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Carbon monoxide inhibits apoptosis during cold storage and protects kidney grafts donated after cardiac death
Authors:Ozaki Kikumi S  Yoshida Junichi  Ueki Shinya  Pettigrew Gaetan L  Ghonem Nisanne  Sico Rita M  Lee Lung-Yi  Shapiro Ron  Lakkis Fadi G  Pacheco-Silva Alvaro  Murase Noriko
Affiliation:Department of Surgery, Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Abstract:Ischemia/reperfusion (I/R) injury remains as a serious deleterious factor in kidney transplantation (KTx). We hypothesized that carbon monoxide (CO), an endogenous potent cytoprotective molecule, inhibits hypothermia-induced apoptosis of kidney grafts. Using the rat KTx model mimicking the conditions of donation after cardiac death (DCD) as well as nontransplantable human kidney grafts, this study examined effects of CO in preservation solution in improving the quality of marginal kidney grafts. After cardiac cessation, rat kidneys underwent 40 min warm ischemia (WI) and 24 h cold storage (CS) in control UW or UW containing CO (CO-UW). At the end of CS, kidney grafts in control UW markedly increased mitochondrial porin release into the cytosol and resulted in increased cleaved caspase-3 and PARP expression. In contrast, grafts in CO-UW had significantly reduced mitochondrial breakdown and caspase pathway activation. After KTx, recipient survival significantly improved with CO-UW with less TUNEL(+) cells and reduced mRNA upregulation for proinflammatory mediators (IL-6, TNF-α, iNOS). Furthermore, when nontransplantable human kidney grafts were stored in CO-UW for 24 h, graft PARP expression, TUNEL(+) cells, and proinflammatory mediators were less than those in control UW. CO in UW inhibited hypothermia-induced apoptosis and significantly improved kidney graft function and outcomes of KTx.
Keywords:apoptosis  carbon monoxide  donation after cardiac death  extended criteria donor  ischemia/reperfusion injury  kidney transplantation
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