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  • Review Article
  • Published:

Anaemia in kidney disease: harnessing hypoxia responses for therapy

Nature Reviews Nephrology volume 11, pages 394–410 (2015)Cite this article

Subjects

Key Points

  • The hypoxia-inducible factor (HIF) oxygen-sensing pathway has a central role in regulating erythropoiesis; it mediates the hypoxic induction of erythropoietin and coordinates erythropoietin and erythrocyte production with iron metabolism

  • Peritubular renal interstitial fibroblast-like cells and pericytes synthesize erythropoietin in an oxygen-regulated and HIF-2-dependent manner; they lose their ability to produce erythropoietin as they transdifferentiate into myofibroblasts following kidney injury

  • In anaemia associated with renal disease, erythropoiesis is suppressed due to the combined and interrelated effects of erythropoietin deficiency, inflammatory cytokines and iron deficiency

  • The pharmacologic activation of hypoxia responses with HIF stabilizers provides a physiologic and comprehensive approach to the treatment of renal anaemia and warrants large, long-term clinical safety and efficacy trials

Abstract

Improved understanding of the oxygen-dependent regulation of erythropoiesis has provided new insights into the pathogenesis of anaemia associated with renal failure and has led to the development of novel therapeutic agents for its treatment. Hypoxia-inducible factor (HIF)-2 is a key regulator of erythropoiesis and iron metabolism. HIF-2 is activated by hypoxic conditions and controls the production of erythropoietin by renal peritubular interstitial fibroblast-like cells and hepatocytes. In anaemia associated with renal disease, erythropoiesis is suppressed due to inadequate erythropoietin production in the kidney, inflammation and iron deficiency; however, pharmacologic agents that activate the HIF axis could provide a physiologic approach to the treatment of renal anaemia by mimicking hypoxia responses that coordinate erythropoiesis with iron metabolism. This Review discusses the functional inter-relationships between erythropoietin, iron and inflammatory mediators under physiologic conditions and in relation to the pathogenesis of renal anaemia, as well as recent insights into the molecular and cellular basis of erythropoietin production in the kidney. It furthermore provides a detailed overview of current clinical experience with pharmacologic activators of HIF signalling as a novel comprehensive and physiologic approach to the treatment of anaemia.

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Figure 1: Overview of erythropoiesis.
Figure 2: Regulation of HIF degradation by PHDs and hypoxic induction of erythropoietin.
Figure 3: HIF coordinates erythropoietin production with iron metabolism.
Figure 4: The number of EPCs regulates renal erythropoietin output.
Figure 5: Cellular basis of erythropoietin deficiency in renal failure.
Figure 6: Mechanisms of renal anaemia.

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Acknowledgements

V.H.H. is affiliated with the Medicine and Research Services, Department of Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, TN, USA and is supported by the Krick-Brooks Chair in Nephrology, by NIH grants (R01-DK081646, R01-DK080821 and R01-DK101791), and by a Department of Veterans Affairs Merit Award (1I01BX002348).

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, D-3100, Medical Center North, Nashville, 37232-2358, TN, USA

    Mark J. Koury

  2. Division of Nephrology and Hypertension, Vanderbilt University Medical Center, D-3100, Medical Center North, Nashville, 37232-2358, TN, USA

    Volker H. Haase

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M.J.K. and V.H.H. contributed equally to writing the article and to review and/or editing of the manuscript before submission.

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Correspondence to Volker H. Haase.

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Competing interests

M.J.K. is a consultant for Keryx Biopharmaceuticals, Inc. V.H.H. has received honoraria from Daiichi Sankyo and serves on the Scientific Advisory Board of Akebia Therapeutics, a company that develops prolyl 4-hydroxylase inhibitors for the treatment of renal anaemia.

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Chemical structures of PHIs. (PDF 74 kb)

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Koury, M., Haase, V. Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol 11, 394–410 (2015). https://doi.org/10.1038/nrneph.2015.82

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