Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD.
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.
Department of Nephrology and Hypertension, Friedrich-Alexander-University, Krankenhausstrasse 12, 91054 Erlangen, Germany. wanja.bernhardt@uk-erlangen
Wanja M
WM
Bernhardt
Michael S
MS
Wiesener
Paul
P
Scigalla
James
J
Chou
Roland E
RE
Schmieder
Volkmar
V
Günzler
Kai-Uwe
KU
Eckardt
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000517:prevention & control; D004921:Erythropoietin / Q000096:biosynthesis* / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects*; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D011393:Procollagen-Proline Dioxygenase / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D012016:Reference Values; D006435:Renal Dialysis; D018570:Risk Assessment; D016896:Treatment Outcome
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004921:Erythropoietin; D011393:Procollagen-Proline Dioxygenase