An Update on Machine Preservation of the Liver

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/14-5-reading-roll a video presentation of this article

Abbreviations

AST

aspartate transaminase

DBD

donation after brain death

EAD

early allograft dysfunction

HOPE

hypothermic oxygenated perfusion

NMP‐L

normothermic machine liver perfusion

PNF

primary nonfunction

SCS

static cold storage

Key Points

• Static cold storage (SCS) is the standard method of liver preservation. The detrimental effects of the concomitant cold ischemia are not suitable for high‐risk livers. Therefore, some potentially transplantable livers currently are being discarded.

• Normothermic machine liver perfusion is an alternative method of preservation that may reduce ischemia/reperfusion injury, biliary complications, early allograft dysfunction (EAD), and primary nonfunction (PNF).

• Normothermic perfusion allows functional assessment of the liver, termed “viability testing.”

• The ability of the liver to reduce lactate in the perfusate is the most widely accepted marker of viability during normothermic machine perfusion, although clinical data are being generated.

• Normothermic machine perfusion can be intended to entirely replace SCS or be used for postischemic graft reconditioning, although the risks and benefits of these strategies are not well defined at this time.

• Hypothermic oxygenated perfusion (HOPE) may result in less biliary ischemic injury compared with normothermic machine perfusion, but viability testing as it is currently understood is not possible.

• Clinical trial data are growing much more rapidly for normothermic preservation compared with hypothermic oxygenated preservation, but the entire field is briskly evolving.

• The potential of these preservation techniques to increase liver utilization is challenging to study in a clinical trial but is important to consider.

SCS has been the gold standard for organ preservation for four decades. This method of preservation works well for livers from young, healthy donors, achieving acceptably low rates of EAD, PNF, and biliary complications, but is limited by the effects of hypoxia during storage. Transplant teams avoid livers that do not tolerate cold ischemia, such as steatotic and older livers, but normothermic machine liver perfusion (NMP‐L) and HOPE may be superior methods of preservation.

NMP‐L preserves the graft in a near‐physiological condition. The liver is quickly prepared by removing excess tissue and cannulating the blood vessels while the liver is briefly in SCS and then connected to a circuit filled with warm, oxygenated blood and nutrients. There are many potential advantages of NMP‐L over SCS. First, the period of SCS, known to be detrimental to the biliary epithelium and hepatocytes, is limited to only the time required for the donor liver explant and graft cannulation (about an hour), after which the liver is in near‐physiological preservation. Second, the near‐physiological state of preservation allows for a real‐time graft function and “viability” assessment. In the case of a well‐functioning liver preserved on NMP‐L, the risk for development of PNF is thought to be exceedingly low even for high‐risk organs. Without NMP‐L, the first test of organ “viability” occurs when the organ is transplanted in the recipient, and a poorly functioning organ results in EAD or PNF. Third, the ischemia/reperfusion injury in the liver, and its resulting effects on the recipient, such as acute renal injury, are thought to be reduced by NMP‐L, because the reperfusion occurs on the circuit. Finally, NMP‐L can significantly extend preservation times and could be a paradigm shift toward allocation parity.

Clinical trials using HOPE have been slower to proliferate, but this preservation strategy may result in less injury to the biliary epithelium. Viability testing, as currently defined, may not be possible because the organ is not at a physiologically active temperature. In addition, HOPE may not extend preservation time to the same degree as NMP‐L.

Review of Human Data

Standard Allografts

The first‐in‐human NMP‐L trial confirmed the safety of the technology. In 20 patients transplanted with livers after NMP‐L, there was 100% graft and patient survival at 6 months.1 This safety study was not designed to evaluate other outcomes, although a reduction in peak aspartate transaminase (AST) was noted. A similarly structured trial in Canada reported one graft loss and noted a prolonged length of stay.2, 3

The efficacy of NMP‐L was evaluated in a multicenter randomized trial that completed enrollment in 2016. This seven‐center European trial that enrolled 272 donors was the first to compare NMP‐L with SCS, and demonstrated that NMP‐L reduced the peak AST by approximately 50% (485 versus 974 IU/L; P < 0.001), with similarly profound improvement in the rate of EAD (12.6% versus 29.9%; P = 0.002). Importantly, the livers randomized to NMP‐L were about half as likely to be discarded compared with livers preserved by SCS. This landmark trial was not designed to demonstrate a difference in utilization, underscoring the potential for NMP‐L to reduce liver discardment. Trials of similar design are enrolling patients in North America.

Randomized clinical trial data comparing HOPE with other preservation techniques are still lacking, but a retrospective case‐matched comparison of HOPE with SCS4 showed less ischemic cholangiopathy (0% versus 22%) and higher 1‐year graft survival (90% versus 69%). Recently, 50 HOPE‐treated livers from donation after cardiac death donors were retrospectively compared with 50 donation after brain death (DBD) donors.5 The HOPE‐treated livers had similar outcomes to the DBD livers preserved with SCS.

Extended Criteria Allografts

In the era of SCS, many livers are discarded because they are too high risk for PNF. NMP‐L theoretically overcomes this risk by allowing functional liver assessment during preservation.

Our current understanding of liver viability testing is based on several experimental studies. Using discarded human donor livers, Sutton et al.6 reported hourly bile production volume to be a marker of liver function, whereas Watson et al.7 suggested sequential perfusate liver transaminase levels may predict the liver function. The most widely accepted method of viability tested was described in a pilot study in humans where five liver transplants were performed using livers initially declined for transplantation subjected to NMP‐L.8 Organ function was assessed based on the perfusate lactate clearance after 2 hours of NMP‐L. All five livers that were able to reduce lactate to levels less than 2.5 mmol/L were successfully transplanted, and none of the recipients have experienced EAD, PNF, or biliary complications at 24 months.

Designing an adequately controlled clinical trial to demonstrate the benefit of NMP‐L over SCS in high‐risk organs has been difficult. Transplanting such livers after SCS for the sake of the trial risks a poor outcome. A trial designed to push the envelope of utilization of the highest‐risk livers has completed enrollment in Europe. This VITTAL trial (Viability Testing and transplantation of discarded donor livers) included only livers declined for transplantation by all transplant centers. The organs underwent 4 hours of NMP‐L, and grafts that met the lactate clearance requirement were transplanted. The initial data were presented at the 2019 American Association for the Study of Liver Diseases Meeting as a plenary session, describing an astonishing 71% utilization.

Macrovesicular steatosis remains one of the primary reasons that livers are discarded because of the risk for EAD and PNF. Pharmacological augmentation of lipid metabolism has been demonstrated in human livers subjected to NMP‐L.9 During this protocol, NMP‐L is initiated and agents that enhance lipid metabolism are added to the perfusate so that the degree of steatosis is actively reduced during preservation and transportation. The defatting cocktail in this protocol included 10 μM forskolin, 1 μM GW7647, 10 μM hypericin, 10 μM scoparone, 0.4 ng/mL visfatin, 1 μM GW501516, and 0.8 mM L‐carnitine. Ten discarded human steatotic livers “defatted” via this process displayed a 40% reduction in macrovesicular steatosis over 6 hours of NMP‐L,9 which would be expected to reduce the risk for EAD and PNF in the recipient, but the enhanced metabolic function demonstrated in these livers must be replicated in a clinical trial.

Logistics

Clinical experience with NMP‐L preservation is based on approximately 500 livers transplanted, of which the great majority were put on the device in the donor hospital. Such a strategy minimizes preservation injury and could be the optimal strategy.10 The technology could also be applied in a less logistically challenging strategy termed “end‐ischemic liver reconditioning,”11 during which the liver is brought to the recipient hospital in SCS and then put on NMP‐L. The device is not transported to the donor hospital, dramatically easing logistics and cost. Although the approach has been used in only a small number of livers, it holds great potential.1, 8, 12 The concept of end‐ischemic perfusion has also been applied to HOPE with encouraging results.13