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Inhibition of Prolyl Hydroxylases Increases Erythropoietin Production in ESRD
Open accessAbstract
The reasons for inadequate production of erythropoietin (EPO) in patients with ESRD are poorly understood. A better understanding of EPO regulation, namely oxygen-dependent hydroxylation of the hypoxia-inducible transcription factor (HIF), may enable targeted pharmacological intervention. Here, we tested the ability of fibrotic kidneys and extrarenal tissues to produce EPO. In this phase 1 study, we used an orally active prolyl-hydroxylase inhibitor, FG-2216, to stabilize HIF independent of oxygen availability in 12 hemodialysis (HD) patients, six of whom were anephric, and in six healthy volunteers. FG-2216 increased plasma EPO levels 30.8-fold in HD patients with kidneys, 14.5-fold in anephric HD patients, and 12.7-fold in healthy volunteers. These data demonstrate that pharmacologic manipulation of the HIF system can stimulate endogenous EPO production. Furthermore, the data indicate that deranged oxygen sensing--not a loss of EPO production capacity--causes renal anemia.
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“Pharmacological inactivation of PHD enzymes with 2OG analogs increases serum EPO levels in animal models and in humans”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [235]
In the citing paper
“and has the potential to benefit patients with anemia that results from inadequate EPO production.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [235]
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“recent phase I studies have shown that systemic treatment with HIF activators is safe and potentially useful in boosting EPO levels in patients with end-stage renal disease [121].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [121]
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“recent phase I studies have shown that systemic treatment with HIF activators is safe and potentially useful in boosting EPO levels in patients with end-stage renal disease [121].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [121]
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Hypoxia-inducible factor–1α–dependent induction of miR122 enhances hepatic ischemia tolerance
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Metadata
- Authors
- Bernhardt, W. M., Wiesener, M. S., Scigalla, P., Chou, J., Schmieder, R. E., Günzler, V., & Eckardt, K.-U.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Venue
- Journal of the American Society of Nephrology
- Published
- 2010-12
- Volume
- 21
- Issue
- 12
- Pages
- 2151-2156
- ISSN
- 1046-6673 (ISSN-L)
- PMC
- PMC3014028
- OpenAlex
- W2136732413
- Cited by
- 340
- References
- 33
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 8 · 2023: 20 · 2022: 23 · 2021: 31 · 2020: 16 · 2019: 13 · 2018: 18 · 2017: 25 · 2016: 28 · 2015: 30 · 2014: 22 · 2013: 34 · 2012: 28
- FWCI
- 17.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of the American Society of Nephrology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- FibroGen
- Topics
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
- Keywords
- erythropoietin, prolyl hydroxylase inhibitors, hypoxia-inducible factor, end-stage renal disease, anemia of chronic kidney disease, hemodialysis, oxygen sensing, anephric patients
- MeSH terms
- Administration, Oral, Adult, Aged, Aged, 80 and over, Anemia, Erythropoietin, Female, Follow-Up Studies, Renal Dialysis, Humans, Kidney Failure, Chronic, Male, Middle Aged, Nephrectomy, Procollagen-Proline Dioxygenase, Reference Values, Treatment Outcome, Risk Assessment, Hypoxia-Inducible Factor 1, alpha Subunit
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