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 has the potential to benefit patients with anemia that results from inadequate EPO production.
“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]
Pharmacological inactivation of PHD enzymes with 2OG analogs increases serum EPO levels in animal models and in humans.
“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]
Systemic treatment with HIF activators is potentially useful in boosting EPO levels in patients with end-stage renal disease.
“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]
Systemic treatment with HIF activators is safe in phase I studies.
“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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- 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 › Cell Biology › 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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