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Thomas, Michael (2011): The effects of Bilirubin and Bilirubin-di-taurate on ischemia reperfusion injruy in a rat model of kidney transplantation. Dissertation, LMU München: Medizinische Fakultät



Background: Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in the conversion of heme into biliverdin, carbon monoxide (CO) and free iron. Biliverdin is then subsequently reduced to bilirubin by the enzyme bilverdin reductase. In the past decades a lot of effort was conducted to investigate the beneficial effects of HO-1 and its end products biliverdin/bilirubin and CO. Due to intensive research, solid organ transplantation can nowadays be seen as clinical routine. However ischemia reperfusion injury (IR), acute rejection episodes and the occurrence of chronic rejection remain main problems. The severity of IRI can be seen as a prognostic factor for early graft function, immunogenecity of grafts as well as for long term graft survival. The goal of our experiments was to investigate the potential beneficial effects of bilirubin and biliverdin on ischemia reperfusion in a kidney transplantation model of the rat. Methods: Two different sets of experiments were performed: First, kidneys of Lewis rats were exposed to 60 minutes of warm ischemia by clamping the renal artery followed by a 24h reperfusion period. This model was used to find the optimal dosing regimen of bilirubin/biliverdin before the more clinical relevant model of kidney transplantation in the rat was performed. We found that three doses of 10mg/Kg bilirubin were the most effective dose regimen to protect kidneys from ischemia reperfusion injury. In the second set of experiments, kidney transplantation was performed in Lewis rats. Kidneys were harvested and stored in 4C cold UW-solution for 18h. Subsequently the kidneys were transplanted isotopically into the recipient rat. Time of warm ischemia was kept in all experiments constantly at 60 minutes. After 24h of reperfusion tissue samples and serum were harvested for further analyses. Results: Systemic treatment of bilirubin led to a significant amelioration of organ function after ischemia reperfusion injury as assessed by measuring serum creatinine levels and BUN levels after 24h of reperfusion. In addition treated animals showed increased eGFR and a better cell integrity as histomorphological analyses could demonstrate. Conclusion: Systemic treatment with bilirubin and bilverdin has beneficial effects on graft function after ischemia rerperfusion injury.