The Molecular and Cellular Basis of ReDerfusion Iniurv Following Orgah Transplaniatibn Wayel Jassem and Justin Roake T he published literature on ischaemia/reperfu- sion injury (IRI) following myocardial infarc- tion, cerebral ischaemia, and organ transplantation (to name a few examples) has expanded explosively. Much of this has become highly technical and impen- etrable to many clinicians who have first-hand experi- ence of the problem in their patients, and have to manage the clinical sequlae. Several good reviews of the various aspects of IRI have been published in the scientiW3 and ~linical”~ literature. This review is written particularly for clinicians involved in organ transplantation and aims to establish a framework for understanding the molecular and cellular events underlying IRI as well as the scientific basis of strategies that might be employed to prevent or overcome the injury. Particular attention will be given to mitochondrial events during IRI because this has not been the subject of other reviews. It is not an exhaustive review of the entire subject, and in the interests of clarity and brevity a certain amount of detail has been omitted. What Is the Impact of IRI on Transplantation as Performed in the 1990’s? The full significance of IRI after organ transplanta- tion is debated, but it is clearly a major determinant of early graft dysfunction. In renal transplantation, this is most commonly recognised as delayed graft function (DGF), which is a largely reversible process that has many of the features of acute tubular necrosis. In Europe and the United States, DGF affects approximately 20% to 30% of cadaveric renal transplants.s*g In liver transplantation, initial poor function is seen in approximately 10% to 20% of casesi”.i3and is associated with a higher graft failure, Fmm the Nu~ld &k~timenl OJSurgey, Uniueni~ oJO@rd, John Raklge Harpiilal, Headington, Odmd, England. A&w rep& mque.b lol’mfior J&in Roake, Uniuenig Lkpartment of Surgery, Christchurch School of Medicine, Chtitchurch Hospital, Chtitchurch, New Zealand. Copright 0 1998 $I WB. Saunders Compagl 0955470X/98l1201-0002$8.00/O retransplantation, and mortality within the lirst 3 months.i3-is However, there is a wide spectrum of injury severity ranging from irreversible injury result- ing in graft loss (primary nonfunction) to clinically insignificant injury. It is likely that all cadaveric organs suffer IRI to some degree, but this may be entirely clinically silent or merely manifest as dysreg- ulation of function (eg, polyuria, reduced creatinine clearance). An analogous situation pertains to liver and cardiac transplantation, but the more severe injuries may have fatal consequences in which there is no viable alternative form of organ replacement while awaiting return of organ function. It is unclear whether IRI manifesting as DGF has long-term sequelae following renal transplantation, but there is increasing evidence that it may compro- mise long-term graft survival’62~ and contribute to the incidence of rejection.g,23,2*For example, long- term survival of cadaveric grafts with good function at one year was dependent on the combined inllu- ence of DGF and acute rejection in one study; DGF alone or acute rejection without preceding DGF had relatively little influence on outcome.25~2G In a review of over 37,000 primary cadaveric renal transplants, DGF was associated with acute rejection episodes and reduced graft smvival, especially if both DGF and acute rejection occurred.g One hypothesis to explain these Iindings is that XI-mediated tissue injury enhances alloantigen presentation and/or in- creases graft immunogenicity, and this predisposes to later chronic rejection especially when a vigorous alloimmune response has been shown by the occur- rence of acute rejection. Other compelling evidence of long-term importance of IRI is provided by a randomised study of superoxide dismutase (SOD) administered intravenously at the time of cadaveric renal transplantation.27 Although in this study there was no short-term benefit with respect to DGF, SOD was associated with improved long-term graft sur- vival. The hypothesis proposed by Land et al. to explain these findings was that early nonspecific reactive oxygen intermediate (ROI)-mediated injury to the graft predisposed to later chronic rejection and that SOD was effective at blocking the early injury.’ 14 Transplantation Revierus, Vol12, No I (January), 1998:pp 14-33