Document Detail


Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD.
MedLine Citation:
PMID:  21115615     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Wanja M Bernhardt; Michael S Wiesener; Paul Scigalla; James Chou; Roland E Schmieder; Volkmar Günzler; Kai-Uwe Eckardt
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Publication Detail:
Type:  Clinical Trial, Phase I; Comparative Study; Journal Article     Date:  2010-11-29
Journal Detail:
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:
Created Date:  2010-12-01     Completed Date:  2011-01-07     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  9013836     Medline TA:  J Am Soc Nephrol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2151-6     Citation Subset:  IM    
Affiliation:
Department of Nephrology and Hypertension, Friedrich-Alexander-University, Krankenhausstrasse 12, 91054 Erlangen, Germany. wanja.bernhardt@uk-erlangen
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MeSH Terms
Descriptor/Qualifier:
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:
0/Hypoxia-Inducible Factor 1, alpha Subunit; 11096-26-7/Erythropoietin; EC 1.14.11.2/Procollagen-Proline Dioxygenase
Comments/Corrections

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