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Cited by 315Erythropoietin and Anemia TreatmentIron Metabolism and DisordersHemoglobin structure and function

The DOI matches its Crossref record; 238 of the 239 references it cites were found in a registry or an index.

Anaemia in kidney disease: harnessing hypoxia responses for therapy

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Koury, Mark J., Haase, Volker H.·2015·Nature Reviews Nephrology
DOI 10.1038/nrneph.2015.82PMC PMC4497972
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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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  1. Yoon, D. et al. HIF-1α-deficiency results in dysregulated EPO signaling and iron homeostasis in mouse development. J. Biol. Chem. 281, 25703–25711 (2006). · DOI
  2. Klaus, S., Langsetmo, I., Neff, T., Lin, A. & Liu, D. beneficial pharmacodynamic effects resulting from 'complete erythropoiesis' induced by novel HIF prolyl hydroxylase inhibitors FG-2216 and FG-4592 [abstract]. J. Am. Soc. Nephrol. 19, 524A (2008).
  3. Besarab, A., Szczech, L., Yu, K. H. P. & Neff, N. B. Impact of iron regimen on iron indices and hepcidin during roxadustat anemia correction in incident dialysis patients [abstract]. J. Am. Soc. Nephrol. 25, 304A (2014).
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  5. Provenzano, R. et al. FG-4592, a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), maintains hemoglobin levels and lowers cholesterol in hemodialysis (HD) patients: phase 2 comparison with epoetin alfa [abstract]. J. Am. Soc. Nephrol. 23, 428A (2012).
  6. Brigandi, R. A. et al. The prolyl hydroxylase inhibitor, GSK1278863A, induced EPO in vitro and efficient erythropoiesis leading to increased hemoglobin in vivo [abstract]. J. Am. Soc. Nephrol. 21, 722A (2010).
  7. Brigandi, R. A. et al. Induction of erythropoiesis in anemic patients by prolylhydroxylase inhibitor in a repeat dose, randomized placebo controlled trial [abstract]. J. Am. Soc. Nephrol. 23, 662A (2012).
  8. Shalwitz, R., Hartman, C., Flinn, C., Shalwitz, I. & Logan, D. K. AKB-6548, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor reduces hepcidin and ferritin while it increases reticulocyte production and total iron binding capacity in healthy adults [abstract]. J. Am. Soc. Nephrol. 22, 45A (2011).
  9. Hartman, C. et al. AKB-6548, a new hypoxia-inducible factor prolyl hydroxylase inhibitor increases hemoglobin while decreasing ferritin in a 28-day, phase 2a dose escalation study in stage 3 and 4 chronic kidney disease patients with anemia [abstract]. J. Am. Soc. Nephrol. 22, 435A (2011).
  10. Shalwitz, R. et al. AKB-6548: A new hypoxia-inducible factor prolyl hydroxylase inhibitor, increases hemoglobin in chronic kidney disease patients without increasing basal erythropoietin levels [abstract]. J. Am. Soc. Nephrol. 23, 56A (2012).
  11. Hartman, C. S. et al. Phase 2 study of AKB-6548, a novel hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) in patients with end stage renal disease (ESRD) undergoing hemodialysis (HD). akebia.com [online] , (2014).
  12. Boettcher, M.-F. et al. First-in-man Study with BAY 85–3934—a new oral selective HIF-PH inhibitor for the treatment of renal anemia. J. Am. Soc. Nephrol. 24, 347A (2013).

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Metadata

Authors
Koury, M. J., & Haase, V. H.
Affiliations
Vanderbilt University Medical Center (US)
Corresponding author
Haase, Volker H.
ORCID
Venue
Nature Reviews Nephrology
Publisher
Springer Science and Business Media LLC
Published
2015-06-09
Volume
11
Issue
7
Pages
394-410
ISSN
  • 1745-8323 (ISSN-L)
  • 1759-5061
  • 1759-507X
DOI
10.1038/nrneph.2015.82
PMC
PMC4497972
OpenAlex
W1893364029
Cited by
313
References
239
Citations by year
2026: 20 · 2025: 28 · 2024: 26 · 2023: 39 · 2022: 45 · 2021: 36 · 2020: 31 · 2019: 20 · 2018: 22 · 2017: 20 · 2016: 20 · 2015: 5
FWCI
3.34
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Nephrology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX002348)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080821, R01DK101791, R01DK081646)
Topics
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
Keywords
anemia of chronic kidney disease, erythropoiesis, erythropoietin, hypoxia-inducible factor, HIF-2, iron metabolism, inflammation, iron deficiency, renal failure, hepatocytes, oxygen sensing
MeSH terms
Endothelial PAS Domain-Containing Protein 1, Anemia, Erythropoiesis, Humans, Signal Transduction, Cell Hypoxia, Renal Insufficiency, Chronic, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1

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