Improvement of the quality of a living donor liver graft and enhancement of regeneration by mechanism-targeted inhibition of preservation injury
Final Report Abstract
In this project we aimed at decreasing preservation injury in living-related liver transplantation and injury to the remnant donor liver along several lines. Pretreatment of the donor: In the model of extensive (90%) liver resection in the rat, pretreatment of the animals with three putatively protective compounds (α-tocopherol, silibinine, glycine; alone or combined) was assessed. The amino acid glycine provided strong protection against the acute liver injury caused by manipulation/resection; liver resection induced HIF-1α accumulation and this was also inhibited by glycine. - Preconditioning with EPO, beneficial in liver resection and partial liver transplantation models, did not have a direct effect on preservation injury as assessed in cellular models for preservation injury. New preservation solution: Based on previous mechanistical studies on cultured cells, we had designed a new organ preservation solution prior to the project. In the first funding period a preliminary, iron chelator-free version of this solution showed no adverse systemic effects and inhibited preservation injury of the isolated rat liver. Here, we showed that the new iron chelator LK 614 improves this protection and that presence of the anion chloride during cold storage, in contrast to current knowledge, is beneficial to the microcirculation (as assessed by intravital microscopy) – and subsequently to postoperative liver function. This finding led to further optimization of the solution and initiated further mechanistic studies. The optimized preservation solution was then tested in collaborative projects against HTK solution in models of rat liver transplantation and – with regard to the interests of the Dept. of Surgery – of continuous hypothermic liver perfusion. In a collaborative project with partners from the Department of Surgery, a safety study in a pig model of liver transplantation was performed. Based on these and other findings, predominantly by local groups, a first feasibility study in living donor kidney transplantation was prepared in Essen. Improvement of the preservation of isolated vessels: Based on the (early version of the) organ preservation solution, a modified solution optimized for the cold storage of blood vessels (for vascular reconstruction) was developed, which yielded highly improved vascular quality and function even after cold storage times of 2-3 weeks; this could recently be confirmed for human vessels. This solution is now approved for clinical use.
Publications
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Improvement of the cold storage of blood vessels with a vascular preservation solution. Study in porcine aortic segments. J Vasc Surg 2008, 47: 422-431
Wille T, de Groot H, Rauen U
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Evaluation of a modified HTK solution containing the new iron chelator LK 614 in an isolated rat liver perfusion model. J Invest Surg 2009, 22: 340-347
Wu S, Wohlschlaeger J, de Groot H, Rauen U
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No evidence for protective erythropoietin alpha signalling in rat hepatocytes. BMC Gastroenterology 2009, 9: 26
Bramey T, Freitag P, Fandrey J, Rauen U, Pamp K, Erhard J, Frede S, de Groot H, Petrat F
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Glycine pretreatment ameliorates liver injury after partial hepatectomy in the rat. J Invest Surg 2010, 23: 12-20
Benko T, Frede S, Gu Y, Best J, Baba HA, Schlaak JF, de Groot H, Fandrey J, Rauen U
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Use of a new modified HTK solution for machine preservation of marginal liver grafts. J Surg Res 2010, 160: 155-162
Stegemann J, Hirner A, Rauen U, Minor T
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Assessment of a chloride-poor vs. a chloride-containing modified HTK solution in a rat liver transplantation model. Liver Transpl 2011, 17: 650-660
Fingas CD, Wu S, Gu Y, Wohlschlaeger J, Scherag A, Dahmen U, Paul A, de Groot H, Rauen U
