Transplantation of High-risk Donor Livers After Ex Situ Resuscitation and Assessment Using Combined Hypo- and Normothermic Machine Perfusion: A Prospective Clinical Trial.

OBJECTIVE: The aim of this study was to evaluate sequential hypothermic and normothermic machine perfusion (NMP) as a tool to resuscitate and assess viability of initially declined donor livers to enable safe transplantation. SUMMARY BACKGROUND DATA: Machine perfusion is increasingly used to resuscitate and test the function of donor livers. Although (dual) hypothermic oxygenated machine perfusion ([D]HOPE) resuscitates livers after cold storage, NMP enables assessment of hepatobiliary function. METHODS: In a prospective clinical trial, nationwide declined livers were subjected to ex situ NMP (viability assessment phase), preceded by 1-hour DHOPE (resuscitation phase) and 1 hour of controlled oxygenated rewarming (COR), using a perfusion fluid containing an hemoglobin-based oxygen carrier. During the first 2.5 hours of NMP, hepatobiliary viability was assessed, using predefined criteria: perfusate lactate <1.7 mmol/L, pH 7.35 to 7.45, bile production >10 mL, and bile pH >7.45. Livers meeting all criteria were accepted for transplantation. Primary endpoint was 3-month graft survival. RESULTS: Sixteen livers underwent DHOPE-COR-NMP. All livers were from donors after circulatory death, with median age of 63 (range 42-82) years and median Eurotransplant donor risk index of 2.82. During NMP, all livers cleared lactate and produced sufficient bile volume, but in 5 livers bile pH remained <7.45. The 11 (69%) livers that met all viability criteria were successfully transplanted, with 100% patient and graft survival at 3 and 6 months. Introduction of DHOPE-COR-NMP increased the number of deceased donor liver transplants by 20%. CONCLUSIONS: Sequential DHOPE-COR-NMP enabled resuscitation and safe selection of initially declined high-risk donor livers, thereby increasing the number of transplantable livers by 20%. TRIAL REGISTRATION: www.trialregister.nl; NTR5972.

Transplantation of high-risk donor livers after resuscitation and viability assessment using a combined protocol of oxygenated hypothermic, rewarming and normothermic machine perfusion: study protocol for a prospective, single-arm study (DHOPE-COR-NMP trial).

INTRODUCTION: Extended criteria donor (ECD) livers are increasingly accepted for transplantation in an attempt to reduce the gap between the number of patients on the waiting list and the available number of donor livers. ECD livers; however, carry an increased risk of developing primary non-function (PNF), early allograft dysfunction (EAD) or post-transplant cholangiopathy. Ischaemia-reperfusion injury (IRI) plays an important role in the development of these complications. Machine perfusion reduces IRI and allows for reconditioning and subsequent evaluation of liver grafts. Single or dual hypothermic oxygenated machine perfusion (DHOPE) (4°C-12°C) decreases IRI by resuscitation of mitochondria. Controlled oxygenated rewarming (COR) may further reduce IRI by preventing sudden temperature shifts. Subsequent normothermic machine perfusion (NMP) (37°C) allows for ex situ viability assessment to facilitate the selection of ECD livers with a low risk of PNF, EAD or post-transplant cholangiopathy. METHODS AND ANALYSIS: This prospective, single-arm study is designed to resuscitate and evaluate initially nationwide declined ECD livers. End-ischaemic DHOPE will be performed for the initial mitochondrial and graft resuscitation, followed by COR of the donor liver to a normothermic temperature. Subsequently, NMP will be continued to assess viability of the liver. Transplantation into eligible recipients will proceed if all predetermined viability criteria are met within the first 150 min of NMP. To facilitate machine perfusion at different temperatures, a perfusion solution containing a haemoglobin-based oxygen carrier will be used. With this protocol, we aim to transplant extra livers. The primary endpoint is graft survival at 3 months after transplantation. ETHICS AND DISSEMINATION: This protocol was approved by the medical ethical committee of Groningen, METc2016.281 in August 2016 and registered in the Dutch Trial registration number TRIAL REGISTRATION NUMBER: NTR5972, NCT02584283.

Outcome of Liver Transplant Patients With High Urgent Priority: Are We Doing the Right Thing?

BACKGROUND: About 15% of liver transplantations (LTs) in Eurotransplant are currently performed in patients with a high-urgency (HU) status. Patients who have acute liver failure (ALF) or require an acute retransplantation can apply for this status. This study aims to evaluate the efficacy of this prioritization. METHODS: Patients who were listed for LT with HU status from January 1, 2007, up to December 31, 2015, were included. Waiting list and posttransplantation outcomes were evaluated and compared with a reference group of patients with laboratory Model for End-Stage Liver Disease (MELD) score (labMELD) scores ≥40 (MELD 40+). RESULTS: In the study period, 2299 HU patients were listed for LT. Ten days after listing, 72% of all HU patients were transplanted and 14% of patients deceased. Patients with HU status for primary ALF showed better patient survival at 3 years (69%) when compared with patients in the MELD 40+ group (57%). HU patients with labMELD ≥45 and patients with HU status for acute retransplantation and labMELD ≥35 have significantly inferior survival at 3-year follow-up of 46% and 42%, respectively. CONCLUSIONS: Current prioritization for patients with ALF is highly effective in preventing mortality on the waiting list. Although patients with HU status for ALF have good outcomes, survival is significantly inferior for patients with a high MELD score or for retransplantations. With the current scarcity of livers in mind, we should discuss whether potential recipients for a second or even third retransplantation should still receive absolute priority, with HU status, over other recipients with an expected, substantially better prognosis after transplantation.

Current policy for allocation of donor livers in the Netherlands advantages primary sclerosing cholangitis patients on the liver transplantation waiting list-a retrospective study.

Studies from the USA and Nordic countries indicate primary sclerosing cholangitis (PSC) patients have low mortality on the liver transplantation (LTx) waiting list. However, this may vary among geographical areas. Therefore, we compared waiting list mortality and post-transplant survival between laboratory model for end-stage liver disease (LM) and MELD exception (ME)-prioritized PSC and non-PSC candidates in a nationwide study in the Netherlands. A retrospective analysis of patients waitlisted from 2006 to 2013 was conducted. A total of 852 candidates (146 PSC) were waitlisted of whom 609 (71.5%) underwent LTx and 159 (18.7%) died before transplantation. None of the ME PSC patients died, and they had a higher probability of LTx than LM PSC [HR obtained by considering ME as a time-dependent covariate (HRME 9.86; 95% CI 6.14-15.85)] and ME non-PSC patients (HRME 4.60; 95% CI 3.78-5.61). After liver transplantation, PSC patients alive at 3 years of follow-up had a higher probability of relisting than non-PSC patients (HR 7.94; 95% CI 1.98-31.85) but a significantly lower mortality (HR 0.51; 95% CI 0.27-0.95). In conclusion, current LTx prioritization advantages PSC patients on the LTx waiting list. Receiving ME points is strongly associated with timely LTx.

The price of donation after cardiac death in liver transplantation: a prospective cost-effectiveness study.

This study aims to perform a detailed prospective observational multicenter cost-effectiveness study by comparing liver transplantations with donation after brain death (DBD) and donation after cardiac death (DCD) grafts. All liver transplantations in the three Dutch liver transplant centers between 2004 and 2009 were included with 1-year follow-up. Primary outcome parameter was cost per life year after transplantation. Secondary outcome parameters were 1-year patient and graft survival, complications, and patient-level costs. From 382 recipients that underwent 423 liver transplantations, 293 were primarily transplanted with DBD and 89 with DCD organs. Baseline characteristics were not different between both groups. The Donor Risk Index was significantly different as were cold and warm ischemic time. Ward stay was significantly longer in DCD transplantations. Patient and graft survival were not significantly different. Patients receiving DCD organs had more and more severe complications. The cost per life year for DBD was € 88,913 compared to € 112,376 for DCD. This difference was statistically significant. DCD livers have more and more severe complications, more reinterventions and consequently higher costs than DBD livers. However, patient and graft survival was not different in this study. Reimbursement should be differentiated to better accommodate DCD transplantations.