Biliary complications after adult-to-adult living-donor liver transplantation: An international multicenter study of 3633 cases.

In living-donor liver transplantation, biliary complications including bile leaks and biliary anastomotic strictures remain significant challenges, with incidences varying across different centers. This multicentric retrospective study (2016-2020) included 3633 adult patients from 18 centers and aimed to identify risk factors for these biliary complications and their impact on patient survival. Incidences of bile leaks and biliary strictures were 11.4% and 20.6%, respectively. Key risk factors for bile leaks included multiple bile duct anastomoses (odds ratio, [OR] 1.8), Roux-en-Y hepaticojejunostomy (OR, 1.4), and a history of major abdominal surgery (OR, 1.4). For biliary anastomotic strictures, risk factors were ABO incompatibility (OR, 1.4), blood loss >1 L (OR, 1.4), and previous abdominal surgery (OR, 1.7). Patients experiencing biliary complications had extended hospital stays, increased incidence of major complications, and higher comprehensive complication index scores. The impact on graft survival became evident after accounting for immortal time bias using time-dependent covariate survival analysis. Bile leaks and biliary anastomotic strictures were associated with adjusted hazard ratios of 1.7 and 1.8 for graft survival, respectively. The study underscores the importance of minimizing these risks through careful donor selection and preoperative planning, as biliary complications significantly affect graft survival, despite the availability of effective treatments.

Long-term outcomes after hypothermic oxygenated machine perfusion and transplantation of 1,202 donor livers in a real-world setting (HOPE-REAL study).

BACKGROUND & AIM: We aimed to assess long-term outcome after transplantation of HOPE-treated donor livers based on real-world data (i.e., IDEAL-D stage 4). METHODS: In this international, multicentre, observational cohort study, we collected data from adult recipients of a HOPE-treated liver transplanted between January 2012 and December 2021. Analyses were stratified for brain-dead (DBD) and circulatory-dead (DCD) donor livers, sub-divided by their respective risk categories. The primary outcome was death-censored graft survival. Secondary outcomes included the incidence of primary non-function (PNF) and ischemic cholangiopathy (IC). RESULTS: We report on 1202 liver transplantations (64% DBD) performed at 22 European centres. For DBD, a total number of 99 benchmark (8%), 176 standard (15%), and 493 extended-criteria (41%) cases were included. For DCD, 117 transplants were classified as low-risk (10%), 186 as high-risk (16%), and 131 as futile (11%), with significant risk profile variations among centres. Actuarial 1-, 3-, and 5-year death-censored graft survival for DBD and DCD was 95%, 92%, and 91%, vs. 92%, 87%, and 81%, respectively (logrank p=0.003). Within DBD and DCD-strata, death-censored graft survival was similar among risk groups (logrank p=0.26, p=0.99). Graft loss due to PNF or IC was 2.3% and 0.4% (DBD), and 5% and 4.1% (DCD). CONCLUSIONS: This study shows excellent 5-year survival after transplantation of HOPE-treated DBD and DCD livers with low rates of graft loss due to PNF or IC, irrespective of their individual risk profile. HOPE-treatment has now reached IDEAL-D stage 4, which further supports the implementation of HOPE in routine clinical practice. IMPACT AND IMPLICATIONS: This study demonstrates the excellent long-term performance of HOPE-treatment of DCD and DBD liver grafts irrespective of their individual risk profile in a real-world setting, outside the evaluation of randomized controlled trials. While previous studies have established safety, feasibility, and efficacy against the current standard, according to the IDEAL-D evaluation framework, HOPE-treatment has now reached the final IDEAL-D Stage 4, which further supports the implementation of HOPE in routine clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05520320.

Revolutionizing Liver Transplantation: Transitioning to an Elective Procedure via ex situ Normothermic Machine Perfusion - A Benefit Analysis.

OBJECTIVE: To assess the impact of Normothermic Machine Perfusion (NMP) on patients, medical teams, and costs by gathering global insights and exploring current limitations. BACKGROUND: NMP for ex-situ liver graft perfusion is gaining increasing attention for its capability to extend graft preservation. It has the potential to transform liver transplantation (LT) from an urgent to a pure elective procedure, which could revolutionize LT logistics, reduce burden on patients and healthcare providers, and decrease costs. METHODS: A 31-item survey was sent to international transplant directors to gather their NMP experiences and vision. Additionally, we performed a systematic review on cost-analysis in LT and assessed studies on cost-benefit in converting urgent-to-elective procedures. We compared the costs of available NMPs and conducted a sensitivity analysis on NMP's cost benefits. RESULTS: Of 120 transplant programs contacted, 64 (53%) responded, spanning North America (31%), Europe (42%), Asia (22%), and South America (5%). Sixty percent had adopted NMP, with larger centers (>100 transplants/year) in North America and Europe more likely to use it. Main NMP systems were OrganOx-metra (39%), XVIVO (36%), and TransMedics-OCS (15%). Despite NMP adoption, 41% of centers still perform >50% of LTs at nights/weekends. Centers recognized NMP's benefits, including improved work satisfaction and patient outcomes, but faced challenges like high costs and machine complexity. 16% would invest $100'000-500'000, 33% $50'000-100'000, 38% $10'000-50'000, and 14% <$10'000 in NMP. These results were strengthened by a cost analysis for NMP in emergency-to-elective LT transition. Accordingly, while liver perfusions with disposables up to $10'000 resulted in overall positive net balances, this effect was lost when disposables' cost amounted to >$40'000/organ. CONCLUSION: The adoption of NMP is hindered by high costs and operational complexity. Making LT elective through NMP could reduce costs and improve outcomes, but overcoming barriers requires national reimbursements and simplified, automated NMP systems for multi-day preservation.

Age Matters: What Affects the Cumulative Lifespan of a Transplanted Liver?

OBJECTIVE: Assess factors affecting the cumulative lifespan of a transplanted liver. SUMMARY BACKGROUND DATA: Liver ageing is different from other solid organs. It is unknown how old a liver can actually get after liver transplantation (LT). METHODS: Deceased donor liver transplants from 1988-2021 were queried from the United States (US) UNOS registry. Cumulative liver age was calculated as donor age + recipient graft survival. RESULTS: In total, 184,515 livers were included. Most were DBD-donors (n=175,343). The percentage of livers achieving >70, 80, 90 and 100years cumulative age was 7.8% (n=14,392), 1.9% (n=3,576), 0.3% (n=528), and 0.01% (n=21), respectively. The youngest donor age contributing to a cumulative liver age >90years was 59years, with post-transplant survival of 34years. In pediatric recipients, 736 (4.4%) and 282 livers (1.7%) survived >50 and 60years overall, respectively. Transplanted livers achieved cumulative age >90years in 2.86-per-1000 and >100years in 0.1-per-1000. The US population at-large has a cumulative "liver age" >90years in 5.35-per-1000 persons, and >100y in 0.2-per-1000. Livers aged>60 years at transplant experienced both improved cumulative survival ( P <0.0001) and interestingly improved survival after transplantation ( P <0.0001). Recipient warm-ischemia-time of >30minutes was most predictive of reduced cumulative liver survival overall (n=184,515, HR=1.126, P <0.001) and excluding patients with mortality in the first 6month (n=151,884, HR=0.973, P <0.001). CONCLUSIONS: In summary, transplanted livers frequently get as old as those in the average population despite ischemic-reperfusion-injury and immunosuppression. The presented results justify using older donor livers regardless of donation type, even in sicker recipients with limited options.

Towards a Standardization of Learning Curve Assessment in Minimally Invasive Liver Surgery.

OBJECTIVE: The aim was to analyze the learning curves of minimal invasive liver surgery(MILS) and propose a standardized reporting. SUMMARY BACKGROUND DATA: MILS offers benefits compared to open resections. For a safe introduction along the learning curve, formal training is recommended. However, definitions of learning curves and methods to assess it lack standardization. METHODS: A systematic review of PubMed, Web of Science, and CENTRAL databases identified studies on learning curves in MILS. The primary outcome was the number needed to overcome the learning curve. Secondary outcomes included endpoints defining learning curves, and characterization of different learning phases(competency, proficiency and mastery). RESULTS: 60 articles with 12'241 patients and 102 learning curve analyses were included. The laparoscopic and robotic approach was evaluated in 71 and 18 analyses and both approaches combined in 13 analyses. Sixty-one analyses (60%) based the learning curve on statistical calculations. The most often used parameters to define learning curves were operative time (n=64), blood loss (n=54), conversion (n=42) and postoperative complications (n=38). Overall competency, proficiency and mastery were reached after 34 (IQR 19-56), 50 (IQR 24-74), 58 (IQR 24-100) procedures respectively. Intraoperative parameters improved earlier (operative time: competency to proficiency to mastery: -13%, 2%; blood loss: competency to proficiency to mastery: -33%, 0%; conversion rate (competency to proficiency to mastery; -21%, -29%), whereas postoperative complications improved later (competency to proficiency to mastery: -25%, -41%). CONCLUSIONS: This review summarizes the highest evidence on learning curves in MILS taking into account different definitions and confounding factors. A standardized three-phase reporting of learning phases (competency, proficiency, mastery) is proposed and should be followed.

Hepatic Artery Infusion Chemotherapy for Primary and Secondary Malignancies of the Liver: State of the Art and Current High-Level Evidence.

BACKGROUND: Hepatic artery infusion chemotherapy (HAI) has been proposed as a valuable adjunct for multimodal therapy of primary and secondary liver malignancies. This review provides an overview of the currently available evidence of HAI, taking into account tumor response and long-term oncologic outcome. SUMMARY: In colorectal liver metastases (CRLM), HAI in combination with systemic therapy leads to high response rates (85-90%) and conversion to resectablity in primary unresectable disease in up to 50%. HAI in combination with systemic therapy in CRLM in the adjuvant setting shows promising long-term outcomes with up to 50% 10-year survival in a large, non-randomized single-center cohort. For hepatocellular carcinoma patients, response rates as high as 20-40% have been reported for HAI and long-term outcomes compare well to other therapies. Similarly, survival for patients with unresectable intrahepatic cholangiocarcinoma 3 years after treatment with HAI is reported as high as 34%, which compares well to trials of systemic therapy where 3-year survival is usually below 5%. However, evidence is mainly limited by highly selected, heterogenous patient groups, and outdated chemotherapy regimens. The largest body of evidence stems from small, often non-randomized cohorts, predominantly from highly specialized single centers. KEY MESSAGE: In well-selected patients with primary and secondary liver malignancies, HAI might improve response rates and, possibly, long-term survival. Results of ongoing randomized trials will show whether a wider adoption of HAI is justified, particularly to increase rates of resectability in advanced malignant diseases confined to the liver.

Experts vs. machine - comparison of machine learning to expert-informed prediction of outcome after major liver surgery.

BACKGROUND: Machine learning (ML) has been successfully implemented for classification tasks (e.g., cancer diagnosis). ML performance for more challenging predictions is largely unexplored. This study's objective was to compare machine learning vs. expert-informed predictions for surgical outcome in patients undergoing major liver surgery. METHODS: Single tertiary center data on preoperative parameters and postoperative complications for elective hepatic surgery patients were included (2008-2021). Expert-informed prediction models were established on 14 parameters identified by two expert liver surgeons to impact on postoperative outcome. ML models used all available preoperative patient variables (n = 62). Model performance was compared for predicting 3-month postoperative overall morbidity. Temporal validation and additional analysis in major liver resection patients were conducted. RESULTS: 889 patients included. Expert-informed models showed low average bias (2-5 CCI points) with high over/underprediction. ML models performed similarly: average prediction 5-10 points higher than observed CCI values with high variability (95% CI -30 to 50). No performance improvement for major liver surgery patients. CONCLUSION: No clinical relevance in the application of ML for predicting postoperative overall morbidity was found. Despite being a novel hype, ML has the potential for application in clinical practice. However, at this stage it does not replace established approaches of prediction modelling.

[Organ donation and organ assessment after primary circulatory death and secondary brain death]. / Organspende und Organassessment nach primärem Herz-Kreislauf-Stillstand und sekundärem Hirntod.

BACKGROUND: The global organ shortage is the biggest obstacle to expand urgently needed liver transplantation activities. In addition to donation after brain death (DBD), donation after primary circulatory death (DCD) has also been introduced in many European countries to increase the number of donated organs. OBJECTIVE: This article summarizes the legal and ethical aspects of DCD, the practical donation process of DCD, the clinical results of DCD liver transplantation with a special focus on organ assessment before a planned DCD liver transplantation. RESULTS: In Europe 11 countries have active DCD liver transplantation programs and a total of 1230 DCD liver transplantations were performed in Europe in 2023. The highest proportion of DCD liver transplantations were recorded in Belgium (52.8%), the Netherlands (42.8%) and Switzerland (32.1%). The adequate selection of donors and recipients is crucial in DCD transplantation and the use of DCD livers particularly depends on the preparedness of the healthcare system for routine machine perfusion. The leaders are Belgium, France and Italy which implant around 68-74% of DCD organs. With an adequate organ assessment, the long-term results of DBD and DCD liver transplantations are comparable. To assess mitochondrial damage and thus organ quality, hypothermic oxygenated machine perfusion (HOPE) was introduced and has the secondary benefit of mitochondrial protection through oxygenation. The establishment of aerobic metabolism in mitochondria under hypothermia leads to a reduction of toxic metabolites and the restoration of ATP storage, which subsequently leads to a reperfusion light during implantation. CONCLUSION: Expanding the donor pool with DCD donors can counteract the global organ shortage. With adequate patient selection and routine organ assessment short-term and also long-term outcomes of DBD and DCD liver transplantation are comparable.

Routine utilization of machine perfusion in liver transplantation: Ready for prime time?

The last decade has been notable for increasing high-quality research and dramatic improvement in outcomes with dynamic liver preservation. Robust evidence from numerous randomized controlled trials has been pooled by meta-analyses, providing the highest available evidence on the protective effect of machine perfusion (MP) over static cold storage in liver transplantation (LT). Based on a protective effect with less complications and improved graft survival, the field has seen a paradigm shift in organ preservation. This editorial focuses on the role of MP in LT and how it could become the new "gold standard". Strong collaborative efforts are needed to explore its effects on long-term outcomes.

Comparative Study of Acute Kidney Injury in Liver Transplantation: Donation after Circulatory Death versus Brain Death.

BACKGROUND Acute kidney injury (AKI) after orthotopic liver transplantation (OLT) contributes to morbidity and mortality. Donation after circulatory death (DCD) has been established to increase the pool of organs. While surgical complications are reported to be comparable in DCD and donation after brain death (DBD) OLT, there is a knowledge gap concerning adverse kidney events in these 2 groups. MATERIAL AND METHODS In this retrospective cohort study, 154 patients received a DBD and 68 received a DCD organ (2016-2020). The primary outcome was a major adverse kidney event within 30 days (MAKE-30). The secondary outcome was dynamics of AKI and kidney replacement therapy (KRT) during the first postoperative week and on postoperative day 30. Incidence and resolution from AKI and KRT and patient survival (PS) 30 days after OLT were compared between the DCD and DBD recipients. RESULTS MAKE-30 incidence after OLT was comparable in DCD (n=27, 40%) vs DBD (n=41, 27%) recipients (risk ratio 1.49 [95% CI 1.01, 2.21], p=0.073). AKI incidence was comparable in DCD (n=58, 94%) vs DBD (n=95, 82%) recipients (risk ratio 1.14 [95% CI: 1.03, 1.27], P=0.057). Overall, 40% (n=88) of patients required KRT, with no difference between DCD (n=27, 40%) vs DBD (n=61, 40%) recipients (risk ratio 1.00 [95% CI 0.71, 1.43], P>0.999). Resolution of AKI by day 30 was lower in DCD (n=29, 50%) than in DBD (n=66, 69%) recipients (risk ratio 0.71 [95% CI: 0.53, 0.95], P=0.032). Survival after 30 days (DCD: n=64, 94% vs DBD: n=146, 95%, risk ratio 0.99 [95% CI 0.93, 1.06], P>0.999) was also comparable. CONCLUSIONS MAKE-30, short-term renal outcome, and survival did not significantly differ between DBD and DCD-OLT. Resolution of AKI by day 30 was lower in DCD than in DBD recipients.

Glucose controls lipolysis through Golgi PtdIns4P-mediated regulation of ATGL.

Metabolic crosstalk of the major nutrients glucose, amino acids and fatty acids (FAs) ensures systemic metabolic homeostasis. The coordination between the supply of glucose and FAs to meet various physiological demands is especially important as improper nutrient levels lead to metabolic disorders, such as diabetes and metabolic dysfunction-associated steatohepatitis (MASH). In response to the oscillations in blood glucose levels, lipolysis is thought to be mainly regulated hormonally to control FA liberation from lipid droplets by insulin, catecholamine and glucagon. However, whether general cell-intrinsic mechanisms exist to directly modulate lipolysis via glucose sensing remains largely unknown. Here we report the identification of such an intrinsic mechanism, which involves Golgi PtdIns4P-mediated regulation of adipose triglyceride lipase (ATGL)-driven lipolysis via intracellular glucose sensing. Mechanistically, depletion of intracellular glucose results in lower Golgi PtdIns4P levels, and thus reduced assembly of the E3 ligase complex CUL7FBXW8 in the Golgi apparatus. Decreased levels of the E3 ligase complex lead to reduced polyubiquitylation of ATGL in the Golgi and enhancement of ATGL-driven lipolysis. This cell-intrinsic mechanism regulates both the pool of intracellular FAs and their extracellular release to meet physiological demands during fasting and glucose deprivation. Moreover, genetic and pharmacological manipulation of the Golgi PtdIns4P-CUL7FBXW8-ATGL axis in mouse models of simple hepatic steatosis and MASH, as well as during ex vivo perfusion of a human steatotic liver graft leads to the amelioration of steatosis, suggesting that this pathway might be a promising target for metabolic dysfunction-associated steatotic liver disease and possibly MASH.

Real-time assessment of kidney allografts during HOPE using flavin mononucleotide (FMN) - a preclinical study.

Introduction: The gap between available donor grafts and patients on the waiting lists is constantly growing. This leads to an increased utilization of high-risk and therefore more vulnerable kidney grafts. The use of high-risk organs requires further optimization of machine preservation and assessment strategies before transplantation. Hypothermic machine perfusion (HMP) is the standard of care for kidneys originating from donation after circulatory death (DCD), whereas the evidence of HMP with additional oxygen (HOPE) is still very limited. Furthermore, an objective quality assessment of HMP-perfused kidneys is lacking. Recently, the release of mitochondria derived fragments, i.e., flavin mononucleotide (FMN) of complex I during machine liver perfusion was shown to be predictive for liver graft function before implantation. Therefore, the aim of this study was to evaluate, if FMN is useful also for assessment of kidney injury before use. Methods: A porcine perfusion model was used to investigate the feasibility of assessment of kidney grafts during hypothermic oxygenated perfusion (HOPE) with either 0, 30 or 60 minutes of warm ischemia. The model with warm ischemia times (WIT) of 30 min and 60 min, was used to mimic a clinically relevant scenario. A group with no warm ischemia time (0' WIT) served as control group. The groups underwent minimal static cold storage (SCS) of 2 h followed by 2 h of end-ischemic HOPE with repeated real-time FMN measurements. In a further step, these values were related to the release of damage-associated molecular patterns (DAMPs) and to the functionality of the respiratory chain, represented by the capacity of ATP production. Results: We demonstrate, first, feasibility of perfusate FMN measurements in perfused kidneys, and secondly its correlation with donor warm ischemia time. Accordingly, FMN measurement showed significantly higher release in the 60-minute WIT group (n = 4) compared to the 30-minute WIT (n = 4) and the control group (n = 4). FMN release correlated also with DAMP signaling, such as the release of 8-OHdG and HMGB1. Finally, ATP replenishment proved to be best in control kidneys, followed by kidneys with 30 min and then by kidneys with 60 min of WIT. Discussion: This study demonstrates the feasibility of FMN measurement in kidneys during HOPE. In addition, we show a correlation between FMN quantification and pre-existing kidney graft injury. Based on this, real-time FMN measurement during HOPE may be an objective assessment tool to accept high-risk kidneys for transplantation while minimizing post-transplant dysfunction, moving away from former "gut feeling" towards objective criteria in accepting marginal kidney grafts for transplantation. Graft evaluation based on these results may close the gap between available grafts and patients on the waiting lists by increasing utilization rates without significant impact for the recipients.