Machine Perfusion for Extended Criteria Donor Livers: What Challenges Remain?

Abstract

Based on the renaissance of dynamic preservation techniques, extended criteria donor (ECD) livers reclaimed a valuable eligibility in the transplantable organ pool. Being more vulnerable to ischemia, ECD livers carry an increased risk of early allograft dysfunction, primary non-function and biliary complications and, hence, unveiled the limitations of static cold storage (SCS). There is growing evidence that dynamic preservation techniques-dissimilar to SCS-mitigate reperfusion injury by reconditioning organs prior transplantation and therefore represent a useful platform to assess viability. Yet, a debate is ongoing about the advantages and disadvantages of different perfusion strategies and their best possible applications for specific categories of marginal livers, including organs from donors after circulatory death (DCD) and brain death (DBD) with extended criteria, split livers and steatotic grafts. This review critically discusses the current clinical spectrum of livers from ECD donors together with the various challenges and posttransplant outcomes in the context of standard cold storage preservation. Based on this, the potential role of machine perfusion techniques is highlighted next. Finally, future perspectives focusing on how to achieve higher utilization rates of the available donor pool are highlighted.

Keywords: donation after circulatory death; extended criteria donors; machine perfusion; mitochondria.

Figure 1

Overview of different types of donor livers classified “extended” based on the functional risk. The livers in Figure 1 were procured from and assessed in the authors’ transplant centers. All livers underwent hypothermic oxygenated perfusion (HOPE) for evaluation, and decision making was based on mitochondrial function and injury during HOPE. DBD: donation after brain death; DCD: donation after circulatory death; ECMO: extracorporeal membrane oxygenation; fDWIT: functional donor warm ischemia time; ICU: intensive care unit; HOPE: hypothermic oxygenated perfusion; micro and macro: micro- and macrosteatosis; OOHCA: out-of-hospital cardiac arrest.

Figure 2

Pathway of injury during organ donation, preservation and after implantation. The reintroduction of oxygen causes IRI immediately and within the first few seconds. Downstream inflammation is only a consequence that unveils the real organ quality. The temperature has a significant effect on the level of IRI, with limited inflammation during cold reoxygenation compared to the warm conditions. The donor and graft quality and the capability to sustain function and recover after brain death and donor treatment in the ICU are the key factors for later organ function and recipient complications in the context of cold storage preservation. * Novel interventions aim to reduce the already established IRI inflammation, instead of focusing on the prevention of this cascade prior to rewarming. DBD: donation after brain death; DCD: donation after circulatory death; HOPE: hypothermic oxygenated perfusion; IFOT: ischemia-free organ transplantation; COR: controlled oxygenated rewarming; NMP: normothermic machine perfusion; NRP: normothermic regional perfusion. Figure done supported by biorender.com (assessed on 21 July 2022).

Figure 3

Cascade of ischemia–reperfusion injury (IRI) based on the liver quality. The metabolic features of IRI with different organ qualities are described in 1–4. Livers from ECD donors convey an elevated risk, sometimes even with short warm and cold ischemia, due to a low donor quality and prolonged ICU treatment. During ischemia, NADH and succinate accumulate to high levels with ATP loss at the same time. When oxygen is reintroduced, the injury becomes immediately visible with ROS, DAMPs and cytokine release throughout the 3 phases: first, the hyperacute and acute responses, which either resolve with recurrent liver function or transform into a chronic phase with ongoing inflammation, severe complications and graft loss; ROS release over time (red line); acute inflammation with Damps, cytokine and chemokine release over time (blue line); chronic inflammation (purple line) (1). When oxygen is reintroduced under warm conditions, the succinate and NADH are immediately and rapidly metabolized to reestablish an electron flow to rebuild ATP, which is urgently needed for all the cell functions, which return to their normal speed with high demands of ATP. This results in the severe proinflammatory status of some ECD livers after reperfusion. This injury is significantly reduced with hypothermic reoxygenation (HOPE and D-HOPE), where succinate and NADH are slowly metabolized with the recovery of the respiratory chain and ATP content without the immediate high demand of energy and full cellular function. Once the mitochondria have recovered, the implantation or normothermic reperfusion is less detrimental with less ROS, DAMPs and cytokines; green line (HOPE) and red line (unperfused controls livers with standard cold storage) demonstrate differences in Succinate, NADH and ATP levels from donation to postreperfusion after transplantation (2). The mechanisms were described in Reference [110]. Template 3 and 4 demonstrate the ischemia-reperfusion injury cascade compared to template 1 with different risk profiles. When ischemia is shorter or the graft of better quality, the acute and chronic injury are lower (3). The 4th panel shows the protective strategies currently applied to reduce the IRI-associated consequences. (4). When HOPE is performed before implantation or the injury reduced to low levels or cold storage replaced by perfusion throughout, the level of inflammation after reperfusion is very limited and shown with low ROS, Damps and cytokine levels, related to those in template 1. DBD: donation after brain death; DCD: donation after circulatory death; ICU: intensive care unit; HOPE: hypothermic oxygenated perfusion; Panel 2: Green line: HOPE and normothermic reperfusion; Red Line: direct normothermic reperfusion. * Rapid Succinate metabolism → ROS and Complex I and II dysfunction, * in Panels 1 and 4: high-risk ECD organs (e.g., extended DCD and macrosteatosis) accumulate enormous levels of NADH and succinate and more loose energy. ATP: adenosine trisphosphate; ECD: extended criteria donors; HOPE: hypothermic oxygenated perfusion; IFOT: ischemia-free organ transplantation; ROS: reactive oxygen species; SCS: standard cold storage. Figure done supported by biorender.com (assessed on 21 July 2022).

Figure 3

Cascade of ischemia–reperfusion injury (IRI) based on the liver quality. The metabolic features of IRI with different organ qualities are described in 1–4. Livers from ECD donors convey an elevated risk, sometimes even with short warm and cold ischemia, due to a low donor quality and prolonged ICU treatment. During ischemia, NADH and succinate accumulate to high levels with ATP loss at the same time. When oxygen is reintroduced, the injury becomes immediately visible with ROS, DAMPs and cytokine release throughout the 3 phases: first, the hyperacute and acute responses, which either resolve with recurrent liver function or transform into a chronic phase with ongoing inflammation, severe complications and graft loss; ROS release over time (red line); acute inflammation with Damps, cytokine and chemokine release over time (blue line); chronic inflammation (purple line) (1). When oxygen is reintroduced under warm conditions, the succinate and NADH are immediately and rapidly metabolized to reestablish an electron flow to rebuild ATP, which is urgently needed for all the cell functions, which return to their normal speed with high demands of ATP. This results in the severe proinflammatory status of some ECD livers after reperfusion. This injury is significantly reduced with hypothermic reoxygenation (HOPE and D-HOPE), where succinate and NADH are slowly metabolized with the recovery of the respiratory chain and ATP content without the immediate high demand of energy and full cellular function. Once the mitochondria have recovered, the implantation or normothermic reperfusion is less detrimental with less ROS, DAMPs and cytokines; green line (HOPE) and red line (unperfused controls livers with standard cold storage) demonstrate differences in Succinate, NADH and ATP levels from donation to postreperfusion after transplantation (2). The mechanisms were described in Reference [110]. Template 3 and 4 demonstrate the ischemia-reperfusion injury cascade compared to template 1 with different risk profiles. When ischemia is shorter or the graft of better quality, the acute and chronic injury are lower (3). The 4th panel shows the protective strategies currently applied to reduce the IRI-associated consequences. (4). When HOPE is performed before implantation or the injury reduced to low levels or cold storage replaced by perfusion throughout, the level of inflammation after reperfusion is very limited and shown with low ROS, Damps and cytokine levels, related to those in template 1. DBD: donation after brain death; DCD: donation after circulatory death; ICU: intensive care unit; HOPE: hypothermic oxygenated perfusion; Panel 2: Green line: HOPE and normothermic reperfusion; Red Line: direct normothermic reperfusion. * Rapid Succinate metabolism → ROS and Complex I and II dysfunction, * in Panels 1 and 4: high-risk ECD organs (e.g., extended DCD and macrosteatosis) accumulate enormous levels of NADH and succinate and more loose energy. ATP: adenosine trisphosphate; ECD: extended criteria donors; HOPE: hypothermic oxygenated perfusion; IFOT: ischemia-free organ transplantation; ROS: reactive oxygen species; SCS: standard cold storage. Figure done supported by biorender.com (assessed on 21 July 2022).

Figure 4

Advantages and disadvantages of different types of liver preservation. ATP: adenosine trisphosphate; DBD: donation after brain death; DCD: donation after circulatory death; FFP: fresh frozen plasma; hope: hypothermic oxygenated perfusion; ICU: intensive care unit; NADH: nicotinamide adenine dinucleotide hydrogen; NMP: normothermic machine perfusion; NRP: normothermic regional perfusion; RBC: red blood cell concentrates; SCS: standard cold storage; TCA: tricarboxylic acid (cycle). Figure done supported by biorender.com (assessed on 21 July 2022).