The Impact of Donor Body Mass Index on Safety and Outcomes in Living Donor Liver Transplantation: An Analysis of the National United States Database.

Background: The prevalence of obesity is rising in the general population. Donor obesity (body mass index ≥30 kg/m2) may potentially reduce the donor pool and impact outcomes in living donor liver transplantation (LDLT). Methods: We utilized the national transplant database to investigate the impact of donor obesity on donor and recipient outcomes. This was a retrospective cohort study of all LDLTs performed in the United States between January 2010 and June 2023. Outcomes of interest were analyzed by univariable and multivariable logistic regression. Patient and graft survival was evaluated using Kaplan-Meier and Cox proportional analysis. Results: Six hundred seventy-four donors with obesity and 3498 donors without obesity were analyzed. Donors with obesity had higher rates of readmission within 1 y of donation (15.9% versus 11.6%; P = 0.003). The risk of readmission was significantly different between 6 wk and 6 mo of donation (8.8% versus 5.9%; P = 0.036). Donor body mass index (odds ratio [OR], 1.460; 95% confidence interval [CI], 1.129-1.999; P = 0.004) and preoperative alkaline phosphatase levels (OR, 1.005; 95% CI, 1.000-1.011; P = 0.038) were independent predictors of donor readmission. High LDLT center volume was associated with reduced odds of donor readmission (OR, 0.509; 95% CI, 0.373-0.694; P < 0.001). Graft and recipient survival was comparable. Conclusions: Selection of living donors with obesity may be a potential avenue to increase the available donor pool without compromising recipient outcomes; however, they are at an increased risk for readmission between 6 wk and 6 mo of donation. The reason for readmission requires further study.

The Potential Utilization of Machine Perfusion to Increase Transplantation of Macrosteatotic Livers.

BACKGROUND: The demand for liver transplantation has led to the utilization of marginal grafts including moderately macrosteatotic livers (macrosteatosis ≥30% [Mas30]), which are associated with an elevated risk of graft failure. Machine perfusion (MP) has emerged as a technique for organ preservation and viability testing; however, little is known about MP in Mas30 livers. This study evaluates the utilization and outcomes of Mas30 livers in the era of MP. METHODS: The Organ Procurement and Transplantation Network database was queried to identify biopsy-proven Mas30 deceased donor liver grafts between June 1, 2016, and June 23, 2023. Univariable and multivariable models were constructed to study the association between MP and graft utilization and survival. RESULTS: The final cohort with 3317 Mas30 livers was identified, of which 72 underwent MP and were compared with 3245 non-MP livers. Among Mas30 livers, 62 (MP) and 1832 (non-MP) were transplanted (utilization of 86.1% versus 56.4%, P < 0.001). Donor and recipient characteristics were comparable between MP and non-MP groups. In adjusted analyses, MP was associated with significantly increased Mas30 graft utilization (odds ratio, 7.89; 95% confidence interval [CI], 3.76-16.58; P < 0.001). In log-rank tests, MP was not associated with 1- and 3-y graft failure (hazard ratio, 0.49; 95% CI, 0.12-1.99; P = 0.319 and hazard ratio 0.43; 95% CI, 0.11-1.73; P = 0.235, respectively). CONCLUSIONS: The utilization rate of Mas30 grafts increases with MP without detriment to graft survival. This early experience may have implications for increasing the available donor pool of Mas30 livers.

National Trends in Utilization of Normothermic Machine Perfusion in DCD Liver Transplantation.

Background: In liver transplantation, advances in ex situ normothermic machine perfusion (NMP) have improved outcomes compared with traditional static cold storage (SCS) in donation after circulatory death (DCD) organs. We aimed to characterize trends in the utilization of NMP versus SCS in DCD liver transplantation in the United States. Methods: This retrospective cohort study used data from the United Network for Organ Sharing database to identify recipient-donor adult liver transplant pairs from DCD donors from January 2016 to June 2022. Utilization of NMP and changes in donor risk index (DRI) and components between NMP and SCS were assessed across transplant year eras (2016-2018, 2019-2020, and 2021-2022). Statistical comparisons were made using the Kruskal-Wallis test or the chi-square test. Results: A total of 3937 SCS and 127 NMP DCD donor transplants were included. Utilization of NMP ranged from ~0.4% to 3.5% from 2016 to 2021 and rose significantly to 11.2% in early 2022. Across transplant eras, median DRI increased significantly for SCS and NMP, but the magnitude of the increase was larger for NMP. With NMP DCDs, there were significant increases in median donor age, national share proportion, and "cold ischemic time" over time. Finally, there was a shift toward including higher DRI donors and higher model for end-stage liver disease score transplant recipients with NMP in later transplant eras. Conclusions: In recent years, NMP utilization has increased and expanded to donors with higher DRI and recipients with higher model for end-stage liver disease score at transplant, suggesting increasing familiarity and risk tolerance with NMP technology. As NMP remains a relatively new technique, ongoing study of patient outcomes, organ allocation practices, and utilization patterns is critical.

Performance of risk prediction models for post-liver transplant patient and graft survival over time.

Given liver transplantation organ scarcity, selection of recipients and donors to maximize post-transplant benefit is paramount. Several scores predict post-transplant outcomes by isolating elements of donor and recipient risk, including the donor risk index, Balance of Risk, pre-allocation score to predict survival outcomes following liver transplantation/survival outcomes following liver transplantation (SOFT), improved donor-to-recipient allocation score for deceased donors only/improved donor-to-recipient allocation score for both deceased and living donors (ID2EAL-D/-DR), and survival benefit (SB) models. No studies have examined the performance of these models over time, which is critical in an ever-evolving transplant landscape. This was a retrospective cohort study of liver transplantation events in the UNOS database from 2002 to 2021. We used Cox regression to evaluate model discrimination (Harrell's C) and calibration (testing of calibration curves) for post-transplant patient and graft survival at specified post-transplant timepoints. Sub-analyses were performed in the modern transplant era (post-2014) and for key donor-recipient characteristics. A total of 112,357 transplants were included. The SB and SOFT scores had the highest discrimination for short-term patient and graft survival, including in the modern transplant era, where only the SB model had good discrimination (C ≥ 0.60) for all patient and graft outcome timepoints. However, these models had evidence of poor calibration at 3- and 5-year patient survival timepoints. The ID2EAL-DR score had lower discrimination but adequate calibration at all patient survival timepoints. In stratified analyses, SB and SOFT scores performed better in younger (< 40 y) and higher Model for End-Stage Liver Disease (≥ 25) patients. All prediction scores had declining discrimination over time, and scores relying on donor factors alone had poor performance. Although the SB and SOFT scores had the best overall performance, all models demonstrated declining performance over time. This underscores the importance of periodically updating and/or developing new prediction models to reflect the evolving transplant field. Scores relying on donor factors alone do not meaningfully inform post-transplant risk.

Significant Reduction in Posttransplant Hepatocellular Carcinoma Recurrence in the Post 6-Mo Waiting Policy Era.

BACKGROUND: In 2015, the United Network for Organ Sharing implemented a policy introducing a 6-mo waiting period before granting model for end-stage liver disease exception points to liver transplant (LT) candidates with hepatocellular carcinoma (HCC). This study analyzes the policy impact on post-LT HCC recurrence. METHODS: This was a United Network for Organ Sharing retrospective cohort study of patients with HCC who underwent LT from January 1, 2010, to May 31, 2019. HCC-specific data included alpha-fetoprotein, tumor characteristics, locoregional therapy (LRT), and explant data used to calculate the Risk Estimation of Tumor Recurrence After Transplant score. The primary exposure was pre-/post-policy era, divided on October 8, 2015. Survival analysis techniques were used to evaluate the unadjusted and sequentially adjusted association between policy era and HCC recurrence, accounting for competing risks. RESULTS: A total of 7940 patients were included, 5879 (74.0%) pre-policy era and 2061 (26.0%) post-policy era. Post-policy patients were older, received more LRT, and had lower alpha-fetoprotein levels and smaller tumor sizes at transplant. Incidence rates of HCC recurrence were 19.8 and 13.7 events per 1000 person-years for pre- and post-policy eras, respectively. Post-policy era was associated with an unadjusted 35% reduction in the risk of HCC recurrence (P < 0.001). After adjusting for recipient, donor, and tumor characteristics at listing this association remained (subhazard ratio 0.69; 95% confidence interval, 0.55-0.86; P = 0.001); however, after additionally adjusting for LRT episodes and Risk Estimation of Tumor Recurrence After Transplant score, there was no longer a statistically significant association (subhazard ratio 0.77; 95% confidence interval, 0.59-1.00; P = 0.054). CONCLUSIONS: We observed a significant reduction in post-LT HCC recurrence after policy implementation. This may be due to waitlist selection of healthier patients, increased LRT utilization, and potential selection of favorable tumor biology.

Preventing Small-for-size Syndrome in Living Donor Liver Transplantation: Guidelines From the ILTS-iLDLT-LTSI Consensus Conference.

Small-for-size syndrome (SFSS) is a well-recognized complication following liver transplantation (LT), with up to 20% developing this following living donor LT (LDLT). Preventing SFSS involves consideration of factors before the surgical procedure, including donor and recipient selection, and factors during the surgical procedure, including adequate outflow reconstruction, graft portal inflow modulation, and management of portosystemic shunts. International Liver Transplantation Society, International Living Donor Liver Transplantation Group, and Liver Transplant Society of India Consensus Conference was convened in January 2023 to develop recommendations for the prediction and management of SFSS in LDLT. The format of the conference was based on the Grading of Recommendations, Assessment, Development, and Evaluation system. International experts in this field were allocated to 4 working groups (diagnosis, prevention, anesthesia, and critical care considerations, and management of established SFSS). The working groups prepared evidence-based recommendations to answer-specific questions considering the currently available literature. The working group members, independent panel, and conference attendees served as jury to edit and confirm the final recommendations presented at the end of the conference by each working group separately. This report presents the final statements and evidence-based recommendations provided by working group 2 that can be implemented to prevent SFSS in LDLT patients.

Association Between Bariatric Surgery and Alcohol Use-Related Hospitalization and All-Cause Mortality in a Veterans Affairs Cohort.

Importance: Bariatric surgery procedures, in particular Roux-en-Y gastric bypass (RYGB), have been associated with subsequent alcohol-related complications. However, previous studies lack data to account for changes in body mass index (BMI) or alcohol use over time, which are key potential confounders. Objective: To evaluate the association between RYGB, sleeve gastrectomy, or gastric banding on subsequent alcohol use disorder (AUD)-related hospitalization and all-cause mortality as compared with referral to a weight management program alone. Design, Setting, and Participants: This cohort study included 127 Veterans Health Administration health centers in the US. Patients who underwent RYGB, sleeve gastrectomy, or gastric banding or who were referred to MOVE!, a weight management program, and had a BMI (calculated as weight in kilograms divided by height in meters squared) of 30 or greater between January 1, 2008, and December 31, 2021, were included in the study. Exposures: RYGB, sleeve gastrectomy, or gastric banding or referral to the MOVE! program. Main Outcomes and Measures: The primary outcome was time to AUD-related hospitalization from the time of bariatric surgery or MOVE! referral. The secondary outcome was time to all-cause mortality. Separate propensity scores were created for each pairwise comparison (RYGB vs MOVE! program, RYGB vs sleeve gastrectomy, sleeve gastrectomy vs MOVE!). Sequential Cox regression approaches were used for each pairwise comparison to estimate the relative hazard of the primary outcome in unadjusted, inverse probability treatment weighting (IPTW)-adjusted (generated from the pairwise logistic regression models), and IPTW-adjusted approaches with additional adjustment for time-updating BMI and categorical Alcohol Use Disorders Identification Test-Concise scores. Results: A total of 1854 patients received RYGB (median [IQR] age, 53 [45-60] years; 1294 men [69.8%]), 4211 received sleeve gastrectomy (median [IQR] age, 52 [44-59] years; 2817 men [66.9%]), 265 received gastric banding (median [IQR] age, 55 [46-61] years; 199 men [75.1%]), and 1364 were referred to MOVE! (median [IQR] age, 59 [49-66] years; 1175 men [86.1%]). In IPTW Cox regression analyses accounting for time-updating alcohol use and BMI, RYGB was associated with an increased hazard of AUD-related hospitalization vs MOVE! (hazard ratio [HR], 1.70; 95% CI, 1.20-2.41; P = .003) and vs sleeve gastrectomy (HR, 1.98; 95% CI, 1.55-2.53; P < .001). There was no significant difference between sleeve gastrectomy and MOVE! (HR, 0.76; 95% CI, 0.56-1.03; P = .08). While RYGB was associated with a reduced mortality risk vs MOVE! (HR, 0.63; 95% CI, 0.49-0.81; P < .001), this association was mitigated by increasing alcohol use over time. Conclusions and Relevance: This cohort study found that RYGB was associated with an increased risk of AUD-related hospitalizations vs both sleeve gastrectomy and the MOVE! program. The mortality benefit associated with RYGB was diminished by increased alcohol use, highlighting the importance of careful patient selection and alcohol-related counseling for patients undergoing this procedure.

Modeling Optimal Clinical Thresholds for Elective Abdominal Hernia Repair in Patients With Cirrhosis.

Importance: Patients with cirrhosis have increased risk of postoperative mortality. Several models have been developed to estimate this risk; however, current risk estimation scores cannot compare surgical risk with the risk of not operating. Objective: To identify clinical optimal thresholds to favor operative or nonoperative management for a common cirrhosis surgical scenario, the symptomatic abdominal hernia. Design, Setting, and Participants: This was a Markov cohort decision analytical modeling study evaluating elective surgery vs nonoperative management for a symptomatic abdominal hernia in a patient with cirrhosis. Transition probabilities and utilities were derived from the literature and from data using an established cirrhosis cohort in the Veterans Health Administration. Participants included patients who were referred to a surgery clinic for a symptomatic abdominal hernia. Data were obtained from patients diagnosed with cirrhosis between January 1, 2008 and December 31, 2018. Data were analyzed from January 1 to May 1, 2022. Main Outcomes and Measures: Expected quality-adjusted life-years (QALYs) were estimated for each pathway and iterated over baseline model for end-stage liver disease-sodium (MELD-Na) scores ranging from 6 to 25. Markov models were cycled over a 5-year time horizon. Results: A total 2740 patients with cirrhosis (median [IQR] age, 62 [56-66] years; 2699 [98.5%] men) were referred to a surgery clinic for a symptomatic abdominal hernia; 1752 patients (63.9%) did not receive surgery. The median (IQR) follow-up was 42.1 (25.3-70.0) months. Using this cohort to estimate the mortality risk of operative and nonoperative pathways, an initial MELD-Na threshold of 21.3 points, below which surgery was associated with maximized QALYs was identified. Nonoperative management was associated with increased QALYs above this MELD-Na threshold. Although more patients experienced death with a surgical treatment decision across all initial MELD-Na values, this was counterbalanced by increased time spent in a resolved hernia state associated with increased utility. Model results were sensitive to the probability of hernia recurrence and hernia incarceration and utility decrement in the symptomatic hernia state. Conclusions and Relevance: This decision analytical model study found that elective surgical treatment for a symptomatic abdominal hernia was favored even in the setting of relatively high MELD-Na scores. Patient symptoms, hernia-specific characteristics, and surgeon and center expertise may potentially impact the optimal strategy, emphasizing the importance of shared decision-making.

Novel Benchmark Values for Redo Liver Transplantation: Does the Outcome Justify the Effort?

OBJECTIVE: To define benchmark cutoffs for redo liver transplantation (redo-LT). BACKGROUND: In the era of organ shortage, redo-LT is frequently discussed in terms of expected poor outcome and wasteful resources. However, there is a lack of benchmark data to reliably evaluate outcomes after redo-LT. METHODS: We collected data on redo-LT between January 2010 and December 2018 from 22 high-volume transplant centers. Benchmark cases were defined as recipients with model of end stage liver disease (MELD) score ≤25, absence of portal vein thrombosis, no mechanical ventilation at the time of surgery, receiving a graft from a donor after brain death. Also, high-urgent priority and early redo-LT including those for primary nonfunction (PNF) or hepatic artery thrombosis were excluded. Benchmark cutoffs were derived from the 75th percentile of the medians of all benchmark centers. RESULTS: Of 1110 redo-LT, 373 (34%) cases qualified as benchmark cases. Among these cases, the rate of postoperative complications until discharge was 76%, and increased up to 87% at 1-year, respectively. One-year overall survival rate was excellent with 90%. Benchmark cutoffs included Comprehensive Complication Index CCI ® at 1-year of ≤72, and in-hospital and 1-year mortality rates of ≤13% and ≤15%, respectively. In contrast, patients who received a redo-LT for PNF showed worse outcomes with some values dramatically outside the redo-LT benchmarks. CONCLUSION: This study shows that redo-LT achieves good outcome when looking at benchmark scenarios. However, this figure changes in high-risk redo-LT, as for example in PNF. This analysis objectifies for the first-time results and efforts for redo-LT and can serve as a basis for discussion about the use of scarce resources.

Generation and characterization of a mouse model for one anastomosis gastric bypass surgery.

One anastomosis gastric bypass (OAGB) surgery became a common bariatric procedure in recent years. In this surgery, the distal stomach, duodenum, and proximal jejunum are bypassed, leading to weight loss, improvement in metabolic parameters, and a change in hormonal secretion. We sought to generate and characterize a mouse model for OAGB. Mice fed for 26 wk on a high-fat diet were assigned to OAGB, sham surgery, or caloric restriction and were followed for 50 more days on a high-fat diet. Physiological and histological parameters of the mice were compared during and at the end of the experiment. OAGB-operated mice lost weight and displayed low levels of plasma lipids, high insulin sensitivity, and rapid glucose metabolism compared with sham-operated mice. OAGB-operated mice had higher energy expenditure, higher levels of glucagon-like peptide (GLP-1), and lower albumin than weight-matched calorie-restricted mice. There was no difference in the histology of the endocrine pancreas. The livers of OAGB mice had little hepatic steatosis yet presented with a large number of phagocytic cells. The OAGB mouse model recapitulates many of the phenotypes described in patients that underwent OAGB and enables molecular and physiological studies on the outcome of this surgery.NEW & NOTEWORTHY A mouse model for one anastomosis gastric bypass (OAGB) surgery displays similar outcomes to clinical reports and enables to study the weight loss-dependent and -independent effects of this bariatric surgery.

ChIP-seq of plasma cell-free nucleosomes identifies gene expression programs of the cells of origin.

Cell-free DNA (cfDNA) in human plasma provides access to molecular information about the pathological processes in the organs or tumors from which it originates. These DNA fragments are derived from fragmented chromatin in dying cells and retain some of the cell-of-origin histone modifications. In this study, we applied chromatin immunoprecipitation of cell-free nucleosomes carrying active chromatin modifications followed by sequencing (cfChIP-seq) to 268 human samples. In healthy donors, we identified bone marrow megakaryocytes, but not erythroblasts, as major contributors to the cfDNA pool. In patients with a range of liver diseases, we showed that we can identify pathology-related changes in hepatocyte transcriptional programs. In patients with metastatic colorectal carcinoma, we detected clinically relevant and patient-specific information, including transcriptionally active human epidermal growth factor receptor 2 (HER2) amplifications. Altogether, cfChIP-seq, using low sequencing depth, provides systemic and genome-wide information and can inform diagnosis and facilitate interrogation of physiological and pathological processes using blood samples.

A single cell atlas of the human liver tumor microenvironment.

Malignant cell growth is fueled by interactions between tumor cells and the stromal cells composing the tumor microenvironment. The human liver is a major site of tumors and metastases, but molecular identities and intercellular interactions of different cell types have not been resolved in these pathologies. Here, we apply single cell RNA-sequencing and spatial analysis of malignant and adjacent non-malignant liver tissues from five patients with cholangiocarcinoma or liver metastases. We find that stromal cells exhibit recurring, patient-independent expression programs, and reconstruct a ligand-receptor map that highlights recurring tumor-stroma interactions. By combining transcriptomics of laser-capture microdissected regions, we reconstruct a zonation atlas of hepatocytes in the non-malignant sites and characterize the spatial distribution of each cell type across the tumor microenvironment. Our analysis provides a resource for understanding human liver malignancies and may expose potential points of interventions.

Prognosis and Treatment of Liver Transplant Recipients in the COVID-19 Era: A Literature Review.

Liver transplantation during the COVID-19 pandemic is challenging. Both donor and recipient issues can be influenced by the risks attributed to the pandemic. Allocation policy may need to be modified and criteria may be influenced by local infection rates and availability of medical facilities. Modifying immunosuppression (IS) protocols is controversial and is not evidence-based. In this study, we review the published literature on liver transplant recipients who were infected with COVID-19. A literature review was performed using PubMed, ScienceDirect, and WHO databases to identify relevant English-language articles published up to May 20, 2020. Fifteen articles reported 120 liver transplant recipients who were infected with COVID-19. Only 10 papers with 22 patients reported full encounter characteristics. Four papers reported 23, 17, 13, and 6 patients, respectively, but with minimal data. One paper reported the authors' own 39 patients' characteristics and demographics. The mean age was 58.2 years with 66% males. The most commonly reported presentations in descending order were fever (91%), cough (36.7%), shortness of breath (SOB) (31.8%), and diarrhea (31.8%). Liver transplant patients infected with COVID-19 were maintained on Tac (79%), mycophenolate (MMF) (48.4%), and Prednisone (29.6%) and were managed by reducing MMF in 14.3% of patients and reducing Tac in 14.3% of patients; 28.6% of patients needed ICU admission, 13.6% of patients had died, and the reported general population COVID-19 mortality rate was 3.4%. The clinical presentation of COVID-19 in liver transplant recipients may be different from the general population, with higher rates of severe disease, complications, and mortality.