Abstract
BackgroundCritical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts.Methods/DesignThe TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation’s definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients.DiscussionTacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage.Trial registerEudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT01564095
Highlights
Organ shortage represents a critical problem in transplantation medicine
Tacrolimus organ perfusion represents a promising strategy to reduce hepatic ischemia reperfusion injury (IRI) following the transplantation of marginal liver grafts
This treatment may help to improve the function of extended donor criteria (EDC) grafts and safely expand the donor pool in light of critical organ shortage
Summary
Organ shortage represents a critical problem in transplantation medicine. In 2010, 1192 liver transplantations were performed in Germany as opposed to 1846 new entries on the waiting list (German Organ Transplantation Foundation (Deutsche Stiftung Organtransplantation, DSO), Annual Report, 2010). In addition to sinusoidal congestion caused by endothelial sticking of migrating neutrophils, an imbalance between vasoconstrictive (endothelin-1) [9] and vasodilatatory substances (NO) [10] may directly disturb the hepatic microcirculation This is considered to be a central pathomechanism for organ dysfunction and primary nonfunction [9,10], especially in marginal liver grafts [11,12]. Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. The aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts
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