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Title: Donor liver optimisation and real-time pre-implant assessment
Authors: Figueiredo, Rodrigo
Issue Date: 2020
Publisher: Newcastle University
Abstract: The number of livers offered for cadaveric donation currently exceeds demand in the United Kingdom. However, the quality of these organs means that nearly a third are rejected for transplantation. In particular utilisation of fatty (steatotic) and organs from donors after circulatory death (DCD) are poor. The aims of this project were to develop novel cost effective ex-situ perfusion viability and reconditioning techniques and explore accurate methods of steatosis quantification. Ex situ perfusion was introduced using our previous experience in kidney perfusion, taking advantage of the inherent safety benefits of hypothermic perfusion before progressing to normothermic perfusion. A novel perfusion setup was utilised for Hypothermic Oxygenated Perfusion of livers (HOPE), with a custom-designed circuit and adapting existing experience of ex-vivo kidney perfusion using Medtronic perfusion equipment. A total of 10 livers were transplanted following HOPE, all with significant donor and recipient risk factors, with very promising results. All recipients are alive with a minimum of 20-months follow-up and none have developed clinically-significant ischaemic cholangiopathy. This compares favourably with a historical local cohort that would have met current inclusion criteria for perfusion. Only 1 recipient has had a retransplant, due to rejection. A number of modalities for assessing livers during perfusion have been explored. We have demonstrated that lactate clearance in normothermic machine perfusion (NMP) cannot be safely relied upon, as livers that had sustained damage well beyond the scope of transplantation still cleared lactate. Bile production has proved to be of some importance in our series, but not all published evidence supports this. Extensive analysis of perfusate biomarkers has identified a potential scoring system that could differentiate between transplantable and untransplantable livers in our series, but needs further validation. We have described an objective method of analysing liver microcirculation, and have demonstrated that NMP improved the arterial microcirculation, but that with extended ischaemia the benefit of NMP is lost. We have demonstrated in rodent cell lines that steatosis adversely affects viability in hypoxia. In addition we have developed a preliminary point-of-care steatosis assessment method, which could prove beneficial with further calibration and validation. Utilising ex-situ perfusion to modulate and treat organs is an exciting potential to further improve marginal organs. We selected Pregnane-X Receptor (PXR) activation as our treatment target for this based on rodent experiments demonstrating its benefit in reducing ischaemia-reperfusion injury. These experiments demonstrate upregulation of the end-targets of PXR during human NMP, proving its potential as a platform for drug delivery. We were unable to demonstrate significant benefits to the livers within the limited timeframe of perfusion, as it is likely that any potential advantages of PXR activation would only become apparent in a much longer time period.
Description: Ph. D. Thesis
Appears in Collections:Institute of Cellular Medicine

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