Transplantation of discarded livers following viability testing with normothermic machine perfusion

Abstract

There is a limited access to liver transplantation, however, many organs are discarded based on subjective assessment only. Here we report the VITTAL clinical trial (ClinicalTrials.gov number NCT02740608) outcomes, using normothermic machine perfusion (NMP) to objectively assess livers discarded by all UK centres meeting specific high-risk criteria. Thirty-one livers were enroled and assessed by viability criteria based on the lactate clearance to levels ≤2.5 mmol/L within 4 h. The viability was achieved by 22 (71%) organs, that were transplanted after a median preservation time of 18 h, with 100% 90-day survival. During the median follow up of 542 days, 4 (18%) patients developed biliary strictures requiring re-transplantation. This trial demonstrates that viability testing with NMP is feasible and in this study enabled successful transplantation of 71% of discarded livers, with 100% 90-day patient and graft survival; it does not seem to prevent non-anastomotic biliary strictures in livers donated after circulatory death with prolonged warm ischaemia.

Conflict of interest statement

P.J.F. is a co-founder, chief medical officer and consultant to OrganOx Ltd and also holds shares in the company, he was involved in the study design and funding application, but was not involved in the conduct of the clinical trial. C.M. is an OrganOx Ltd employee and provided the device technical support. H.M. received consultancy fees for lecturing and training activities for OrganOx Ltd. All other co-authors declare no competing interests. This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Figures

Fig. 1. Information about discarded livers in the UK between November 2016 and February 2018.

a The study livers inclusion flowchart. Over the 16-month study period there were 185 discarded liver research offers, of which 59 (32%) were not eligible for the trial due to an incidental finding of cancer, macroscopically apparent cirrhosis or advanced fibrosis, severe organ damage or previous machine perfusion. There were 126 livers suitable for the trial, with steatosis being the leading cause of organ discard with 78 (42%) offers. Stringent donor inclusion criteria were not met in 25 (14%) offers and on 21 (11%) occasions the research team was already committed to the perfusion of another study liver. A liver was considered for the trial only if it could be allocated to a consented, potential blood group- and size-matched low-risk recipient. Many recipients were apprehensive to participate in such a high-risk clinical trial, and as a consequence, at any given time there were usually only one to three patients consented. A significant proportion of approached patients declined to take part, or were transplanted with a standard quality liver before agreeing to take part in this study. Eventually, thirty-one livers were enroled to the trial, of which 22 (71%) grafts met the viability criteria and were successfully transplanted. b A summary of reasons for livers being discarded in the United Kingdom between November 2016 and February 2018. A total of 64 livers were discarded for severe steatosis on visual assessment, with 14 discarded for severe steatosis based on urgent liver biopsy. A percentage of livers were declined due to intra-abdominal or lung malignancies (e.g. colonic cancer in donor 22). This did not include primary brain tumours or small renal cell cancers which are almost always considered for donation. The reasons for logistic discard, include the transplant team already being committed to one or more transplantations, lack of a suitable recipient or too long an anticipated cold ischaemia time due to delays with transportation.

Fig. 2. CONSORT flow diagram displaying the progress of patients through the trial.

One hundred and sixty-four patients on the waiting list were approached for potential trial participation. Of those, 111 were excluded; 48 patients met exclusion criteria and were not suitable for a marginal liver graft. Twenty-two patients declined to take part and 41 patients either received a transplant before they provided study consent, or were de-listed, or subsequently met exclusion criteria. Eventually 53 patients consented to the study, of which 29 underwent transplantation with a standard quality liver allocated outside the trial. Twenty-two patients were enroled in the trial and received a salvaged liver.

Fig. 3. The study liver photographs.

The figure shows all 31 livers included in the trial. The red frames designate non-transplanted organs and the yellow dot livers donated after circulatory death.

Fig. 4. The study liver lactate clearance.

Plots of individual liver arterial lactate clearance measured during the NMP perfusion, showing transplantation eligibility thresholds with red lines for lactate levels less than or equal to 2.5 mmol/L. Graphs with grey shading designate livers that were not transplanted. Liver number 22 was from a donor that was unexpectedly diagnosed with a cancer following organ donation.

Fig. 5. Comparison of 1-year graft survival estimate.

Conditional logistic regression was carried out on the matched case–control data to determine the relative risk for graft survival at 1 year between matched case–control groups. The median (range) days follow-up data were included in the survival analyses, but the plot was truncated at 12 months. The ticks on the top of each Kaplan–Meier curve relate to the numbers of patients being censored at that particular time point. There are 2 cases of graft failure in the perfusion group at days 119 and 209; the control group contains 5 graft failures (2 at day 5, 1 at day 14, 1 at day 165 and 1 at day 182). The graft survival was similar in both groups. Findings showed that the odds ratio (relative risk) estimate for graft survival at 6 months was determined as 2.0 (95% CI: 0.2–17.9; p = 0.535). Due to the small sample sizes and that this statistical comparison test was not powered,these results should be interpreted with caution.