages, and deliberate over safety concerns regarding long-term administration in patients with renal anemia.

Keywords: Anemia; Chronic kidney disease; Erythropoietin; Hypoxia-inducible factor; Prolyl hydroxylase domain.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest statement: VHH serves on the scientific advisory board of Akebia Therapeutics, Inc., a company that develops PHD inhibitors for the treatment of anemia.

Figures

Figure 1:
Figure 1:. HIF-prolyl hydroxylase inhibitors activate HIF signaling.
Overview of HIF activity regulation by proly hydroxylase domain (PHD) dioxygenases. Shown on the right are the chemical structures of HIF-prolyl hydroxylase inhibitors (HIF-PHI) currently in phase III clinical development. The oxygen-sensitive hypoxia-inducible factor (HIF)-α subunit is constitutively synthesized and rapidly degraded under normoxic conditions. Proteasomal degradation of HIF-α is mediated by the von Hippel-Lindau (VHL)-E3-ubiquitin ligase complex and requires prolyl hydroxylation. PHD1, PHD2 and PHD3 are dioxygenases that utilize molecular oxygen (O2) and 2-oxoglutarate (2-OG, also known as α-ketoglutarate) for HIF-α hydroxylation. PHD2 is the main regulator of HIF activity in most cells. A reduction in PHD catalytic activity, either under hypoxia or as a result of pharmacologic inhibition, results in a shift of the balance between HIF-α synthesis and degradation towards synthesis, intracellular HIF-α accumulation and nuclear translocation of HIF-α. In the nucleus HIF-α forms a heterodimer with HIF-β, which increases the transcription of HIF-regulated genes such as erythropoietin (EPO), vascular endothelial growth factor (VEGF), phosphoglycerate kinase 1 (PGK1), lactate dehydrogenase (LDH) and others. Also shown are examples of HIF-regulated biological processes. A common feature of HIF-PHIs is the presence of a carbonylglycine side chain, which is structurally analogous to 2-OG (daprodustat, roxadustat and vadadustat). Molidustat is structurally different and does not contain a carbonylglycine side chain. With regard to specificity, HIF-PHIs appear to selectively target PHDs over FIH and other 2-OG-dpependent dioxygenases.
Figure 2:
Figure 2:. HIF-prolyl hydroxylase inhibitors coordinate erythropoiesis with iron metabolism.
Simplified overview of the role of HIF in the regulation of iron metabolism. HIF-2 induces renal and hepatic erythropoietin (EPO) synthesis in response to hypoxia or administration of hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) inhibitors (HIF-PHI), which stimulate erythropoiesis. An adjustment in iron mobilization is needed to match increased iron demand in erythroid precursor cells in the bone marrow (BM). In the duodenum, duodenal cytochrome b (DCYTB) reduces ferric iron (Fe3+) to its ferrous form (Fe2+), which is then transported into the cytosol of enterocytes by divalent metal transporter-1 (DMT-1). DCYTB and DMT1 are HIF-2-regulated. Absorbed iron is released into the circulation by ferroportin (FPN; HIF-2-regulated), the only known cellular iron exporter and then transported in complex with transferrin (TF) to the liver, reticule-endothelial system (RES) cells, BM and other organs. TF is HIF regulated and hypoxia increases its serum levels. Low serum iron and increased ‘erythropoietic drive’ inhibit hepcidin synthesis in the liver resulting in increased FPN cell surface expression, as hepcidin promotes FPN degradation and lowers its cell surface expression. Erythroferrone (FAM132B) is produced by erythroblasts and suppresses hepatic hepcidin transcription when erythropoiesis is stimulated. Growth differentiation factor 15 (GDF15) is another factor with hepcidin-suppressing properties, however, its role in vivo is not clear. As a result of hepcidin suppression more iron is released from enterocytes, hepatocytes and RES cells. Whether HIF-PHI effects on iron mobilization are mediated through the hepcidin/FPN axis or reflect a direct transcriptional activation of iron metabolism gene expression is unclear (dashed lines). Phase II studies reported consistent increases in TIBC suggesting a direct effect on transferrin synthesis. Plasma transferrin was measured in some of the studies and found to be increased., , , It is unclear whether HIF-PHIs affect the BM directly as HIF has been shown to be involved in erythroid maturation and hgb synthesis.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Koury MJ, Haase VH. Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol. 2015;11(7):394–410. - PMC - PubMed
    1. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355(20):2071–2084. - PubMed
    1. Parfrey PS, Lauve M, Latremouille-Viau D, Lefebvre P. Erythropoietin therapy and left ventricular mass index in CKD and ESRD patients: a meta-analysis. Clin J Am Soc Nephrol. 2009;4(4):755–762. - PMC - PubMed
    1. Finkelstein FO, Story K, Firanek C, et al. Health-related quality of life and hemoglobin levels in chronic kidney disease patients. Clin J Am Soc Nephrol. 2009;4(1):33–38. - PMC - PubMed
    1. Lewis EF, Pfeffer MA, Feng A, et al. Darbepoetin alfa impact on health status in diabetes patients with kidney disease: a randomized trial. Clin J Am Soc Nephrol. 2011;6(4):845–855. - PMC - PubMed

Publication types

MeSH terms