Taner, C. Burcin

Importance Normothermic regional perfusion (NRP) is an emerging recovery modality for transplantable allografts from controlled donation after circulatory death (cDCD) donors. In the US, only 11.4% of liver recipients who are transplanted from a deceased donor receive a cDCD liver. NRP has the potential to safely expand the US donor pool with improved transplant outcomes as compared with standard super rapid recovery (SRR). Objective To assess outcomes of US liver transplants using controlled donation after circulatory death livers recovered with normothermic regional perfusion vs standard super rapid recovery. Design, Setting, and Participants This was a retrospective, observational cohort study comparing liver transplant outcomes from cDCD donors recovered by NRP vs SRR. Outcomes of cDCD liver transplant from January 2017 to May 2023 were collated from 17 US transplant centers and included livers recovered by SRR and NRP (thoracoabdominal NRP [TA-NRP] and abdominal NRP [A-NRP]). Seven transplant centers used NRP, allowing for liver allografts to be transplanted at 17 centers; 10 centers imported livers recovered via NRP from other centers. Exposures cDCD livers were recovered by either NRP or SRR. Main Outcomes and Measures The primary outcome was ischemic cholangiopathy (IC). Secondary end points included primary nonfunction (PNF), early allograft dysfunction (EAD), biliary anastomotic strictures, posttransplant length of stay (LOS), and patient and graft survival. Results A total of 242 cDCD livers were included in this study: 136 recovered by SRR and 106 recovered by NRP (TA-NRP, 79 and A-NRP, 27). Median (IQR) NRP and SRR donor age was 30.5 (22-44) years and 36 (27-49) years, respectively. Median (IQR) posttransplant LOS was significantly shorter in the NRP cohort (7 [5-11] days vs 10 [7-16] days; P < .001). PNF occurred only in the SRR allografts group (n = 2). EAD was more common in the SRR cohort (123 of 136 [56.1%] vs 77 of 106 [36.4%]; P = .007). Biliary anastomotic strictures were increased 2.8-fold in SRR recipients (7 of 105 [6.7%] vs 30 of 134 [22.4%]; P = .001). Only SRR recipients had IC (0 vs 12 of 133 [9.0%]; P = .002); IC-free survival by Kaplan-Meier was significantly improved in NRP recipients. Patient and graft survival were comparable between cohorts. Conclusion and Relevance There was comparable patient and graft survival in liver transplant recipients of cDCD donors recovered by NRP vs SRR, with reduced rates of IC, biliary complications, and EAD in NRP recipients. The feasibility of A-NRP and TA-NRP implementation across multiple US transplant centers supports increasing adoption of NRP to improve organ use, access to transplant, and risk of wait-list mortality.

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.

Transplant pathology plays a critical role in ensuring that transplanted organs function properly and the immune systems of the recipients do not reject them. To improve outcomes for transplant recipients, accurate diagnosis and timely treatment are essential. Recent advances in artificial intelligence (AI)-empowered digital pathology could help monitor allograft rejection and weaning of immunosuppressive drugs. To explore the role of AI in transplant pathology, we conducted a systematic search of electronic databases from January 2010 to April 2023. The PRISMA checklist was used as a guide for screening article titles, abstracts, and full texts, and we selected articles that met our inclusion criteria. Through this search, we identified 68 articles from multiple databases. After careful screening, only 14 articles were included based on title and abstract. Our review focuses on the AI approaches applied to four transplant organs: heart, lungs, liver, and kidneys. Specifically, we found that several deep learning-based AI models have been developed to analyze digital pathology slides of biopsy specimens from transplant organs. The use of AI models could improve clinicians’ decision-making capabilities and reduce diagnostic variability. In conclusion, our review highlights the advancements and limitations of AI in transplant pathology. We believe that these AI technologies have the potential to significantly improve transplant outcomes and pave the way for future advancements in this field.

Abstract Background and Aims Individuals who are most susceptible to developing PTLD are those who are EBV-negative and receive organs from EBV-positive donors (EBV R-/D+). The evidence regarding the connection between ATG induction therapy and PTLD is inconsistent. No studies have specifically examined the relationship between ATG use and PTLD in subgroups of EBV-negative transplant recipients (EBV R-). Using the UNOS database, we studied the association between the use of induction agents and PTLD in EBV R- patients. Method We analyzed data from 2007 to 2022 of EBV R- patients who underwent their first kidney-only transplant and excluded those who received induction agents other than ATG, basiliximab, or alemtuzumab. We used logistic regression to evaluate the association between induction agents and PTLD. Results Of 20,531 recipients, 50.7% received ATG, 19.13% received basiliximab, 13.42% received alemtuzumab, and 16.75% received no induction. The overall PTLD incidence was 2.14%. ATG recipients had higher rates of deceased donor transplants, higher degree of HLA mismatch, longer dialysis vintage, and were less likely to be white, compared to non-ATG recipients. Multivariate analysis showed ATG recipients had a higher risk of PTLD compared to non-ATG (odds ratio = 1.47, p<0.001). After excluding recipients who did not receive induction, ATG remained a significant independent risk factor for PTLD when compared to recipients who received either basiliximab or alemtuzumab (odds ratio = 1.35, p = 0.007). There was no statistically significant difference in PTLD risk among patients treated with basiliximab, alemtuzumab, or no induction (refer to Table 1). Conclusion The use of ATG induction in EBV-negative kidney transplant recipients is associated with a higher risk of PTLD compared to basiliximab, alemtuzumab, and no induction. The risk of PTLD should be considered when choosing induction therapy for this patient population.

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.

Background. The age of a liver transplant (LT) candidate is one of many variables used in the transplant selection process. Most research about the age at transplant has used prespecified age ranges or categories in assessing associations with transplant outcomes. However, there is a lack of knowledge about the age at transplant and survival. This study aimed to examine associations of age at transplant as a continuous variable, in conjunction with other patient and disease-related factors, with patient and graft survival after LT. Methods. We used the Standard Transplant Analysis and Research data to identify LT recipients between January 2002 and June 2018. Cox regression models with a restricted cubic spline term for age examined associations with graft and patient survival after LT. We assessed the interactions of age with recipients’ sex, race/ethnicity, region, indication for transplant, body mass index, model for end-stage liver disease score, diabetes, functional status at transplant, and donor risk index. Results. Age at the time of LT showed a nonlinear association with both graft and patient survival. Each demographic, clinical, transplant-related, and donor-related factor influenced these relationships differently. Conclusions. Our results suggest that some older LT candidates may be better than some younger candidates and that clinicians should not exclusively use age to determine who receives LT.