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

• Applicants: Professor Dr. Andreas L. Birkenfeld; Professor Dr. Nathanael Raschzok
• Subject Area: General and Visceral Surgery
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 410718027

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.

• DFG Programme: Research Grants