Machine perfusion strategies in liver transplantation

Abstract

Machine perfusion is a hot topic in liver transplantation and several new perfusion concepts are currently developed. Prior to introduction into routine clinical practice, however, such perfusion approaches need to demonstrate their impact on liver function, post-transplant complications, utilization rates of high-risk organs, and cost benefits. Therefore, based on results of experimental and clinical studies, the community has to recognize the limitations of this technology. In this review, we summarize current perfusion concepts and differences between protective mechanisms of ex- and in-situ perfusion techniques. Next, we discuss which graft types may benefit most from perfusion techniques, and highlight the current understanding of liver viability testing. Finally, we present results from recent clinical trials involving machine liver perfusion, and analyze the value of different outcome parameters, currently used as endpoints for randomized controlled trials in the field.

Keywords: Machine perfusion; clinical trials; viability assessment.

Figure 1

Survival of liver grafts after transplantation in-situ and ex-situ under the best possible normothermic conditions on different devices. Despite recent improvements of machine perfusion technology, liver graft survival during ex-situ perfusion remains limited and strongly depends on the perfusion device and the creation of a near physiological environment. Sophisticated and automatic devices, which include centrifugal pumps, oxygenators with a prolonged capability, dialysis, nutrition and diaphragm simulation may potentially prolong ex-situ survival of healthy livers for up to several day or weeks. Importantly, all devices fail to prevent the initiation of reperfusion injury and also the clearance, which lead therefore to an ongoing inflammation during prolonged perfusion of injured or high-risk liver grafts.

Figure 2

Currently available preservation technology for in-situ and ex-situ machine liver perfusion. Multiple new technologies for liver graft treatment and assessment are currently used and tested. Two main concepts include first the replacement of cold storage by perfusion or and endischemic approach, where livers are perfused after cold storage. Different temperatures and perfusate compositions are in use and one main interest is the definition of clinically relevant viability criteria, to decide if an injured or suboptimal liver can be utilized for transplantation or not. Importantly, multiple reasons apply for the decline of a certain graft at different categories and timepoints between the first donor allocation, liver procurement and implantation at the recipient centre. Clinical trials and case series, which are designed to assess the impact of machine perfusion technology should report such reasons and also the risk factors for livers of the declined cohort.

Figure 3

Mechanism of reoxygenation of ischemic liver tissue at different temperatures. Ischemic cells, experience a rapid loss of energy, and most adenosine triphosphate (ATP)—dependent processes are therefore on hold. This phenomenon is paralleled by a significant accumulation of NADH, citric acid cycle- and purine-metabolites, mainly succinate, hypoxanthine, and xanthine. Upon normothermic liver reperfusion, accumulated electron donors, such as NADH and succinate, deliver high amounts of electrons to mitochondrial complex I and II, while ADP is not yet available for the ATP synthetase (complex V), due to previous nucleotide breakdown during ischemia (“wheel is blocked”). This results in an intermittent blockage of proton back flow through the inner mitochondrial membrane, with consecutive high proton motive force, and subsequently reverse electron transfer (RET) between complex II and I, leading to the release of reactive oxygen species (ROS)—from complex I, which occurs within the first few minutes after normothermic reoxygenation. Further parameters, including DAMPs and different cytokines, which are used for viability assessment, appear just downstream. To minimize upfront mitochondrial injury during reoxygenation, reintroduction of oxygen at temperatures below the Arrhenius breakpoint temperature of 15 °C is required. Subsequently, the reactivity of mitochondrial transfer processes is significantly different and appears comparable to hibernating animals or plants. Mitochondria work more effectively at hypothermic temperatures and upload cellular ATP (Complex V; “wheel works properly”), while consuming cell processes are shut down. Hypothermic oxygenated perfusion (HOPE) after ischemia enables slower but congruent proton pumping through complex I, III and IV and protects therefore, first, from significant mitochondrial ROS-release from complex I, and secondly provides uploaded cellular energy reserves prior to organ rewarming and implantation.

Figure 4

Decision making based on clinical assessment and viability testing in DCD liver transplantation. Throughout the entire process of organ offer, donation, preservation, transport and implantation, decision making is becoming increasingly important and liver grafts are declines at different time points and for various reasons. DCD, donation after circulatory death.