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Purpose of Review: With advances in the field of congenital cardiac surgery and in the management of congenital heart defects in early life, the population of adult congenital heart disease (ACHD) patients is increasing. End-stage heart failure is currently the main cause of cardiovascular mortality and is expected to increase in the coming years. This review summarizes recent innovations in transplant techniques, with special attention to what is known in the population of ACHD recipients., Recent Findings: The use of machine perfusion for heart preservation enables longer preservation times. Normothermic (organ care system - OCS) and hypothermic (hypothermic oxygenated perfusion - HOPE) machine perfusion will alleviate the time pressure associated with heart transplantation in the ACHD population, may allow for expansion of the geographical range in which donors can be matched and may improve graft quality. Donation after circulatory death (DCD) heart transplantation, either through direct procurement-machine perfusion (DP-MP) or thoraco-abdominal normothermic regional perfusion (TA-NRP) is a viable strategy to further expand the donor pool., Summary: The use of machine perfusion and DCD donors in ACHD is feasible and shows promise. Time pressure and shortage of donors is even more critical in ACHD than in other patient populations, making these innovations particularly relevant. Further clinical experience and research is needed to elucidate their impact., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Machine perfusion has been adopted into clinical practice in Europe since the mid-2010s and, more recently, in the United States (US) following approval of normothermic machine perfusion (NMP). We aim to review recent advances, provide discussion of potential future directions, and summarize challenges currently facing the field., Recent Findings: Both NMP and hypothermic-oxygenated perfusion (HOPE) improve overall outcomes after liver transplantation versus traditional static cold storage (SCS) and offer improved logistical flexibility. HOPE offers additional protection to the biliary system stemming from its' protection of mitochondria and lessening of ischemia-reperfusion injury. Normothermic regional perfusion (NRP) is touted to offer similar protective effects on the biliary system, though this has not been studied prospectively.The most critical question remaining is the optimal use cases for each of the three techniques (NMP, HOPE, and NRP), particularly as HOPE and NRP become more available in the US. There are additional questions regarding the most effective criteria for viability assessment and the true economic impact of these techniques. Finally, with each technique purported to allow well tolerated use of riskier grafts, there is an urgent need to define terminology for graft risk, as baseline population differences make comparison of current data challenging., Summary: Machine perfusion is now widely available in all western countries and has become an essential tool in liver transplantation. Identification of the ideal technique for each graft, optimization of viability assessment, cost-effectiveness analyses, and proper definition of graft risk are the next steps to maximizing the utility of these powerful tools., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: In an attempt to reduce waiting list mortality in liver transplantation, less-than-ideal quality donor livers from extended criteria donors are increasingly accepted. Predicting the outcome of these organs remains a challenge. Machine perfusion provides the unique possibility to assess donor liver viability pretransplantation and predict postreperfusion organ function., Recent Findings: Assessing liver viability during hypothermic machine perfusion remains challenging, as the liver is not metabolically active. Nevertheless, the levels of flavin mononucleotide, transaminases, lactate dehydrogenase, glucose and pH in the perfusate have proven to be predictors of liver viability. During normothermic machine perfusion, the liver is metabolically active and in addition to the perfusate levels of pH, transaminases, glucose and lactate, the production of bile is a crucial criterion for hepatocyte viability. Cholangiocyte viability can be determined by analyzing bile composition. The differences between perfusate and bile levels of pH, bicarbonate and glucose are good predictors of freedom from ischemic cholangiopathy., Summary: Although consensus is lacking regarding precise cut-off values during machine perfusion, there is general consensus on the importance of evaluating both hepatocyte and cholangiocyte compartments. The challenge is to reach consensus for increased organ utilization, while at the same time pushing the boundaries by expanding the possibilities for viability testing., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: Normothermic regional perfusion (NRP) is a novel procurement technique for donation after circulatory death (DCD) in the United States. It was pioneered by cardiothoracic surgery programs and is now being applied to abdominal-only organ donors by abdominal transplant programs. Multiple technical approaches can be used for abdominal-only NRP DCD donors and this review describes these techniques., Recent Findings: NRP has been associated with higher utilization of organs, particularly liver and heart grafts, from DCD donors and with better recipient outcomes. There are lower rates of delayed graft function in kidney transplant recipients and lower rates of ischemic cholangiopathy in liver transplant recipients. These benefits are driving increased interest from abdominal transplant programs in using NRP for DCD procurements., Summary: This paper describes the technical aspects of NRP DCD that allow for maximization of its use based on different donor and policy characteristics., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Normothermic ex situ liver perfusion (NESLiP) has the potential to increase organ utilization. Radiological evidence of localized liver injury due to compression at the time of NESLiP, termed cradle compression, is a recognized phenomenon but is poorly characterized., Methods: A retrospective analysis of a prospectively collected database was performed of transplanted livers that underwent NESLiP and subsequently had a computed tomography performed within the first 14 d posttransplant. The primary study outcome was 1-y graft survival., Results: Seventy livers (63%) were included in the analysis. Radiological evidence of cradle compression was observed in 21 of 70 (30%). There was no difference in rate of cradle compression between donor after circulatory death and donated after brain death donors ( P  = 0.37) or with duration of NESLiP. Univariate analysis demonstrated younger (area under the receiver operating characteristic, 0.68; P = 0.008; 95% confidence interval [CI], 0.55-0.82) and heavier (area under the receiver operating characteristic, 0.80; P  < 0.001; 95% CI, 0.69-0.91) livers to be at risk of cradle compression. Only liver weight was associated with cradle compression on multivariate analysis (odds ratio, 1.003; P  = 0.005; 95% CI, 1.001-1.005). There was no difference in 1-y graft survival (16/17 [94.1%] versus 44/48 [91.6%]; odds ratio, 0.69; P  = 0.75; 95% CI, 0.07-6.62)., Conclusions: This is the first study assessing the impact of cradle compression on outcome. We have identified increased donor liver weight and younger age as risk factors for the development of this phenomenon. Increasing utilization of NESLiP will result in the increased incidence of cradle compression but the apparent absence of long-term sequelae is reassuring. Routine postoperative axial imaging may be warranted., Competing Interests: J.L.M. and L.S. have received consultancy fees from OrganOx. C.J.E.W. has received speaker fees from OrganOx. A.J.B. is coholder of a patent on the circuit used in the OrganOx metra. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: The number of patients on the liver transplant waitlist continues to grow and far exceeds the number of livers available for transplantation. Normothermic machine perfusion (NMP) allows for ex-vivo perfusion under physiologic conditions with the potential to significantly increase organ yield and expand the donor pool., Recent Findings: Several studies have found increased utilization of donation after cardiac death and extended criteria brain-dead donor livers with implementation of NMP, largely due to the ability to perform viability testing during machine perfusion. Recently, proposed viability criteria include lactate clearance, maintenance of perfusate pH more than 7.2, ALT less than 6000 u/l, evidence of glucose metabolism and bile production. Optimization of liver grafts during NMP is an active area of research and includes interventions for defatting steatotic livers, preventing ischemic cholangiopathy and rejection, and minimizing ischemia reperfusion injury., Summary: NMP has resulted in increased organ utilization from marginal donors with acceptable outcomes. The added flexibility of prolonged organ storage times has the potential to improve time constraints and transplant logistics. Further research to determine ideal viability criteria and investigate ways to optimize marginal and otherwise nontransplantable liver grafts during NMP is warranted., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: With the increase in life expectancy and the aging of the population, chronic kidney disease has become increasingly prevalent in our environment. Kidney transplantation remains the gold standard treatment for end-stage renal disease, but the supply of renal grafts has not been able to keep pace with growing demand. Because of this rationale, organ selection criteria have been extended (expanded criteria donation), and alternative donation types, such as donation after circulatory death, have been evaluated. These approaches aim to increase the pool of potential donors, albeit with organs of potentially lower quality. Various forms of donations, including donation after circulatory death, have also undergone assessment. This approach aims to augment the pool of potential donors, notwithstanding the compromised quality of organs associated with such methods. Diverse strategies have been explored to enhance graft function, with one of the most promising being the utilization of pulsatile machine perfusion., Materials and Methods: We conducted a retrospective analysis on 28 transplant recipients who met the inclusion criterion of sharing the same donor, wherein one organ was preserved by cold storage and the other by pulsatile machine perfusion. We performed statistical analysis on posttransplant recovery parameters throughout the patients' hospitalization, including admission and discharge phases., Results: Statistically significant differences were noted in delayed graft function (P = .04), blood transfusions requirements, and Clavien-Dindo complications. Furthermore, an overall trend of improvement in discharge parameters and hospital stay was in favor of the pulsatile machine perfusion group., Conclusions: The use of pulsatile machine perfusion as a method of renal preservation results in graft optimization, leading to earlier recovery and fewer complications compared with cold storage in the context of donation after circulatory death.

Aims: There is wide variability in the practice of cardiac preservation for heart transplantation. Prior reports suggest that the type of solution may be linked with a reduced incidence of posttransplantation complications., Methods: Adult (≥18 years old) heart recipients who underwent transplantation between 2015 and 2021 in the United States were examined. Recipients were stratified by solution utilized for their grafts at the time of recovery: University of Wisconsin, histidine-tryptophan-ketoglutarate (HTK), or Celsior solution. The primary endpoint was a composite of 30-day mortality, primary graft dysfunction, or re-transplantation. Risk adjustment was performed for the recipient, donor, and procedural characteristics using regression modeling., Results: Among 16 884 recipients, the group distribution was University of Wisconsin solution 53%, HTK 22%, Celsior solution 15%, and other 10%. The observed incidence of the composite endpoint (University of Wisconsin solution = 3.6%, HTK = 4.0%, Celsior solution = 3.7%, P = 0.301) and 1-year survival (University of Wisconsin solution = 91.7%, HTK = 91.3%, Celsior solution = 91.7%, log-rank P = 0.777) were similar between groups. After adjustment, HTK was associated with a higher risk of the composite endpoint [odds ratio (OR) 1.249, 95% confidence interval (CI) 1.019-1.525, P = 0.030] in reference to University of Wisconsin solution. This association was substantially increased among recipients with ischemic periods of greater than 4 h (OR 1.817, 95% CI 1.188-2.730, P = 0.005). The risks were similar between University of Wisconsin solution and Celsior solution (P = 0.454)., Conclusion: The use of the histidine-tryptophan-ketoglutarate solution during cold static storage for cardiac preservation is associated with increased rates of early mortality or primary graft dysfunction. Clinician discretion should guide its use, especially when prolonged ischemic times (>4 h) are anticipated., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Given the current severe shortage of available livers for transplantation, there is an urgent need to maximize the utilization of donor organs. One of the strategies to increase the number of available livers for transplantation is to improve organ utilization through the use of elderly, overweight, or organs donated after circulatory death. However, the utilization of these "marginal" organs was associated with an increased risk of early allograft dysfunction, primary nonfunction, ischemic biliary complications, or even re-transplantation. Ischemia-reperfusion injury is a key mechanism in the pathogenesis of these complications., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In Italy, 20 minutes of continuous, flat-line electrocardiogram are required for death declaration, which significantly increases the risks of donation after circulatory death (DCD) LT. Despite prolonged warm ischemia time, Italian centers reported good outcomes in controlled donation after circulatory death LT by combining normothermic regional and end-ischemic machine perfusion. However, data on uncontrolled DCD (uDCD) LT performed by this approach are lacking. This was a multicenter, retrospective study performed at 3 large-volume centers comparing clinical outcomes of uncontrolled versus controlled DCD LT. The aim of the study was to assess outcomes of sequential normothermic regional perfusion and end-ischemic machine perfusion in uncontrolled DCD liver transplantation (LT). Of 153 DCD donors evaluated during the study period, 40 uDCD and 59 donation after circulatory death grafts were transplanted (utilization rate 52% vs. 78%, p = 0.004). Recipients of uDCD grafts had higher MEAF (4.9 vs. 3.5, p < 0.001) and CCI scores at discharge (24.4 vs. 8.7, p = 0.026), longer ICU stay (5 vs. 4 d, p = 0.047), and a trend toward more severe AKI. At multivariate analysis, 90-day graft loss was associated with recipient BMI and lactate downtrend during normothermic regional perfusion. One-year graft survival was lower in uDCD (75% vs. 90%, p = 0.007) but became comparable when non-liver-related graft losses were treated as censors (77% vs. 90%, p = 0.100). The incidence of ischemic cholangiopathy was 10% in uDCD versus 3% in donation after circulatory death, p = 0.356. uDCD LT with prolonged warm ischemia is feasible by the sequential use of normothermic regional perfusion and end-ischemic machine perfusion. Proper donor and recipient selection are key to achieving good outcomes in this setting., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Introduction: Renal allograft hypothermic machine perfusion results in a decreased incidence of delayed graft function compared with static cold storage. Ensuring perfusate temperatures remain within the target range of 4-10 °C may impact delayed graft function rates. Project Aims: To identify whether this target was achieved and, if not, whether higher perfusate temperature was associated with delayed graft function. Design: In this retrospective cohort study, transplanted grafts from deceased donors placed on hypothermic machine perfusion pump from June 2019 to August 2020 were analyzed. Measurements were recovered after 5, 15, 60, and 180 min of perfusion. Univariable and multivariable analyses were performed to identify predictors of delayed graft function. Results: A total of 113 grafts from 94 donors were analyzed. Of these, 21 (19%) developed delayed graft function. On univariable logistic regression, variables associated with delayed graft function included older donor age (OR 1.08, P  = .002), higher Kidney Donor Profile Index score (OR 1.03, P  = .024), and higher 5-min perfusate temperature (T5 min; OR 1.49, P  = .014). A higher T5 min was also associated with delayed graft function in multivariable logistic regression models (OR 1.58, P  = .005; OR 1.37, P  = .08). Grafts with T5 min >10 °C were more likely to experience delayed graft function than those with T5 min <10 °C (OR 4.5, P  = .006). Conclusion: Higher early perfusate temperature was an independent predictor of delayed graft function and may be due to inadequate cooling of the circuit prior to placing grafts on pump. Quality improvement initiatives targeting early perfusate temperatures of ≤10 °C may reduce delayed graft function incidence., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with the research, authorship, and/or publication of this article.

Background: Simultaneous pancreas-kidney transplantation is the optimal treatment for patients with type 1 diabetes and renal failure. The use of pancreas grafts from donation after circulatory death (DCD), using normothermic regional perfusion (NRP), is still marginal worldwide, mainly due to possible additional risks of graft dysfunction and complications compared with grafts from donors after brain death., Methods: Case series of patients who underwent simultaneous pancreas-kidney transplantation after DCD-NRP between January 2018 and September 2022. This study evaluated early postoperative grafts and survival outcomes., Results: Four patients were included. One patient lost the pancreatic graft due to arterial thrombosis requiring transplantectomy. Another patient required a laparotomy due to hemoperitoneum. Overall, 1-year pancreas and kidney graft survival was 75% and 100%, respectively. One patient developed a lymphoma during the follow-up., Conclusion: The use of pancreas grafts from DCD after NRP preservation is safe and feasible. Comparative studies with donors after brain death grafts and larger series are required to confirm the feasibility of DCD-NRP pancreas transplantation., Competing Interests: Declaration of Competing Interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The standard Conventional Cold Storage (CCS) during heart transplantation procurement is associated with time-dependent ischemic injury to the graft, which is a significant independent risk factor for post-transplant early morbidity and mortality - especially when cold ischemic time exceeds four hours. Since 2018, Rigshospitalet (Copenhagen, Denmark) has been utilising ex vivo perfusion (Organ Care System, OCS) in selected cases. The objective of this study was to compare the short-term clinical outcomes of patients transplanted with OCS compared to CCS. Methods : This retrospective single-centre study was based on consecutive patients undergoing a heart transplant between January 2018 and April 2021. Patients were selected for the OCS group when the cold ischemic time was expected to exceed four hours. The primary outcome measure was six-month event-free survival. Results : In total, 48 patients were included in the study; nine were transplanted with an OCS heart. The two groups had no significant differences in baseline characteristics. Six-month event-free survival was 77.8% [95% CI: 54.9-100%] in the OCS group and 79.5% [95% CI: 67.8-93.2%] in the CCS group ( p  = 0.91). While the OCS group had a median out-of-body time that was 183 min longer ( p  < 0.0001), the cold ischemic time was reduced by 51 min ( p  = 0.007). Conclusion: In a Scandinavian setting, our data confirms that utilising OCS in heart procurement allows for a longer out-of-body time and a reduced cold ischemic time without negatively affecting safety or early post-transplant outcomes.

Background: Given the scarce donor supply, an increasing number of so-called marginal or extended criteria donor (ECD) organs are used for liver transplantation. These ECD liver grafts are however known to be associated with a higher rate of early allograft dysfunction and primary non-function because of a greater vulnerability to ischemia-reperfusion injury. The end-ischemic hypothermic oxygenated machine perfusion (HOPE) technique may improve outcomes of liver transplantation with ECD grafts by decreasing reperfusion injury., Methods: HOPExt trial is a comparative open-label, multicenter, national, prospective, randomized, controlled study, in two parallel groups, using static cold storage, the gold standard procedure, as control. The trial will enroll adult patients on the transplant waiting list for liver failure or liver cirrhosis and/or liver malignancy requiring liver transplantation and receiving an ECD liver graft from a brain-dead donor. In the experimental group, ECD liver grafts will first undergo a classical static cold (4 °C) storage followed by a hypothermic oxygenated perfusion (HOPE) for a period of 1 to 4 h. The control group will consist of the classic static cold storage which is the gold standard procedure in liver transplantation. The primary objective of this trial is to study the efficacy of HOPE used before transplantation of ECD liver grafts from brain-dead donors in reducing postoperative early allograft dysfunction within the first 7 postoperative days compared to simple cold static storage., Discussion: We present in this protocol all study procedures in regard to the achievement of the HOPExt trial, to prevent biased analysis of trial outcomes and improve the transparency of the trial results. Enrollment of patients in the HOPExt trial has started on September 10, 2019, and is ongoing., Trial Registration: ClinicalTrials.gov NCT03929523. Registered on April 29, 2019, before the start of inclusion., (© 2023. The Author(s).)

Background: Optimal organ preservation remains a critical hallmark event in renal transplantation as it is the supply line. Previous studies have shown that the choice of preservation solution may affect transplant outcomes. In this study, we aimed to present the early follow-up results of the graft and patients, using lactated Ringer to preserve kidney allografts with living donors., Methods: The results of 97 living donor transplant operations performed in Sanko University Hospital were evaluated retrospectively. The patient's evaluation included demographics, dialysis time duration, renal replacement method, primary disease, comorbidity, surgical and clinical complications in the acute period, graft functions, blood levels of calcineurin inhibitor drugs, anastomotic renal artery, warm ischemia, and cold ischemia times., Results: Donor (49 men, 50.5%) and recipient (58 men, 59.7%) demographics, HLA compatibility (mismatch), hospitalization days, and length of warm and cold ischemic time are summarized in Table 1. Primary nonfunction was not defined in any patients, but delayed graft function was observed during the follow-up of 3 patients (3.09%), who were all hypotensive in the post-transplantation period, and positive inotropic infusion was needed for hemodynamic stability., Conclusions: Lactated Ringer demonstrated efficacy in terms of patient and graft survival, and its lower cost represents a financial advantage, so it can be used in living donor kidney transplantation because it is safe, effective, and inexpensive. Standard preservation solutions may still be recommended in cases with long cold ischemia times, such as paired exchange transplants and cadaveric transplants. Thus, randomized controlled studies are needed for further investigation., Competing Interests: Declaration of Competing Interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose of Review: This article will review the evidence behind elements of the lung preservation process that have remained relatively stable over the past decade as well as summarize recent developments in ex-vivo lung perfusion and new research challenging the standard temperature for static cold storage., Recent Findings: Ex-vivo lung perfusion is becoming an increasingly well established means to facilitate greater travel distance and allow for continued reassessment of marginal donor lungs. Preliminary reports of the use of normothermic regional perfusion to allow utilization of lungs after DCD recovery exist, but further research is needed to determine its ability to improve upon the current method of DCD lung recovery. Also, research from the University of Toronto is re-assessing the optimal temperature for static cold storage; pilot studies suggest it is a feasible means to allow for storage of lungs overnight to allow for daytime transplantation, but ongoing research is awaited to determine if outcomes are superior to traditional static cold storage., Summary: It is crucial to understand the fundamental principles of organ preservation to ensure optimal lung function posttransplant. Recent advances in the past several years have the potential to challenge standards of the past decade and reshape how lung transplantation is performed., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The shortage of donor organs has led to the use of marginal extended criteria donor (ECD) livers to increase access to liver transplant. Ex-vivo machine perfusion allows for treatment and assessment of organs during preservation, potentially facilitating safe use of ECD livers at risk for worse clinical outcomes. This article reviews the latest published literature on the application of ex-vivo machine perfusion technologies in liver transplantation., Recent Findings: Multiple randomized controlled trials on the use of hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) have been published in the past 5 years demonstrating improved graft function and decreased biliary complications after machine perfusion. Novel applications of machine perfusion include pretransplant organ viability testing, expansion to pediatric transplant, and prolonged preservation., Summary: There is now a body of evidence that HMP and NMP treatment improves clinical outcomes in ECD livers. There is a wide horizon for future applications of these preservation techniques to further optimize donor livers and to facilitate more liver transplants for those on the waitlist., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Therapeutic hypothermia in brain-dead organ donors has been shown to reduce delayed graft function in kidney recipients after transplantation. Data are needed on the effect of hypothermia as compared with machine perfusion on outcomes after kidney transplantation., Methods: At six organ-procurement facilities in the United States, we randomly assigned brain-dead kidney donors to undergo therapeutic hypothermia (hypothermia group), ex situ kidney hypothermic machine perfusion (machine-perfusion group), or both (combination-therapy group). The primary outcome was delayed graft function in the kidney transplant recipients (defined as the initiation of dialysis during the first 7 days after transplantation). We also evaluated whether hypothermia alone was noninferior to machine perfusion alone and whether the combination of both methods was superior to each of the individual therapies. Secondary outcomes included graft survival at 1 year after transplantation., Results: From 725 enrolled donors, 1349 kidneys were transplanted: 359 kidneys in the hypothermia group, 511 in the machine-perfusion group, and 479 in the combined-therapy group. Delayed graft function occurred in 109 patients (30%) in the hypothermia group, in 99 patients (19%) in the machine-perfusion group, and in 103 patients (22%) in the combination-therapy group. Adjusted risk ratios for delayed graft function were 1.72 (95% confidence interval [CI], 1.35 to 2.17) for hypothermia as compared with machine perfusion, 1.57 (95% CI, 1.26 to 1.96) for hypothermia as compared with combination therapy, and 1.09 (95% CI, 0.85 to 1.40) for combination therapy as compared with machine perfusion. At 1 year, the frequency of graft survival was similar in the three groups. A total of 10 adverse events were reported, including cardiovascular instability in 9 donors and organ loss in 1 donor owing to perfusion malfunction., Conclusions: Among brain-dead organ donors, therapeutic hypothermia was inferior to machine perfusion of the kidney in reducing delayed graft function after transplantation. The combination of hypothermia and machine perfusion did not provide additional protection. (Funded by Arnold Ventures; ClinicalTrials.gov number, NCT02525510.)., (Copyright © 2023 Massachusetts Medical Society.)

To alleviate the persistent shortage of donor livers, high-risk liver grafts are increasingly being considered for liver transplantation. Conventional preservation with static cold storage falls short in protecting these high-risk livers from ischemia-reperfusion injury, as evident from higher rates of post-transplant complications such as early allograft dysfunction and ischemic cholangiopathy. Moreover, static cold storage does not allow for a functional assessment of the liver prior to transplantation. To overcome these limitations, dynamic strategies of liver preservation have been proposed, designed to provide a protective effect while allowing pre-transplant functional assessment. In this review, we discuss how different dynamic preservation strategies exert their effects, where we stand in assessing liver function and what challenges are lying ahead., (© 2022 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Abrupt return to normothermia has been shown a genuine factor contributing to graft dysfunction after transplantation. This study tested the concept to mitigate reperfusion injury of liver grafts by gentle warming-up using ex vivo machine perfusion prior to reperfusion. In a single center randomized controlled study, livers were assigned to conventional static cold storage (SCS) alone or to SCS followed by 90 min of ex vivo machine perfusion including controlled oxygenated rewarming (COR) by gentle and protracted elevation of the perfusate temperature from 10°C to 20°C. Primary outcome mean peak aspartate aminotransferase (AST) was 1371 U/L (SD 2871) after SCS versus 767 U/L (SD 1157) after COR (p = 0.273). Liver function test (LiMAx) on postoperative day 1 yielded 187 μg/kg/h (SD 121) after SCS, but rose to 294 μg/kg/h (SD 106) after COR (p = 0.006). Likewise, hepatic synthesis of coagulation factor V was significantly accelerated in the COR group immediately after transplantation (103% [SD 34] vs. 66% [SD 26]; p = 0.001). Fewer severe complications (Clavien-Dindo grade ≥3b) were reported in the COR group (8) than in the SCS group (15). Rewarming/reperfusion injury of liver grafts can be safely and effectively mitigated by controlling of the rewarming kinetics prior to blood reperfusion using end-ischemic ex vivo machine perfusion after cold storage., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: The number of kidney transplants obtained from controlled donations after circulatory death is increasing, with long-term outcomes similar to those obtained with donations after brain death. Extraction using normothermic regional perfusion can improve results with controlled donors after circulatory death; however, information on the histological impact and extraction procedure is scarce., Materials and Methods: We retrospectively investigated all kidney transplants performed from October 2014 to December 2019, in which a follow-up kidney biopsy had been performed at 1-year follow-up, comparing controlled procedures with donors after circulatory death and normothermic regional perfusion versus donors after brain death. Interstitial fibrosis/tubular atrophy was assessed by adding the values of interstitial fibrosis and tubular atrophy, according to the Banff classification of renal allograft pathology., Results: When we compared histological data from 66 transplants with donations after brain death versus 24 transplants with donations after circulatory death and normothermic regional perfusion, no differences were found in the degree of fibrosis in the 1-year follow-up biopsy (1.7 ± 1.3 vs 1.7 ± 1.1; P = .971) or in the ratio of patients with increased fibrosis calculated as interstitial fibrosis/tubular atrophy >2 (18% vs 13%; P = .522). In our multivariate analysis, which included acute rejection, expanded criteria donation, and the type of donation, no variable was independently related to an increased risk of interstitial fibrosis/tubular atrophy >2., Conclusions: The outcomes of kidney grafts procured in our center using controlled procedures with donors after circulatory death and normothermic regional perfusion were indistinguishable from those obtained from donors after brain death, showing the same degree of fibrosis in the 1-year posttransplant surveillance biopsy. Our data support the conclusion that normothermic regional perfusion should be the method of choice for extraction in donors after circulatory death.

Purpose of Review: This review aims to summarize the latest original preclinical and clinical articles in the setting of normothermic machine perfusion (NMP) of kidney grafts., Recent Findings: Kidney NMP can be safely translated into the clinical routine and there is increasing evidence that NMP may be beneficial in graft preservation especially in marginal kidney grafts. Due to the near-physiological state during NMP, this technology may be used as an ex-vivo organ assessment and treatment platform. There are reports on the application of mesenchymal stromal/stem cells, multipotent adult progenitor cells and microRNA during kidney NMP, with first data indicating that these therapies indeed lead to a decrease in inflammatory response and kidney injury. Together with the demonstrated possibility of prolonged ex-vivo perfusion without significant graft damage, NMP could not only be used as a tool to perform preimplant graft assessment. Some evidence exists that it truly has the potential to be a platform to treat and repair injured kidney grafts, thereby significantly reducing the number of declined organs., Summary: Kidney NMP is feasible and can potentially increase the donor pool not only by preimplant graft assessment, but also by ex-vivo graft treatment., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Viability assessment is one of the main indications for machine perfusion (MP) in liver transplantation. This review summarizes the rationale, evolution and limitations of proposed viability criteria and suggests a framework for future studies., Recent Findings: Liver viability is most frequently assessed during normothermic MP by combining parameters relative to perfusate and bile composition, vascular flows and macroscopic aspect. Assessment protocols are largely heterogeneous and have significantly evolved over time, also within the same group, reflecting the ongoing evolution of the subject. Several recent preclinical studies using discarded human livers or animal models have explored other approaches to viability assessment. During hypothermic MP, perfusate flavin mononucleotide has emerged as a promising biomarker of mitochondrial injury and function. Most studies on the subject suffer from limitations, including low numbers, lack of multicenter validation, and subjective interpretation of some viability parameters., Summary: MP adds a further element of complexity in the process of assessing the quality of a liver graft. Understanding the physiology of the parameters included in the different assessment protocols is necessary for their correct interpretation. Despite the possibility of assessing liver viability during MP, the importance of donor-recipient matching and operational variables should not be disregarded., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Partial liver grafts from ex situ splitting are considered marginal due to prolonged static cold storage. The use of ex situ hypothermic oxygenated perfusion (HOPE) may offer a strategy to improve preservation of ex situ split grafts. In this single-center pilot study, we prospectively performed ex situ liver splitting during HOPE (HOPE-Split) for adult and pediatric partial grafts over a 1-year period (November 1, 2020 to December 1, 2021). The primary safety endpoint was based on the number of liver graft-related adverse events (LGRAEs) per recipient, including primary nonfunction, biliary complications, hepatic vascular complications, and early relaparotomies and was compared with consecutive single-center standard ex situ split transplantations (Static-Split) performed from 2018 to 2020. Secondary endpoints included preservation characteristics and early outcomes. Sixteen consecutive HOPE-Split liver transplantations (8 HOPE-Split procedures) were included and compared with 24 Static-Splits. All HOPE-Split grafts were successfully transplanted, and no graft loss nor recipient death was encountered during the median follow-up of 7.5 months (interquartile range, 5.5-12.5). Mean LGRAE per recipient was similar in both groups (0.31 ± 0.60 vs. 0.46 ± 0.83; p = 0.78) and split duration was not significantly increased for HOPE-Split (216 vs. 180 min; p = 0.45). HOPE-Split grafts underwent perfusion for a median of 125 min, which significantly shortened static cold storage (472 vs. 544 min; p = 0.001), whereas it prolonged total ex vivo preservation (595 vs. 544 min; p = 0.007) and reduced neutrophil infiltration on reperfusion biopsies (p = 0.04) compared with Static-Split. This clinical pilot study presents first feasibility and safety data for transplantation of partial liver grafts undergoing ex situ split during HOPE and suggests improved preservation compared with static ex situ splitting. These preliminary results will allow to set up large-scale trials on the use of machine perfusion in pediatric and split-liver transplantation., (© 2022 American Association for the Study of Liver Diseases.)

Acceptance of liver grafts from donations after circulatory death (DCD) largely remains a "black box," particularly due to the unpredictability of the agonal phase. Abdominal normothermic regional perfusion (aNRP) can reverse ischemic injury early during the procurement procedure, and it simultaneously enables graft viability testing to unravel this black box. This review evaluates current protocols for liver viability assessment to decide upon acceptance or decline during aNRP. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was used, and relevant literature databases were searched. The primary outcome consisted of criteria for liver graft viability assessment. Secondary outcomes included survival, primary nonfunction (PNF), early dysfunction, and biliary complications. A total of 14 articles were included in the analysis. In all protocols, a combination of criteria was used to assess suitability of the liver for transplantation. As many as 12 studies (86%) used macroscopic assessment, 12 studies (86%) used alanine transaminase (ALT) levels in perfusate, 9 studies (64%) used microscopic assessment, and 7 studies (50%) used lactate levels as assessment criteria. The organ utilization rate (OUR) was 16% for uncontrolled donation after circulatory death (uDCD) and 64% for controlled donation after circulatory death (cDCD). The most used acceptation criterion in uDCD is ALT level (31%), while in cDCD macroscopic aspect (48%) is most used. Regarding postoperative complications, PNF occurred in 13% (6%-25%) of uDCD livers and 3% (2%-4%) of cDCD livers. In uDCD, the 1-year graft and patient survival rates were 75% (66%-82%) and 82% (75%-88%). In cDCD, the 1-year graft and patient survival rates were 91% (89%-93%) and 93% (91%-94%), respectively. In conclusion, the currently used assessment criteria consist of macroscopic aspect and transaminase levels. The acceptance criteria should be tailored according to donor type to prevent an unacceptable PNF rate in uDCD and to increase the relatively modest OUR in cDCD., (© 2022 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Organs from donation after circulatory death (DCD) are increasingly used for liver transplantation, due to the persisting organ shortage and waiting list mortality. However, the use of DCD grafts is still limited by the inferior graft survival rate and the increased risk of primary non-function and biliary complications when compared to brain death donors' grafts., Methods: Abdominal normothermic regional perfusion with extracorporeal membrane oxygenation (ECMO) is an in situ preservation strategy. which may mitigate ischemia-reperfusion injuries. and has been proposed to restore blood perfusion after the determination of death thus optimizing liver function before implantation., Results: In this systematic review, we highlighted the clinical evidence supporting the use of normothermic regional perfusion in DCD liver underlying the pathophysiological mechanisms, and technical, logistic, and regulatory aspects., Conclusions: Despite the lack of properly designed, prospective, randomized trials, the current available data suggest beneficial effects of normothermic regional perfusion on clinical outcomes after liver transplantation., (© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: Normothermic ex vivo kidney perfusion (NEVKP) has shown promising results for preservation, assessment, and reconditioning of kidney allografts in preclinical studies. Here, we report the first North American safety and feasibility study of deceased donor kidneys grafts transplanted following preservation with NEVKP., Methods: Outcomes of 13 human kidney grafts that received 1 to 3 h of NEVKP after being transported in an anoxic hypothermic machine perfusion device were compared with a matched control group of 26 grafts that were preserved with anoxic hypothermic machine perfusion alone., Results: Grafts were perfused for a median of 171 min (range, 44-275 min). The delayed graft function rate in NEVKP versus control patients was 30.8% versus 46.2% ( P = 0.51). During the 1-y follow-up, no differences in postoperative graft function, measured by serum creatinine, necessity for dialysis, and urine production, were found between the study group and the control group. There were no differences in 1 y posttransplantation graft or patient survival between the 2 groups., Conclusions: Our study demonstrates the safety and feasibility of NEVKP for human deceased donor kidney transplantation. Further studies are warranted to explore how this technology can minimize cold ischemia, improve posttransplant graft function, and assess and repair expanded criteria kidney grafts., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: This review describes recent developments in the field of liver perfusion techniques., Recent Findings: Dynamic preservation techniques are increasingly tested due to the urgent need to improve the overall poor donor utilization. With their exposure to warm ischemia, livers from donors after circulatory death (DCD) transmit additional risk for severe complications after transplantation. Although the superiority of dynamic approaches compared to static-cold-storage is widely accepted, the number of good quality studies remains limited. Most risk factors, particularly donor warm ischemia, and accepted thresholds are inconsistently reported, leading to difficulties to assess the impact of new preservation technologies. Normothermic regional perfusion (NRP) leads to good outcomes after DCD liver transplantation, with however short ischemia times. While randomized controlled trials (RCT) with NRP are lacking, results from the first RCTs with ex-situ perfusion were reported. Hypothermic oxygenated perfusion was shown to protect DCD liver recipients from ischemic cholangiopathy. In contrast, endischemic normothermic perfusion seems to not impact on the development of biliary complications, although this evidence is only available from retrospective studies., Summary: Dynamic perfusion strategies impact posttransplant outcomes and are increasingly commissioned in various countries along with more evidence from RCTs. Transparent reporting of risk and utilization with uniform definitions is required to compare the role of different preservation strategies in DCD livers with prolonged ischemia times., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Traditional liver transplant strategies with cold preservation usually result in ischemia-reperfusion injury (IRI) to the donor liver. Regular normothermic machine perfusion (NMP) donor livers suffer IRI twice. Here, we aimed to introduce a novel technique called continuous NMP without recooling to avoid a second IRI and its application in livers from extended criteria donors., Methods: Seven donor livers transplanted following continuous NMP without recooling, 7 donor livers transplanted following standard NMP, and 14 livers under static cold storage (SCS) were included in this study. Perioperative outcomes were recorded and analyzed between groups., Results: During the NMP without a recooling procedure, all livers cleared lactate quickly to normal levels in a median time of 100 min (interquartile range, 60-180) and remained stable until the end of perfusion. In the NMP without recooling and standard NMP groups, posttransplant peak aspartate aminotransferase and alanine aminotransferase levels were both significantly lower than those in the SCS group (P = 0.0015 and 0.016, respectively). The occurrence rate of early allograft dysfunction was significantly lower in the NMP without recooling group than in the SCS group (P = 0.022), whereas there was no difference in the NMP group with or without recooling (P = 0.462)., Conclusions: Our pilot study revealed a novel technique designed to avoid secondary IRI. This novel technique is shown to have at least a comparable effect on the standard NMP, although more data are needed to show its superiority in the future., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Recently, continuous nonoxygenated hypothermic machine perfusion (HMP) has been implemented as standard preservation method for deceased donor kidneys in the Netherlands. This study was designed to assess the effect of the implementation of HMP on early outcomes after transplantation., Methods: Kidneys donated in the Netherlands in 2016 and 2017 were intended to be preserved by HMP. A historical cohort (2010-2014) preserved by static cold storage was chosen as the control group. Primary outcome was delayed graft function (DGF). Additional analyses were performed on safety, graft function, and survival up until 2 y after transplantation., Results: Data were collected on 2493 kidneys. Analyses showed significantly more donation after circulatory death, preemptive transplantation, and retransplants in the project cohort. Of the 681 kidneys that were transplanted during the project, 81% were preserved by HMP. No kidneys were discarded due to HMP-related complications. DGF occurred in 38.2% of the project cohort versus 43.7% of the historical cohort (P < 0.001), with a significantly shorter duration within the project cohort (7 versus 9 d, P = 0.003). Multivariate regression analysis showed an odds ratio of 0.69 (95% confidence interval, 0.553-0.855) for the risk of DGF when using HMP compared with cold storage (P = 0.001). There was no significant difference in kidney function, graft survival, and recipient survival up until 2 y posttransplantation., Conclusions: This study showed that HMP as a standard preservation method for deceased donor kidneys is safe and feasible. HMP was associated with a significant reduction of DGF., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

The transplant community continues to be challenged by the disparity between the need for liver transplantation and the shortage of suitable donor organs. At the same time, the number of unused donor livers continues to increase, most likely attributed to the worsening quality of these organs. To date, there is no reliable marker of liver graft viability that can predict good posttransplant outcomes. Ex situ machine perfusion offers additional data to assess the viability of donor livers before transplantation. Hence, livers initially considered unsuitable for transplantation can be assessed during machine perfusion in terms of appearance and consistency, hemodynamics, and metabolic and excretory function. In addition, postoperative complications such as primary nonfunction or posttransplant cholangiopathy may be predicted and avoided. A variety of viability criteria have been used in machine perfusion, and to date there is no widely accepted composition of criteria for clinical use. This review discusses potential viability markers for hepatobiliary function during machine perfusion, describes current limitations, and provides future recommendations for the use of viability criteria in clinical liver transplantation., (Copyright © 2021 by the American Association for the Study of Liver Diseases.)

Purpose of Review: Intestinal donation is currently restricted to 'perfect' donors, as the intestine is extremely vulnerable to ischemia. With generally deteriorating donor quality and increasing indications for intestinal transplantation (ITx), the potential to safely increase the donor pool should be evaluated., Recent Findings: Increasing awareness on intestinal donation (often forgotten) and cautiously broadening the strict donor criteria (increasing age, resuscitation time and ICU stay) could expand the potential donor pool. Donors after circulatory death (DCD) have so far not been considered for ITx, due to the particularly detrimental effect of warm ischemia on the intestine. However, normothermic regional perfusion might be a well tolerated strategy to render the use of DCD intestinal grafts feasible. Furthermore, machine perfusion is under continuous development and might improve preservation of the intestine and potentially offer a platform to modulate the intestinal graft. Lastly, living donation currently represents only a minority of all ITxs performed worldwide. Various studies and registry analysis show that it can be performed safely for the donor and successfully in the recipient., Summary: Several potential strategies are available to expand the current intestinal donor pool. Most of them require further investigation or technical developments before they can be implemented in the clinical routine., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Ex-vivo machine perfusion has emerged as a promising alternative to static cold storage (SCS) for preservation of liver grafts over the last decade. This review describes the mechanistic benefits associated with hypothermic machine perfusion (HMP) for preservation of liver grafts and highlights clinical outcomes of liver transplantation using HMP technology., Recent Findings: Over the last decade, several single-centre studies have shown decreased biliary complications, decreased early allograft dysfunction (EAD) rates and improved patient survival in liver transplant recipients after application of HMP for liver graft preservation. This has led to initiation of prospective, multicentre, randomized controlled trials (RCTs) in both Europe and North America focused on clinical outcomes in liver transplant recipients using HMP-preserved liver grafts. In addition, recent single-centre studies have shown the utility of perfusate biomarker analysis during HMP in predicting EAD after liver transplantation., Summary: HMP technology has potential to increase the available donor liver organ pool for liver transplant recipients and improve clinical outcomes after liver transplantation. Broader clinical application of HMP in resuscitation and preservation of liver grafts is anticipated over the next decade once regulatory, logistical and financial challenges are overcome., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: High-dose nitric oxide (NO) has been shown effective against a variety of micro-organisms in vitro, including common bacteria found in donor organs. However, clinical obstacles related to its implementation in vivo are the formation of methemoglobin and the accumulation of toxic nitrogen compounds. Ex vivo lung perfusion (EVLP) is a platform that allows for organ maintenance with an acellular perfusion solution, thus overcoming these limitations. The present study explores the safety of continuous high-dose inhaled (iNO) during EVLP for an extended period of 12 hours., Methods: Lungs procured from Yorkshire pigs were randomized into control (standard ventilation) and treatment (standard ventilation + 200 ppm iNO) groups, then perfused with an acellular solution for 12 hours (n = 4/group). Lung physiology and biological markers were evaluated., Results: After 12 hours of either standard EVLP or EVLP + 200 ppm iNO, we did not notice any significant physiologic difference between the groups: pulmonary oxygenation (P = .586), peak airway pressures (P = .998), and dynamic (P = .997) and static (P = .908) lung compliances. In addition, no significant differences were seen among proinflammatory cytokines measured in perfusate and lung tissue. Importantly, most common toxic compounds were kept at safe levels throughout the treatment course., Conclusions: High-dose inhaled NO delivered continuously over 12 hours appears to be safe without inducing any significant pulmonary inflammation or deterioration in lung function. These findings support further efficacy studies to explore the use of iNO for the treatment of infections in donor lungs during EVLP., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Robust viability assessment of grafts during normothermic liver perfusion is a prerequisite for organ use. Coagulation parameters are used commonly for liver assessment in patients. However, they are not yet included in viability assessment during ex situ perfusion. In this study, we analysed coagulation parameters during one week ex situ perfusion at 34℃. Eight discarded human livers were perfused with blood-based, heparinised perfusate for one week; perfusions in a further four livers were terminated on day 4 due to massive ongoing cell death. Coagulation parameters were well below the physiologic range at perfusion start. Physiologic levels were achieved within the first two perfusion days for factor V (68.5 ± 35.5%), factor VII (83.5 ± 26.2%), fibrinogen (2.1 ± 0.4 g/L) and antithrombin (107 ± 26.5%) in the livers perfused for one week. Despite the increased production of coagulation factors, INR was detectable only at 24h of perfusion (2.1 ± 0.3) and prolonged thereafter (INR > 9). The prolongation of INR was related to the high heparin level in the perfusate (anti-FXa > 3 U/mL). Intriguingly, livers with ongoing massive cell death also disclosed synthesis of factor V and improved INR. In summary, perfused livers were able to produce coagulation factors at a physiological level ex situ. We propose that single coagulation factor analysis is more reliable for assessing the synthetic function of perfused livers as compared to INR when using a heparinised perfusate., (© 2021 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Cold storage/rewarming is an inevitable process for kidney transplantation from deceased donors, which correlates closely with renal ischemia-reperfusion injury (IRI) and the occurrence of delayed graft function. Histone deacetylases (HDAC) are important epigenetic regulators, but their involvement in cold storage/rewarming injury in kidney transplantation is unclear. In the present study, we showed a dynamic change of HDAC3 in a mouse model of kidney cold storage followed by transplantation. We then demonstrated that the selective HDAC3 inhibitor RGFP966 could reduce acute tubular injury and cell death after prolonged cold storage with transplantation. RGFP966 also improved renal function, kidney repair and tubular integrity when the transplanted kidney became the sole life-supporting graft in the recipient mouse. In vitro, cold storage of proximal tubular cells followed by rewarming induced remarkable cell death, which was suppressed by RGFP966 or knockdown of HDAC3 with shRNA. Inhibition of HDAC3 decreased the mitochondrial pathway of apoptosis and preserved mitochondrial membrane potential. Collectively, HDAC3 plays a pathogenic role in cold storage/rewarming injury in kidney transplantation, and its inhibition may be a therapeutic option., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Introduction: End-ischaemic preservation of a donor liver by dual hypothermic oxygenated machine perfusion (DHOPE) for 2 hours prior to transplantation is sufficient to mitigate ischaemia-reperfusion damage and fully restore cellular energy levels. Clinical studies have shown beneficial outcomes after transplantation of liver grafts preserved by DHOPE compared with static cold storage. In addition to graft reconditioning, DHOPE may also be used to prolong preservation time, which could facilitate logistics for allocation and transplantation globally., Methods and Analysis: This is a prospective, pseudo-randomised, dual-arm, IDEAL-D (Idea, Development, Exploration, Assessment, Long term study-Framework for Devices) stage 2 clinical device trial designed to determine safety and feasibility of prolonged DHOPE (DHOPE-PRO). The end-time of the donor hepatectomy will determine whether the graft will be assigned to the intervention (16:00-3:59 hour) or to the control arm (4:00-15:59 hour). In total, 36 livers will be included in the study. Livers in the intervention group (n=18) will undergo DHOPE-PRO (≥4 hours) until implantation the following morning, whereas livers in the control group (n=18) will undergo regular DHOPE (2 hours) prior to implantation. The primary endpoint of this study is a composite of the occurrence of all (serious) adverse events during DHOPE and up to 30 days after liver transplantation., Ethics and Dissemination: The protocol was approved by the Medical Ethical Committee of Groningen, METc2020.126 in June 2020, and the study was registered in the Netherlands National Trial Registry (https://www.trialregister.nl/) prior to initiation., Trial Registration Number: NL8740., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Livers procured via donation after cardiac death have produced good outcomes. Some centers use only aortic perfusion; others add portal perfusion., Materials and Methods: We report a series of organ procurements in which portal perfusion was performed via cannulation of the splenic vein instead of the inferior mesenteric vein in 4 donors after cardiac death and 2 donors after brain death., Results: After declaration of death, donors were brought to the operating room and prepared and draped. During procurement, first the aorta was cannulated, and then the atrium or inferior vena cava was opened and perfusion was started.The spleen was mobilized, the splenic vein was dissected out and cannulated, and portal perfusion was performed with 2 L of University of Wisconsin solution. Five liver allografts were transplanted: 3 at our center, and 2 at outside centers. One liver from a donor after cardiac death was declined because of a high fat content. All 5 transplanted grafts showed good initial function; there was no sign of primary nonfunction, and no vascular or biliary complications developed., Conclusions: For livers from donors after cardiac death, cannulation of the splenic vein was easier than access via the inferior mesenteric vein. For donors after brain death, we also found this technique was suitable for livers with intra-abdominal adhesions or a small inferior mesenteric vein. Graft outcomes in this series were excellent.

Objectives: Machine perfusionfor kidney preservation is a common practice. There is no consensus on the best formula for perfusion solutions. We aimed to discern the additives that organ procurement organizations in the United States include in their perfusate and the impact of these additives on transplant outcomes., Materials and Methods: A telephone survey of all 58 organ procurement organizations in the United States regarding additives to their perfusion solutions was conducted. The survey data were merged with transplant recipient outcome data from the United Network for Organ Sharing database.The final analysis included perfused kidneys between January 2014 and March 2019. Logistic regressions were performed to investigate whether a particular perfusion formula was associated with delayed graft function, primary nonfunction, or early graft failure., Results: Additives correlated with decreased rates of graft failure were mannitol in all kidneys and kidneys of lower quality (P < .01) and penicillin/ampicillin in all kidneys (P < .05). Additives associated with increased graft failure regardless of type included verapamil in all kidneys (P < .05) and kidneys of lower quality (P < .01) and arginine with glutathione in all kidneys and low-quality kidneys alone (P < .01)., Conclusions: Further outcomes research and standardized guidelines for additives in machine perfusion of kidneys across all organ procurement organizations are needed.

Background: Donation after circulatory death (DCD) in Italy, given its 20-min stand-off period, provides a unique bench test for normothermic regional perfusion (NRP) and dual hypothermic oxygenated machine perfusion (D-HOPE)., Methods: We coordinated a multicenter retrospective Italian cohort study with 44 controlled DCD donors, who underwent NRP, to present transplant characteristics and results. To rank our results according to the high donor risk, we matched and compared a subgroup of 37 controlled DCD livers, preserved with NRP and D-HOPE, with static-preserved controlled DCD transplants from an established European program., Results: In the Italian cohort, D-HOPE was used in 84% of cases, and the primary nonfunction rate was 5%. Compared with the matched comparator group, the NRP + D-HOPE group showed a lower incidence of moderate and severe acute kidney injury (stage 2: 8% versus 27% and stage 3: 3% versus 27%; P = 0.001). Ischemic cholangiopathy remained low (2-y proportion free: 97% versus 92%; P = 0.317), despite the high-risk profile resulting from the longer donor warm ischemia in Italy (40 versus 18 min; P < 0.001)., Conclusions: These data suggest that NRP and D-HOPE yield good results in DCD livers with prolonged warm ischemia., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Donation after circulatory death (DCD) grafts are commonly used in liver transplantation. Attributable to the additional ischemic event during the donor warm ischemia time (DWIT), DCD grafts carry an increased risk for severe ischemia/reperfusion injury and postoperative complications, such as ischemic cholangiopathy. The actual ischemia during DWIT depends on the course of vital parameters after withdrawal of life support and varies widely between donors. The ischemic period (functional DWIT) starts when either Spo2 or blood pressure drop below a certain point and lasts until the start of cold perfusion during organ retrieval. Over the years, multiple definitions and thresholds of functional DWIT duration have been used. The International Liver Transplantation Society organized a Consensus Conference on DCD, Liver Preservation, and Machine Perfusion on January 31, 2020 in Venice, Italy. The aim of this conference was to reach consensus about various aspects of DCD liver transplantation in context of currently available evidence. Here we present the recommendations with regards to the definitions used for DWIT and functional DWIT, the importance of vital parameters after withdrawal of life support, and acceptable thresholds of duration of functional DWIT to proceed with liver transplantation., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

For 2 centuries, researchers have studied ex vivo perfusion intending to preserve the physiologic function of isolated organs. If it were indeed possible to maintain ex vivo organ viability for days, transplantation could become an elective operation with clinicians methodically surveilling and reconditioning allografts before surgery. To this day, experimental reports of successfully prolonged (≥24 hours) organ perfusion are rare and have not translated into clinical practice. To identify the crucial factors necessary for successful perfusion, this review summarizes the history of prolonged normothermic ex vivo organ perfusion. By examining successful techniques and protocols used, this review outlines the essential elements of successful perfusion, limitations of current perfusion systems, and areas where further research in preservation science is required., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Donation after circulatory death (DCD) donors are an increasingly more common source of livers for transplantation in many parts of the world. Events that occur during DCD liver recovery have a significant impact on the success of subsequent transplantation. This working group of the International Liver Transplantation Society evaluated current evidence as well as combined experience and created this guidance on DCD liver procurement. Best practices for the recovery and transplantation of livers arising through DCD after euthanasia and organ procurement with super-rapid cold preservation and recovery as well as postmortem normothermic regional perfusion are described, as are the use of adjuncts during DCD liver procurement., Competing Interests: A.J.H. has received consultancy fees from Guanguong Shunde Innovative Design Institute, Guangdong, China. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

There is a severe shortage in the availability of donor organs for lung transplantation. Novel strategies are needed to optimize usage of available organs to address the growing global needs. Ex vivo lung perfusion has emerged as a powerful tool for the assessment, rehabilitation, and optimization of donor lungs before transplantation. In this review, we discuss the history of ex vivo lung perfusion, current evidence on its use for standard and extended criteria donors, and consider the exciting future opportunities that this technology provides for lung transplantation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Recent trials in liver machine perfusion (MP) have revealed unique challenges beyond those seen in most clinical studies. Correct trial design and interpretation of data are essential to avoid drawing conclusions that may compromise patient safety and increase costs., Methods: The International Liver Transplantation Society, through the Special Interest Group "DCD, Preservation and Machine Perfusion," established a working group to write consensus statements and guidelines on how future clinical trials in liver perfusion should be designed, with particular focus on relevant clinical endpoints and how different techniques of liver perfusion should be compared. Protocols, abstracts, and full published papers of clinical trials using liver MP were reviewed. The use of a simplified Grading of Recommendations Assessment, Development, and Evaluation working group (GRADE) system was attempted to assess the level of evidence. The working group presented its conclusions at the International Liver Transplantation Society consensus conference "DCD, Liver Preservation, and Machine Perfusion" held in Venice, Italy, on January 31, 2020., Results: Twelve recommendations were proposed with the main conclusions that clinical trials investigating the effect of MP in liver transplantation should (1) make the protocol publicly available before the start of the trial, (2) be adequately powered, and (3) carefully consider timing of randomization in function of the primary outcome., Conclusions: There are issues with using accepted primary outcomes of liver transplantation trials in the context of MP trials, and no ideal endpoint could be defined by the working group. The setup of an international registry was considered vital by the working group., Competing Interests: PF is a co-founder, Chief Medical Officer, and stock-holder in OrganOx Ltd, a spin-out company from the University of Oxford established to develop machine perfusion technology. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This study aimed to evaluate how cold ischemia time (CIT) interferes with liver graft function in the first 7 days after surgery for Custodiol (HTK) preserved organs., Methods: This retrospective observational study analyzed the medical records of 38 transplantation patients at Hospital Leforte Liberdade, São Paulo, in 2018. The study population was divided into 2 groups (group A, CIT < 8 hours; group B, CIT > 8 hours). Postoperative parameters-such as international normalized ratio, total bilirubin, aspartate aminotransferase/alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase (GGT), lactate dehydrogenase, lactate, creatinine, red blood cell transfusion, need for hemodialysis, use of vasoactive drugs, endotracheal intubation time, length of stay in the intensive care unit (ICU), and length of hospital stay-were compared., Results: Group A (CIT < 8 hours) presented less need for red blood cell transfusions (odds ratio 0.29; confidence interval 0.06-0.98; P = .04), had a shorter hospital stay (P = .024), and had lower levels of total bilirubin (P = .05) and GGT (P = .05) in the first 7 postoperative days. The other variables showed no statistically significant difference., Conclusion: In livers preserved with Custodiol, CIT > 8 hours generated higher levels of total bilirubin and GGT in the postoperative period, in addition to higher hospital costs; greater need for red blood cell transfusions; and longer hospitalization, including longer stays in the ICU., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Ischemia-reperfusion (I/R) injury causes present challenges in the field of graft transplantation which is also a major contributor to early graft dysfunction or failure after organ transplantation. The study focuses on the effects of prolonged cold-ischemia (CI) on the autophagic activity in the graft lung in a rat orthotopic lung transplantation model., Material and Methods: Donor lungs were preserved under CI conditions for different periods. An orthotopic lung transplantation model was developed, and the lung tissues from donor lungs subjected to CI preservation and reperfusion were harvested. We evaluated the effects of different CI periods on autophagy, reactive oxygen species (ROS) and glucose consumption. Additionally, the mechanism by which prolonged CI affected autophagy was investigated through determination of the molecules related to the mTOR pathway after treatment with 3-Methyladenine (3-MA), rapamycin and an adenosine triphosphate (ATP) synthase inhibitor oligomycin (OM)., Results: Prolonged CI led to increased activities of key glycolytic enzymes, glucose consumption and lactic acid production. Autophagy, ROS and glucose consumption were induced in the graft lung after I/R, which reached peak levels after 6 h and was gradually decreased. Most importantly, the perfusion treatment of 3-MA or OM decreased ROS level and autophagy, but increased the extent of mTOR phosphorylation, while the perfusion treatment of rapamycin induced ROS and autophagy., Conclusion: Taken together, autophagy mediated by a prolonged CI preservation affects the glucose consumption and ROS production in the graft lung via the mTOR signaling pathway., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Ischemia-reperfusion injury (IRI) is the major cause of primary graft dysfunction in organ transplantation. The mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) signaling pathway plays a crucial role in cell physiological and pathological processes including IRI. This study aims to investigate whether inhibition of ERK signaling with U0126 can prevent prolonged cold IRI in heart transplantation., Methods: Rat cardiac cell line H9c2 cells were treated with U0126 before exposure to hypothermic hypoxia/reoxygenation (H/R) conditions. The effect of U0126 on H9c2 cells in response to H/R stress was determined by measuring cell death, reactive oxygen species production, mitochondrial membrane potential, and ERK signaling activation. Mouse syngeneic heterotopic heart transplantation was conducted, where a donor heart was preserved in the University of Wisconsin (UW) solution supplemented with U0126 for 24 hours at 4°C before transplantation. Heart graft function, histopathologic changes, apoptosis, and fibrosis were measured to assess IRI., Results: Phosphorylated ERK was increased in both in vitro H/R-injured H9c2 cells and in vivo heart grafts with IRI. Pretreatment with U0126 inhibited ERK phosphorylation and prevented H9c2 cells from cell death, reactive oxygen species generation, and mitochondrial membrane potential loss in response to H/R. Preservation of donor hearts with U0126-supplemented solution improved graft function and reduced IRI by reductions in cell apoptosis/death, neutrophil infiltration, and fibrosis of the graft., Conclusions: Addition of U0126 to UW solution reduces ERK signal activation and attenuates prolonged cold IRI in a heart transplantation model. ERK inhibition with U0126 may be a useful strategy to minimize IRI in organ transplantation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)