Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model.
Long-term survival of renal allografts depends on the chronic immune response and is probably influenced by the initial injury caused by ischemia and reperfusion. Hypoxia-inducible transcription factors (HIFs) are essential for adaptation to low oxygen. Normoxic inactivation of HIFs is regulated by oxygen-dependent hydroxylation of specific prolyl-residues by prolyl-hydroxylases (PHDs). Pharmacological inhibition of PHDs results in HIF accumulation with subsequent activation of tissue-protective genes. We examined the effect of donor treatment with a specific PHD inhibitor (FG-4497) on graft function in the Fisher-Lewis rat model of allogenic kidney transplantation (KTx). Orthotopic transplantation of the left donor kidney was performed after 24 h of cold storage. The right kidney was removed at the time of KTx (acute model) or at day 10 (chronic model). Donor animals received a single dose of FG-4497 (40 mg/kg i.v.) or vehicle 6 h before donor nephrectomy. Recipients were followed up for 10 days (acute model) or 24 weeks (chronic model). Donor preconditioning with FG-4497 resulted in HIF accumulation and induction of HIF target genes, which persisted beyond cold storage. It reduced acute renal injury (serum creatinine at day 10: 0.66 +/- 0.20 vs. 1.49 +/- 1.36 mg/dL; P < 0.05) and early mortality in the acute model and improved long-term survival of recipient animals in the chronic model (mortality at 24 weeks: 3 of 16 vs. 7 of 13 vehicle-treated animals; P < 0.05). In conclusion, pretreatment of organ donors with FG-4497 improves short- and long-term outcomes after allogenic KTx. Inhibition of PHDs appears to be an attractive strategy for organ preservation that deserves clinical evaluation.
Bernhardt
W M
WM
Department of Nephrology and Hypertension, Friedrich-Alexander University, Erlangen-Nuremberg, Germany. wanja.bernhardt@ukerlangen.de
Gottmann
U
U
Doyon
F
F
Buchholz
B
B
Campean
V
V
Schödel
J
J
Reisenbuechler
A
A
Klaus
S
S
Arend
M
M
Flippin
L
L
Willam
C
C
Wiesener
M S
MS
Yard
B
B
Warnecke
C
C
Eckardt
K-U
KU
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006085:Graft Survival / Q000187:drug effects*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism*; D016030:Kidney Transplantation / Q000379:methods*; D023421:Models, Animal; D009926:Organ Preservation / Q000379:methods; D055031:Primary Graft Dysfunction / Q000517:prevention & control*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D051381:Rats; D011916:Rats, Inbred F344; D015996:Survival Rate; D014019:Tissue Donors; D015533:Transcriptional Activation
D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011393:Procollagen-Proline Dioxygenase