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      Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD.

      Journal of the American Society of Nephrology : JASN

      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

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          Abstract

          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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          Author and article information

          Journal
          21115615
          3014028
          10.1681/ASN.2010010116

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