Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD.

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Bernhardt WM, Wiesener MS, Scigalla P, Chou J, Schmieder RE, Gunzler V, Eckardt KU

Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD.

J Am Soc Nephrol. 2010 Dec;21(12):2151-6. doi: 10.1681/ASN.2010010116. Epub 2010 Nov 29.

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21115615 [ View in PubMed
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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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