ORGAN THERAPEUTICS DURING EX-SITU DYNAMIC PRESERVATION. A LOOK INTO THE FUTURE

editorial reviewe

The effect of continuous liver normothermic machine perfusion on the severity of histological bile duct injury

Static Cold Storage (SCS) injures the bile duct, while the effect of Normothermic Machine Perfusion (NMP) is unknown. In a sub-study of the COPE trial on liver NMP, we investigated the impact of preservation type on histological bile duct injury score (BDIS). Transplants with at least one bile duct biopsy, either at end of preservation or 1 h post-reperfusion, were considered. BDIS was determined by assessing peribiliary glands injury, stromal and mural loss, haemorrhage, and thrombosis. A bivariate linear model compared BDIS (estimate, CI) between groups. Sixty-five transplants and 85 biopsies were analysed. Twenty-three grafts were preserved with SCS and 42 with NMP, with comparable baseline characteristics except for a shorter cold ischemic time in NMP. The BDIS increased over time regardless of preservation type (p = 0.04). The BDIS estimate was higher in NMP [8.02 (7.40–8.65)] than in SCS [5.39 (4.52–6.26), p < 0.0001] regardless of time. One patient in each group developed ischemic cholangiopathy, with a BDIS of 6 for the NMP-preserved liver. In six other NMP grafts, BDIS ranged 7–12 without development of ischemic cholangiopathy. In conclusion, BDIS increases over time, and the higher BDIS in NMP did not increase ischemic cholangiopathy. Thus, BDIS may overestimate this risk after liver NMP

Organ Repair and Regeneration During Ex Situ Dynamic Preservation: The Future is Nano

peer reviewedOrgan preservation and assessment with machine perfusion (MP) has provided transplant physicians with the ability to evaluate and select grafts suitable for transplantation. Nevertheless, the discard of organs considered too damaged still sustains the imbalance between donor organs supply and demands. Therefore, there is the pressing clinical need for strategies to repair and/or regenerate organs before transplantation, and MP is uniquely positioned to satisfy this need. The systemic administration of mesenchymal stromal cells (MSC) was shown to reduce ischemia-reperfusion injury in pre-clinical organ transplant models but could not be reproduced in clinical transplantation, largely because of inefficient cell delivery. The administration of MSC during MP is one strategy that recently gained much attention as an alternative delivery method to target MSC directly to the donor organ. However, careful reinterpretation of preliminary results reveals that this approach is equally limited by a suboptimal delivery of short-lived MSC to the target organ. In contrast, the use of MSC secretome and/or extracellular vesicles therapy during MP seems to be more efficient in harnessing MSC properties during MP. In this mini review we speculate on the future of the novel niche of ex situ organ repair and regeneration before transplantation

Porcine Liver Normothermic Machine Perfusion: Methodological Framework and Potential Pitfalls

peer reviewedPorcine models of liver normothermic machine perfusion (NMP) are increasingly used in transplant research, although known to be challenging because of their complex methodology and their scarcely documented operational aspects. Here, we aimed to provide a methodological framework for researchers looking to adopt NMP technology in research setting by giving an in-detail account of the implementation of a previously validated porcine liver NMP model. We subjected groups of 3-5 porcine livers to 24 h NMP and, using a trial-and-error principle, introduced stepwise changes in the NMP setting with the objective to obtain stable preservation of liver function and histology for 24 h. Female porcine livers were procured, and packed red-blood-cell perfusate was prepared. Perfusate oxygenation, hemodynamics, markers of hepatic injury (aspartate transaminase [AST]), function (lactate, perfusate pH, bile production), and histology were analyzed. Intermediate analysis was performed within groups and a minimum of 3 (out of 5) failed experiments prompted methodological reevaluation. Overall, 13 liver NMP experiments were needed in 3 phases. In phase 1, loss of oxygenator performance occurred from 6 h onward in 3 consecutive experiments because of perfusate leakage. In phase 2, a plasma-tight hollow fiber oxygenator ensured adequate perfusate oxygenation in 5 experiments. However, portal vein resistance increased during all liver NMP, associated with high perfusate AST levels (range, 106-322 IU/L/100 g) and pan-lobular sinusoidal dilation and hemorrhage, suggesting liver outflow impairment. In phase 3, an improved inferior vena cava cannulation technique avoided liver outflow impairment, resulting in lower AST release (range, 29-101 IU/L/100 g), improved lactate clearance, preserved biliary excretion, and normal histology in 5 experiments. This study underscores the critical importance of auditing all equipment and operational components of NMP circuits to obtain successful and reproducible perfusion setup and advocates for in-detail reporting of methodological aspects and potential pitfalls. © 2021 Wolters Kluwer Health. All rights reserved

The effect of organ preservation solutions on short-term outcomes after liver transplantation: a single-center retrospective study

peer reviewedThe effect of preservation solutions on outcomes has been subject of many debates but the relative benefits of the various solutions remain unclear. We retrospectively compared short-term outcomes of 885 liver transplantations performed between 1/2000 and 12/2017 and preserved with either Histidine–Tryptophan–Ketoglutarate (HTK, n = 190), University of Wisconsin (UW, n = 557), or Institute George Lopez 1 preservation solution (IGL-1, n = 139). Inverse probability of treatment weighting (IPTW) was performed to account for baseline differences between groups and analyses were adjusted for confounders. In the IPTW analyses, peak AST within 7 days was 44% higher (95% CI 15–81%, P < 0.001) in HTK than in UW. Mean model of early allograft function (MEAF) score was 0.61 points (95% CI 0.12–1.10, P = 0.01) higher in HTK than in UW. Early allograft dysfunction (EAD) was more likely to occur with HTK compared to IGL-1 (IPTW OR = 2.87, 95% CI = 1.00–8.19, P = 0.049) and UW (IPTW OR = 1.75, 95% CI = 1.06–2.88, P = 0.023). The type of preservation solution had no impact on hospital stay, ICU stay, incidence of biliary strictures, or graft and recipient survival. HTK was the least effective on reducing graft injury and increased the probability of graft dysfunction after transplantation. UW and IGL-1 were equally effective in reducing graft injury and dysfunction. © 2020 Steunstichting ESOT. Published by John Wiley & Sons Ltd

Potential importance of early treatment of SARS-CoV-2 infection in intestinal transplant patient: A case report.

peer reviewed[en] BACKGROUND: Predispositions for severe coronavirus disease 2019 (COVID-19) are age, immunosuppression, and co-morbidity. High levels of maintenance immunosuppression render intestinal transplant (ITx) patients vulnerable for severe COVID-19. COVID-19 also provokes several gastroenterological pathologies which have not been discussed in ITx, so far. CASE SUMMARY: During the second European COVID-19 wave in November 2020, an ITx recipient was admitted to the hospital because of electrolyte disturbances due to dehydration. Immunosuppression consisted of tacrolimus, azathioprine, and low-dose corticosteroids. During hospitalization, she tested positive on screening COVID-19 nasopharyngeal polymerase chain reaction swab, while her initial test was negative. She was initially asymptomatic and had normal inflammatory markers. Tacrolimus levels were slightly raised, as Azathioprine was temporarily halted. Due to elevated D-dimers at that time, prophylactic low-molecular weight heparin was started. Seven days after the positive test, dyspnea, anosmia, and C-reactive protein increase (25 mg/L) were noted. Remdesivir was administered during 5 d in total. High stomal output was noted in two consecutive days and several days thereafter. To exclude infection or rejection, an ileoscopy and biopsy were performed and excluded these. Four weeks later, she was discharged from the hospital and remains in good health since then. CONCLUSION: Early eradication of severe acute respiratory syndrome coronavirus 2 in ITx recipients may be warranted to prevent acute rejection provocation by it

Development of a Model for Simultaneous Normothermic Perfusion in Porcine Kidney Grafts

peer reviewe

Multivisceral Transplantation for Diffuse Portomesenteric Thrombosis: Lessons Learned for Surgical Optimization

peer reviewedBackground: Multivisceral transplantation entails the en-bloc transplantation of stomach, duodenum, pancreas, liver and bowel following resection of the native organs. Diffuse portomesenteric thrombosis, defined as the complete occlusion of the portal system, can lead to life-threatening gastrointestinal bleeding, malnutrition and can be associated with liver and intestinal failure. Multivisceral transplantation is the only procedure that offers a definitive solution by completely replacing the portal system. However, this procedure is technically challenging in this setting. The aim of this study is to describe our experience, highlight the challenges and propose technical solutions. Materials and Methods: We performed a retrospective analysis of our cohort undergoing multivisceral transplantation for diffuse portomesenteric thrombosis at our institution from 2000 to 2020. Donor and recipient demographics and surgical strategies were reviewed in detail and posttransplant complications and survival were analyzed. Results: Five patients underwent MVTx. Median age was 47 years (23–62). All had diffuse portomesenteric thrombosis with life-threatening variceal bleeding. Major blood loss during exenteration was avoided by combining two techniques: embolization of the native organs followed by a novel, staged extraction. This prevented major perioperative blood loss [median intra-operative transfusion of 3 packed red blood cell units (0–5)]. Median CIT was 330 min (316–416). There was no perioperative death. One patient died due to invasive aspergillosis. Four others are alive and well with a median follow-up of 4.1 years (0.3–5.9). Conclusions: Multivisceral transplantation should be considered in patients with diffuse portomesenteric thrombosis that cannot be treated by any other means. We propose a standardized surgical approach to limit the operative risk and improve the outcome. © Copyright © 2021 Canovai, Ceulemans, Gilbo, Duchateau, De Hertogh, Hiele, Jochmans, Vanuytsel, Maleux, Verhaegen, Monbaliu and Pirenne

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