Valoracion de la calidad del injerto hepático mediante la determinación de los patrones metabonómicos en biopsia del hígado donante

El trasplante de hígado (TH) constituye en el tratamiento de elección para las enfermedades hepáticas en estadio terminal, sin embargo, el desequilibrio entre el número de donantes y pacientes en lista de espera ha conducido a la utilización de injertos procedentes de donantes con criterios extendidos. Esta práctica, se ha traducido en una reducción de la tasa de mortalidad entre los pacientes en lista de espera, a expensas de un aumento de las complicaciones post-trasplante, como la disfunción temprana del injerto (EAD). Actualmente, sigue faltando un test fiable que evalúe la calidad del injerto hepático y permita predecir su funcionalidad. En este proyecto proponemos la realización de un análisis metabonómico mediante espectrometría de masas acoplada a cromatografía líquida de tejido hepático del donante en el momento de la extracción, que permitiría obtener un conjunto de biomarcadores de disfunción del injerto, que podrían estar relacionados con la calidad del injerto hepático y así, anticipar la función del órgano. El primer objetivo de este proyecto consistió en la búsqueda de una firma metabonómica en biopsias de hígado de donantes, asociada con la EAD. Los injertos hepáticos de los que se obtuvo biopsia para el análisis metabonómico fueron clasificados en dos grupos, de acuerdo a su función en el receptor: i) pacientes con EAD, ii) pacientes con función inmediata del injerto (IGF). Con el objetivo de investigar la relación entre los perfiles metabonómicos presentes en los hígados de los donantes antes del trasplante y su función en el receptor, realizamos un análisis multivariante de los datos, tratando de identificar el conjunto de biomarcadores asociados a EAD. Los principales cambios metabonómicos observados incluyeron un aumento significativo de los niveles de sales biliares, lisofosfolípidos, fosfolípidos, esfingomielinas y productos del metabolismo de la histidina. Una vez identificamos un perfil metabonómico en los hígados donantes capaz de predecir la EAD, echamos en falta la existencia de una clasificación clínica de EAD más precisa con el fin de poder correlacionar de un modo más exacto el perfil metabonómico del hígado donante con el grado de disfunción tras el TH. Por lo tanto, el segundo objetivo de este proyecto consistió en el desarrollo de un modelo continuo para la evaluación temprana de la función del injerto al que llamamos “model for early allograft function” (MEAF). Mediante el estudio retrospectivo incluyendo 1.026 trasplantes hepáticos consecutivos pertenecientes a un mismo centro, construimos un modelo basado en parámetros clínicos (ALT, INR y bilirrubina), con el objetivo de puntuar la función hepática del injerto tras el TH entre 0 y 10. La puntuación MEAF mostró una asociación significativa con la supervivencia del paciente y del injerto. Valores elevados del MEAF score pueden alertar a los médicos que el paciente está en riesgo de sufrir complicaciones relacionadas con la disfunción del injerto y también puede ayudar en los estudios traslacionales que requieren una clasificación más precisa y objetiva de la función del injerto. Nuestro tercer y último objetivo del trabajo fue estudiar la asociación entre el MEAF score y los niveles de los marcadores de EAD encontrados mediante el análisis metabonómico, lo que nos permitió asignar una puntuación reflejo de la calidad del injerto para cada hígado donante

Hypothermic Machine Perfusion in Liver Transplantation - A Randomized Trial

BACKGROUND Transplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited. METHODS In this multicenter, controlled trial, we randomly assigned patients who were undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional static cold storage alone (control group). The primary end point was the incidence of nonanastomotic biliary strictures within 6 months after transplantation. Secondary end points included other graft-related and general complications. RESULTS A total of 160 patients were enrolled, of whom 78 received a machine-perfused liver and 78 received a liver after static cold storage only (4 patients did not receive a liver in this trial). Nonanastomotic biliary strictures occurred in 6% of the patients in the machine-perfusion group and in 18% of those in the control group (risk ratio, 0.36; 95% confidence interval [CI], 0.14 to 0.94; P=0.03). Postreperfusion syndrome occurred in 12% of the recipients of a machine-perfused liver and in 27% of those in the control group (risk ratio, 0.43; 95% CI, 0.20 to 0.91). Early allograft dysfunction occurred in 26% of the machine-perfused livers, as compared with 40% of control livers (risk ratio, 0.61; 95% CI, 0.39 to 0.96). The cumulative number of treatments for nonanastomotic biliary strictures was lower by a factor of almost 4 after machine perfusion, as compared with control. The incidence of adverse events was similar in the two groups. CONCLUSIONS Hypothermic oxygenated machine perfusion led to a lower risk of nonanastomotic biliary strictures following the transplantation of livers obtained from donors after circulatory death than conventional static cold storage

Utilization of livers donated after circulatory death for transplantation - An international comparison.

BACKGROUND AND AIM Liver graft utilization rates are a hot topic due to the worldwide organ shortage and an increasing number of transplant candidates on waiting lists. Liver perfusion techniques have been introduced in several countries, and may help to increase the organ supply, as they potentially allow the assessment of livers before use. METHODS Liver offers were counted from donation after circulatory death (DCD) donors (Maastricht-type-III) arising during the past decade in eight countries, including Belgium, France, Italy, the Netherlands, Spain, Switzerland, UK, and US. Initial DCD-type-III liver offers were correlated with accepted, recovered and implanted livers. RESULTS A total number of 34`269 DCD livers were offered, resulting in 9`780 liver transplants (28.5%). The discard rates were highest in UK and US, ranging between 70 and 80%. In contrast, much lower DCD liver discard rates, e.g., between 30-40%, were found in Belgium, France, Italy, Spain and Switzerland. In addition, large differences were recognized in the use of various machine perfusion techniques, and in terms of risk factors in the cohorts of implanted livers. For example, the median donor age and functional donor warm ischemia were highest in Italy, e.g., >40minutes, followed by Switzerland, France, and the Netherlands. Importantly, such varying risk profiles of accepted DCD livers between countries did not translate into large differences in five-year graft survival rates, which ranged between 60-82% in this analysis. CONCLUSIONS We highlight a significant number of discarded and consequently unused DCD liver offers. Countries with more routine use of in- and ex-situ machine perfusion strategies showed better DCD utilization rates without compromised outcome. IMPACT AND IMPLICATIONS A significant number of Maastricht type III DCD livers are discarded across Europe and North America today. The overall utilization rate among eight Western countries is 28.5%, but varies significantly between 18.9% and 74.2%. For example, the median DCD III liver utilization in five countries, e.g., Belgium, France, Italy, Switzerland, and Spain is 65%, in contrast to 24% in the Netherlands, UK and US. Despite this, and despite different rules and strategies for organ acceptance and preservation, the one and five-year graft survival remains currently relatively comparable among all participating countries. Factors which impact on DCD liver acceptance rates include the national pre-selections of donors, before the offer is made, as well as cutoffs for key risk factors, including donor age and donor warm ischemia time. In addition, a highly varying experience with modern machine perfusion technology is noticed. In situ and ex situ liver perfusion concepts, and assessment tools for type III DCD livers before transplantation may be one key part for the observed differences in better DCD III utilization

Liver Transplantation for Biliary Atresia in Adulthood: Single-Centre Surgical Experience

Background: Biliary atresia (BA) is the most common indicator for liver transplant (LT) in children, however, approximately 22% will reach adulthood with their native liver, and of these, half will require transplantation later in life. The aim of this study was to analyse the surgical challenges and outcomes of patients with BA undergoing LT in adulthood. Methods: Patients with BA requiring LT at the age of 16 or older in our unit between 1989 and 2020 were included. Pretransplant, perioperative variables and outcomes were analysed. Pretransplant imaging was reviewed to assess liver appearance, spontaneous visceral portosystemic shunting (SPSS), splenomegaly, splenic artery (SA) size, and aneurysms. Results: Thirty-four patients who underwent LT for BA fulfilled the inclusion criteria, at a median age of 24 years. The main indicators for LT were synthetic failure and recurrent cholangitis. In total, 57.6% had significant enlargement of the SA, 21% had multiple SA aneurysm, and SPSS was present in 72.7% of the patients. Graft and patient survival at 1, 5, and 10 years was 97.1%, 91.2%, 91.2% and 100%, 94%, 94%, respectively Conclusions: Good outcomes after LT for BA in young patients can be achieved with careful donor selection and surgery to minimise the risk of complications. Identification of anatomical variants and shunting are helpful in guiding attitude at the time of transplant

Minimally-invasive liver resection for liver tumors in children: a snapshot of the current landscape

Minimally-invasive liver resection (MILR) is a promising approach and has become a standard therapy option for a variety of indications, including liver tumors, in adults. Although minimally-invasive techniques are common practices in children, the usage and literature regarding MILR in children is scarce. In this article, we give an update on the current literature, share some of our own experience and give a future outlook of the potential benefits and shortcomings regarding MILR in children

British Transplantation Society guidelines on abdominal organ transplantation from deceased donors after circulatory death

The British Transplantation Society (BTS) ‘Guideline on transplantation from deceased donors after circulatory death’ has recently been updated and this manuscript summarises the relevant recommendations in abdominal organ transplantation from Donation after Circulatory Death (DCD) donors, encompassing the chapters on liver, kidney, pancreas and islet cell transplantation.<br/

A multicenter randomized-controlled trial of hypothermic oxygenated perfusion (HOPE) for human liver grafts before transplantation

BACKGROUND & AIMS Machine perfusion is a novel method intended to optimize livers before transplantation. However, its effect on morbidity within a 1-year period after transplantation has remained unclear. METHODS In this multicenter controlled trial, we randomly assigned livers donated after brain death (DBD) for liver transplantation (LT). Livers were either conventionally cold stored (control group), or cold stored and subsequently treated by 1-2 h hypothermic oxygenated perfusion (HOPE) before implantation (HOPE group). The primary endpoint was the occurrence of at least one post-transplant complication per patient, graded by the Clavien score of ≥III, within 1-year after LT. The comprehensive complication index (CCI), laboratory parameters, as well as duration of hospital and intensive care unit stay, graft survival, patient survival, and biliary complications served as secondary endpoints. RESULTS Between April 2015 and August 2019, we randomized 177 livers, resulting in 170 liver transplantations (85 in the HOPE group and 85 in the control group). The number of patients with at least one Clavien ≥III complication was 46/85 (54.1%) in the control group and 44/85 (51.8%) in the HOPE group (odds ratio 0.91; 95% CI 0.50-1.66; p = 0.76). Secondary endpoints were also not significantly different between groups. A post hoc analysis revealed that liver-related Clavien ≥IIIb complications occurred less frequently in the HOPE group compared to the control group (risk ratio 0.26; 95% CI 0.07-0.77; p = 0.027). Likewise, graft failure due to liver-related complications did not occur in the HOPE group, but occurred in 7% (6 of 85) of the control group (log-rank test, p = 0.004, Gray test, p = 0.015). CONCLUSIONS HOPE after cold storage of DBD livers resulted in similar proportions of patients with at least one Clavien ≥III complication compared to controls. Exploratory findings suggest that HOPE decreases the risk of severe liver graft-related events. IMPACT AND IMPLICATIONS This randomized controlled phase III trial is the first to investigate the impact of hypothermic oxygenated perfusion (HOPE) on cumulative complications within a 12-month period after liver transplantation. Compared to conventional cold storage, HOPE did not have a significant effect on the number of patients with at least one Clavien ≥III complication. However, we believe that HOPE may have a beneficial effect on the quantity of complications per patient, based on its application leading to fewer severe liver graft-related complications, and to a lower risk of liver-related graft loss. The HOPE approach can be applied easily after organ transport during recipient hepatectomy. This appears fundamental for wide acceptance since concurring perfusion technologies need either perfusion at donor sites or continuous perfusion during organ transport, which are much costlier and more laborious. We conclude therefore that the post hoc findings of this trial should be further validated in future studies