Defatting of steatotic liver grafts by normothermic ex vivo machine perfusion with DNP

肝移植是终末期肝病的治疗选择，但潜在受体的数量不断超过器官供应。为了增加可用肝移植物的数量，使用所谓的边缘肝同种异体移植物。不幸的是，这些器官的移植与移植物功能延迟、原发性功能障碍以及移植物和患者存活率较低有关。肝脂肪炎是术后移植物功能障碍的重要危险因素。 大泡性脂肪变性超过60%的肝移植物通常被丢弃，由于一般人群中脂肪性肝炎的患病率上升，因此假设整体肝移植物利用率将明显下降。在文献中，已经提出通过机器灌注进行肝脏脱脂作为脂肪变性肝移植物的预处理的概念。然而，脱脂移植物的移植结果在文献中不可用，可能是由于所应用的试剂和灌注条件。假设常温离体机器灌注DNP可以降低脂肪变性肝移植物的肝内脂肪含量，而不会对移植物产生不良影响。DNP导致轻度线粒体解偶联。在初步工作中，申请人开发了用于大鼠肝脏的常温离体机器灌注的模型，并获得了关于用DNP进行肝脏脱脂的第一个结果。拟议拨款申请的目的是确定在常温灌注条件下使用DNP脱脂的最佳条件。将在大鼠肝移植模型中对脱脂肝移植物的移植进行体内评价。将对脱脂肝脏进行广泛表征，以排除脱脂方案的不良影响。为了证明DNP肝脏脱脂可以成功地转化为临床，将与德国器官移植基金会（Deutsche Stiftung Organtransplantation，DSO）合作进行一项试点研究，对因大泡性脂肪变性而被移植排斥的人肝移植物进行脱脂。

Liver transplantation is the treatment of choice for end-stage liver disease, but the number of potential recipients constantly exceeds the organ supply. In order to increase the number of available liver grafts, so-called marginal liver allografts are used. Unfortunately, transplantation of these organs is associated with delayed graft function, primary dysfunction, and lower graft and patient survival rates. Steatotis hepatis is an important risk factor for postoperative graft dysfunction. Liver grafts with macrovesicular steatosis above 60% are usually discarded and it is assumed that the overall liver graft utilization will noticeable fall due to the rising prevalence of steatotis hepatis in the general population. Liver defatting by machine perfusion has been proposed as a concept for conditioning of steatotic liver grafts in literature. However, results of transplantation of defatted grafts are not available in literature, presumably due to the applied agents and perfusion conditions. It is hypothesized that normothermic ex vivo machine perfusion with DNP can decrease the intrahepatic fat content of steatotic liver grafts without adverse effects on the graft. DNP leads to mild mitochondrial uncoupling. In preliminary work, the applicants developed a model for normothermic ex vivo machine perfusion of rat livers and achieved first results on liver defatting with DNP. The objectives of the proposed grant application are to define optimal conditions for defatting with DNP under normothermic perfusion conditions. Transplantation of defatted liver grafts will be evaluated in vivo in a rat model of liver transplantation. Defatted livers will be extensively characterized in order to exclude adverse effects of the defatting protocol. In order to demonstrate that liver defatting with DNP can be successfully translated into the clinic, a pilot study will be performed in cooperation with the German Organ Transplantation Foundation (Deutsche Stiftung Organtransplantation, DSO) on defatting of human liver grafts rejected from transplantation due to macrovesicular steatosis.