Machine perfusion of the liver: Which is the best technique to mitigate ischaemia-reperfusion injury?

Abstract

Longstanding research describes the mechanisms whereby the restoration of blood flow and reoxygenation (reperfusion) aggravates the ischaemic injury caused by a period of anoxia to a donor liver. This phenomenon, called ischaemia-reperfusion injury (IRI), leads to parenchymal cell death, microcirculatory failure, and inflammatory immune response. Clinically, IRI is the main factor responsible for the occurrence of posttransplant graft dysfunction and ischaemic-type biliary lesions. While extended criteria donor livers are more vulnerable to IRI, their utilisation is required to address the shortfall in donor organs. Thus, the mitigation of IRI should drive the setting of a new benchmark for marginal organ preservation. Herein, strategies incorporating different modalities of machine perfusion of the liver to alleviate IRI are discussed in conjunction with advantages and disadvantages of individual protocols. Techniques leading to reperfusion of the liver during machine perfusion (in situ normothermic regional perfusion and ex situ normothermic machine perfusion) may mitigate IRI by shortening the ischaemic period of the organs. This benefit potentially escalates from the minimum level, obtained following just partial alleviation of the ischaemic period, to the maximum level, which can be potentially achieved with ischaemia-free organ transplantation. Techniques that do not lead to reperfusion of the liver during machine perfusion (hypothermic, subnormothermic, and controlled-oxygenated rewarming) optimise mitochondrial oxidative function and replenish cellular energy stores, thereby lowering reactive oxygen species production as well as the activation of downstream inflammatory pathways during reperfusion. Further mechanistic insights into IRI may guide the development of donor-specific protocols of machine perfusion on the basis of the limitations of individual categories of extended criteria donor organs.

Keywords: Machine perfusion of the liver, Ischaemia-reperfusion injury, Liver transplantation, Organ preservation, Organ reconditioning

Core tip: Hepatic ischaemia-reperfusion injury (IRI) is the main culprit of post-transplantation graft dysfunction and ischaemic-type biliary lesions. Despite the increased demand, extended-criteria donor livers are more vulnerable to IRI, thereby presenting inferior postoperative outcomes. Hence, the mitigation of IRI should drive the setting of a new benchmark for extended-criteria donor organ preservation. Machine perfusion of the liver has the potential to mitigate IRI via a shortening of the ischaemic period of the livers or the reconditioning of their bioenergetic status. Interventions to further alleviate IRI, such as pharmacological or nonpharmacological metabolic modulation of donor organs, may amplify this effect.