Donor pre-treatment with everolimus or cyclosporine does not reduce ischaemia-reperfusion injury in a rat kidney transplant model.
BACKGROUND
Immunosuppressive agents have been investigated in renal ischaemia-reperfusion injury (IRI) and have frequently demonstrated a beneficial effect. Most studies focused on treatment of the recipient at the time of transplantation. Pre-treatment of these organs before injury (pharmacological pre-conditioning) may particularly protect these organs. This study aimed to investigate the possible protective effects of donor pre-treatment with cyclosporine (CsA) or the mTOR inhibitor everolimus or their combination against IRI during renal transplantation in a rat model.


METHODS
Donors received vehicle, CsA (5 mg/kg), everolimus (0.5 mg/kg) or CsA + everolimus. Two oral doses were administered to the donors at 24 h and again at 6 h prior to donor kidney removal. Syngeneic rat kidneys were preserved in UW solution for 24 h prior to transplantation. After 24 h of reperfusion, blood and tissue samples were collected from recipients for further analysis.


RESULTS
Renal functions as determined by creatinine and necrosis scores were not different between the experimental groups. Cleaved caspase-3, heat shock protein 70 (HSP70), tumor-necrosis factor-alpha (TNF-α) and nitrotyrosine protein levels were not statistically different between the four treatment groups at 24 h post-transplantation. Blood NMR analysis on metabolic markers for IRI reveals no beneficial effects of donor pre-treatment on the 24-h outcome in transplantation.


CONCLUSIONS
When given alone or as a combination to donors before organ recovery, cyclosporine or everolimus does not appear to ameliorate IRI.
Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA.
Graciela
G
Martinez-Palli
Ryutaro
R
Hirose
Tao
T
Liu
Fengyun
F
Xu
Kim
K
Dang
John
J
Feiner
Natalie J
NJ
Serkova
Claus U
CU
Niemann
D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use*; D000068338:Everolimus; D006084:Graft Rejection / Q000209:etiology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014019:Tissue Donors; D019172:Transplantation Conditioning; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus