Taner, Burcin

Hepatic steatosis, characterized by the accumulation of triacylglycerol in hepatocytes, complicates liver transplantation by increasing the risk of ischemia-reperfusion injury (IRI), leading to suboptimal graft outcomes. This condition has become a major cause of liver graft discarding, exacerbating the ongoing organ shortage for transplantation. Recent advances in ex vivo normothermic perfusion machines (NMPs) have provided promising solutions for reconditioning and preserving steatotic liver. NMP supports cellular metabolism and mitigates IRI by maintaining the physiological conditions. In addition, pharmacological strategies to reduce hepatic steatosis have been explored to increase graft viability. In this review, we summarize current insights into hepatic lipid metabolism and the molecular mechanisms underlying steatosis, while discussing emerging pharmacological defatting approaches. These interventions have the potential to address the challenges posed by hepatic steatosis, improve graft quality, expand the availability of transplantable livers, and enhance clinical outcomes of transplant candidates. Finally, we highlight current limitations and outline directions for future research and clinical applications.

Extracorporeal membrane oxygenation (ECMO) use during liver transplantation is a complex and evolving aspect of critical care. This retrospective analysis presents the largest North American case series to date, offering a detailed comparison of survival outcomes in liver transplant (LT) patients supported by ECMO. A total of 15 patients were supported with ECMO, eight were supported on venoarterial (VA) ECMO and the remaining seven on venovenous (VV) ECMO. The median duration of ECMO support was 10 days. Mean intensive care unit (ICU) and hospital stays were 34.8 (interquartile range [IQR]: 1–158) and 49.2 days (IQR: 1–121), respectively. Overall survival was 33.3%, comparable to published rates (20–30%). Survival was based on ECMO initiation timing: preoperative 33.3% (1/3); intraoperative 50% (3/6); postoperative, 16.6% (1/6). All the patients (five) discharged from hospital were alive at 1 year follow-up. Significant ECMO-related complications included acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) (40%, n = 6/15), neurological complications (40%, n = 6/15), and bleeding requiring transfusion (26.6%, n = 4/15). Literature review suggests better outcomes with intraoperative or postoperative ECMO. While ECMO use is increasing in LT, outcomes remain poor. Improved survival may depend on careful patient selection, optimal timing of initiation, and distinguishing reversible pathology from irreversible one.

Despite European colorectal liver metastases (CRLM) transplant trials having been performed entirely using deceased donor liver transplant (DDLT), there has been speculation about whether similar results can be achieved in the United States, given the lack of MELD score prioritization. A formal transplant protocol for unresectable CRLM was implemented in our center at the start of 2022 with the plan to utilize DDLT. Between 2022 and 2025, 86 patients with CRLM were referred to our program, and 19 patients underwent a formal transplant evaluation. Median time from listing until transplant was 31 days (range 3–115 d). Median allocation MELD was 8 (range 6–15). The donor livers were from DCDs, older donors, or National Share livers, which had been declined by all other centers. All but 2 of the cases underwent advanced perfusion. There were no cases of primary nonfunction, postreperfusion syndrome, acute kidney injury, hepatic artery thrombosis, or ischemic cholangiopathy. The length of stay for the median posttransplant was 5 days. Graft and patient survival were 100% at the time of maximal follow-up. Recurrence developed in 3 recipients (25.0%), 1 of whom was treated and has no evidence of disease. These findings support the viability of DDLT for CRLM using advanced perfusion, contingent on strict protocol adherence. Center-specific waitlist dynamics must inform the choice between DDLT and living donor liver transplant (LDLT).

ABSTRACTBackground and AimsOne strategy to minimize the risk of posttransplant lymphoproliferative disorder (PTLD) is to avoid an Epstein–Barr Virus (EBV) mismatch through kidney paired donation. We aimed to estimate the incidence of PTLD in EBV‐negative kidney transplant recipients with EBV‐positive donors (D+/R−) and evaluate the excess risk of death following the occurrence of PTLD.MethodsWe included adult patients in OPTN database who underwent kidney transplants between 2012 and 2022. Cox regression analysis was employed to evaluate the impact of EBV serostatus on the development of PTLD, and to assess mortality following PTLD diagnosis in D+/R− individuals.ResultsA total of 179 068 patients were included, with 92.8% in the R+, 6.4% in the D+/R−, and 0.8% in the D−/R− group. D+/R− exhibited a significantly higher risk of PTLD compared to R+ and D−/R− groups. D+/R− had a greater risk of PTLD when compared to D−/R− recipients (aHR: 3.82; p < 0.001). Among D+/R− recipients, those who developed PTLD had a significantly higher risk of mortality (aHR: 2.28; p < 0.001 in deceased donor kidney transplant [DDKT] and aHR: 5.22; p < 0.001 in living donor kidney transplant [LDKT]).ConclusionsD+/R− recipients have nearly a fourfold higher risk of PTLD compared to D−/R− recipients, suggesting that choosing an EBV D−/R− transplant could reduce the PTLD risk by about 73%. This data is crucial for counseling EBV‐negative patients considering kidney paired donation to avoid an EBV serostatus mismatch.

There is a paucity of data on the impact of cold ischemia time before the initiation of normothermic machine perfusion (NMP), particularly in more susceptible organs such as livers from donation after circulatory death (DCD) donors. The present analysis aimed to investigate the impact of prolonged time from cross-clamp until NMP start on early allograft dysfunction and other peri–liver transplant (LT) outcomes. All DCD LT performed and placed on NMP at Mayo Clinic Arizona, Florida, and Rochester from January 2022 to March 2024 were included. The decision was made a priori to divide the population into 2 groups based on terciles: typical cross-clamp to on-pump time (lower 2 terciles) versus prolonged cross-clamp to on-pump time (upper tercile; >2 h 45.6 min). Three hundred eighty-four DCD LT undergoing NMP met the inclusion criteria. The rate of early allograft dysfunction was significantly higher in the prolonged cross-clamp to on-pump group (51.2%) compared to the typical cross-clamp to on-pump group (37.6%) (p = 0.01). The prolonged cross-clamp to on-pump group also had higher rates of acute kidney injury and the number of packed red blood cells transfused during LT. No significant difference in ischemic cholangiopathy (2.4% vs. 3.1%; p = 0.68) or graft survival at 12 months was seen between the prolonged cross-clamp to on-pump and typical cross-clamp to on-pump group, respectively. Following cross-clamp, DCD liver grafts should be placed on the NMP pump as quickly as is safely and logistically possible. In cases where delays are unavoidable, such as waiting for biopsy results or liver reallocation with another center, acceptable results can still be achieved, and therefore, livers with prolonged times should still be used.

INTRODUCTION: Liver disease is a significant public health problem in the United States, with notable racial disparities in mortality. This study examines liver disease mortality trends among Black and White populations during 1999–2020. METHODS: We used CDC WONDER database to ascertain liver disease age-standardized mortality rates in Black and White Americans. Annual percent change was calculated. Age-standardized absolute rate difference and rate ratios were computed by subtracting and dividing the White population's rate from that of the Black population. RESULTS: Liver diseases accounted for 171,627 Black and 1,314,903 White deaths during 1999–2020. Age-standardized mortality rates for Blacks decreased from 22.5 to 20.1 per 100,000 person-years (annual percentage change −0.4%, −0.6% to −0.2%), whereas an increase was observed for Whites, from 17.9 to 25.3 per 100,000 person-years (annual percentage change 1.4%, 1.4% to 1.7%). The rate ratio decreased from 1.26 (1.22–1.29) in 1999 to 0.79 (0.78–0.81) in 2020. This pattern was evident in all census regions, more pronounced among the younger (age 25–64 years) than older (age 65+ years) population and observed across different urbanization levels. The pattern may be attributable to increasing alcohol-related liver disease and metabolic dysfunction–associated steatotic liver disease–related deaths in Whites and tapering in viral hepatitis and primary liver cancer–related deaths in Blacks. Despite notable improvement, racial disparities persist in primary liver cancer and viral hepatitis among the Black population. DISCUSSION: The rise in alcohol-related liver disease and metabolic dysfunction–associated steatotic liver disease–related deaths among Whites, and enduring liver cancer and viral hepatitis disparities in the Black population, underscores the urgent need for tailored public health interventions.

In situ abdominal normothermic regional perfusion (A-NRP) has been used for liver transplantation (LT) with donation after circulatory death (DCD) liver grafts in Europe with excellent results; however, adoption of A-NRP in the United States has been lacking. The current report describes the implementation and results of a portable, self-reliant A-NRP program in the United States. Isolated abdominal in situ perfusion with an extracorporeal circuit was achieved through cannulation in the abdomen or femoral vessels and inflation of a supraceliac aortic balloon and cross-clamp. The Quantum Transport System by Spectrum was used. The decision to use livers for LT was made through an assessment of perfusate lactate (q15min). From May to November 2022, 14 A-NRP donation after circulatory death procurements were performed by our abdominal transplant team (N = 11 LT, N = 20 kidney transplants, and 1 kidney-pancreas transplant). The median A-NRP run time was 68 minutes. None of the LT recipients had post-reperfusion syndrome, nor were there any cases of primary nonfunction. All livers were functioning well at the time of maximal follow-up with zero cases of ischemic cholangiopathy. The current report describes the feasibility of a portable A-NRP program that can be used in the United States. Excellent short-term post-transplant results were achieved with both livers and kidneys procured from A-NRP.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22–1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04–1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35–1.73, p < 0.001), microvascular (HR = 2.37, 95%–CI, 1.87–2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41–4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29–2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54–3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

NAFLD will soon be the most common indication for liver transplantation (LT). In NAFLD, HCC may occur at earlier stages of fibrosis and present with more advanced tumor stage, raising concern for aggressive disease. Thus, adult LT recipients with HCC from 20 US centers transplanted between 2002 and 2013 were analyzed to determine whether NAFLD impacts recurrence-free post-LT survival. Five hundred and thirty-eight (10.8%) of 4981 total patients had NAFLD. Patients with NAFLD were significantly older (63 vs. 58, p<0.001), had higher body mass index (30.5 vs. 27.4, p<0.001), and were more likely to have diabetes (57.3% vs. 28.8%, p<0.001). Patients with NAFLD were less likely to receive pre-LT locoregional therapy (63.6% vs. 72.9%, p<0.001), had higher median lab MELD (15 vs. 13, p<0.001) and neutrophil-lymphocyte ratio (3.8 vs. 2.9, p<0.001), and were more likely to have their maximum pre-LT alpha fetoprotein at time of LT (44.1% vs. 36.1%, p<0.001). NAFLD patients were more likely to have an incidental HCC on explant (19.4% vs. 10.4%, p<0.001); however, explant characteristics including tumor differentiation and vascular invasion were not different between groups. Comparing NAFLD and non-NAFLD patients, the 1, 3, and 5-year cumulative incidence of recurrence (3.1%, 9.1%, 11.5% vs. 4.9%, 10.1%, 12.6%, p=0.36) and recurrence-free survival rates (87%, 76%, and 67% vs. 87%, 75%, and 67%, p=0.97) were not different. In competing risks analysis, NAFLD did not significantly impact recurrence in univariable (HR: 0.88, p=0.36) nor in adjusted analysis (HR: 0.91, p=0.49). With NAFLD among the most common causes of HCC and poised to become the leading indication for LT, a better understanding of disease-specific models to predict recurrence is needed. In this NAFLD cohort, incidental HCCs were common, raising concerns about early detection. However, despite less locoregional therapy and high neutrophil-lymphocyte ratio, explant tumor characteristics and post-transplant recurrence-free survival were not different compared to non-NAFLD patients.