Attenuation of ischemia-reperfusion injury in a canine model of autologous renal transplantation.
BACKGROUND
This study examined the potential therapeutic effects of a combination therapy consisting of 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR) and N-acetyl cysteine (NAC) to attenuate ischemia-reperfusion (I/R) injury in a canine model of autologous renal transplantation.


METHODS
Male mongrel dogs (15-20 kg) underwent left nephrectomy followed by flushing and static preservation of the kidney in University of Wisconsin (UW) solution for 48 hr. The treatment group received AICAR (50 mg/kg) plus NAC (100 mg/kg) intravenously before the left nephrectomy. The compounds were added to the UW solution as well. All dogs underwent right nephrectomy 48 hr later followed by autotransplantation of the preserved left kidney. Treated dogs received a second dose of AICAR and NAC before implantation of the renal autograft.


RESULTS
The treated dogs had excellent urine output posttransplant, with peak serum creatinine of 7.26 mg/dL on postoperative day (POD) 3 that normalized after 14 days. The control group were anuric and developed clinical symptoms of uremia on POD 1. Morphologic evaluation supported the protective effects of combination therapy. Immunohistochemical analysis revealed decrease of tumor necrosis factor-alpha, interferon-gamma, and inducible nitric oxide synthase; and TUNEL assay showed decreased apoptosis in the treated group.


CONCLUSIONS
Combination therapy with AICAR and NAC attenuates renal I/R injury and improves the outcome of the transplanted kidney after prolonged cold preservation.
Lin
Angello
A
Division of Transplant Surgery, Department of Surgery, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA.
Sekhon
Charanpal
C
Sekhon
Bipanjeet
B
Smith
Allyson
A
Chavin
Kenneth
K
Orak
John
J
Singh
Inderjit
I
Singh
Avtar
A
D000111:Acetylcysteine / Q000627:therapeutic use; D000241:Adenosine; D000493:Allopurinol; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004285:Dogs; D005978:Glutathione; D006085:Graft Survival / Q000276:immunology / Q000502:physiology; D007150:Immunohistochemistry; D007328:Insulin; D007668:Kidney / Q000166:cytology / Q000473:pathology; D016030:Kidney Transplantation / Q000379:methods / Q000473:pathology* / Q000502:physiology; D008297:Male; D009392:Nephrectomy; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009926:Organ Preservation / Q000379:methods; D019188:Organ Preservation Solutions; D011887:Raffinose; D015427:Reperfusion Injury / Q000517:prevention & control*; D012265:Ribonucleotides / Q000627:therapeutic use; D014182:Transplantation, Autologous; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics
D007328:Insulin; D019188:Organ Preservation Solutions; D012265:Ribonucleotides; D014409:Tumor Necrosis Factor-alpha; C055206:University of Wisconsin-lactobionate solution; D000620:Aminoimidazole Carboxamide; D000493:Allopurinol; D003404:Creatinine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C031143:AICA ribonucleotide; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose; D000111:Acetylcysteine