INTRODUCTION:Hepatic artery thrombosis (HAT) is a leading cause of graft loss after liver transplantation. While aspirin is used for prophylaxis, its benefit is debated due to potential bleeding risks. We performed a systematic review and meta-analysis to assess the efficacy and safety of aspirin prophylaxis in liver transplant recipients. METHODS:We searched PubMed, Embase, and Cochrane Library for studies comparing aspirin prophylaxis to no aspirin. We computed risk ratios (RR) for binary outcomes, with 95% confidence intervals (CIs), and assessed heterogeneity using I2 statistics. RESULTS:We included five studies with 4983 patients (2299 on aspirin). Aspirin significantly reduced HAT risk (RR 0.47; 95% CI: 0.24-0.94; p = 0.03) without increasing major bleeding risk (RR 0.81; 95% CI: 0.54-1.22; p = 0.31). Graft survival was higher in the aspirin group at 1 year (RR 1.06; p = 0.003) and 5 years (RR 1.06; p < 0.0001). Aspirin also reduced the incidence of acute cellular rejection at 1 year (RR 0.71; p = 0.03). CONCLUSION:Our meta-analysis suggests that aspirin prophylaxis after liver transplantation may reduce the incidence of hepatic artery thrombosis, particularly among high-risk patients, without a significant increase in major bleeding events.

Background:Combined lung+liver transplant (CLLT) is a rare procedure for patients with end-stage lung and liver failure, but has recently gained traction, with many academic centers performing CLLT for the first time. This study describes the state of CLLT in the United States and assesses outcomes. Methods:The United Network for Organ Sharing Database was queried for all CLLT between October 1994 and March 2024. Transplant sequence was determined by utilizing individual organ ischemic times. Cumulative risk was assessed to determine primary causes of graft failure or death after CLLT, and risk stratification was defined based on patient survival status, lung-graft status, or liver-graft status. Posttransplant survival was further assessed utilizing Kaplan-Meier survival analysis. Results:A total of 193 CLLTs were analyzed across 39 centers. The number of CLLTs has increased over the last decade. Most of the transplants were lung(s) followed by liver (157 of 179, 87.7%). Most were male (121 of 179, 67.6%), and the median age at transplant was 47 years (interquartile range, 25-59 years). Kaplan-Meier survival at 1 month, 6 months, 1 year, 3 years, 5 years, and 10 years was: 96.3% (95% CI, 92.6%-99.0%), 85.1% (95% CI, 80.1%-90.5%), 81.5% (95% CI, 76.0%-87.4%), 70.4% (95% CI, 63.7%-77.9%), 63.2% (95% CI, 55.7%-71.6%), and 53.3% (95% CI, 44.1%-64.3%). No difference was evident in survival between lung-first or liver-first sequences. Most deaths were due to non-graft-related causes. Conclusions:CLLT is growing in popularity and serves as a viable option for patients with combined end-stage lung disease and end-stage liver disease. CLLT shows excellent longitudinal survival. No difference exists in survival between a lung-first approach and a liver-first approach. Most deaths after CLLT are unrelated to liver-graft or lung-graft failure.

ObjectivesReview our clinical experience with eight patients at the University of Florida undergoing En-bloc combined heart+liver transplantation (ECH + LTX).MethodsContinuous variables are reported as median (interquartile range = IQR) and categorical variables are reported as N (%).ResultsEight patients underwent ECH + LTX between August 2020 and May 2023 at the University of Florida, with triple heart+liver+kidney transplantation performed in 2/8 = 25%. Median age at ECH + LTX was 47.34 years (IQR = 33.66-53.37), and all eight patients were >18 years of age. Six out of eight patients (75%) had congenital heart disease (CHD): one had biventricular CHD and five had functionally univentricular circulation and Fontan failure. Two out of eight patients (25%) had structurally normal hearts and acquired heart disease: one patient with hemochromatosis and combined cardiac and hepatic failure with nonischemic restrictive cardiomyopathy and one patient with nonischemic cardiomyopathy and alcoholic cirrhosis. Median wait list time was 93 days (IQR = 27.50-176.25). Three patients (3/8 = 37.5%) were supported with an intra-aortic balloon pump prior to ECH + LTX, and two of these three patients were subsequently also supported with extracorporeal membrane oxygenation secondary to progressive decompensation prior to ECH + LTX. Median hospital length of stay was 147 days. Median posttransplant length of stay was of 29 days. Seven of eight patients survived ECH + LTX and are alive today. One patient died two days after ECH + LTX. Mean length of follow-up after ECH + LTX of seven surviving patients (years) is 3.60 ± 0.38 (median = 3.79, IQR = 3.05-4.38, range = 1.91-4.64).ConclusionEn-bloc heart-liver transplantation is an effective treatment option for patients with combined heart and liver failure.

Background Intestinal transplantation (IT) is a complex procedure that requires nuanced immunosuppressive strategies to optimize patient outcomes. Despite advancements, significant variability remains in immunosuppressive protocols across transplant centers due to a lack of consensus on the optimal approaches for induction, maintenance, and clinical testing. This variability complicates standardization and identification of best practices for IT recipients. Methods A descriptive survey study was conducted to characterize immunosuppressive and testing strategies in IT at major transplant centers in the United States. Ten centers known to have performed over 10 ITs since 2015 were selected from the Scientific Registry of Transplant Recipients database. A 22-question survey was distributed to surgical directors, collecting data on pre-, peri-, and post-transplant immunological testing, desensitization strategies, immunosuppressive regimens, and management of antibody-mediated rejection (AMR) and acute cellular rejection (ACR). Results Nine centers (90%) responded. All centers conducted pretransplant human leukocyte antigen (HLA) and donor-specific antibody (DSA) testing, with varying frequencies and methodologies. Desensitization was reported by 44% of centers for isolated IT and by 22% for multivisceral transplants. Induction therapy predominantly involved antithymocyte globulin (89%) and rituximab (44%). Tacrolimus was universally used for maintenance, with varying trough level targets across centers. Post-transplant DSA testing was performed by all centers, and protocol-driven endoscopic bowel biopsies were routine at 67% of centers. AMR was diagnosed at 89% of centers, with plasmapheresis and IVIG being the most common treatments. Variability was noted in desensitization practices and AMR management. Conclusion This survey highlights considerable consistency in pre- and post-transplant testing and immunosuppressive regimens for IT recipients, while significant variability exists in desensitization strategies and AMR management. Further research is needed to standardize these practices to improve patient outcomes across transplant centers

Background. Hypothermic machine perfusion (HMP) has greatly improved kidney allograft preservation. However, tissue damage still occurs during HMP, affecting posttransplant graft function. Therefore, better methods are needed to continuously assess organ quality and to predict posttransplant graft function and survival. We propose that soluble DNA (sDNA) concentration in HMP perfusate can be used as a noninvasive biomarker for this purpose. Methods. Perfusate samples of kidney grafts placed on HMP were collected 5 min after the initiation of HMP and again at the conclusion of HMP. sDNA of nuclear origin from the perfusate was quantified by real-time polymerase chain reaction and correlated with HMP parameters and posttransplant clinical outcomes. Results. Kidney grafts from 52 deceased donors placed on HMP were studied. Perfusate sDNA concentration was significantly higher in transplanted kidneys with delayed graft function. Higher concentrations of perfusate sDNA at 5 min and at HMP conclusion were also correlated with lower graft function in the initial posttransplant period, as measured by postoperative day 2, 3, and 4 creatinine reduction ratios. Standard pump parameters such as renal vascular resistance and renal vascular flow were poor indicators of early posttransplant graft function. Conclusions. sDNA concentration in HMP perfusate of kidney grafts can indicate the quality of kidney graft preservation and predict posttransplant renal function. This biomarker should be explored further to improve renal organ assessment and transplantation outcomes.

Tacrolimus is the most commonly used immunosuppression drug after solid organ transplantation; however, its dosing is challenging due to substantial inter-individual variability, often resulting in blood levels that deviate from the target therapeutic range. We explored whether a dynamically customized, phenotypic-outcome-guided drug dosing method could improve maintenance of drug trough levels within pre-determined target ranges, focusing on tacrolimus immediately after liver transplantation. This single-center, partially blinded, completed clinical trial involved 62 adults undergoing liver transplantation, block randomized into parallel groups: standard-of-care (SOC) clinician-determined or Phenotypic Personalized Medicine (PPM)-guided tacrolimus dosing. The primary outcome was percentage of post-transplant days with large (>2 ng/mL) deviations from the target range. At trial completion, analysis found statistically significant improvement in the PPM group (n = 27): 24.2% of days showing large deviations compared to 38.4% in the SOC group (n = 29) (difference -14.2%, 95% CI: -26.7 to -1.5 %, P = 0.029) with no increase in adverse events. These results demonstrate that PPM-guided tacrolimus dosing more effectively maintains drug levels within the target range compared to SOC, suggesting a promising approach to improving drug dosing. The trial was registered at ClinicalTrials.gov with the identifier NCT03527238.

This review delves into the complexities of managing portal vein thrombosis (PVT) in the context of liver transplantation (LT). PVT, which is a common finding in cirrhotic livers, can significantly jeopardize LT outcomes. Here, we explore the incidence, underlying mechanisms, and comprehensive management strategies for PVT throughout the pre-, intra-, and postoperative phases of LT in cirrhotic patients. Before transplantation, key interventions include anticoagulation therapies, transjugular intrahepatic portosystemic shunts (TIPS), and various endovascular techniques aimed at recanalizing the portal vein. During LT, surgical approaches range from straightforward eversion thrombectomy to more intricate procedures, such as jump grafts from the superior mesenteric vein (SMV), renoportal anastomosis (RPA), and portocaval hemitransposition, tailored to the extent of the thrombosis. In cases of extensive PVT, multivisceral transplantation (MVT) emerges as a viable option. Post-transplant management centers on thromboprophylaxis and anticoagulation, balancing the prevention of thrombotic events with the risk of bleeding complications. This review underscores the critical importance of early identification and proactive management of PVT to enhance outcomes for LT candidates.

BACKGROUND: Noninvasive, precision monitoring of hepatocellular carcinoma (HCC) treatment efficacy would greatly facilitate personalized therapy and improve patient outcomes. We hypothesize that quantifying methylated circulating tumor DNA (ctDNA) can be used to effectively monitor HCC burden without the need for biopsy. STUDY DESIGN: Blood samples were collected from 25 patients, 21 with HCC and 4 with benign liver masses, at various timepoints throughout the course of treatment at a high-volume academic medical center. Quantification of methylated ctDNA molecules assessed CpG sites on more than 550 preselected cancer-specific amplicons. The tumor methylation score (TMS) was calculated by measuring the difference between the amount of methylation in the plasma and buffy coat with a normal cutoff value of 120 or less. RESULTS: Among 10 patients with surgical HCC (5 surgical resections and 5 liver transplants), TMS revealed a statistically significant, rapid postoperative decline in 9. One patient who had a persistently elevated TMS on postoperative day 1 was subsequently found to have had metastatic disease. Patients in the negative control cohort all had normal-range pre- and postoperative TMS. Preoperative TMS correlated moderately with tumor burden on pathology (Spearman r = 0.54) of surgical specimens. From 11 subjects undergoing systemic therapy or Y90 radioembolization, analysis of 16 time periods demonstrated that the change in TMS (ΔTMS) was better associated with tumor progression than the change in Δalpha-fetoprotein (area under the curve 0.800 and 0.783, respectively). A composite score combining ΔTMS and Δalpha-fetoprotein further improved performance for detecting tumor progression with an area under the curve of 0.892. CONCLUSIONS: These findings indicate that ctDNA methylation scores can effectively evaluate changes in tumor burden without the need for tumor biopsy.

BACKGROUND:Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by misfolding and accumulation of mutant alpha-1 antitrypsin (ZAAT) in the endoplasmic reticulum of hepatocytes. Hepatic ZAAT aggregates acquire a toxic gain-of-function that impacts the endoplasmic reticulum which is theorized to cause liver disease in individuals with AATD who present asymptomatic until late-stage cirrhosis. Currently, there is no treatment for AATD-mediated liver disease except liver transplantation. In our study of mitochondrial RNA, we identified that Sirtuin3 (SIRT3) plays a role in the hepatic phenotype of AATD. METHODS:Utilizing RNA and protein analysis in an in vitro AATD model, we investigated the role of SIRT3 in the pathophysiology of AATD-mediated liver disease while also characterizing our novel, transgenic AATD mouse model. RESULTS:We show lower expression of SIRT3 in ZAAT-expressing hepatocytes. In contrast, the overexpression of SIRT3 increases hepatic ZAAT degradation. ZAAT degradation mediated by SIRT3 appeared independent of proteasomal degradation and regular autophagy pathways. We observed that ZAAT-expressing hepatocytes have aberrant accumulation of lipid droplets, with ZAAT polymers localizing on the lipid droplet surface in a direct interaction with Perilipin2, which coats intracellular lipid droplets. SIRT3 overexpression also induced the degradation of lipid droplets in ZAAT-expressing hepatocytes. We observed that SIRT3 overexpression induces lipophagy by enhancing the interaction of Perilipin2 with HSC70. ZAAT polymers then degrade as a consequence of the mobilization of lipids through this process. CONCLUSIONS:In this context, SIRT3 activation may eliminate the hepatic toxic gain-of-function associated with the polymerization of ZAAT, providing a rationale for a potential novel therapeutic approach to the treatment of AATD-mediated liver disease.

A combined heart+liver transplant is the only option for survival in some patients with end-stage combined cardiac and hepatic disease. These patients may suffer from congenital or acquired cardiac disease. The potential aetiologies of the associated hepatic disease are heterogeneous and include systemic disease that impacts the liver as well as venous congestion in patients with functionally univentricular circulation. In the latter scenario, patients with functionally univentricular circulation often require complex cardiac reconstruction in the setting of a cardiac transplant after staged palliation. During cardiac procurement, our approach is to dissect the entire ascending aorta and aortic arch in continuity; the entire superior caval vein and innominate vein in continuity; and the pulmonary arteries from hilum to hilum if the donor is not a candidate for recovery of the lungs. The cardiac and abdominal organ procurement teams work in parallel during dissection and combined en bloc cardio-hepatectomy. This technique minimizes exposure of both organs to cold ischaemia. This video tutorial demonstrates the key steps for combined en bloc heart+liver organ procurement.