HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond
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Publication Date
2015-12-14Journal Title
Nature Reviews Nephrology
ISSN
1759-5061
Publisher
Nature Publishing Group
Volume
12
Pages
157-168
Language
English
Type
Article
Metadata
Show full item recordCitation
Maxwell, P., & Eckardt, K. (2015). HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nature Reviews Nephrology, 12 157-168. https://doi.org/10.1038/nrneph.2015.193
Abstract
Small-molecule stabilizers of hypoxia inducible factor (HIF) are being developed for the treatment of renal anaemia. These molecules inhibit prolyl hydroxylase domain-containing (PHD) enzymes, resulting in HIF activation and increased production of erythropoietin. Currently, renal anaemia is treated with recombinant human erythropoietin or related analogues, referred to as conventional erythropoiesis stimulating agents (ESAs). Advantages of PHD enzyme inhibitors over conventional ESAs include their oral administration and their simpler — and potentially cheaper — production. Importantly, inhibition of PHD enzymes is likely to have a range of consequences other than increasing levels of erythropoietin, and these effects could be beneficial — for instance by reducing the need for parenteral iron — but might in some instances be harmful. Several companies are currently testing PHD enzyme inhibitors in patients with renal anaemia and have reported clear evidence of efficacy without serious safety concerns. A central question that current studies are beginning to address is whether using PHD enzyme inhibitors will influence hard end points, including mortality and the rate of cardiovascular events. In terms of approaches to therapy, the exquisite specificity of conventional ESAs is a striking contrast to the pleiotropic effects of activating HIF. Excitingly, PHD inhibitors could also be useful for conditions besides renal anaemia, such as protection from ischaemic injury.
Keywords
anaemia, chronic kidney disease, drug development, erythropoietin
Sponsorship
Wellcome Trust (096956/Z/11/Z)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0514-10122)
Identifiers
External DOI: https://doi.org/10.1038/nrneph.2015.193
This record's URL: https://www.repository.cam.ac.uk/handle/1810/253687
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