| Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. | |
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MedLine Citation:
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PMID: 21115615 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Wanja M Bernhardt; Michael S Wiesener; Paul Scigalla; James Chou; Roland E Schmieder; Volkmar Günzler; Kai-Uwe Eckardt |
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Publication Detail:
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Type: Clinical Trial, Phase I; Comparative Study; Journal Article Date: 2010-11-29 |
Journal Detail:
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Title: Journal of the American Society of Nephrology : JASN Volume: 21 ISSN: 1533-3450 ISO Abbreviation: J. Am. Soc. Nephrol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-01 Completed Date: 2011-01-07 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 9013836 Medline TA: J Am Soc Nephrol Country: United States |
Other Details:
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Languages: eng Pagination: 2151-6 Citation Subset: IM |
Affiliation:
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Department of Nephrology and Hypertension, Friedrich-Alexander-University, Krankenhausstrasse 12, 91054 Erlangen, Germany. wanja.bernhardt@uk-erlangen |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Administration, Oral Adult Aged Aged, 80 and over Anemia / prevention & control Erythropoietin / biosynthesis*, blood Female Follow-Up Studies Humans Hypoxia-Inducible Factor 1, alpha Subunit / drug effects* Kidney Failure, Chronic / metabolism*, therapy* Male Middle Aged Nephrectomy Procollagen-Proline Dioxygenase / administration & dosage, antagonists & inhibitors*, pharmacokinetics Reference Values Renal Dialysis Risk Assessment Treatment Outcome |
| Chemical | |
Reg. No./Substance:
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0/Hypoxia-Inducible Factor 1, alpha Subunit; 11096-26-7/Erythropoietin; EC 1.14.11.2/Procollagen-Proline Dioxygenase |
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