Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD

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.

Figure 1.

FG-2216 increases plasma-EPO levels in healthy controls and in HD patients with and without remaining renal tissue. Twenty-four-hour kinetics of plasma EPO levels after a single dose of FG-2216. (A through C) Individual values are depicted for control subjects (A), nephric HD patients (B), and anephric HD patients (C). All individuals except one received FG-2216 at a dosage of 20 mg/kg; patient 4 in the anephric group (blue line in C) was accidentally underdosed with approximately 4 mg/kg.