Over the past two decades, the application of machine perfusion (MP) in human liver transplantation has moved from the realm of clinical exploration to routine clinical practice. Both in situ and ex situ perfusion strategies are feasible, safe, and may offer improvements in relevant post-transplant outcomes. An important utility of these strategies is the ability to transplant grafts traditionally considered too risky to transplant using conventional cold storage alone. While dynamic assessment and ultimately transplantation of such livers is an important goal for the international liver transplant community, its clinical application is inconsistent. To this end, ELITA (the European Liver and Intestine Transplant Association) gathered a panel of experts to create consensus guidelines regarding selection, approach, and criteria for deceased donor liver assessment in the MP era. An eight-member steering committee (SC) convened a panel of 44 professionals working in 14 countries in Europe and North America. The SC identified topics related to liver utilisation and assessment for transplantation. For each topic, subtopics were created to answer specific clinical questions. A systematic literature review was performed, and the panel graded relevant evidence. The SC drafted initial statements addressing each clinical question. Statements were presented at the in-person Consensus Meeting on Liver Discard and Viability Assessment during the ELITA Summit held from April 19-20, 2024, in Madrid, Spain. Online voting was held to approve statements according to a modified Delphi method; statements reaching ≥85% agreement were approved. Statements addressing liver utilisation, the definition of high-risk livers, and strategies and criteria for dynamic liver assessment are presented.

Published work evaluating machine perfusion of DCD (donation after circulatory death) liver grafts in situ and ex situ is rapidly evolving, with several landmark studies published in the last 6 months. The central question in DCD liver transplant remains; which strategies most effectively reduce cholangiopathy? This condition, which results in repeated hospital admissions, interventions, re-transplantation and death, is a major deterrent to DCD utilization. This review considers current evidence in the mitigation of transplant cholangiopathy by machine perfusion in DCD liver grafts.

Studies which directly address DCD cholangiopathy as a primary outcome are few in number, despite their critical importance. In systematic reviews, Normothermic Regional Perfusion and Hypothermic Machine Perfusion consistently and significantly reduce transplant cholangiopathy rates. By contrast, the efficacy of Normothermic Machine Perfusion performed at donor or recipient centres is less well described and cautious interpretation is required. The most recent development, namely hypothermic followed by normothermic perfusion, has only now appeared in the literature but appears to offer advantages compared to either technology alone.

To reduce DCD cholangiopathy, current data best support the use of donor centre NRP or recipient centre HMP. However, utilization is also improved when warm perfusion is involved.

Background: Anastomotic biliary strictures (BSs) are among the most common complications after liver transplantation (LT), accounting for 5-15% of adult recipients after deceased-donor transplantation. For some reason, this percentage increased in our center in recent years, and the goal of this study was to find out the reasons behind this to avoid this complication in the future. Material and Methods: We retrospectively analyzed the occurrence of anastomotic biliary strictures in 230 cadaveric-donor LTs performed in our center between January 2019 and December 2023. Many variables related to the donor, recipient, and surgical procedure were compared between patients who experienced BS and those without this complication. Statistical analysis was performed using Fisher's exact test, a one-way ANOVA test, and Pearson's correlation coefficient. Results: Altogether, 51 patients (22.17%) developed BSs. This percentage was especially high in 2023 (32%). The only significant differences found in study group compared to the control group were the requirement of additional doses of vasopressors during surgery (45 (86.53%) vs. 138 (77.09%), p = 0.0001) and more frequent instances of reperfusion syndrome (8/51 (15.68%) vs. 11/179 (6.11%), p = 0.00001). Conclusions: We conclude that ischemia during LT has an advantage over technical parameters in the development of BSs after LT. Appropriate blood volume resuscitation as opposed to inotropic treatment may reduce the risk of this complication.

Ex situ machine perfusion of the donor liver, such as dual hypothermic oxygenated machine perfusion (DHOPE), is increasingly used in liver transplantation. Although DHOPE reduces ischemia/reperfusion-related complications after liver transplantation, data on cost-effectiveness are lacking. Our objective was to evaluate the cost-effectiveness of DHOPE in donation after circulatory death (DCD) liver transplantation.

We performed an economic evaluation of DHOPE versus static cold storage (SCS) based on a multicenter randomized controlled trial in DCD liver transplantation (DHOPE-DCD trial; ClinicalTrials.gov number, NCT02584283). All patients enrolled in the 3 participating centers in the Netherlands were included. Costs related to the transplant procedure, hospital stay, readmissions, and outpatients treatments up to 1 y posttransplant were calculated. The cost for machine perfusion was calculated using 3 scenarios: (1) costs for machine perfusion, (2) machine perfusion costs plus costs for personnel, and (3) scenario 2 plus depreciation expenses for a dedicated organ perfusion room.

Of 119 patients, 60 received a liver after DHOPE and 59 received a liver after SCS alone. The mean total cost per patient up to 1 y posttransplant was €126 221 for the SCS group and €110 794 for the DHOPE group. The most significant reduction occurred in intensive care costs (28.4%), followed by nonsurgical interventions (24.3%). In cost scenario 1, DHOPE was cost-effective after 1 procedure. In scenarios 2 and 3, cost-effectiveness was achieved after 25 and 30 procedures per year, respectively.

Compared with conventional SCS, machine perfusion using DHOPE is cost-effective in DCD liver transplantation, reducing the total medical costs up to 1 y posttransplant.

Limited data exists regarding impact of graft type on outcomes following liver transplantation (LT) in Primary Sclerosing Cholangitis (PSC). Our goal was to evaluate the impact of graft type on outcomes following LT in PSC and determine predictors of outcomes.

Using the Scientific registry of transplant recipients (SRTR), retrospective cohorts were constructed of recipients with PSC over the time period 2010-2020, divided into 2 eras: 2010-2014, 2015-2020, stratified by graft type: living donor (LDLT), donation after circulatory death (DCD) and donation after brain death (DBD). Outcome measures evaluated were graft and patient survival. Survival comparison was performed using Kaplan-Meier method and multivariable analysis using Cox proportional hazard models.

2966 recipients underwent LT for PSC over the study period: LDLT-PSC 153 (5.2%), DCD-PSC 131 (4.4%) and DBD-PSC 2682 (90.4%). While LDLT utilization was higher in PSC (5.2% vs. 1.3%; p < 0.001), DCD use was lower (4.4% vs. 7.2%; p < 0.001) but increased over time (era 1 vs. era 2: 3.3% vs. 5.2%; p = 0.02). Outcomes following DCD-PSC were comparable to DBD and improved over time. Compared to DBD-PSC, there was a trend toward lower short-term graft survival following LDLT-PSC (1 Yr. 85.3 vs. 91.9; p = 0.07) with higher retransplant rate (LDLT-PSC vs. DCD-PSC vs. DBD-PSC: 15% vs 11% vs 7%; p < 0.001). Compared to recipients without PSC, long-term patient survival was superior in LDLT-PSC (5 Yr. 90.1 vs. 83.7%; p = 0.05) and DCD-PSC (93.3 vs. 79.7%, p = 0.01). On multivariable analysis, LDLT but not DCD graft type, was associated with inferior graft survival in PSC (adjusted hazard Ratio = 1.65 (1.16-2.34); p = 0.005).

In PSC, utilization of LDLT is higher, while DCD use is lower but increased over time. Outcomes following DCD LT in PSC are comparable to DBD and superior to recipients without PSC. Reduced graft survival and higher re-transplant rate following LDLT in PSC warrants further study. Consideration of DCD could help expand the donor pool in PSC.

We assessed the value of the diffusion-weighted image (DWI) for predicting intrahepatic biliary complications (IHBC) after ABO-incompatible liver transplantation (ABOi-LT), potentially leading to refractory cholangitis.

In this retrospective study at a single center, 56 patients who underwent ABOi-LT from March 2021 to January 2023 were analyzed. All received magnetic resonance cholangiopancreatography (MRCP) and DWI during the postoperative hospitalization. MRCP findings, including bile duct DWI hyperintensity, were assessed. Participants suspected of having a biliary infection or obstructive jaundice underwent endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic biliary drainage (PTBD) during the follow-up. Non-anastomotic biliary strictures on cholangiography were classified as IHBC, as either perihilar or diffuse form. DWI hyperintensity was compared between groups with and without IHBC. Logistic regression analysis was performed to identify independent risk factors for IHBC.

Of the 55 participants (median age 55 years, 39 males), IHBC was diagnosed in eight patients over a median follow-up of 15.9 months (range 5.6-31.1). Bile duct DWI hyperintensity was observed in 18 patients. Those with DWI hyperintensity exhibited a higher IHBC incidence (6/18, 33.3% vs. 2/36, 5.6%; p = 0.01), and more frequently developed the diffuse type IHBC (4/18, 22.2% vs. 1/36, 2.8%; p = 0.04). Regression analysis indicated that bile duct DWI hyperintensity is an independent risk factor for IHBC (odds ratio (OR) 10.1; 95% confidence interval (CI) 1.4, 71.2; p = 0.02) and its diffuse form (OR 15.3; 95% CI 1.2, 187.8; p = 0.03).

Postoperative DWI hyperintensity of bile ducts can serve as a biomarker predicting IHBC after ABOi-LT.

Postoperative diffusion-weighted image hyperintensity of the bile duct can be used as a biomarker to predict intrahepatic biliary complications and aid in identifying candidates who may benefit from additional management for antibody-mediated rejection.

Intrahepatic biliary complications following ABO-incompatible liver transplantation can cause biliary stricture and biloma formation. Bile duct hyperintensity on early postoperative diffusion-weighted imaging was associated with increased intrahepatic biliary complication risk. This marker is an additional method for identifying individuals who require intensive management to prevent complications.

Biliary complications are a major cause of morbidity and mortality in liver transplantation. Up to 25% of patients that develop biliary complications require additional surgical procedures, re-transplantation or die in the absence of a suitable regraft. Here, we investigate the role of the primary cilium, a highly specialised sensory organelle, in biliary injury leading to post-transplant biliary complications.

Human biopsies were used to study the structure and function of primary cilia in liver transplant recipients that develop biliary complications (n = 7) in comparison with recipients without biliary complications (n = 12). To study the biological effects of the primary cilia during transplantation, we generated murine models that recapitulate liver procurement and cold storage, and assessed the elimination of the primary cilia in biliary epithelial cells in the K19CreERTKif3afl/fl mouse model. To explore the molecular mechanisms responsible for the observed phenotypes we used in vitro models of ischemia, cellular senescence and primary cilia ablation. Finally, we used pharmacological and genetic approaches to target cellular senescence and the primary cilia, both in mouse models and discarded human donor livers.

Prolonged ischemic periods before transplantation result in ciliary shortening and cellular senescence, an irreversible cell cycle arrest that blocks regeneration. Our results indicate that primary cilia damage results in biliary injury and a loss of regenerative potential. Senescence negatively impacts primary cilia structure and triggers a negative feedback loop that further impairs regeneration. Finally, we explore how targeted interventions for cellular senescence and/or the stabilisation of the primary cilia improve biliary regeneration following ischemic injury.

Primary cilia play an essential role in biliary regeneration and we demonstrate that senolytics and cilia-stabilising treatments provide a potential therapeutic opportunity to reduce the rate of biliary complications and improve clinical outcomes in liver transplantation.

Up to 25% of liver transplants result in biliary complications, leading to additional surgery, retransplants, or death. We found that the incidence of biliary complications is increased by damage to the primary cilium, an antenna that protrudes from the cell and is key to regeneration. Here, we show that treatments that preserve the primary cilia during the transplant process provide a potential solution to reduce the rates of biliary complications.

Ischemic cholangiopathy (IC) is the leading cause of inferior long-term outcomes following donation after circulatory death (DCD) liver transplant. Biliary strictures related to IC are nonanastomotic strictures (NASs) by definition and involve the donor hepatic ducts proximal to the anastomosis, compared with postsurgical anastomotic strictures that form due to fibrotic healing. IC-related NASs can be microangiopathic with patent hepatic artery or macroangiopathic with occluded or stenotic hepatic artery. Recently, IC with NASs have been described to have four distinct patterns at imaging: diffuse necrosis, multifocal progressive, confluence dominant, and minor form, which correlate clinically with graft prognosis. Severe IC can lead to ductal wall breakdown with subsequent bile leaks that can cause significant patient morbidity, with imaging playing a vital role in diagnosis and guiding intervention. IC also predisposes the transplanted liver to biliary stasis and subsequent formation of stones, casts, and sludge. Some cases of posttransplant biliary stricturing are not IC but are a sequela of reflux cholangitis seen with choledochojejunal anastomosis. Other biliary findings in the posttransplant liver can be explained by sphincter of Oddi dysfunction that results from denervation. The authors describe and comprehensively categorize the various IC types and their imaging patterns at MRI and MR cholangiopancreatography, review the prognostic significance of these imaging patterns, and discuss imaging features of additional biliary complications associated with IC after DCD liver transplant. ©RSNA, 2024 Supplemental material is available for this article.

In an effort to reduce waitlist mortality, extended criteria donor organs, including those from donation after circulatory death (DCD), are being used with increasing frequency. These donors carry an increased risk for postoperative complications, and balancing donor-recipient risks is currently based on generalized nomograms. Abdominal normothermic regional perfusion (aNRP) enables individual evaluation of DCD organs, but a gold standard to determine suitability for transplantation is lacking. This study aimed to incorporate individualized and predictive measurements of the liver maximum capacity (LiMAx) test to objectively grade liver function during aNRP and prevent post-op complications.

aNRP was performed to salvage 18 DCD liver grafts, otherwise discarded. Continuous variables were presented as the median with the interquartile range.

The liver function maximum capacity (LiMAx) test was successfully performed within the aNRP circuit in 17 aNRPs (94%). Donor livers with good lactate clearance during aNRP demonstrated significantly higher LiMAx scores (396 (301-451) µg/kg/h versus those who did not 105 (70-158) µg/kg/h; P = 0.006). This was also true for manifesting stress hyperglycemia > 20 mmol/l (P = 0.032). LiMAx score correlated with alanine aminotransferase (ALT; R =  - 0.755) and aspartate transaminase (AST; R =  - 0.800) levels during perfusion and distinguished livers that were selected for transplantation (397 (346-453) µg/kg/h) from those who were discarded (155 (87-206) µg/kg/h; P < 0.001). Twelve livers were accepted for transplantation, blinded for LiMAx results, and all had LiMAx scores of > 241 µg/kg/h. Postoperatively, LiMAx during aNRP displayed correlation with 24-h lactate levels.

This study shows for the first time the feasibility to assess liver function during aNRP in individual donor livers. LiMAx presents an objective tool to predict donor liver function and risk of complications in the recipient, thus enabling individualized matching of donor livers for an individual recipient. The LiMAx test may present a valuable test for the prediction of donor liver function, preventing post-transplant complication, and personalizing the selection of donor livers for individual recipients.

The online version contains supplementary material available at 10.1007/s13167-024-00371-7.

With changing donor characteristics (advanced age, obesity), an increase in the use of extended criteria donor (ECD) livers in liver transplantation is seen. Machine perfusion allows graft viability assessment, but still many donor livers are considered nontransplantable. Besides being used as graft viability assessment tool, ex situ machine perfusion offers a platform for therapeutic strategies to ameliorate grafts prior to transplantation. This review describes the current landscape of graft repair during machine perfusion.

Explored anti-inflammatory therapies, including inflammasome inhibitors, hemoabsorption, and cellular therapies mitigate the inflammatory response and improve hepatic function. Cholangiocyte organoids show promise in repairing the damaged biliary tree. Defatting during normothermic machine perfusion shows a reduction of steatosis and improved hepatobiliary function compared to nontreated livers. Uptake of RNA interference therapies during machine perfusion paves the way for an additional treatment modality.

The possibility to repair injured donor livers during ex situ machine perfusion might increase the utilization of ECD-livers. Application of defatting agents is currently explored in clinical trials, whereas other therapeutics require further research or optimization before entering clinical research.

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.

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.

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.

Normothermic regional perfusion (NRP) is an emerging recovery modality for transplantable allografts from controlled donation after circulatory death (cDCD) donors. In the US, only 11.4% of liver recipients who are transplanted from a deceased donor receive a cDCD liver. NRP has the potential to safely expand the US donor pool with improved transplant outcomes as compared with standard super rapid recovery (SRR).

To assess outcomes of US liver transplants using controlled donation after circulatory death livers recovered with normothermic regional perfusion vs standard super rapid recovery.

This was a retrospective, observational cohort study comparing liver transplant outcomes from cDCD donors recovered by NRP vs SRR. Outcomes of cDCD liver transplant from January 2017 to May 2023 were collated from 17 US transplant centers and included livers recovered by SRR and NRP (thoracoabdominal NRP [TA-NRP] and abdominal NRP [A-NRP]). Seven transplant centers used NRP, allowing for liver allografts to be transplanted at 17 centers; 10 centers imported livers recovered via NRP from other centers.

cDCD livers were recovered by either NRP or SRR.

The primary outcome was ischemic cholangiopathy (IC). Secondary end points included primary nonfunction (PNF), early allograft dysfunction (EAD), biliary anastomotic strictures, posttransplant length of stay (LOS), and patient and graft survival.

A total of 242 cDCD livers were included in this study: 136 recovered by SRR and 106 recovered by NRP (TA-NRP, 79 and A-NRP, 27). Median (IQR) NRP and SRR donor age was 30.5 (22-44) years and 36 (27-49) years, respectively. Median (IQR) posttransplant LOS was significantly shorter in the NRP cohort (7 [5-11] days vs 10 [7-16] days; P < .001). PNF occurred only in the SRR allografts group (n = 2). EAD was more common in the SRR cohort (123 of 136 [56.1%] vs 77 of 106 [36.4%]; P = .007). Biliary anastomotic strictures were increased 2.8-fold in SRR recipients (7 of 105 [6.7%] vs 30 of 134 [22.4%]; P = .001). Only SRR recipients had IC (0 vs 12 of 133 [9.0%]; P = .002); IC-free survival by Kaplan-Meier was significantly improved in NRP recipients. Patient and graft survival were comparable between cohorts.

There was comparable patient and graft survival in liver transplant recipients of cDCD donors recovered by NRP vs SRR, with reduced rates of IC, biliary complications, and EAD in NRP recipients. The feasibility of A-NRP and TA-NRP implementation across multiple US transplant centers supports increasing adoption of NRP to improve organ use, access to transplant, and risk of wait-list mortality.

The purpose of this study was to explore the relevant risk factors associated with biliary complications (BCs) in patients with end-stage hepatic alveolar echinococcosis (HAE) following ex vivo liver resection and autotransplantation (ELRA) and to establish and visualize a nomogram model.

This study retrospectively analysed patients with end-stage HAE who received ELRA treatment at the First Affiliated Hospital of Xinjiang Medical University between August 1, 2010 and May 10, 2023. The least absolute shrinkage and selection operator (LASSO) regression model was applied to optimize the feature variables for predicting the incidence of BCs following ELRA. Multivariate logistic regression analysis was used to develop a prognostic model by incorporating the selected feature variables from the LASSO regression model. The predictive ability, discrimination, consistency with the actual risk, and clinical utility of the candidate prediction model were evaluated using receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA). Internal validation was performed by the bootstrapping method.

The candidate prediction nomogram included predictors such as age, hepatic bile duct dilation, portal hypertension, and regular resection based on hepatic segments. The model demonstrated good discrimination ability and a satisfactory calibration curve, with an area under the ROC curve (AUC) of 0.818 (95% CI 0.7417-0.8958). According to DCA, this prediction model can predict the risk of BCs occurrence within a probability threshold range of 9% to 85% to achieve clinical net benefit.

A prognostic nomogram with good discriminative ability and high accuracy was developed and validated to predict BCs after ELRA in patients with end-stage HAE.

Despite the increased usage of livers from donation after circulatory death (DCD) donors in the last decade, many patients remaining on the waitlist who need a liver transplant. Recent efforts have focused on maximizing the utilization and outcomes of these allografts using advances in machine perfusion technology and other perioperative strategies such as normothermic regional perfusion (NRP). In addition to the standard donor and recipient matching that is required with DCD donation, new data regarding the impact of graft steatosis, extensive European experience with NRP, and the increasing use of normothermic and hypothermic machine perfusion have shown immense potential in increasing DCD organ overall utilization and improved outcomes. These techniques, along with viability testing of extended criteria donors, have generated early promising data to consider the use of higher-risk donor organs and more widespread adoption of these techniques in the United States. This review explores the most recent international literature regarding strategies to optimize the utilization and outcomes of DCD liver allografts, including donor-recipient matching, perioperative strategies including NRP versus rapid controlled DCD recovery, viability assessment of discarded livers, and postoperative strategies including machine perfusion versus pharmacologic interventions.

Orthotopic liver transplantation remains the definitive treatment for patients with end-stage liver disease. Unfortunately, the increasing demand for donor livers and the limited supply of viable organs have both led to a critical need for innovative strategies to expand the pool of transplantable organs. The mitochondrion, central to hepatic cellular function, plays a pivotal role in hepatic ischemic injury, with impaired mitochondrial function and oxidative stress leading to cell death. Mitochondrial protection strategies have shown promise in mitigating IRI and resuscitating marginal organs for transplant. Machine perfusion (MP) has been proven a valuable tool for reviving marginal organs with very promising results. Evaluation of liver viability during perfusion traditionally relies on parameters including lactate clearance, bile production, and transaminase levels. Nevertheless, the quest for more comprehensive and universally applicable viability markers persists. Normothermic regional perfusion has gained robust attention, offering extended recovery time for organs from donation after cardiac death donors. This approach has shown remarkable success in improving organ quality and reducing ischemic injury using the body's physiological conditions. The current challenge lies in the absence of a reliable assessment tool for predicting graft viability and post-transplant outcomes. To address this, exploring insights from mitochondrial function in the context of ischemia-reperfusion injury could offer a promising path toward better patient outcomes and graft longevity. Indeed, hypoxia-induced mitochondrial injury may serve as a surrogate marker of organ viability following oxygenated resuscitation techniques in the future.

United States transplant centers have low rates of liver allograft utilization from donation after circulatory death (DCD) donors. Prolonged functional donor warm ischemic time (f-DWIT) is associated with worse outcomes; however, center practices regarding f-DWIT are unclear. As emerging technologies are changing the landscape of DCD liver transplantation, this study aims to gain insights into the practices of US centers around DCD liver allograft utilization.

An electronic survey was distributed to transplant surgeons at US transplant centers from May to July 2022.

Responses were received from 108 transplant surgeons, of which, 44.4% reported their center's annual DCD liver transplant volume as <10%, and 40.7% reported volumes of 10% to 30%. Warm ischemic time (WIT) was the principal donor variable considered by accepting surgeons (72.2%). Center definition of f-DWIT varied widely, with at least 14 definitions being used. Nearly half of the surgeons (48.6%) defined f-DWIT as time from systolic blood pressure (SBP) <80 mm Hg or oxygen saturation (Sp02) <80% to flush; 21.5% defined f-DWIT as ≤30 minutes from withdrawal of life-sustaining therapy to flush. Nearly 13% of centers use normothermic machine perfusion for most of their DCD liver allografts. More than half of surgeons transplanted at least 1 DCD liver allograft recovered after normothermic regional perfusion.

Differences in the definition of f-DWIT and acceptance patterns of DCD liver allografts limit the ability to evaluate patient and allograft outcomes. As the DCD landscape is evolving, consensus definitions and granular databases can improve the transplant community's ability to evaluate outcome data and utilization from DCD liver allografts.

Liver transplantation is the only chance of cure for people with end-stage liver disease and some people with advanced liver cancers or acute liver failure. The increasing prevalence of these conditions drives demand and necessitates the increasing use of donated livers which have traditionally been considered suboptimal. Several novel machine perfusion preservation technologies have been developed, which attempt to ameliorate some of the deleterious effects of ischaemia reperfusion injury. Machine perfusion technology aims to improve organ quality, thereby improving outcomes in recipients of suboptimal livers when compared to traditional static cold storage (SCS; ice box).

To evaluate the effects of different methods of machine perfusion (including hypothermic oxygenated machine perfusion (HOPE), normothermic machine perfusion (NMP), controlled oxygenated rewarming, and normothermic regional perfusion) versus each other or versus static cold storage (SCS) in people undergoing liver transplantation.

We used standard, extensive Cochrane search methods. The latest search date was 10 January 2023.

We included randomised clinical trials which compared different methods of machine perfusion, either with each other or with SCS. Studies comparing HOPE via both hepatic artery and portal vein, or via portal vein only, were grouped. The protocol detailed that we also planned to include quasi-randomised studies to assess treatment harms.

We used standard Cochrane methods. Our primary outcomes were 1. overall participant survival, 2. quality of life, and 3. serious adverse events. Secondary outcomes were 4. graft survival, 5. ischaemic biliary complications, 6. primary non-function of the graft, 7. early allograft function, 8. non-serious adverse events, 9. transplant utilisation, and 10. transaminase release during the first week post-transplant. We assessed bias using Cochrane's RoB 2 tool and used GRADE to assess certainty of evidence.

We included seven randomised trials (1024 transplant recipients from 1301 randomised/included livers). All trials were parallel two-group trials; four compared HOPE versus SCS, and three compared NMP versus SCS. No trials used normothermic regional perfusion. When compared with SCS, it was uncertain whether overall participant survival was improved with either HOPE (hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.42 to 1.98; P = 0.81, I2 = 0%; 4 trials, 482 recipients; low-certainty evidence due to imprecision because of low number of events) or NMP (HR 1.08, 95% CI 0.31 to 3.80; P = 0.90; 1 trial, 222 recipients; very low-certainty evidence due to imprecision and risk of bias). No trials reported quality of life. When compared with SCS alone, HOPE was associated with improvement in the following clinically relevant outcomes: graft survival (HR 0.45, 95% CI 0.23 to 0.87; P = 0.02, I2 = 0%; 4 trials, 482 recipients; high-certainty evidence), serious adverse events in extended criteria DBD liver transplants (OR 0.45, 95% CI 0.22 to 0.91; P = 0.03, I2 = 0%; 2 trials, 156 participants; moderate-certainty evidence) and clinically significant ischaemic cholangiopathy in recipients of DCD livers (OR 0.31, 95% CI 0.11 to 0.92; P = 0.03; 1 trial, 156 recipients; high-certainty evidence). In contrast, NMP was not associated with improvement in any of these clinically relevant outcomes. NMP was associated with improved utilisation compared with SCS (one trial found a 50% lower rate of organ discard; P = 0.008), but the reasons underlying this effect are unknown. We identified 11 ongoing studies investigating machine perfusion technologies.

In situations where the decision has been made to transplant a liver donated after circulatory death or donated following brain death, end-ischaemic HOPE will provide superior clinically relevant outcomes compared with SCS alone. Specifically, graft survival is improved (high-certainty evidence), serious adverse events are reduced (moderate-certainty evidence), and in donors after circulatory death, clinically relevant ischaemic biliary complications are reduced (high-certainty evidence). There is no good evidence that NMP has the same benefits over SCS in terms of these clinically relevant outcomes. NMP does appear to improve utilisation of grafts that would otherwise be discarded with SCS; however, the reasons for this, and whether this effect is specific to NMP, is not clear. Further studies into NMP viability criteria and utilisation, as well as head-to-head trials with other perfusion technologies are needed. In the setting of donation following circulatory death transplantation, further trials are needed to assess the effect of these ex situ machine perfusion methods against, or in combination with, normothermic regional perfusion.

The scarcity of suitable donor livers highlights a continuing need for innovation to recover organs with reversible injuries in liver transplantation.

Explanted human donor livers (n = 5) declined for transplantation were supported using xenogeneic cross-circulation of whole blood between livers and xeno-support swine. Livers and swine were assessed over 24 hours of xeno-support. Livers maintained normal global appearance, uniform perfusion, and preservation of histologic and subcellular architecture. Oxygen consumption increased by 75% ( p = 0.16). Lactate clearance increased from -0.4 ± 15.5% to 31.4 ± 19.0% ( p = 0.02). Blinded histopathologic assessment demonstrated improved injury scores at 24 hours compared with 12 hours. Vascular integrity and vasoconstrictive function were preserved. Bile volume and cholangiocellular viability markers improved for all livers. Biliary structural integrity was maintained.

Xenogeneic cross-circulation provided multisystem physiological regulation of ex vivo human livers that enabled functional rehabilitation, histopathologic recovery, and improvement of viability markers. We envision xenogeneic cross-circulation as a complementary technique to other organ-preservation technologies in the recovery of marginal donor livers or as a research tool in the development of advanced bioengineering and pharmacologic strategies for organ recovery and rehabilitation.

Biomarkers are powerful clinical diagnostics and predictors of patient outcome. However, robust measurements often require time and expensive laboratory equipment, which is insufficient to track rapid changes and limits direct use in the operating room. Here, this study presents a portable spectrophotometric device for continuous real-time measurements of fluorescent and non-fluorescent biomarkers at the point of care. This study measures the mitochondrial damage biomarker flavin mononucleotide (FMN) in 26 extended criteria human liver grafts undergoing hypothermic oxygenated perfusion to guide clinical graft assessment. Real-time data identified seven organs unsuitable for transplant that are discarded. The remaining grafts are transplanted and FMN values correlated with post-transplant indicators of liver function and patient recovery. Further, this study shows how this device can be used to monitor dialysis patients by measuring creatinine in real-time. Our approach provides a simple method to monitor biomarkers directly within biological fluids to improve organ assessment, patient care, and biomarker discovery.

Liver transplant for patients with hepatocellular carcinoma involves 3 main types of donor allografts: donation after brain death, donation after cardiac death, and donation after brain and cardiac death. Data on this topic are limited, and controversies exist regarding liver transplant outcomes in hepatocellular carcinoma patients who have received these allografts.

Data from 490 hepatocellular carcinoma patients who received liver transplant from 2015 to 2021 at the Shulan (Hangzhou) Hospital were retrospectively analyzed. Participants were divided into 3 cohorts according to allograft type: donation after brain death, donation after cardiac death, and donation after brain and cardiac death. Kaplan-Meier and Cox regression methods were used to evaluate patient survival, graft survival, and recurrence-free survival rates after liver transplant.

Kaplan-Meier analysis revealed that 3-year patient survival rates were 69.2% for donations after brain death, 69.2% for donations after cardiac death, and 46.6% for donations after brain and cardiac death (P = .42); the 3-year graft survival rates were 53.3% for donations after brain death, 56.4% for donations after cardiac death, and 46.6% for donations after brain and cardiac death (P = .44); and 3-year recurrence-free survival rates were 55% for donations after brain death, 56.6% for donations after cardiac death, and 39.5% for donations after brain and cardiac death (P = .46). Complications were also similar across the 3 cohorts (P = .36). Multivariable analysis showed that intraoperative red blood cell transfusion (hazard ratio: 1.820; P = .042) and early allograft dysfunction (hazard ratio: 3.240; P = .041) were independent risk factors for graft survival.

Similar outcomes can be achieved for hepatocellular carcinoma patients who undergo liver transplant with donations after brain death, donations after cardiac death, or donations after brain and cardiac death allografts, especially when strict donor selection criteria are applied.

Liver transplantation as a treatment option for end-stage liver diseases is associated with a relevant risk for complications. On the one hand, immunological factors and associated chronic graft rejection are major causes of morbidity and carry an increased risk of mortality due to liver graft failure. On the other hand, infectious complications have a major impact on patient outcomes. In addition, abdominal or pulmonary infections, and biliary complications, including cholangitis, are common complications in patients after liver transplantation and can also be associated with a risk for mortality. Thereby, these patients already suffer from gut dysbiosis at the time of liver transplantation due to their severe underlying disease, causing end-stage liver failure. Despite an impaired gut-liver axis, repeated antibiotic therapies can cause major changes in the gut microbiome. Due to repeated biliary interventions, the biliary tract is often colonized by several bacteria with a high risk for multi-drug resistant germs causing local and systemic infections before and after liver transplantation. Growing evidence about the role of gut microbiota in the perioperative course and their impact on patient outcomes in liver transplantation is available. However, data about biliary microbiota and their impact on infectious and biliary complications are still sparse. In this comprehensive review, we compile the current evidence for the role of microbiome research in liver transplantation with a focus on biliary complications and infections due to multi-drug resistant germs.

Liver transplantation (LT) is the final treatment option for patients with end-stage liver disease. The increasing donor shortage results in the wide usage of grafts from extended criteria donors across the world. Using such grafts is associated with the elevated incidences of post-transplant complications including initial nonfunction and ischemic biliary tract diseases, which significantly reduce recipient survival. Although several clinical factors have been demonstrated to impact donor liver quality, accurate, comprehensive, and effective assessment systems to guide decision-making for organ usage, restoration or discard are lacking. In addition, the development of biochemical technologies and bioinformatic analysis in recent years helps us better understand graft injury during the perioperative period and find potential ways to restore graft function. Moreover, such advances reveal the molecular profiles of grafts or perfusate that are susceptible to poor graft function and provide insight into finding novel biomarkers for graft quality assessment. Focusing on donors and grafts, we updated potential biomarkers in donor blood, liver tissue, or perfusates that predict graft quality following LT, and summarized strategies for restoring graft function in the era of extended criteria donors. In this review, we also discuss the advantages and drawbacks of these potential biomarkers and offer suggestions for future research.

The discrepancy between the number of patients awaiting liver transplantation and the number of available donors has become a key issue in the transplant setting. There is a limited access to liver transplantation, as a result, it is increasingly dependent on the use of extended criteria donors (ECD) to increase the organ donor pool and address rising demand. However, there are still many unknown risks associated with the use of ECD, among which preservation before liver transplantation is important in determining whether patients would experience complications survive after liver transplantation. In contrast to traditional static cold preservation of donor livers, normothermic machine perfusion (NMP) may reduce preservation injury, improve graft viability, and potentially ex vivo assessment of graft viability before transplantation. Data seem to suggest that NMP can enhance the preservation of liver transplantation to some extent and improve the early outcome after transplantation. In this review, we provided an overview of NMP and its application in ex vivo liver preservation and pre-transplantation, and we summarized the data from current clinical trials of normothermic liver perfusion.

We retrospectively compared outcomes between recipients of donation after circulatory death (DCD) and donation after brain death (DBD) liver allografts using days alive and out of hospital (DAOH), a composite outcome of mortality, morbidity, and burden of care from patient perspective. The initial length of stay and duration of any subsequent readmission for the first year after liver transplantation were recorded. Donor category and perioperative and intraoperative characteristics pertinent to liver transplantation were included. The primary outcome was DAOH₃₆₅. Secondary outcomes included early allograft dysfunction and hepatic arterial and biliary complications. Although the incidence of both early allograft dysfunction (P < .001) and ischemic cholangiopathy (P < .001) was significantly greater in the recipients of DCD, there were no significant differences in the length of stay and DAOH₃₆₅. The median DAOH₃₆₅ was 355 days for recipients of DBD allografts and 353 days for recipients of DCD allografts (P = .34). Increased transfusion burden, longer cold ischemic time, and non-White recipients were associated with decreased DAOH. There were no significant differences in graft failure (P = .67), retransplantation (P = .67), or 1-year mortality (P = .96) between the 2 groups. DAOH is a practical and attainable measure of outcome after liver transplantation. This metric should be considered for quality measurement and reporting in liver transplantation.

Donation-after-circulatory-death (DCD), donation-after-brain-death (DBD), and living-donation (LD) are the three possible options for liver transplantation (LT), each with unique benefits and complication rates. We aimed to compare DCD-, DBD-, and LD-LT-specific graft survival and biliary complications (BC). We collected data on 138 DCD-, 3,027 DBD- and 318 LD-LTs adult recipients from a single center and analyzed patient/graft survival. BC (leak and anastomotic/non-anastomotic stricture (AS/NAS)) were analyzed in a subset of 414 patients. One-/five-year graft survival were 88.6%/70.0% for DCD-LT, 92.6%/79.9% for DBD-LT, and, 91.7%/82.9% for LD-LT. DCD-LTs had a 1.7-/1.3-fold adjusted risk of losing their graft compared to DBD-LT and LD-LT, respectively (p < 0.010/0.403). Bile leaks were present in 10.1% (DCD-LTs), 7.2% (DBD-LTs), and 36.2% (LD-LTs) (ORs, DBD/LD vs. DCD: 0.7/4.2, p = 0.402/<0.001). AS developed in 28.3% DCD-LTs, 18.1% DBD-LTs, and 43.5% LD-LTs (ORs, DBD/LD vs. DCD: 0.5/1.8, p = 0.018/0.006). NAS was present in 15.2% DCD-LTs, 1.4% DBDs-LT, and 4.3% LD-LTs (ORs, DBD/LD vs. DCD: 0.1/0.3, p = 0.001/0.005). LTs w/o BC had better liver graft survival compared to any other groups with BC. DCD-LT and LD-LT had excellent graft survival despite significantly higher BC rates compared to DBD-LT. DCD-LT represents a valid alternative whose importance should increase further with machine/perfusion systems.

Liver transplantation is the only curative option for patients with end-stage liver disease. Despite improvements in surgical techniques, nonanastomotic strictures (characterized by the progressive loss of biliary tract architecture) continue to occur after liver transplantation, negatively affecting liver function and frequently leading to graft loss and retransplantation. To study the biological effects of organ preservation before liver transplantation, we generated murine models that recapitulate liver procurement and static cold storage. In these models, we explored the response of cholangiocytes and hepatocytes to cold storage, focusing on responses that affect liver regeneration, including DNA damage, apoptosis, and cellular senescence. We show that biliary senescence was induced during organ retrieval and exacerbated during static cold storage, resulting in impaired biliary regeneration. We identified decoy receptor 2 (DCR2)-dependent responses in cholangiocytes and hepatocytes, which differentially affected the outcome of those populations during cold storage. Moreover, CRISPR-mediated DCR2 knockdown in vitro increased cholangiocyte proliferation and decreased cellular senescence but had the opposite effect in hepatocytes. Using the p21KO model to inhibit senescence onset, we showed that biliary tract architecture was better preserved during cold storage. Similar results were achieved by administering senolytic ABT737 to mice before procurement. Last, we perfused senolytics into discarded human donor livers and showed that biliary architecture and regenerative capacities were better preserved. Our results indicate that cholangiocytes are susceptible to senescence and identify the use of senolytics and the combination of senotherapies and machine-perfusion preservation to prevent this phenotype and reduce the incidence of biliary injury after transplantation.

In situ normothermic regional perfusion (NRP) and ex situ normothermic machine perfusion (NMP) aim to improve the outcomes of liver transplantation (LT) using controlled donation after circulatory death (cDCD). NRP and NMP have not yet been compared directly. In this international observational study, outcomes of LT performed between 2015 and 2019 for organs procured from cDCD donors subjected to NRP or NMP commenced at the donor center were compared using propensity score matching (PSM). Of the 224 cDCD donations in the NRP cohort that proceeded to asystole, 193 livers were procured, resulting in 157 transplants. In the NMP cohort, perfusion was commenced in all 40 cases and resulted in 34 transplants (use rates: 70% vs. 85% [p = 0.052], respectively). After PSM, 34 NMP liver recipients were matched with 68 NRP liver recipients. The two cohorts were similar for donor functional warm ischemia time (21 min after NRP vs. 20 min after NMP; p = 0.17), UK-Donation After Circulatory Death risk score (5 vs. 5 points; p = 0.38), and laboratory Model for End-Stage Liver Disease scores (12 vs. 12 points; p = 0.83). The incidence of nonanastomotic biliary strictures (1.5% vs. 2.9%; p > 0.99), early allograft dysfunction (20.6% vs. 8.8%; p = 0.13), and 30-day graft loss (4.4% vs. 8.8%; p = 0.40) were similar, although peak posttransplant aspartate aminotransferase levels were higher in the NRP cohort (872 vs. 344 IU/L; p < 0.001). NRP livers were more frequently allocated to recipients suffering from hepatocellular carcinoma (HCC; 60.3% vs. 20.6%; p < 0.001). HCC-censored 2-year graft and patient survival rates were 91.5% versus 88.2% (p = 0.52) and 97.9% versus 94.1% (p = 0.25) after NRP and NMP, respectively. Both perfusion techniques achieved similar outcomes and appeared to match benchmarks expected for donation after brain death livers. This study may inform the design of a definitive trial.

We perform routine preprocurement image-guided percutaneous liver biopsies on potential donation after circulatory death (DCD) liver donors. The purpose of this study was to examine the impact of preprocurement liver biopsy on the use of livers from DCD donors. We retrospectively reviewed demographics, liver histology, and disposition of DCD liver donors within a single organ procurement organization (OPO) who underwent preprocurement liver biopsy from January 2000 through December 2019. A total of 212 potential donors underwent prerecovery biopsy. No donors were lost as a result of complications of biopsy. Of these, 183 (86.3%) had acceptable biopsies: 146 (79.8%) were successfully transplanted and 37 (20.2%) were deemed not suitable for transplant. In contrast, of 120 DCD livers recovered with the intent to transplant that were not biopsied prior to recovery, 59 (49.2%) were successfully transplanted, and 61 (50.8%) were deemed not suitable for transplant. A total of 14 donors were ruled out for transplant based on prerecovery histology. Successfully transplanted livers that underwent preprocurement biopsy were more likely to come from donors aged older than 50 years or with body mass index more than 30 kg/m² compared with successfully transplanted livers without a prerecovery biopsy. Biopsy excluded 6.6% of DCD donor livers for transplant prior to recovery and facilitated the successful recovery and transplant of two-thirds of potential DCD donor livers. Livers intended for transplant at the time of recovery that did not undergo preprocurement biopsy were more likely to not be recovered or to be discarded. Preprocurement biopsy provides additional histologic information prior to deploying resources and helps to identify usable livers that might otherwise be declined for transplant. Consideration of liver biopsy in this group benefits OPOs and transplant centers by maximizing organ use and optimizing resource deployment.

Based on the renaissance of dynamic preservation techniques, extended criteria donor (ECD) livers reclaimed a valuable eligibility in the transplantable organ pool. Being more vulnerable to ischemia, ECD livers carry an increased risk of early allograft dysfunction, primary non-function and biliary complications and, hence, unveiled the limitations of static cold storage (SCS). There is growing evidence that dynamic preservation techniques-dissimilar to SCS-mitigate reperfusion injury by reconditioning organs prior transplantation and therefore represent a useful platform to assess viability. Yet, a debate is ongoing about the advantages and disadvantages of different perfusion strategies and their best possible applications for specific categories of marginal livers, including organs from donors after circulatory death (DCD) and brain death (DBD) with extended criteria, split livers and steatotic grafts. This review critically discusses the current clinical spectrum of livers from ECD donors together with the various challenges and posttransplant outcomes in the context of standard cold storage preservation. Based on this, the potential role of machine perfusion techniques is highlighted next. Finally, future perspectives focusing on how to achieve higher utilization rates of the available donor pool are highlighted.

Donation after cardiac death(DCD) has been proposed as an avenue to expand the liver donor pool.

We examined factors associated with nonrecovery of DCD livers using UNOS data from 2015 to 2019.

There 265 non-recovered potential(NRP) DCD livers. Blood type AB (7.8% vs. 1.1%) and B (16.9% vs. 9.8%) were more frequent in the NRP versus actual donors (p < 0.001). The median driving time between donor hospital and transplant center was similar for NRP and actual donors (30.1 min vs. 30.0 min; p = 0.689), as was the percentage located within a transplant hospital (20.8% vs. 20.9%; p = 0.984).The donation service area(DSA) of a donor hospital explained 27.9% (p = 0.001) of the variability in whether a DCD liver was recovered.

A number of potentially high quality DCD donor livers go unrecovered each year, which may be partially explained by donor blood type and variation in regional and DSA level practice patterns.

Tumor recurrence after liver transplantation has been linked to multiple factors, including the recipient's tumor burden, donor factors, and ischemia-reperfusion injury (IRI). The increasing number of livers accepted from extended criteria donors has forced the transplant community to push the development of dynamic perfusion strategies. The reason behind this progress is the urgent need to reduce the clinical consequences of IRI. Two concepts appear most beneficial and include either the avoidance of ischemia, e.g., the replacement of cold storage by machine perfusion, or secondly, an endischemic organ improvement through perfusion in the recipient center prior to implantation. While several concepts, including normothermic perfusion, were found to reduce recipient transaminase levels and early allograft dysfunction, hypothermic oxygenated perfusion also reduced IRI-associated post-transplant complications and costs. With the impact on mitochondrial injury and subsequent less IRI-inflammation, this endischemic perfusion was also found to reduce the recurrence of hepatocellular carcinoma after liver transplantation. Firstly, this article highlights the contributing factors to tumor recurrence, including the surgical and medical tissue trauma and underlying mechanisms of IRI-associated inflammation. Secondly, it focuses on the role of mitochondria and associated interventions to reduce cancer recurrence. Finally, the role of machine perfusion technology as a delivery tool and as an individual treatment is discussed together with the currently available clinical studies.