Abstract
Liver transplantation is increasingly dependent on the use of extended criteria donors (ECD) to increase the organ donor pool and address rising demand. This has necessitated the adoption of innovative technologies and strategies to protect these higher-risk grafts from the deleterious effects of traditional preservation and ischaemia reperfusion injury (IRI). The advent of normothermic machine perfusion (NMP) and rapid growth in the clinical adoption of this technology has accelerated efforts to utilise NMP as a platform for therapeutic intervention to optimise donor livers. In this review we will explore the emerging preclinical data related to ameliorating the effects of IRI, protecting the microcirculation and reducing the immunogenicity of donor organs during NMP. Exploiting the window of opportunity afforded by NMP, whereby the liver can be continuously supported and functionally assessed while therapies are directly delivered during the preservation period, has clear logistical and theoretical advantages over current preservation methods. The clinical translation of many of the therapeutic agents and strategies we will describe is becoming more feasible with widespread adaptation of NMP devices and rapid advances in molecular biology and gene therapy, which have substantially improved the performance of these agents. The delivery of novel therapeutics during NMP represents one of the new frontiers in transplantation research and offers real potential for successfully tackling fundamental challenges in transplantation such as IRI.
Highlights
Liver transplantation is the only successful treatment option for many patients with end-stage liver disease
Following the Consortium for Organ Preservation in Europe (COPE) international clinical trial of normothermic machine perfusion (NMP) for liver transplantation, we found that immune-mediated processes were found to be positively impacted by NMP corroborating pre-clinical work previously conducted within the group [12,14,31]
The recent studies of ex-situ defatting in discarded human livers have demonstrated a “proof of concept”, and if these were translated into clinical practice, it would significantly increase the number of safely transplantable high-risk donor organs
Summary
Liver transplantation is the only successful treatment option for many patients with end-stage liver disease. Donor livers are preserved at 4 ◦C in static cold storage (SCS) prior to implantation, but if prolonged, this can be harmful, if the organ is of marginal quality or deemed ‘high-risk’ owing to donor characteristics. These extended criteria donor (ECD) livers typically come from older, higher body mass index (BMI), medically co-morbid donors and donors after circulatory death (DCD). The underlying mechanism or pathological process driving these complications is the increased susceptibility of ECD livers to severe ischaemia-reperfusion injury (IRI) [4,5] which is itself exacerbated by prolonged cold storage. ECDs have been limited in use to situations where preservation times, in particular cold ischaemia times (CIT), are very short and no other suitable donor options exist [6,7,8]
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