Establishment and validation of a predictive model of immune tolerance after pediatric liver transplantation (ITPLT): A multicenter cohort study.

Side-effect of life-long immunosuppressants (IS) administration is a major obstacle for the long-term survival of pediatric liver transplantation (LT) recipients. Immunotolerance is the status that recipients discontinued IS with normal liver function and intrahepatic histology. So far, only a few clinical parameters were identified related with tolerance but failed to accurately discriminate tolerant recipients in clinical practice. Here we aimed to provide a comprehensive view of pre- and post-LT risk factors associated with the achievement of tolerance after pediatric LT and established a tolerance predictive nomogram (ITPLT) with high accuracy and specificity. We enrolled 2228 pediatric recipients who received LT in XX Hospital between October 2006 and December 2020. All participants survived over 3 years after transplantation with comprehensive and intact medical history and follow-up data. They were randomly assigned to training and validation cohorts in accordance with a ratio of 1:1. Univariate and multivariable Logistic regression were used to identify clinical factors associated with post-LT immune tolerance and establish a predictive model. The model was further validated in an independent external validation cohort from YY Hospital. Among all participants, 6% recipients successfully tapered IS with intact allograft function. The most common reason for IS discontinuity was pneumonia. Univariate analysis identified 15 clinical factors associated with tolerance achievement, including age at LT, follow-up time, preoperative total bilirubin, creatinine, INR, CYP polymorphism, types of transplantation, massive postoperative ascites, episodes of acute rejection, and the severity of EBV and CMV infection. Using multivariable Logistic regression, we established the predictive ITPLT model for post-LT tolerance, which included seven easily accessible clinical factors (age at LT, CYP3A5 genotype, types of transplantation, post-LT massive ascites, preoperative INR, creatinine, and total bilirubin levels). Then we visualized the model using nomogram. The c-statistics for predicting tolerance achievement in the training, internal validation, and external validation cohorts were 0.854, 0.787, and 0.746 respectively. Multiple pre- and post-LT clinical factors affected the process of immune remodeling after pediatric liver transplantation. The predictive ITPLT model, composed of seven easily accessible clinical factors, could comprehensively reveal the effect of these clinical parameters on immune remodeling and accurately identify tolerant recipients after pediatric LT. The application of ITPLT could facilitate the individualized IS strategy in the future.

Long-term outcomes and risk factors for early bacterial infection after pediatric liver transplantation: a prospective cohort study.

BACKGROUND: Liver transplantation (LT) is the most efficient treatment for pediatric patients with end-stage liver diseases, while bacterial infection is the leading reason for posttransplant mortality. The present study is to explore the outcomes and risk factors of early bacterial infection (within 1 mo) after pediatric LT. METHODS: In this prospective cohort study, 1316 pediatric recipients (median [IQR] age: 9.1 [6.3-28.0] months; male: 48.0%; median [IQR] follow-up time: 40.6 [29.1-51.4] months) who received LT from September 2018 to April 2022 were included. Bacterial culture samples such as sputum, abdominal drainage, blood and so on were collected when recipients were presented with infective symptoms. Kaplan-Meier analysis was applied to estimate the long-term survival rates and logistic regression was used to identify independent risk factors. To explore the role of pretransplant rectal swab culture (RSC) in reducing posttransplant bacterial infection rate, 188 infant LT recipients (median [IQR] age: 6.8 [5.5-8.1] months; male: 50.5%) from May 2022 to September 2023 were included. Log-binomial regression was used to measure the association of pretransplant RSC screening and posttransplant bacterial infection. The "Expectation Maximization" algorithm was used to impute the missing data. RESULTS: Bacterial infection was the primary cause for early (38.9%) and overall mortality (35.6%) after pediatric LT. Kaplan-Meier analysis revealed inferior 1- and 5-year survival rates for recipients with posttransplant bacterial infection (92.6% vs. 97.1%, 91.8% vs. 96.4% respectively; P<0.001). Among all detected bacteria, Staphylococcus spp. (34.3%) and methicillin-resistant coagulase-negative Staphylococci (43.2%) were the dominant species and multi-drug resistant organisms, respectively. Multivariable analysis revealed that infant recipients (adjusted odds ratio [aOR], 1.49; 95% CI, 1.01-2.20), male recipients (aOR, 1.43; 95% CI, 1.08-1.89), high graft-to-recipient weight ratio (aOR, 1.64; 95% CI, 1.17-2.30), positive posttransplant RSC (aOR, 1.45; 95% CI, 1.04-2.02) and nasopharyngeal swab culture (aOR 2.46; 95% CI, 1.72-3.52) were independent risk factors for early bacterial infection. Furthermore, RSC screening and antibiotic prophylaxis before transplantation could result in a relatively lower posttransplant infection rate, albeit without statistical significance (adjusted RR, 0.53; 95% CI, 0.25-1.16). CONCLUSION: In this cohort study, posttransplant bacterial infection resulted in an inferior long-term patient survival rate. The five identified independent risk factors for posttransplant bacterial infection could guide the prophylaxis strategy of posttransplant bacterial infection in the future. Additionally, pretransplant RSC might decrease posttransplant bacterial infection rate.

Cellular strategies to induce immune tolerance after liver transplantation: Clinical perspectives.

Liver transplantation (LT) has become the most efficient treatment for pediatric and adult end-stage liver disease and the survival time after transplantation is becoming longer due to the development of surgical techniques and perioperative management. However, long-term side-effects of immunosuppressants, like infection, metabolic disorders and malignant tumor are gaining more attention. Immune tolerance is the status in which LT recipients no longer need to take any immunosuppressants, but the liver function and intrahepatic histology maintain normal. The approaches to achieve immune tolerance after transplantation include spontaneous, operational and induced tolerance. The first two means require no specific intervention but withdrawing immunosuppressant gradually during follow-up. No clinical factors or biomarkers so far could accurately predict who are suitable for immunosuppressant withdraw after transplantation. With the understanding to the underlying mechanisms of immune tolerance, many strategies have been developed to induce tolerance in LT recipients. Cellular strategy is one of the most promising methods for immune tolerance induction, including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory immune cells. The safety and efficacy of various cell products have been evaluated by prospective preclinical and clinical trials, while obstacles still exist before translating into clinical practice. Here, we will summarize the latest perspectives and concerns on the clinical application of cellular strategies in LT recipients.

Adenosinergic metabolism pathway: an emerging target for improving outcomes of solid organ transplantation.

Extracellular nucleotides are widely recognized as crucial modulators of immune responses in peripheral tissues. Adenosine triphosphate (ATP) and adenosine are key components of extracellular nucleotides, the balance of which contributes to immune homeostasis. Under tissue injury, ATP exerts its pro-inflammatory function, while the adenosinergic pathway rapidly degrades ATP to immunosuppressive adenosine, thus inhibiting excessive and uncontrolled inflammatory responses. Previous reviews have explored the immunoregulatory role of extracellular adenosine in various pathological conditions, especially inflammation and malignancy. However, current knowledge regarding adenosine and adenosinergic metabolism in the context of solid organ transplantation remains fragmented. In this review, we summarize the latest information on adenosine metabolism and the mechanisms by which it suppresses the effector function of immune cells, as well as highlight the protective role of adenosine in all stages of solid organ transplantation, including reducing ischemia reperfusion injury during organ procurement, alleviating rejection, and promoting graft regeneration after transplantation. Finally, we discuss the potential for future clinical translation of adenosinergic pathway in solid organ transplantation.