November 3, 2007
American Society of Nephrology (ASN) Renal Week 2007, San Francisco, CA
Abstract SA-FC135

Donor Pre-treatment with a HIF Prolyl Hydroxylase Inhibitor Improves Function and Increases Long-Term Graft survival in an Allogenic Rat Transplant Model. W.M. Bernhardt¹, U. Göttmann², F. Doyon², B. Buchholz¹, V. Campean³, S. Klaus⁴, L. Flippin⁴, M. Arend⁴, C. Willam¹, B. Yard², C. Warnecke¹, K.-U. Eckardt¹.

1 Dept. of Nephrology and Hypertension, FAU Erlangen-Nuremberg, 2 Med. Klinik 4/Nephrologie Mannheim, 3 Institut for Pathology, FAU Erlangen-Nuremberg, 4 FibroGen, Inc., South San Francisco, CA, USA.

Abstract: Besides immunological aspects, the long-term survival of a renal allograft depends on the initial injury caused by the sequence of cold ischemia, warm ischemia and reperfusion and is thus already determined at the time of transplantation. Hypoxia-inducible transcription factors (HIF) are essential for adaptation to low oxygen. Normoxic inactivation of HIF is regulated by oxygen-dependent hydroxylation of specific prolyl-residues of HIF by prolyl-hydroxylases (PHD). Pharmacological inhibition of the PHD results in HIF accumulation with subsequent activation of a number of nephroprotective genes.

We examined the effect of donor treatment with a specific inhibitor of the PHD (FG-4497) on graft-function in a rat model of allogenic kidney transplantation (KTx). The Fisher-Lewis rat model of KTx was used. Isogenic transplantations served as controls. Orthotopic transplantation of the left donor-kidney was performed after 24h of cold storage. The right kidney was removed at the time of KTx (acute) or at day 10 (chronic). 6h prior to kidney explantation, donor animals were treated with a single dose of FG-4497 (40mg/kg i.v.) or vehicle (Veh) Recipients were followed up for 10 days (acute, n=6-8) or 24 weeks (chronic, n=13-14).

Donor-preconditioning with FG-4497 resulted in HIF accumulation and induction of HIF target genes, which persisted beyond the period of cold storage. It reduced acute renal injury (Serum creatinine FG-4497: 0.66±0.20 vs Veh 1.49±1.36; p<0.05) and improved histomorphology at 10 days. Donor-preconditioning improved long term survival of recipient animals (mortality after 24 wks: 7/13 Veh vs. 3/14 FG-4497 and 0/13 in the isogenic control group; p<0.05 FG-4497 vs. Veh).

In conclusion, pretreatment of organ donors with FG-4497 improves short- and long-term outcome after prolonged cold storage and subsequent allogeneic KTx. These findings may have significant clinical implications.

See also November 7, 2007 press release