Intraoperative administration of inhaled carbon monoxide reduces delayed graft function in kidney allografts in Swine.
Ischemia/reperfusion injury and delayed graft function (DGF) following organ transplantation adversely affect graft function and survival. A large animal model has not been characterized. We developed a pig kidney allograft model of DGF and evaluated the cytoprotective effects of inhaled carbon monoxide (CO). We demonstrate that donor warm ischemia time is a critical determinant of DGF as evidenced by a transient (4-6 days) increase in serum creatinine and blood urea nitrogen following transplantation before returning to baseline. CO administered to recipients intraoperatively for 1 h restored kidney function more rapidly versus air-treated controls. CO reduced acute tubular necrosis, apoptosis, tissue factor expression and P-selectin expression and enhanced proliferative repair as measured by phosphorylation of retinol binding protein and histone H3. Gene microarray analyses with confirmatory PCR of biopsy specimens showed that CO blocked proinflammatory gene expression of MCP-1 and heat shock proteins. In vitro in pig renal epithelial cells, CO blocks anoxia-reoxygenation-induced cell death while promoting proliferation. This large animal model of DGF can be utilized for testing therapeutic strategies to reduce or prevent DGF in humans. The efficacy of CO on improving graft function posttransplant validates the model and offers a potentially important therapeutic strategy to improve transplant outcomes.
Hanto
D W
DW
Harvard Medical School, the Transplant Institute and the Department of Surgery, Division of Transplantation at Beth Israel Deaconess Medical Center, Boston, MA, USA. dhanto@bidmc.harvard.edu
Maki
T
T
Yoon
M H
MH
Csizmadia
E
E
Chin
B Y
BY
Gallo
D
D
Konduru
B
B
Kuramitsu
K
K
Smith
N R
NR
Berssenbrugge
A
A
Attanasio
C
C
Thomas
M
M
Wegiel
B
B
Otterbein
L E
LE
D000818:Animals; D002248:Carbon Monoxide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051799:Delayed Graft Function / Q000188:drug therapy*; D005260:Female; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000517:prevention & control; D007668:Kidney / Q000378:metabolism; D016030:Kidney Transplantation / Q000502:physiology*; D007683:Kidney Tubular Necrosis, Acute / Q000209:etiology / Q000276:immunology; D015427:Reperfusion Injury / Q000517:prevention & control; D013552:Swine; D016559:Tacrolimus / Q000493:pharmacokinetics
D002248:Carbon Monoxide; D016559:Tacrolimus