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Outcome of liver transplantation with grafts from brain-dead donors treated with dual hypothermic oxygenated machine perfusion, with particular reference to elderly donors.

ABSTRACT: Prompted by the utilization of extended criteria donors, dual hypothermic oxygenated machine perfusion (D-HOPE) was introduced in liver transplantation to improve preservation. When donors after neurological determination of death (DBD) are used, D-HOPE effect on graft outcomes is unclear. To assess D-HOPE value in this setting and to identify ideal scenarios for its use, data on primary adult liver transplant recipients from January 2014 to April 2021 were analyzed using inverse probability of treatment weighting, comparing outcomes of D-HOPE-treated grafts (n = 121) with those preserved by static cold storage (n = 723). End-ischemic D-HOPE was systematically applied since November 2017 based on donor and recipient characteristics and transplant logistics. D-HOPE use was associated with a significant reduction of early allograft failure (OR: 0.24; 0.83; p = .024), grade ≥3 complications (OR: 0.57; p = .046), comprehensive complication index (-7.20 points; p = .003), and improved patient and graft survival. These results were confirmed in the subset of elderly donors (>75-year-old). Although D-HOPE did not reduce the incidence of biliary complications, its use was associated with a reduced severity of ischemic cholangiopathy. In conclusion, D-HOPE improves postoperative outcomes and reduces early allograft loss in extended criteria DBD grafts.

SUBMITTER: Patrono D

PROVIDER: S-EPMC9303789 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Outcome of liver transplantation with grafts from brain-dead donors treated with dual hypothermic oxygenated machine perfusion, with particular reference to elderly donors.

Patrono Damiano D Cussa Davide D Sciannameo Veronica V Montanari Elena E Panconesi Rebecca R Berchialla Paola P Lepore Mirella M Gambella Alessandro A Rizza Giorgia G Catalano Giorgia G Mirabella Stefano S Tandoi Francesco F Lupo Francesco F Balagna Roberto R Salizzoni Mauro M Romagnoli Renato R

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20220222 5

Prompted by the utilization of extended criteria donors, dual hypothermic oxygenated machine perfusion (D-HOPE) was introduced in liver transplantation to improve preservation. When donors after neurological determination of death (DBD) are used, D-HOPE effect on graft outcomes is unclear. To assess D-HOPE value in this setting and to identify ideal scenarios for its use, data on primary adult liver transplant recipients from January 2014 to April 2021 were analyzed using inverse probability of ...[more]

PMID: 35150050

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Project description:BACKGROUND:Kidney transplantation is the only curative treatment option for end-stage renal disease. The unavailability of adequate organs for transplantation has resulted in a substantial organ shortage. As such, kidney donor allografts that would have previously been deemed unsuitable for transplantation have become an essential organ pool of extended criteria donor allografts that are now routinely being transplanted on a global scale. However, these extended criteria donor allografts are associated with significant graft-related complications. As a result, hypothermic oxygenated machine perfusion (HOPE) has emerged as a powerful, novel technique in organ preservation, and it has recently been tested in preclinical trials in kidney transplantation. In addition, HOPE has already provided promising results in a few clinical series of liver transplantations where the liver was donated after cardiac death. OBJECTIVE:The present trial is an investigator-initiated prospective pilot study on the effects of HOPE on extended criteria donor allografts donated after brain death and used in kidney transplantation. METHODS:A total of 15 kidney allografts with defined inclusion/exclusion criteria will be submitted to two hours of HOPE via the renal artery before implantation, and are going to be compared to a case-matched group of 30 patients (1:2 matching) who had kidneys transplanted after conventional cold storage. Primary (posttransplant dialysis within 7 days) and secondary (postoperative complications, early graft function, duration of hospital and intensive care unit stay, and six-month graft survival) endpoints will be analyzed within a six-month follow-up period. The extent of ischemia-reperfusion injury will be assessed using kidney tissue, perfusate, and serum samples taken during the perioperative phase of kidney transplantation. RESULTS:The results of this trial are expected in the first quarter of 2020 and will be presented at national and international scientific meetings and published in international peer-reviewed medical journals. The trial was funded in the third quarter of 2017 and patient enrollment is currently ongoing. CONCLUSIONS:This prospective study is designed to explore the effects of HOPE on extended criteria donor kidney allografts donated after brain death. The present report represents the preresults phase. TRIAL REGISTRATION:Clinicaltrials.gov NCT03378817; https://clinicaltrials.gov/ct2/show/NCT03378817.

Project description:BackgroundMitochondrial succinate accumulation has been suggested as key event for ischemia reperfusion injury in mice. No specific data are however available on behavior of liver mitochondria during ex situ machine perfusion in clinical transplant models.MethodsWe investigated mitochondrial metabolism of isolated perfused rat livers before transplantation. Livers were exposed to warm and cold ischemia to simulate donation after circulatory death (DCD) and organ transport. Subsequently, livers were perfused with oxygenated Belzer-MPS for 1h, at hypothermic or normothermic conditions. Various experiments were performed with supplemented succinate and/or mitochondrial inhibitors. The perfusate, liver tissues, and isolated mitochondria were analyzed by mass-spectroscopy and fluorimetry. Additionally, rat DCD livers were transplanted after 1h hypothermic or normothermic oxygenated perfusion. In parallel, perfusate samples were analysed during HOPE-treatment of human DCD livers before transplantation.FindingsSuccinate exposure during rat liver perfusion triggered a dose-dependent release of mitochondrial Flavin-Mononucleotide (FMN) and NADH in perfusates under normothermic conditions. In contrast, perfusate FMN was 3-8 fold lower under hypothermic conditions, suggesting less mitochondrial injury during cold re-oxygenation compared to normothermic conditions. HOPE-treatment induced a mitochondrial reprogramming with uploading of the nucleotide pool and effective succinate metabolism. This resulted in a clear superiority after liver transplantation compared to normothermic perfusion. Finally, the degree of mitochondrial injury during HOPE of human DCD livers, quantified by perfusate FMN and NADH, was predictive for liver function.InterpretationMitochondrial injury determines outcome of transplanted rodent and human livers. Hypothermic oxygenated perfusion improves mitochondrial function, and allows viability assessment of liver grafts before implantation.Fundingdetailed information can be found in Acknowledgments.

Project description:BACKGROUND:Extended criteria donors (ECD) are widely utilized due to organ shortage, but they may increase the risk of graft dysfunction and poorer outcomes. Hypothermic oxygenated perfusion (HOPE) is a recent organ preservation strategy for marginal kidney and liver grafts, allowing a redirect from anaerobic metabolism to aerobic metabolism under hypothermic conditions and protecting grafts from oxidative species-related damage. These mechanisms may improve graft function and survival. OBJECTIVE:With this study, we will evaluate the benefit of end-ischemic HOPE on ECD grafts for livers and kidneys as compared to static cold storage (SCS). The aim of the study is to demonstrate the ability of HOPE to improve graft function and postoperative outcomes of ECD kidney and liver recipients. METHODS:This is an open-label, single-center randomized clinical trial with the aim of comparing HOPE with SCS in ECD kidney and liver transplantation. In the study protocol, which has been approved by the ethics committee, 220 patients (110 liver recipients and 110 kidney recipients) will be enrolled. Livers and kidneys assigned to the HOPE group undergo machine perfusion with cold Belzer solution (4-10°C) and continuous oxygenation (partial pressure of oxygen of 500-600 mm Hg). In the control group, livers and kidneys undergoing SCS are steeped in Celsior solution and stored on ice. Using the same perfusion machine for both liver and kidney grafts, organs are perfused from the start of the back-table procedure until implantation, without increasing the cold ischemia time. For each group, we will evaluate clinical outcomes, graft function tests, histologic findings, perfusate, and the number of allocated organs. Publication of the results is expected to begin in 2021. RESULTS:Dynamic preservation methods for organs from high-risk donors should improve graft dysfunction after transplantation. To date, we have recruited 108 participants. The study is ongoing, and recruitment of participants will continue until January 2020. CONCLUSIONS:The proposed preservation method should improve ECD graft function and consequently the postoperative patient outcomes. TRIAL REGISTRATION:ClinicalTrials.gov NCT03837197; https://clinicaltrials.gov/ct2/show/NCT03837197 ; Archived by WebCite® at http://www.webcitation.org/76fSutT3R. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):DERR1-10.2196/13922.

Project description:BackgroundNormothermic regional perfusion (NRP) and hypothermic-oxygenated-perfusion (HOPE), were both shown to improve outcomes after liver transplantation from donors after circulatory death (DCD). Comparative clinical and mechanistical studies are however lacking.MethodsA rodent model of NRP and HOPE, both in the donor, was developed. Following asystolic donor warm ischemia time (DWIT), the abdominal compartment was perfused either with a donor-blood-based-perfusate at 37 °C (NRP) or with oxygenated Belzer-MPS at 10 °C (donor-HOPE) for 2 h. Livers were then procured and underwent 5 h static cold storage (CS), followed by transplantation. Un-perfused and HOPE-treated DCD-livers (after CS) and healthy livers (DBD) with direct implantation after NRP served as controls. Endpoints included the entire spectrum of ischemia-reperfusion-injury.FindingsHealthy control livers (DBD) showed minimal signs of inflammation during 2 h NRP and achieved 100% posttransplant recipient survival. In contrast, DCD livers with 30 and 60 min DWIT suffered from greater mitochondrial injury and inflammation as measured by increased perfusate Lactate, FMN- and HMGB-1-levels with subsequent Toll-like-receptor activation during NRP. In contrast, donor-HOPE (instead of NRP) led to significantly less mitochondrial-complex-I-injury and inflammation. Results after donor-HOPE were comparable to ex-situ HOPE after CS. Most DCD-liver recipients survived when treated with one HOPE-technique (86%), compared to only 40% after NRP (p = 0.0053). Following a reduction of DWIT (15 min), DCD liver recipients achieved comparable survivals with NRP (80%).InterpretationHigh-risk DCD livers benefit more from HOPE-treatment, either immediately in the donor or after cold storage. Comparative prospective clinical studies are required to translate the results.FundingFunding was provided by the Swiss National Science Foundation (grant no: 32003B-140776/1, 3200B-153012/1, 320030-189055/1, and 31IC30-166909) and supported by University Careggi (grant no 32003B-140776/1) and the OTT (grant No.: DRGT641/2019, cod.prog. 19CT03) and the Max Planck Society. Work in the A.G. laboratory was partially supported by the NIH R01NS112381 and R21NS125466 grants.

Dataset Information

Outcome of liver transplantation with grafts from brain-dead donors treated with dual hypothermic oxygenated machine perfusion, with particular reference to elderly donors.

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Outcome of liver transplantation with grafts from brain-dead donors treated with dual hypothermic oxygenated machine perfusion, with particular reference to elderly donors.

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