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Background: Liver disease is the third leading cause of premature death in the UK. Transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs. As a result, up to 20% of patients on liver transplant waiting lists die before receiving a transplant. A third of donated livers are not suitable for transplant, often due to steatosis. Hepatic steatosis, which affects 33% of the UK population, is strongly associated with obesity, an increasing problem in the potential donor pool. We have recently tested defatting interventions during normothermic machine perfusion (NMP) in discarded steatotic human livers that were not transplanted. A combination of therapies including forskolin (NKH477) and L-carnitine to defat liver cells and lipoprotein apheresis filtration were investigated. These interventions resulted in functional improvement during perfusion and reduced the intrahepatocellular triglyceride (IHTG) content. We hypothesise that defatting during NMP will allow more steatotic livers to be transplanted with improved outcomes., Methods: In the proposed multi-centre clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim to test the safety and feasibility of the defatting intervention and will explore efficacy by comparing ex-situ and post-reperfusion liver function between the groups. The primary endpoint will be the proportion of livers that achieve predefined functional criteria during perfusion which indicate potential suitability for transplantation. These criteria reflect hepatic metabolism and injury and include lactate clearance, perfusate pH, glucose metabolism, bile composition, vascular flows and transaminase levels. Clinical secondary endpoints will include proportion of livers transplanted in the two arms, graft function; cell-free DNA (cfDNA) at follow-up visits; patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); non-anastomotic biliary strictures and recurrence of steatosis (determined on MRI at 6 months)., Discussion: This study explores ex-situ pharmacological optimisation of steatotic donor livers during NMP. If the intervention proves effective, it will allow the safe transplantation of livers that are currently very likely to be discarded, thereby reducing waiting list deaths., Trial Registration: ISRCTN ISRCTN14957538. Registered in October 2022., (© 2024. The Author(s).)

Dynamic organ preservation is a relatively old technique which has regained significant interest in the last decade. Machine perfusion (MP) techniques are applied in various fields of solid organ transplantation today. The first clinical series of ex situ MP in liver transplantation was presented in 2010. Since then, the number of research and clinical applications has substantially increased. Despite the notable beneficial effect on organ quality and recipient outcome, MP is still not routinely used in liver transplantation. Based on the enormous need to better preserve organs and the subsequent demand to continuously innovate and develop perfusion equipment further, this technology is also beneficial to test and deliver future therapeutic strategies to livers before implantation. This article summarizes the various challenges observed during the current shift from static to dynamic liver preservation in the clinical setting. The different organ perfusion strategies are discussed first, together with ongoing clinical trials and future study design. The current status of research and the impact of costs and regulations is highlighted next. Factors contributing to costs and other required resources for a worldwide successful implementation and reimbursement are presented third. The impact of research on cost-utility and effectivity to guide the tailored decision-making regarding the optimal perfusion strategy is discussed next. Finally, this article provides potential solutions to the challenging field of innovation in healthcare considering the various social and economic factors and the role of clinical, regulatory, and financial stakeholders worldwide., Competing Interests: J.V.G. consults for and received grants from Organ Recovery Systems (Itasca, IL) and consults for GATT Technologies. The other authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Normothermic machine perfusion (NMP) enables pretransplant assessment of high-risk donor livers. The VITTAL trial demonstrated that 71% of the currently discarded organs could be transplanted with 100% 90-day patient and graft survivals. Here, we report secondary end points and 5-year outcomes of this prospective, open-label, phase 2 adaptive single-arm study. The patient and graft survivals at 60 months were 82% and 72%, respectively. Four patients lost their graft due to nonanastomotic biliary strictures, one caused by hepatic artery thrombosis in a liver donated following brain death, and 3 in elderly livers donated after circulatory death (DCD), which all clinically manifested within 6 months after transplantation. There were no late graft losses for other reasons. All the 4 patients who died during the study follow-up had functioning grafts. Nonanastomotic biliary strictures developed in donated after circulatory death livers that failed to produce bile with pH >7.65 and bicarbonate levels >25 mmol/L. Histological assessment in these livers revealed high bile duct injury scores characterized by arterial medial necrosis. The quality of life at 6 months significantly improved in all but 4 patients suffering from nonanastomotic biliary strictures. This first report of long-term outcomes of high-risk livers assessed by normothermic machine perfusion demonstrated excellent 5-year survival without adverse effects in all organs functioning beyond 1 year (ClinicalTrials.gov number NCT02740608)., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Extended duration of normothermic machine perfusion (NMP) provides opportunities to resuscitate suboptimal donor livers. This intervention requires adequate oxygen delivery typically provided by a blood-based perfusion solution. Methaemoglobin (MetHb) results from the oxidation of iron within haemoglobin and represents a serious problem in perfusions lasting > 24 h. We explored the effects of anti-oxidant, N-acetylcysteine (NAC) on the accumulation of methaemoglobin. NMP was performed on nine human donor livers declined for transplantation: three were perfused without NAC (no-NAC group), and six organs perfused with an initial NAC bolus, followed by continuous infusion (NAC group), with hourly methaemoglobin perfusate measurements. In-vitro experiments examined the impact of NAC (3 mg) on red cells (30 ml) in the absence of liver tissue. The no-NAC group sustained perfusions for an average of 96 (range 87-102) h, universally developing methaemoglobinaemia (≥ 2%) observed after an average of 45 h, with subsequent steep rise. The NAC group was perfused for an average of 148 (range 90-184) h. Only 2 livers developed methaemoglobinaemia (peak MetHb of 6%), with an average onset of 116.5 h. Addition of NAC efficiently limits formation and accumulation of methaemoglobin during NMP, and allows the significant extension of perfusion duration., (© 2023. The Author(s).)

With the increasing number of accepted candidates on waiting lists worldwide, there is an urgent need to expand the number and the quality of donor livers. Dynamic preservation approaches have demonstrated various benefits, including improving liver function and graft survival, and reducing liver injury and post-transplant complications. Consequently, organ perfusion techniques are being used in clinical practice in many countries. Despite this success, a proportion of livers do not meet current viability tests required for transplantation, even with the use of modern perfusion techniques. Therefore, devices are needed to further optimise machine liver perfusion - one promising option is to prolong machine liver perfusion for several days, with ex situ treatment of perfused livers. For example, stem cells, senolytics, or molecules targeting mitochondria or downstream signalling can be administered during long-term liver perfusion to modulate repair mechanisms and regeneration. Besides, today's perfusion equipment is also designed to enable the use of various liver bioengineering techniques, to develop scaffolds or for their re-cellularisation. Cells or entire livers can also undergo gene modulation to modify animal livers for xenotransplantation, to directly treat injured organs or to repopulate such scaffolds with "repaired" autologous cells. This review first discusses current strategies to improve the quality of donor livers, and secondly reports on bioengineering techniques to design optimised organs during machine perfusion. Current practice, as well as the benefits and challenges associated with these different perfusion strategies are discussed., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The widespread uptake of different machine perfusion (MP) strategies for liver transplant has been driven by an effort to minimize graft injury. Damage to the cholangiocytes during the liver donation, preservation, or early posttransplant period may result in stricturing of the biliary tree and inadequate biliary drainage. This problem continues to trouble clinicians, and may have catastrophic consequences for the graft and patient. Ischemic injury, as a result of compromised hepatic artery flow, is a well-known cause of biliary strictures, sepsis, and graft failure. However, very similar lesions can appear with a patent hepatic artery and these are known as ischemic type biliary lesions (ITBL) that are attributed to microcirculatory dysfunction rather than main hepatic arterial compromise. Both the warm and cold ischemic period duration appear to influence the onset of ITBL. All of the commonly used MP techniques deliver oxygen to the graft cells, and therefore may minimize the cholangiocyte injury and subsequently reduce the incidence of ITBL. As clinical experience and published evidence grows for these modalities, the impact they have on ITBL rates is important to consider. In this review, the evidence for the three commonly used MP strategies (abdominal normothermic regional perfusion [A-NRP], hypothermic oxygenated perfusion [HOPE], and normothermic machine perfusion [NMP] for ITBL prevention has been critically reviewed. Inconsistencies with ITBL definitions used in trials, coupled with variations in techniques of MP, make interpretation challenging. Overall, the evidence suggests that both HOPE and A-NRP prevent ITBL in donated after circulatory death grafts compared to cold storage. The evidence for ITBL prevention in donor after brain death grafts with any MP technique is weak., Competing Interests: Conflict-of-interest statement: The funding provided for normothermic machine perfusion consumables generously donated by the Ann Fox Foundation, under the umbrella of University Hospital Birmingham Charities., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

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., (© 2022 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Normothermic machine perfusion (NMP) allows objective assessment of donor liver transplantability. Several viability evaluation protocols have been established, consisting of parameters such as perfusate lactate clearance, pH, transaminase levels, and the production and composition of bile. The aims of this study were to assess 3 such protocols, namely, those introduced by the teams from Birmingham (BP), Cambridge (CP), and Groningen (GP), using a cohort of high-risk marginal livers that had initially been deemed unsuitable for transplantation and to introduce the concept of the viability assessment sensitivity and specificity. To demonstrate and quantify the diagnostic accuracy of these protocols, we used a composite outcome of organ use and 24-month graft survival as a surrogate endpoint. The effects of assessment modifications, including the removal of the most stringent components of the protocols, were also assessed. Of the 31 organs, 22 were transplanted after a period of NMP, of which 18 achieved the outcome of 24-month graft survival. The BP yielded 94% sensitivity and 50% specificity when predicting this outcome. The GP and CP both seemed overly conservative, with 1 and 0 organs, respectively, meeting these protocols. Modification of the GP and CP to exclude their most stringent components increased this to 11 and 8 organs, respectively, and resulted in moderate sensitivity (56% and 44%) but high specificity (92% and 100%, respectively) with respect to the composite outcome. This study shows that the normothermic assessment protocols can be useful in identifying potentially viable organs but that the balance of risk of underuse and overuse varies by protocol., (© 2021 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

The increasing disparity between the number of patients listed for transplantation and the number of suitable organs has led to the increasing use of extended criteria donors (ECDs). ECDs are at increased risk of developing ischaemia reperfusion injury and greater risk of post-transplant complications. Ischaemia reperfusion injury is a major complication of organ transplantation defined as the inflammatory changes seen following the disruption and restoration of blood flow to an organ-it is a multifactorial process with the potential to cause both local and systemic organ failure. The utilisation of machine perfusion under normothermic (37 degrees Celsius) and hypothermic (4-10 degrees Celsius) has proven to be a significant advancement in organ preservation and restoration. One of the key benefits is its ability to optimise suboptimal organs for successful transplantation. This review is focused on examining ischaemia reperfusion injury and how machine perfusion ameliorates the graft's response to this.

Purpose of Review: To summarize key studies in liver preservation published over the last 3 years and evaluate benefits and limitations of the different perfusion techniques. Selected experimental applications that may be translated to the clinical use will be also discussed., Recent Findings: Normothermic machine perfusion (NMP) has transitioned into clinical practice. Viability assessment is a reliable tool for clinical decision-making, and safety of the back-to-base approach has facilitated adoption of the technology. Data supporting well tolerated use of declined livers after NMP and new protocols selecting complex recipients aim to improve access to suitable organs. Hypothermic machine perfusion (HMP) is showing promising clinical results by decreasing biliary complications in recipients' receiving organs donated after circulatory death (DCD) and improving early graft function in extended criteria organs. Long-term data of HMP on DCD livers shows improved graft survival over standard SCS. Novel approaches utilizing sequential HMP--NMP or ischaemia-free preservation aim to improve outcomes of extended criteria organs., Summary: Machine perfusion for organ transplantation has become an established technique but the field is rapidly evolving. Ongoing research focuses on evaluation of the intervention efficacy and finding optimal indications to use each perfusion strategy according to graft type and clinical scenario., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pre-clinical research with multi-potent adult progenitor cells (MAPC® cells, Multistem, Athersys Inc., Cleveland, Ohio) suggests their potential as an anti-inflammatory and immunomodulatory therapy in organ transplantation. Normothermic machine perfusion of the liver (NMP-L) has been proposed as a way of introducing therapeutic agents into the donor organ. Delivery of cellular therapy to human donor livers using this technique has not yet been described in the literature. The primary objectives of this study were to develop a technique for delivering cellular therapy to human donor livers using NMP-L and demonstrate engraftment. Methods: Six discarded human livers were perfused for 6 h at 37°C using the Liver Assist (Organ Assist, Groningen). 50 × 106 CMPTX-labeled MAPC cells were infused directly into the right lobe via the hepatic artery (HA, n = 3) or portal vein (PV, n = 3) over 20 min at different time points during the perfusion. Perfusion parameters were recorded and central and peripheral biopsies were taken at multiple time-points from both lobes and subjected to standard histological stains and confocal microscopy. Perfusate was analyzed using a 35-plex multiplex assay and proteomic analysis. Results: There was no detrimental effect on perfusion flow parameters on infusion of MAPC cells by either route. Three out of six livers met established criteria for organ viability. Confocal microscopy demonstrated engraftment of MAPC cells across vascular endothelium when perfused via the artery. 35-plex multiplex analysis of perfusate yielded 13 positive targets, 9 of which appeared to be related to the infusion of MAPC cells (including Interleukin's 1b, 4, 5, 6, 8, 10, MCP-1, GM-CSF, SDF-1a). Proteomic analysis revealed 295 unique proteins in the perfusate from time-points following the infusion of cellular therapy, many of which have strong links to MAPC cells and mesenchymal stem cells in the literature. Functional enrichment analysis demonstrated their immunomodulatory potential. Conclusion: We have demonstrated that cells can be delivered directly to the target organ, prior to host immune cell population exposure and without compromising the perfusion. Transendothelial migration occurs following arterial infusion. MAPC cells appear to secrete a host of soluble factors that would have anti-inflammatory and immunomodulatory benefits in a human model of liver transplantation., (Copyright © 2020 Laing, Stubblefield, Wallace, Roobrouck, Bhogal, Schlegel, Boteon, Reynolds, Ting, Mirza, Newsome, Mergental and Afford.)

There is a limited access to liver transplantation, however, many organs are discarded based on subjective assessment only. Here we report the VITTAL clinical trial (ClinicalTrials.gov number NCT02740608) outcomes, using normothermic machine perfusion (NMP) to objectively assess livers discarded by all UK centres meeting specific high-risk criteria. Thirty-one livers were enroled and assessed by viability criteria based on the lactate clearance to levels ≤2.5 mmol/L within 4 h. The viability was achieved by 22 (71%) organs, that were transplanted after a median preservation time of 18 h, with 100% 90-day survival. During the median follow up of 542 days, 4 (18%) patients developed biliary strictures requiring re-transplantation. This trial demonstrates that viability testing with NMP is feasible and in this study enabled successful transplantation of 71% of discarded livers, with 100% 90-day patient and graft survival; it does not seem to prevent non-anastomotic biliary strictures in livers donated after circulatory death with prolonged warm ischaemia.

Liver ischaemia-reperfusion injury (IRI) is an intrinsic part of the transplantation process and damages the parenchymal cells of the liver including hepatocytes, endothelial cells and cholangiocytes. Many biomarkers of IRI have been described over the past two decades that have attempted to quantify the extent of IRI involving different hepatic cellular compartments, with the aim to allow clinicians to predict the suitability of donor livers for transplantation. The advent of machine perfusion has added an additional layer of complexity to this field and has forced researchers to re-evaluate the utility of IRI biomarkers in different machine preservation techniques. In this review, we summarise the current understanding of liver IRI biomarkers and discuss them in the context of machine perfusion.

Liver transplantation is an effective intervention for end-stage liver disease, fulminant hepatic failure, and early hepatocellular carcinoma. Yet, there is marked patient-to-patient variation in liver transplantation outcomes. This calls for novel diagnostics to enable rational deployment of donor livers. Metabolomics is a postgenomic high-throughput systems biology approach to diagnostic innovation in clinical medicine. We report here an original systematic review of the metabolomic studies that have identified putative biomarkers in the context of liver transplantation. Eighteen studies met the inclusion criteria that involved sampling of blood ( n  = 4), dialysate fluid ( n  = 4), bile ( n  = 5), and liver tissue ( n  = 5). Metabolites of amino acid and nitrogen metabolism, anaerobic glycolysis, lipid breakdown products, and bile acid metabolism were significantly different in transplanted livers with and without graft dysfunction. However, criteria for defining the graft dysfunction varied across studies. This systematic review demonstrates that metabolomics can be deployed in identification of metabolic indicators of graft dysfunction with a view to implicated molecular mechanisms. We conclude the article with a horizon scanning of metabolomics technology in liver transplantation and its future prospects and challenges in research and clinical practice.

Clinical adoption of normothermic machine perfusion (NMP) may be facilitated by simplifying logistics and reducing costs. This can be achieved by cold storage of livers for transportation to recipient centers before commencing NMP. The purpose of this study was to assess the safety and feasibility of post-static cold storage normothermic machine perfusion (pSCS-NMP) in liver transplantation. In this multicenter prospective study, 31 livers were transplanted. The primary endpoint was 30-day graft survival. Secondary endpoints included the following: peak posttransplant aspartate aminotransferase (AST), early allograft dysfunction (EAD), postreperfusion syndrome (PRS), adverse events, critical care and hospital stay, biliary complications, and 12-month graft survival. The 30-day graft survival rate was 94%. Livers were preserved for a total of 14 hours 10 minutes ± 4 hours 46 minutes, which included 6 hours 1 minute ± 1 hour 19 minutes of static cold storage before 8 hours 24 minutes ± 4 hours 4 minutes of NMP. Median peak serum AST in the first 7 days postoperatively was 457 U/L (92-8669 U/L), and 4 (13%) patients developed EAD. PRS was observed in 3 (10%) livers. The median duration of initial critical care stay was 3 days (1-20 days), and median hospital stay was 13 days (7-31 days). There were 7 (23%) patients who developed complications of grade 3b severity or above, and 2 (6%) patients developed biliary complications: 1 bile leak and 1 anastomotic stricture with no cases of ischemic cholangiopathy. The 12-month overall graft survival rate (including death with a functioning graft) was 84%. In conclusion, this study demonstrates that pSCS-NMP was feasible and safe, which may facilitate clinical adoption., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Background: Normothermic machine perfusion (NMP) of liver grafts is increasingly being incorporated in clinical practice. Current evidence has shown NMP plays a role in reconditioning the synthetic and energy capabilities of grafts. Intraoperative coagulation profile is a surrogate of graft quality and preservation status; however, to date this aspect has not been documented., Methods: The liver transplantation recipients who received NMP liver grafts in the QEHB between 2013 and 2016 were compared in terms of intraoperative thromboelastography characteristics (R time, K time, α-angle, maximum amplitude, G value, and LY30) to a propensity score-matched control group, where the grafts were preserved by traditional static cold storage (SCS)., Results: After propensity matching, none of the thromboelastography characteristics were found to differ significantly between the 72 pairs of SCS and NMP organs when measured preimplantation. However, postimplantation, NMP organs had significantly shorter K time (median: 2.8 vs 3.6 min, P = 0.010) and R + K time (11.4 vs 13.7 min, P = 0.016), as well as significantly larger α-angle (55.9° vs 44.8°, P = 0.002), maximum amplitude (53.5 vs 49.6 mm, P = 0.044), and G values (5.8 vs 4.9k dynes/cm, P = 0.043) than SCS organs. Hyperfibrinolysis after implantation was also mitigated by NMP, with fewer patients requiring aggressive factor correction during surgery (LY30 = 0, NMP vs SCS: 83% vs 60%, P = 0.004). Consequently, NMP organs required significantly fewer platelet units to be transfused during the transplant procedure (median: 0 vs 5, P = 0.001)., Conclusions: In this study, we have shown that NMP liver grafts return better coagulation profiles intraoperatively, which could be attributed to the preservation of liver grafts under physiological conditions.

Strategies to increase the use of steatotic donor livers are required to tackle the mortality on the transplant waiting list. We aimed to test the efficacy of pharmacological enhancement of the lipid metabolism of human livers during ex situ normothermic machine perfusion to promote defatting and improve the functional recovery of the organs. Because of steatosis, 10 livers were discarded and were allocated either to a defatting group that had the perfusate supplemented with a combination of drugs to enhance lipid metabolism or to a control group that received perfusion fluid with vehicle only. Steatosis was assessed using tissue homogenate and histological analyses. Markers for lipid oxidation and solubilization, oxidative injury, inflammation, and biliary function were evaluated by enzyme-linked immunosorbent assay, immunohistochemistry, and in-gel protein detection. Treatment reduced tissue triglycerides by 38% and macrovesicular steatosis by 40% over 6 hours. This effect was driven by increased solubility of the triglycerides (P = 0.04), and mitochondrial oxidation as assessed by increased ketogenesis (P = 0.008) and adenosine triphosphate synthesis (P = 0.01) were associated with increased levels of the enzymes acyl-coenzyme A oxidase 1, carnitine palmitoyltransferase 1A, and acetyl-coenzyme A synthetase. Concomitantly, defatted livers exhibited enhanced metabolic functional parameters such as urea production (P = 0.03), lower vascular resistance, lower release of alanine aminotransferase (P = 0.049), and higher bile production (P = 0.008) with a higher bile pH (P = 0.03). The treatment down-regulated the expression of markers for oxidative injury as well as activation of immune cells (CD14; CD11b) and reduced the release of inflammatory cytokines in the perfusate (tumor necrosis factor α; interleukin 1β). In conclusion, pharmacological enhancement of intracellular lipid metabolism during normothermic machine perfusion decreased the lipid content of human livers within 6 hours. It also improved the intracellular metabolic support to the organs, leading to successful functional recovery and decreased expression of markers of reperfusion injury., (Copyright © 2019 The Authors. Liver Transplantation published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

Parameters of retrieval surgery are meticulously documented in the United Kingdom, where up to 40% of livers are donation after circulatory death (DCD) donations. This retrospective analysis focuses on outcomes after transplantation of DCD livers, retrieved by different UK centers between 2011 and 2016. Donor and recipient risk factors and the donor retrieval technique were assessed. A total of 236 DCD livers from 9 retrieval centers with a median UK DCD risk score of 5 (low risk) to 7 points (high risk) were compared. The majority used University of Wisconsin solution for aortic flush with a median hepatectomy time of 27-44 minutes. The overall liver injury rate appeared relatively high (27.1%) with an observed tendency toward more retrieval injuries from centers performing a quicker hepatectomy. Among all included risk factors, the UK DCD risk score remained the best predictor for overall graft loss in the multivariate analysis (P < 0.001). In high-risk and futile donor-recipient combinations, the occurrence of liver retrieval injuries had negative impact on graft survival (P = 0.023). Expectedly, more ischemic cholangiopathies (P = 0.003) were found in livers transplanted with a higher cumulative donor-recipient risk. Although more biliary complications with subsequent graft loss were found in high-risk donor-recipient combinations, the impact of the standardized national retrieval practice on outcomes after DCD liver transplantation was minimal., (Copyright © 2018 by the American Association for the Study of Liver Diseases.)

Background: Strategies for successful transplantation are much needed in the era of organ shortage, and there has been a resurgence of interest on the impact of revascularization time (RT) on outcomes in liver transplantation (LT)., Methods: All primary LT performed in Birmingham between 2009 and 2014 (n = 678) with portal reperfusion first were stratified according to RT (<44 minutes vs ≥44 minutes) and graft quality (standard liver graft [SLG], Donor Risk Index < 2.3 vs marginal liver graft [MLG], Donor Risk Index ≥ 2.3)., Results: Revascularization time of 44 minutes or longer resulted in significantly greater incidence of early allograft dysfunction (EAD) (29% vs 47%, P < 0.001), posttransplant acute kidney injury (AKI) (39% vs 60%, P < 0.001), and new-onset AKI (37% vs 56%, P < 0.001), along with poor long-term outcome (3-year graft survival 92% vs 83%, P = 0.001; 3-year patient survival 87% vs 79%, P = 0.004). On multivariable analysis, RT ≥ 44 was a significant independent predictor of EAD, renal dysfunction, and overall graft survival, but not patient survival. The cumulative effect of prolonged revascularization in marginal grafts (MLG) resulted in the worst transplant outcome compared with all other groups, which could be mitigated by rapid revascularization (SLG, SLG, MLG vs MLG; EAD 24%, 39%, 39% vs 69%; AKI 32%, 46%, 51% vs 70%; 3-year graft survival 94%, 87%, 88% vs 70%, respectively; each P < 0.001). Factors associated with lack of abdominal space, larger grafts, and surgical skills were predictive of RT ≥ 44., Conclusions: Shorter graft revascularization is a protective factor in LT, particularly in the setting of graft marginality. Careful graft-recipient matching and emphasis on surgical expertise may aid in achieving better outcomes in LT.

Hypothermic oxygenated perfusion (HOPE) and normothermic perfusion are seen as distinct techniques of ex situ machine perfusion of the liver. We aimed to demonstrate the feasibility of combining both techniques and whether it would improve functional parameters of donor livers into transplant standards. Ten discarded human donor livers had either 6 hours of normothermic perfusion (n = 5) or 2 hours of HOPE followed by 4 hours of normothermic perfusion (n = 5). Liver function was assessed according to our viability criteria; markers of tissue injury and hepatic metabolic activity were compared between groups. Donor characteristics were comparable. During the hypothermic perfusion phase, livers down-regulated mitochondrial respiration (oxygen uptake, P = 0.04; partial pressure of carbon dioxide perfusate, P = 0.04) and increased adenosine triphosphate levels 1.8-fold. Following normothermic perfusion, those organs achieved lower tissue expression of markers of oxidative injury (4-hydroxynonenal, P = 0.008; CD14 expression, P = 0.008) and inflammation (CD11b, P = 0.02; vascular cell adhesion molecule 1, P = 0.05) compared with livers that had normothermic perfusion alone. All livers in the combined group achieved viability criteria, whereas 40% (2/5) in the normothermic group failed (P = 0.22). In conclusion, this study suggests that a combined protocol of hypothermic oxygenated and normothermic perfusions might attenuate oxidative stress, tissue inflammation, and improve metabolic recovery of the highest-risk donor livers compared with normothermic perfusion alone., (Copyright © 2018 The Authors. Liver Transplantation published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.)

Ischemia/reperfusion injury (IRI) is the main cause of complications following liver transplantation. Reactive oxygen species (ROS) were thought to be the main regulators of IRI. However, recent studies demonstrate that ROS activate the cytoprotective mechanism of autophagy promoting cell survival. Liver IRI initially damages the liver endothelial cells (LEC), but whether ROS-autophagy promotes cell survival in LEC during IRI is not known. Primary human LEC were isolated from human liver tissue and exposed to an in vitro model of IRI to assess the role of autophagy in LEC. The role of autophagy during liver IRI in vivo was assessed using a murine model of partial liver IRI. During IRI, ROS specifically activate autophagy-related protein (ATG) 7 promoting autophagic flux and the formation of LC3B-positive puncta around mitochondria in primary human LEC. Inhibition of ROS reduces autophagic flux in LEC during IRI inducing necrosis. In addition, small interfering RNA knockdown of ATG7 sensitized LEC to necrosis during IRI. In vivo murine livers in uninjured liver lobes demonstrate autophagy within LEC that is reduced following IRI with concomitant reduction in autophagic flux and increased cell death. In conclusion, these findings demonstrate that during liver IRI ROS-dependent autophagy promotes the survival of LEC, and therapeutic targeting of this signaling pathway may reduce liver IRI following transplantation., (© 2018 by the American Association for the Study of Liver Diseases.)

Increased use of high-risk allografts is critical to meet the demand for liver transplantation. We aimed to identify criteria predicting viability of organs, currently declined for clinical transplantation, using functional assessment during normothermic machine perfusion (NMP). Twelve discarded human livers were subjected to NMP following static cold storage. Livers were perfused with a packed red cell-based fluid at 37°C for 6 hours. Multilevel statistical models for repeated measures were employed to investigate the trend of perfusate blood gas profiles and vascular flow characteristics over time and the effect of lactate-clearing (LC) and non-lactate-clearing (non-LC) ability of the livers. The relationship of lactate clearance capability with bile production and histological and molecular findings were also examined. After 2 hours of perfusion, median lactate concentrations were 3.0 and 14.6 mmol/L in the LC and non-LC groups, respectively. LC livers produced more bile and maintained a stable perfusate pH and vascular flow >150 and 500 mL/minute through the hepatic artery and portal vein, respectively. Histology revealed discrepancies between subjectively discarded livers compared with objective findings. There were minimal morphological changes in the LC group, whereas non-LC livers often showed hepatocellular injury and reduced glycogen deposition. Adenosine triphosphate levels in the LC group increased compared with the non-LC livers. We propose composite viability criteria consisting of lactate clearance, pH maintenance, bile production, vascular flow patterns, and liver macroscopic appearance. These have been tested successfully in clinical transplantation. In conclusion, NMP allows an objective assessment of liver function that may reduce the risk and permit use of currently unused high-risk livers., (© 2018 by the American Association for the Study of Liver Diseases.)

Long-standing research has shown that increased lipid content in donor livers is associated with inferior graft outcomes posttransplant. The global epidemic that is obesity has increased the prevalence of steatosis in organ donors, to the extent that it has become one of the main reasons for declining livers for transplantation. Consequently, it is one of the major culprits behind the discrepancy between the number of donor livers offered for transplantation and those that go on to be transplanted. Steatotic livers are characterized by poor microcirculation, depleted energy stores because of an impaired capacity for mitochondrial recovery, and a propensity for an exaggerated inflammatory response following reperfusion injury culminating in poorer graft function postoperatively. Ex situ machine perfusion, currently a novel method in graft preservation, is showing great promise in providing a tool for the recovery and reconditioning of marginal livers. Hence, reconditioning these steatotic livers using machine perfusion has the potential to increase the number of liver transplants performed. In this review, we consider the problematic issues associated with fatty livers in the realm of transplantation and discuss pharmacological and nonpharmacological options that are being developed to enhance recovery of these organs using machine perfusion and defatting strategies., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Causes of severe cholestasis after liver transplantation (LT) are multi-factorial. Although the etiology is predictable in some, others culminate in graft/patient loss without a definitive cause identified. Severe cholestasis is usually associated with overlapped histological findings of rejection and biliary features, and diagnostic interpretation may pose a challenge., Methods: This is 10-year retrospective analysis of patients with unexplained severe cholestasis resulting in death/graft loss within 90 days of LT. Of 1 583 LT during the study period, 90-day graft failure occurred in 129 (8%) cases; a total of 45 (3%) patients had unresolving severe cholestasis (bilirubin, >100 μmol/L; alkaline phosphatase, >400 UI/L after 15 days from LT), excluding those due to primary nonfunction/sepsis/vascular causes (n = 84). Demographics, allograft biopsies, radiological investigations, and clinical outcome were analyzed., Results: All patients had persistent abnormal liver biochemistry. Doppler ultrasound scan was normal in all cases. Thirty-five (78%) recipients had at least 1 allograft biopsy (2 [1-9]). On the first biopsy, 22 (63%) patients had acute rejection, 4 (18%) early-chronic rejection, 12 (34%) antibody-mediated rejection. In subsequent biopsies chronic rejection was evident in 5 (14%) cases. Donor-specific antibodies were detected in all patients tested. Biliary anatomy was studied in detail in 9 (20%) patients, all presenting biliary strictures. The majority (n = 39; 87%) died within 32 (10-91) days, only survivors were from retransplantation (n = 3;6.5%) and biliary intervention (n = 3;6.5%)., Conclusions: Unresolving severe cholestasis after LT is a key parameter predicting patient/allograft outcome. Histologically, rejection seems to overlap with biliary strictures; hence, allograft biopsy with signs of rejection should not be a reason to overlook biliary problems, in particular when biliary features are present. Only extensive radiological investigation/intervention or retransplantation prevents patient/allograft loss.

While majority of liver transplants worldwide continue to be performed using deceased donor organs, the demands for donor livers continues to exceed the current supply. In an attempt to maximize the number of potentially usable donor livers and expand the current donor pool, there is intense global research by various groups exploring the role of machine perfusion in the liver transplantation, particularly with respect to the machine perfusion of extended-criteria liver donors. In this review, the authors summarize the current field of machine perfusion strategies as applied to deceased donor liver transplantation and how therapeutic targeting of the liver sinusoidal endothelial cell may improve the quality of donor livers., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality.

Background: Loco-regional complications of transarterial chemoembolization (TACE) may adversely affect technical aspects of the liver transplantation (LT). This study reviewed the impact of those complications on postoperative outcomes encompassing implications on graft selection., Methods: A retrospective, propensity score matching (1:1) analysis accounting for donor and recipient confounders was performed on a dataset of patients undergoing LT for hepatocellular carcinoma. Outcomes of patients who had TACE (TACE-group) were compared with those who did not (NoTACE-group)., Results: A total of 57 matched pairs were analyzed. TACE achieved effective tumor control (Pre-TACE vs Post-TACE; Median: 44 mm [interquartile range: 43-50] vs 17 mm [0-36]; P = .002) on imaging follow-up. TACE group had, at the hepatectomy, higher incidence of ischemia-related complications (adhesions of the necrotic tumor, cholecystitis, and/or bile duct necrosis) (40.4% vs 10.5%; P = .001). Overall major post-LT complications rate (Dindo-Clavien ≥3) were similar (P = .134). Those in the TACE group with donors after circulatory death (DCD) had 4.6% 90-day mortality and 54.3% major complication rate compared to 6.9% and 77.3% (P = .380 and P = .112, respectively)., Conclusion: TACE was an effective bridging procedure that may complicate LT inducing ischemic-related complications; nevertheless, it has not shown repercussions on mortality or morbidity after the procedure, even using donors after circulatory death., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: In the United Kingdom, up to 20% of liver graft offers are not used for transplantation, and the reasons for graft refusal are multifactorial and not consistent among transplant units., Methods: Liver grafts previously declined by other transplant centers in the United Kingdom but transplanted in our unit in Birmingham between 2011 and 2015 were analyzed. According to the indicated reason for previous declines, liver grafts were categorized into 3 refusal groups: "quality," "logistics," and "other reasons." Results were compared with a matched, low-risk cohort of livers primarily accepted and transplanted at our center., Results: During the study period, 206 livers (donation after brain death: n = 141 (68.4%); donation after circulatory arrest: n = 65 (31.6%) were transplanted, which were previously discarded by a median of 4 other UK centers. The majority of declines were donor quality (n = 102; 49.5%), refusals followed by logistics (n = 45; 21.8%), and other reasons (n = 59; 28.6%). Transplantation from both graft types (donation after brain death and donation after circulatory arrest) and all 3 refusal groups achieved equally good outcomes with an overall low complication rate. The incidence of primary nonfunction (2.4% vs 1.7%; P = 0.5483), in-hospital mortality (6.3% vs 4.1%; P = 0.2293) and 3-year graft (82.5% vs 84.1%; P = 0.6872) and patient (85.4% vs 87.6%; P = 0.8623) survival was comparable between livers previously declined and livers primarily accepted and transplanted at our center., Conclusions: Transplantation of declined livers can achieve comparable outcomes to primary liver low-risk graft offers. Previous refusal should not be taken as a barrier to use the graft, and with appropriate recipient selection, more lives could be saved.

Background & Aims: Primary non-function and ischaemic cholangiopathy are the most feared complications following donation-after-circulatory-death (DCD) liver transplantation. The aim of this study was to design a new score on risk assessment in liver-transplantation DCD based on donor-and-recipient parameters., Methods: Using the UK national DCD database, a risk analysis was performed in adult recipients of DCD liver grafts in the UK between 2000 and 2015 (n = 1,153). A new risk score was calculated (UK DCD Risk Score) on the basis of a regression analysis. This is validated using the United Network for Organ Sharing database (n = 1,617) and our own DCD liver-transplant database (n = 315). Finally, the new score was compared with two other available prediction systems: the DCD risk scores from the University of California, Los Angeles and King's College Hospital, London., Results: The following seven strongest predictors of DCD graft survival were identified: functional donor warm ischaemia, cold ischaemia, recipient model for end-stage liver disease, recipient age, donor age, previous orthotopic liver transplantation, and donor body mass index. A combination of these risk factors (UK DCD risk model) stratified the best recipients in terms of graft survival in the entire UK DCD database, as well as in the United Network for Organ Sharing and in our own DCD population. Importantly, the UK DCD Risk Score significantly predicted graft loss caused by primary non-function or ischaemic cholangiopathy in the futile group (>10 score points). The new prediction model demonstrated a better C statistic of 0.79 compared to the two other available systems (0.71 and 0.64, respectively)., Conclusions: The UK DCD Risk Score is a reliable tool to detect high-risk and futile combinations of donor-and-recipient factors in DCD liver transplantation. It is simple to use and offers a great potential for making better decisions on which DCD graft should be rejected or may benefit from functional assessment and further optimization by machine perfusion., Lay Summary: In this study, we provide a new prediction model for graft loss in donation-after-circulatory-death (DCD) liver transplantation. Based on UK national data, the new UK DCD Risk Score involves the following seven clinically relevant risk factors: donor age, donor body mass index, functional donor warm ischaemia, cold storage, recipient age, recipient laboratory model for end-stage liver disease, and retransplantation. Three risk classes were defined: low risk (0-5 points), high risk (6-10 points), and futile (>10 points). This new model stratified best in terms of graft survival compared to other available models. Futile combinations (>10 points) achieved an only very limited 1- and 5-year graft survival of 37% and less than 20%, respectively. In contrast, an excellent graft survival has been shown in low-risk combinations (≤5 points). The new model is easy to calculate at the time of liver acceptance. It may help to decide which risk combination will benefit from additional graft treatment, or which DCD liver should be declined for a certain recipient., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Advanced donor age has been identified as a risk factor when combined with donor warm ischemia time (WIT), eg, in donation after circulatory death (DCD). In several countries, DCD livers older than 60 years are not considered suitable due to concerns related to poor graft function and development of ischemic cholangiopathy. In this study, we evaluate outcomes after DCD liver transplantation using grafts from donors older than 60 years. We analyzed outcomes after DCD liver transplantation (n = 315), comparing donors > 60 years (n = 93) and donors ≤ 60 years (n = 222) from our center between 2005 and 2015. End points included graft function and complications and patient and graft survival. Multivariate risk analysis was performed to define further key factors that predicted inferior outcome. Donor age at the cutoff 60 years failed to stratify patient and graft survival. The rate of vascular, biliary, and overall complications was comparably low in both cohorts, and the median comprehensive complication index was 42.7 points, independent from the donor age. Second, donor body mass index (BMI) above a threshold of 25 kg/m 2 significantly impacted on graft and patient survival at any donor age, whereas donor WIT and cold ischemia times were not predictive for graft loss. In conclusion, older DCD donors can be successfully used for liver transplantation with good longterm outcomes when further risk factors are limited. Additional risk is transmitted by an increased donor BMI regardless of donor age. Liver Transplantation 24 352-362 2018 AASLD., (© 2017 by the American Association for the Study of Liver Diseases.)

Ischaemia-reperfusion injury (IRI) is the leading cause of injury seen in the liver following transplantation. IRI also causes injury following liver surgery and haemodynamic shock. The first cells within the liver to be injured by IRI are the liver sinusoidal endothelial cells (LSEC). Recent evidence suggests that LSEC co-ordinate and regulates the livers response to a variety of injuries. It is becoming increasingly apparent that the cyto-protective cellular process of autophagy is a key regulator of IRI. In particular LSEC autophagy may be an essential gatekeeper to the development of IRI. The recent availability of liver perfusion devices has allowed for the therapeutic targeting of autophagy to reduce IRI. In particular normothermic machine liver perfusion (NMP-L) allow the delivery of pharmacological agents to donor livers whilst maintaining physiological temperature and hepatic flow rates. In this review we summarise the current understanding of endothelial autophagy and how this may be manipulated during NMP-L to reduce liver IRI., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.

Introduction: Due to the current organ shortage, nearly 20% of patients die waiting for a liver transplant (LT). The average donor age is on the rise, and grafts from elderly donors are offered as extended criteria grafts., Methods: This is a meta-analysis comparing the outcome differences of adult patients undergoing LT using grafts from <70-year-old donors vs >70-year-old donors. The primary end-points were graft and patient survival. Secondary outcomes were biliary and vascular complications as well as graft function. The odds ratio (OR) is a summary statistic with the corresponding 95% confidence interval; P < .05 was considered to be statistically significant., Results: Eight nonrandomized comparative studies with 4376 LT recipients were included. About 79.9% and 20.1% of the grafts were from <70-year-old and >70-year-old donors, respectively. Graft survival at 1 year was similar between the two groups (P = .11), but there was better 3-year and 5-year graft survival in the >70-year-old group (P = .006 and P < .0001, respectively). Patient survival was also similar between the groups at 1 year (P = .54), but with better survival at 3-year and 5-year follow-ups (P = .007 and P < .0001, respectively) in the >70-year-old group. There were no statistically significant differences in the incidence of biliary, vascular, and graft functional-related complications., Conclusion: Liver grafts from selected >70-year-old donors do not pose added organ-specific risks and thus have comparable transplantation outcomes., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: The use of marginal or extended criteria donor livers is increasing. These organs carry a greater risk of initial dysfunction and early failure, as well as inferior long-term outcomes. As such, many are rejected due to a perceived risk of use and use varies widely between centres. Ex situ normothermic machine perfusion of the liver (NMP-L) may enable the safe transplantation of organs that meet defined objective criteria denoting their high-risk status and are currently being declined for use by all the UK transplant centres., Methods and Analysis: Viability testing and transplantation of marginal livers is an open-label, non-randomised, prospective, single-arm trial designed to determine whether currently unused donor livers can be salvaged and safely transplanted with equivalent outcomes in terms of patient survival. The procured rejected livers must meet predefined criteria that objectively denote their marginal condition. The liver is subjected to NMP-L following a period of static cold storage. Organs metabolising lactate to ≤2.5 mmol/L within 4 hours of the perfusion commencing in combination with two or more of the following parameters-bile production, metabolism of glucose, a hepatic arterial flow rate ≥150 mL/min and a portal venous flow rate ≥500 mL/min, a pH ≥7.30 and/or maintain a homogeneous perfusion-will be considered viable and transplanted into a suitable consented recipient. The coprimary outcome measures are the success rate of NMP-L to produce a transplantable organ and 90-day patient post-transplant survival., Ethics and Dissemination: The protocol was approved by the National Research Ethics Service (London-Dulwich Research Ethics Committee, 16/LO/1056), the Medicines and Healthcare Products Regulatory Agency and is endorsed by the National Health Service Blood and Transplant Research, Innovation and Novel Technologies Advisory Group. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications., Trial Registration Number: NCT02740608; Pre-results., Competing Interests: Competing interests: RWL and YB receive salary as Wellcome Trust research fellows., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: The primary aim of this study is to evaluate the role of split liver transplantation (SLT) in a combined pediatric and adult liver transplant center. The secondary aim is to reflect on our clinical practice and discuss strategies to build a successful split program using an "intention to split policy.", Background: SLT is an established procedure to expand the organ pool and reduce wait list mortality; however, technical and logistic issues are limiting factors., Methods: Prospectively collected data and outcomes of SLT procedures performed between November 1992 and March 2014 were analyzed retrospectively. To assess the effect of standardization and learning curve, the experience was divided into 2 time periods., Results: Out of 3449 liver transplant procedures performed, 516(15%) were SLT. The recipients included 266 children (290 grafts; 56%) and 212 adults (226 grafts; 44%). The median donor age was 25(7-63 years) and the median weight was 70(22-111 kg). The cold and warm ischemic times improved significantly during the second period (SP) (2001-2014). With experience, there was a significant reduction in the biliary complications for both grafts. The introduction of "intention to split policy" resulted in a significantly increased usage of SLT. There was no mortality on the pediatric wait list for last 4 years. Over the last decade 65% of our pediatric transplants were SLT. The overall 1-, 5-, 10-year patient and graft survival of left graft recipients was 91%, 90%, and 89% and 90%, 87%, and 86%. For right grafts it was 87%, 82%, and 81% and 82%, 81%, and 79%, respectively., Conclusions: SLT is an effective surgical strategy to meet the demands in a combined adult and pediatric transplant center. Good outcomes can be achieved with a standardized technique.

The process of ageing has an impact on the entire human body including the organ systems. In transplantation, professionals are daily faced with risk assessment of suitable donor offers , whether to accept a liver graft for a specific recipient. In this context, livers from elderly donors are more frequently accepted for transplantation, to increase the donor pool and compensate the high waiting list mortality. In the current practice it is not unusual to accept 60-year old donor livers for transplantation, as the donor demographics have significantly changed over the years. However, controversy exists regarding the use of livers from donors above 70 or 80 years, particular in combination with other risk factors, e.g. liver steatosis, warm ischaemia or long cold storage. This review focuses first on the impact of ageing on liver morphology and function. Second, we will highlight outcome after transplantation from elderly donors. Finally, we describe further risk factors and donor-recipient selection under the scope of old donor organs and include our institutional experience and policy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Whilst causes of hepatic artery thrombosis (HAT) after liver transplantation (LT) are multifactorial, early HAT (E-HAT) remains pertinent complication impacting on graft and patient survival. Currently there is no screening tool that would identify patients with increased risk of developing E-HAT., Methods: We analyzed the native procoagulant state of LT recipients, identified through pretransplant thromboelastographic (TEG) data among other known risk factors, to identify risk factors for E-HAT., Results: The outcomes of 828 adult patients undergoing LT between 2008 and 2013 were analyzed. Overall, 79 (9.5%) patients experienced HAT, E-HAT was diagnosed in 23, and in the remainder this was "late" HAT. The maximum amplitude (MA) on preoperative TEG was significantly higher in patients diagnosed with E-HAT compared with those who did not (71.2 mm vs 57.9 mm; P < 0.0001). Receiver operating characteristic analysis with the cutoff value for MA of 65 mm or greater returned area under the curve of 0.750 (P < 0.001) predicting E-HAT with a sensitivity of 70%. A total of 7% of patients with an MA of 65 mm or greater went on to develop E-HAT (hazard ratio, 5.28; 95% confidence interval, 2.10-12.29; P < 0.001), whereas only 1.2% patients with an MA less than 65 mm experienced E-HAT., Conclusions: Preoperative TEG may reliably identify group of recipients at greater risk of developing E-HAT, and intense surveillance and anticoagulation prophylaxis may avoid this serious complication after LT.

Hepatic venous outflow obstruction (HVOO) is a rare complication after liver transplantation (LT) associated with significant morbidity and reduced graft survival. Endovascular intervention has become the first-line treatment for HVOO, but data on long-term outcomes are lacking. We have analysed outcomes after endovascular intervention for HVOO in 905 consecutive patients who received 965 full-size LT at our unit from January 2007 to June 2014. There were 27 (3%) patients who underwent hepatic venogram for suspected HVOO, with persistent ascites being the most common symptom triggering the investigation (n = 19, 70%). Of those, only 10 patients demonstrated either stricture or pressure gradient over 10 mmHg on venogram, which represents a 1% incidence of HVOO. The endovascular interventions were balloon dilatation (n = 3), hepatic vein stenting (n = 4) and stenting with dilatation (n = 3). Two patients required restenting due to stent migration. The symptoms of HVOO completely resolved in all but one patient, with a median follow-up period of 74 (interquartile range 39-89) months. There were no procedure-related complications or mortality. In conclusion, the incidence of HVOO in patients receiving full-size LT is currently very low. Endovascular intervention is an effective and safe procedure providing symptom relief with long-lasting primary patency., (© 2016 Steunstichting ESOT.)

Impact of performing multiple liver transplants (LT) in a short period of time is unknown. Consecutively performed LT potentially increase complication rates through team fatigue and overutilization of resources and increase ischemia time. We analyzed the impact of undertaking consecutive LT (Consecutive liver transplant, CLT; LT preceded by another transplant performed not more than 12 h before, both transplants grouped together) on outcomes. Of 1702 LT performed, 314 (18.4%) were CLT. Outcome data was compared with solitary LT (SLT; not more than one LT in 12-h period). Recipient, donor, and graft characteristics were evenly matched between SLT and CLT; second LT of CLT group utilized younger donors grafts with longer cold ischemic times (P = 0.015). Implantation and operative time were significantly lower in CLT recipients on intergroup analysis (P = 0.0001 and 0.002, respectively). Early hepatic artery thrombosis (E-HAT) was higher in CLT versus SLT (P = 0.038), despite absolute number of E-HAT being low in all groups. Intragroup analysis demonstrated a trend toward more frequent E-HAT in first LT, compared to subsequent transplants; however, difference did not reach statistical significance (P = 0.135). In era of organ scarcity, CLT performed at high-volume center is safe and allows pragmatic utilization of organs, potentially reducing number of discarded grafts and reducing waiting list mortality., (© 2015 Steunstichting ESOT.)

Objectives: Orthotopic liver transplant is the treatment of choice for hepatocellular carcinoma in cirrhotic patients with satisfactory oncologic and survival outcomes. Incidental hepatocellular carcinoma is frequently a reported finding in the explant pathology after orthotopic liver transplant., Material and Methods: The present study retrospectively analyzed the tumor characteristics and outcomes of 50 incidental hepatocellular carcinomas compared with 252 transplants for known hepatocellular carcinoma., Results: Patients with incidental hepatocellular carcinoma had lower peak alpha-fetoprotein level (P = .001), lower pretransplant alpha-fetoprotein level (P = .002), smaller total tumor size (P = .0001), fewer tumor numbers (P = .0001), lower level of microvascular invasion (P = .001), more cases within Milan criteria (P = .005), and more well-differentiated tumors (P = .017). However, no difference in survival rates was observed between the 2 groups. In 35 patients (70%) who had incidental hepatocellular carcinoma, pretransplant imaging studies were normal; ultrasonography was used as the only screening tool in 25 of 35 patients (71%) who had incidental hepatocellular carcinoma, and 15 patients (30%) who had incidental hepatocellular carcinoma had regenerative or dysplastic nodules. The accuracy of ultrasonography in our unit for diagnosing hepatocellular carcinoma was 97.5%. A quarter of hepatitis B recipients had incidental hepatocellular carcinoma with a younger median recipient age. Tumor recurrence was higher with incidental hepatocellular carcinoma in hepatitis C recipients (22%). However, the overall recurrence was similar between all hepatitis and nonhepatitis recipients who were transplanted for incidental or known hepatocellular carcinoma., Conclusions: Incidental hepatocellular carcinoma has similar outcome as known hepatocellular carcinoma. Early screening of hepatitis B patients is recommended, and cross-sectional imaging is not mandatory for hepatocellular carcinoma screening in patients who are on the waiting list.

Background & Aims: We studied new-onset diabetes after transplantation (NODAT) in liver transplantation with grafts donated after brain death (DBD) or circulatory death (DCD), focusing on the early post-transplant period., Methods: A total of 430 non-diabetic primary liver transplant recipients [DCD, n = 90 (21%)] were followed up for 30 months (range 5-69). NODAT was defined as the composite endpoint of one of following: (i) Two non-fasting plasma glucose levels > 11.1 mmol/L ≥ 30 days apart, (ii) oral hypoglycaemic drugs ≥ 30 days consecutively (iii) insulin therapy ≥ 30 days and (iv) HbA1c ≥ 48 mmol/L. Resolution of NODAT was defined as cessation of treatment or hyperglycaemia., Results: Total of 81/430 (19%) patients developed NODAT. Incidence and resolution of NODAT over time showed significantly different patterns between DCD and DBD liver graft recipients; early occurrence, high peak incidence and early resolution were seen in DCD. In multivariate logistic regression including age, ethnicity, HCV, tacrolimus level and pulsed steroids, only DCD was independently associated with NODAT at day 15 post-transplant (OR 6.5, 95% CI 2.3-18.4, P < 0.001), whereas age and pulsed steroids were significant factors between 30-90 days. Combined in multivariate Cox regression model for NODAT-free survival, graft type, age and pulsed steroids were each independent predictor for decreased NODAT-free survival in the first 90-postoperative days., Conclusion: Early peak of NODAT in DCD graft recipients is a novel finding, occurring independently from known risk factors. Donor warm ischaemia and impact on insulin sensitivity should be further studied and could perhaps be associated with graft function., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)