This review provides a summary of the diagnostic approach to pediatric liver transplantation (LT) pathology. It emphasizes the pathologic features of T-cell-mediated rejection, the most common finding on liver allograft biopsies, and discusses other forms of rejection, including the less frequent antibody-mediated rejection. The article incorporates insights from the recently published Banff 2022 Liver Group Meeting Report. Additionally, it covers other complications such as biliary and vascular issues, infections, and disease recurrence. Finally, the review summarizes the potential applications of novel technologies, including next-generation pathology and artificial intelligence, in the context of pediatric LT pathology.

Lymphocytes are widely recognized as the primary mediators of cellular rejection post-liver transplantation. However, conventional immunosuppressive regimens that target lymphocytes, such as calcineurin phosphatase inhibitors, corticosteroids, or lymphocyte-depleting antibodies, can only partially mitigate rejection while inducing severe adverse effects. This necessitates the search for novel immunotherapeutic targets.

We harnessed the power of single-cell RNA sequencing and spatial transcriptome in 24 rat transplanted liver and peripheral blood single nucleated cells (PBMCs) samples to derive gene expression signatures recapitulating 13 cell phenotypes. We used flow cytometry, multifactor assays and multiple recombinant assays to validate in vitro and in vivo the role of the target protein Resistin on human T-cell function, as well as the Resistin-CAP1 interaction. Gold nanoparticles were used to package Retn siRNA sequences to validate the role of Retn knockdown on acute rejection after liver transplantation.

By distinguishing between donor and recipient cells, we delineate the dynamic landscape of immune cells during allograft rejection and their spatial distributions across donors and recipients. Our findings underscore the pivotal role of recipient derived intermediate monocytes in cellular rejection. Using CellChat ligand-receptor analysis, we identify the Resistin-CAP1 pathway as a key mechanism by which intermediate monocytes participate in T cell-mediated rejection reactions. We confirm that Resistin knockdown significantly alleviates acute rejection after rat liver transplantation, markedly extending the survival of recipients using innovative nanogold technology.

These findings offer insights into the dynamic changes in the alloimmune microenvironment, pinpointing intermediate monocytes as potential diagnostic and immunotherapeutic targets during allograft rejection. This study holds significant importance in advancing non-invasive diagnostic technologies and immunotherapeutic strategies for allogeneic rejection.

This study pioneers the application of spatial transcriptomics in liver transplantation, providing a comprehensive analysis of immune cell spatial distribution, complemented by Souporcell-based chimerism assessment. We demonstrate that intermediate monocytes play a pivotal role in T cell-mediated acute rejection via the Resistin-CAP1 signaling axis. Targeting this pathway using nanogold-siRNA technology effectively mitigates rejection and enhances graft survival. These findings contribute novel insights into the mechanisms of transplant rejection and present promising avenues for the development of targeted therapeutic and diagnostic strategies in liver transplantation.

Liver transplantation (LT) is the ultimate treatment for patients with end-stage liver disease or early hepatocellular carcinoma. In the context of LT, because of the unique immunological characteristics of human liver allograft, 5%-20% of selected LT recipients can achieve operational tolerance. Nonetheless, there remains a risk of rejection in LT patients. Maintaining immune homeostasis is thus crucial for improving clinical outcomes in these patients. In mechanism, several immune cells, including dendritic cells, Kupffer cells, myeloid-derived suppressor cells, hepatic stellate cells, regulatory B cells, and CD4 + regulatory T cells (Treg), contribute to achieving tolerance following LT. In terms of Treg, it plays a role in successfully minimizing immunosuppression or achieving tolerance post-LT while also reducing the risk of rejection. Furthermore, the gut microbiome modulates systemic immune functions along the gut-liver axis. Recent studies have explored changes in the microbiome and its metabolites under various conditions, including post-LT, acute rejection, and tolerance. Certain functional microbiomes and metabolites exhibit immunomodulatory functions, such as the augmentation of Treg, influencing immune homeostasis. Therefore, understanding the mechanisms of tolerance in LT, the role of Treg in tolerance and rejection, as well as their interactions with gut microbiome, is vital for the management of LT patients.

Interleukin-21 (IL-21) is a cytokine that plays a crucial role in regulating immune responses, affecting various immune cell types, including T cells, B cells, natural killer (NK) cells, and dendritic cells. IL-21 is primarily produced by CD4+ T cells, particularly follicular helper T (Tfh) cells and Th17 cells, and has been shown to be extensively involved in regulating both innate and adaptive immunity. IL-21 is particularly significant in the differentiation, proliferation, and effector functions of T cells and B cells. In the context of organ transplantation, IL-21 contributes to the promotion of acute transplant rejection and the development of chronic rejection, which is primarily antibody-mediated. This review summarizes relevant studies on IL-21 and discusses its multifaceted roles in transplant immune rejection, providing insights into therapeutic strategies for either inhibiting graft rejection or promoting tolerance. It also explores the feasibility of blocking the IL-21 signaling pathway within current immunosuppressive regimens, aiming to provide further clinical references.

In solid organ transplantation, especially renal transplantation, for the induction of immune tolerance, accumulating evidence has revealed that Regulatory B cells (Breg) play a crucial role in stimulating immune tolerance, alleviating immune responses, and improving graft survival. We describe the heterogeneous nature of Bregs, focusing on their defining surface markers and regulatory functions. Meanwhile, the major cytokine secretion function and the correlation between Breg and Treg or other immune checkpoints to balance the immune responses are addressed. Furthermore, we summarized the intrinsic and extrinsic pathways or costimulatory stimuli for the differentiation from naïve B cells. More importantly, we summarized the progression of the immune tolerance induction role of Breg in solid organ (kidney, liver, heart, lung, and islet) transplantation. This is an up-to-date review from the origin of Breg to the function of Breg in solid organ transplantation and how it induces immune tolerance in both murine models and human solid organ transplantation.

Annually, approximately 3.5 % of the world's population dies of cirrhosis or liver cancer, and the burden of liver disease is steadily expanding owing to multiple factors such as alcohol consumption, irrational diets, viral transmission, and exposure to drugs and toxins. However, the lack of effective therapies and the adverse effects of some medications remain a threat to the management of liver disease. Recently, immunometabolism, as an emerging discipline, appears to be the focus of unprecedented research. As a natural metabolite that regulates cellular functions, itaconate is a crucial bridge connecting metabolism and immune response. Remodeling immune function through metabolic modulation may be a promising alternative for disease intervention strategies. In this review, we first briefly describe the historical origin of itaconate and the development of its derivatives. This was followed by a review of the molecular mechanisms by which itaconate regulated immune-metabolic responses. Furthermore, we analyzed the effects of itaconate regulation on immune cells of the hepatic system. Finally, we summarized the experimental evidence for itaconate and its derivatives in the therapeutic application of liver diseases. Itaconate is potentially an invaluable component of emerging therapeutic strategies for liver disease.

T cell-mediated rejection (TCMR) is a major concern following liver transplantation (LT), and identifying its predictors could help improve post-transplant prognosis. This study aimed to develop a model to predict the risk of TCMR in children and adults after LT.

Pre-transplant demographic characteristics, intraoperative parameters, and especially early post-transplant laboratory data for 1221 LT recipients (1096 adults and 125 children) were obtained from the Hospital, University, between 1 January 2015, and 1 January 2022. These data were analyzed to develop the prediction model.

The incidence of TCMR was higher in pediatric LT recipients than in adults (17.6% vs. 6.4%, P < 0.001). In adult recipients, seven predictors were identified: donor sex, recipient age, recipient height, and post-transplant levels of serum direct bilirubin, urea, platelets, and neutrophil-to-lymphocyte ratio. In pediatric recipients, four predictors were identified: post-transplant levels of serum monocyte percentage, direct bilirubin, albumin, and gamma-glutamyl transferase. The area under the model's curve incorporating these variables for predicting TCMR after LT was 0.713 (95% confidence interval, CI: 0.655-0.770) in adults and 0.786 (95% CI: 0.675-0.896) in children. Decision curve analyses demonstrated the clinical significance of the model.

This study developed a prediction model that may be useful in identifying high-TCMR-risk populations in both adult and pediatric LT recipients.

Liver transplantation (LT) is a well-established therapy for patients with decompensated cirrhosis and early-stage hepatocellular carcinoma. Liver transplantation activity varies sharply across Latin American (LATAM) countries due to differences in resources, expertise, and funding and local attitudes toward organ donation and transplantation. This current guidance of postoperative care after LT is the first position paper of the Latin American Association for the Study of the Liver (ALEH) Special Interest Group (SIG), drawing evidence-based recommendations regarding immediate and long-term postoperative care of LT recipients, taking into consideration their applicability in Latin America.

Liver transplantation (LT) is a curative strategy for hepatocellular carcinoma (HCC), but the risk of HCC recurrence remains a challenging problem. In patients with HCC recurrence after LT (HCC-R_LT), the locoregional and surgical approaches are complex, and the guidelines do not report evidence-based strategies for the management of immunosuppression. In recent years, immunotherapy has become an effective option for patients with advanced HCC in pre-transplant settings. However, due to the risk of potentially fatal allograft rejection, the use of immunotherapy is avoided in post-transplant settings. Combining immunosuppressants with immunotherapy in transplant patients is also challenging due to the complex tumor microenvironment and immunoreactivity. The fear of acute liver rejection and the lack of predictive factors hinder the successful clinical application of immunotherapy for post-liver transplantation HCC recurrence. This review aims to comprehensively summarize the risk of HCC-R_LT, the available evidence for the efficacy of immunotherapy in patients with HCC-R_LT, and the clinical issues regarding the innovative management of this patient population.

Post-Liver transplantation (LT) survival rates stagnate, with biliary complications (BC) as a major cause of death. We analyzed longitudinal data with a median 19-month follow-up. BC was diagnosed with ultrasounds and MRCP. Missing data was imputed using mean and median. Data preprocessing involved feature scaling and one-hot encoding. Survival analysis used filter (Cox-P, Cox-c) and embedded (RSF, LASSO) feature selection methods. Seven survival machine learning algorithms were used: LASSO, Ridge, RSF, E-NET, GBS, C-GBS, and FS-SVM. Model development employed 5-fold cross-validation, random oversampling, and hyperparameter tuning. Random oversampling addressed data imbalance. Optimal hyperparameters were determined based on average C-index. Features importance was assessed using standardized regression coefficients and permutation importance for top models. Stability was evaluated using 5-fold cross-validation standard deviation. Finally, 1799 observations with 40 outcome predictors were included. RSF with Ridge achieved the highest performance (C-index: 0.699) for BC prediction, while RSF with RSF had the highest performance (C-index: 0.784) for mortality prediction. Top BC predictors were LT graft types, IBD in recipients, recipient's BMI, recipient's history of PVT, and previous LT history. For mortality, they were post-transplant AST, creatinine, recipient's age, post-transplant ALT, and tacrolimus consumption. We identified BC and mortality risk factors, improving decision-making and outcomes.

Liver cirrhosis represents the advanced pathological stage of chronic liver disease, characterized by the progressive destruction and regeneration of the hepatic parenchyma over years, culminating in fibrosis and disruption of the vascular architecture. As a leading global cause of morbidity and mortality, it continues to affect millions worldwide, imposing a substantial burden on healthcare systems. Alcoholic/nonalcoholic fatty liver disease and chronic viral hepatitis infection, hepatitis C (HCV) in particular, remain leading causes of cirrhosis. Despite significant advances in understanding the pathogenesis of cirrhosis, its management is still complex due to the multifaceted complications, including ascites, hepatic encephalopathy, variceal bleeding, and hepatocellular carcinoma, all of which severely compromise the patient outcomes and quality of life. This review aims at filling a critical gap by providing a comprehensive summary of the latest evidence on the complications and management of liver cirrhosis. Evidence-based therapies targeting both the etiologies and complications of cirrhosis are essential for improving outcomes. While liver transplantation is considered a definitive cure, advancements in pharmacological therapies offer promising avenues for halting and potentially reversing disease progression. This review summarizes the latest management strategies for cirrhosis and its associated complications, emphasizing the importance of early intervention and novel therapeutic options for improving outcomes and quality of life in affected individuals.

Radiotherapy can be used as a bridge therapy prior to liver transplantation. Radiotherapy generates immune reactions involving T cells, which are the main effectors of acute cellular rejection after transplantation. Here, we investigated the impact of radiotherapy on acute cellular rejection.

We retrospectively reviewed the data of oncological patients who benefited from liver transplantation. Patients who received radiotherapy prior to liver transplantation ("RT cohort", n=17) were compared to a matched cohort ("NoRTmatched cohort", n=17) obtained through propensity score-matching analysis of the total non-irradiated cohort ("NoRTall" cohort, n=136). The acute cellular rejection was evaluated using the Banff score for rejection (mild:<5, moderate: 5-6, and severe: 7-9) obtained on an early post-transplantation biopsy. Overall and disease-free survival were reported for patients with hepatocellular carcinoma.

Median Banff scores was significantly lower for the RT cohort compared to the NoRTall cohort (2.5 versus 5, respectively, P=0.043) but this statistical difference was eliminated after comparison with the NoRTmatched cohort (median: 4, P=0.62). The 5-year overall and disease-free survival rates were 62 % and 69 %, respectively, for hepatocellular carcinoma patients of the RT cohort (n=14) and did not differ from the 5-year overall (83 %, P=0.15) and disease-free survival rates (90 %, P=0.05) of those of the NoRTmatched cohort (n=16).

Radiotherapy given prior to liver transplantation did not impact the rate or severity of acute cellular rejection. Furthermore, overall and disease-free survival rates were not impacted by radiotherapy.

Liver transplantation has been at the forefront of medical research, with efforts concentrated on understanding the intricate cellular and molecular dynamics involved this complex procedure. This body of work has chronicled critical clinical advancements, identified challenges, and highlighted progressive improvements in surgical practices. These concerted efforts have significantly contributed to the evolution and enhancement of liver transplantation, elevating it to its current level of sophistication. A successful liver transplant now demands an integrated, multidisciplinary approach that includes not only expanding the donor pool from deceased to living donors but also embracing advances in surgical methods, efficiently managing post-transplant complications, and, importantly, achieving operational tolerance. The latter, operational tolerance, is a state wherein the recipient's immune system is coaxed into accepting the transplanted organ without the long-term use of immunosuppressive drugs, thereby minimizing potential side effects, and improving quality of life. Understanding the critical immune mechanisms that aim to prevent graft rejection is essential from an immunological perspective. This review aims to highlight the crucial areas of host versus graft immune responses, making a clear distinction between organs received from living and deceased donors. It examines how these immune responses, both innate and adaptive, are initiated and proposes the exploration of molecular docking sites as a strategy to curb unwanted immune reactions. Additionally, this review explores the promising potential of biomarkers in predicting graft rejection, and emphasizes the importance of achieving tolerance and the continuous quest for innovative strategies to enhance the success and longevity of liver transplants.

Initial analysis of liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov; unique identifier NCT03193151) using rejection-associated transcripts failed to find an antibody-mediated rejection state (ie, rich in natural killer [NK] cells and with interferon-gamma effects). We recently developed an optimization strategy in lung transplants that isolated an NK cell-enriched rejection-like (NKRL) state that was molecularly distinct from T cell-mediated rejection (TCMR). Here we apply the same strategy to a liver transplant biopsy population.

We used this strategy to search for a molecular NKRL state in 765 consented liver transplant biopsies collected at participating international centers for gold-standard histology and molecular assessment by genome-wide microarrays. Validation through a training set-test set approach of an optimized selection of variables as inputs into unsupervised rejection classification identified an NKRL state in livers.

The full model classified 765 biopsies into the following molecular phenotypes, characterized by their gene expression: no-rejection 54%, TCMR 16%, NKRL 13%, and injury 16%. Top TCMR transcripts were expressed in effector T cells; top NKRL transcripts were almost exclusively expressed in NK cells; and both had increased interferon-γ-inducible transcripts, which were more pronounced in TCMR. Most TCMR biopsies had significant parenchymal injury, molecular fibrosis, and abnormal biochemistry. NKRL biopsies had no excess of injury, fibrosis, or biochemistry abnormalities.

Optimized rejection algorithms indicate that some liver transplants manifest an NKRL state that is well tolerated in the short term postbiopsy and with minimal injury and relatively normal biochemistry, while also underscoring the potential of TCMR to produce extensive parenchymal injury.

Acute cellular rejection (ACR) remains a common complication causing significant morbidity post-liver transplantation. Non-human leukocyte antigen (non-HLA) mismatches were associated with an increased risk of ACR in kidney transplantation. Therefore, we hypothesized that donor-recipient non-HLA genetic mismatch is associated with increased ACR incidence post-liver transplantation.

We conducted an international multicenter case-control genome-wide association study of donor-recipient liver transplant pairs in 3 independent cohorts, totaling 1846 pairs. To assess genetic mismatch burden, we calculated sum scores for single-nucleotide polymorphism (SNP) mismatch based on all non-HLA functional SNPs, specifically SNPs coding for transmembrane or secreted proteins as they more likely affect the immune system. We analyzed the association between the non-HLA mismatch scores and ACR in a multivariable Cox regression model per cohort, followed by a weighted meta-analysis.

During the first year post-transplantation, 90 of 689 (13%), 161 of 720 (22%), and 48 of 437 (11%) recipients experienced ACR in cohorts 1-3, respectively. Weighted meta-analyses showed that higher mismatch in functional non-HLA SNPs was associated with an increased incidence of ACR (HR 5.99; 95% CI: 1.39-20.08; p=0.011). Moreover, we found a larger effect of mismatch in SNPs coding for transmembrane or secreted proteins on ACR (HR 7.54; 95% CI 1.95-28.79; p=0.003). Sensitivity analyses showed that imputed HLA mismatch did not affect the associations between both non-HLA mismatch scores and ACR.

Donor-recipient mismatch of functional non-HLA SNPs overall and, especially, of SNPs encoding transmembrane or secreted proteins correlated with 1-year ACR post-liver transplantation. Identifying high-risk immunological burdens between pairs may prevent early graft rejection and aid in personalizing immunosuppressive therapy. Future studies are, however, needed to validate our findings using a genotyped HLA cohort.

Five to 10% of the annual liver transplants in the United States are performed in prior liver recipients with 70% occurring within 1 year of transplantation. Fortunately, the incidence of primary non-function (PNF) has significantly decreased from 8% in the 1980's to < 2%, but PNF and hepatic artery thromboses remain the leading reasons for early emergency retransplantation. Other indications for early retransplantation include severe biliary or vascular complications and refractory rejection. Fortunately, the need for late retransplantation (> 1 year) has also declined due to improved immunosuppression, earlier detection of recurrent disease, and use of oral antiviral agents for recurrent hepatitis C. Patient survival with retransplantation is consistently lower than with primary liver transplantation. Risk factors for poor outcomes with retransplantation include a higher MELD score, ICU status, renal failure, and use of marginal allografts. Therefore, most centers use younger, whole deceased brain-dead donor organs whenever possible. However, increased use of machine perfused livers has expanded the donor pool for these more complex and technically challenging cases. Retransplant recipients have a higher rate of early technical, infectious, and cardiovascular complications compared to primary LT recipients. Going forward, LT recipients with recurrent steatotic and alcoholic liver disease will likely pose ethical, medical, and surgical challenges to the transplant community.

Hepatic ductopenia is a pathologic diagnosis characterized by a decrease in the number of intrahepatic bile ducts as a consequence of various underlying etiologies. Some etiologies, such as primary sclerosing cholangitis, primary biliary cholangitis, and ischemic cholangitis, often have distinctive imaging findings. In contrast, other causes such as chronic rejection following liver transplantation, drug-induced biliary injury, infection, malignancy such as lymphoma, and graft-versus-host disease may only have ancillary or non-specific imaging findings. Thus, diagnosing ductopenia in conditions with nonspecific imaging findings requires a multidimensional approach, including clinical evaluation, serological testing, imaging, and liver histology to identify the underlying cause. These etiologies lead to impaired bile flow, resulting in cholestasis, liver dysfunction, and, ultimately, cirrhosis and liver failure if the underlying cause remains untreated or undetected. In the majority of instances, individuals diagnosed with ductopenia exhibit a positive response to treatment addressing the root cause or cessation of the causative agent. This article focuses on acquired causes of ductopenia, its clinical manifestation, histopathology, imaging diagnosis, and management.

Exposure to post-transplant liver biopsies varies among pathology residencies and largely depends on the institution's training program, particularly if the hospital has a liver transplant program. The interpretation of biopsies from transplanted livers presents its own set of challenges, even for those with a solid understanding of non-transplant medical liver biopsies. In this review, we aim to provide a succinct, step-by-step approach to help you interpret liver transplant biopsies. This article may be beneficial for residents interested in liver pathology, gastrointestinal and liver pathology fellows in the early stages of training, clinical gastroenterology and hepatology fellows, hepatologists and general pathologists who are curious about this niche.

Tacrolimus and mycophenolate are important immunosuppressive agents used to prevent organ rejection in post-transplant patients. While highly effective, their use is associated with significant toxicity, requiring careful management. Tacrolimus, a calcineurin inhibitor, is linked to nephrotoxicity, neurotoxicity, metabolic disturbances such as diabetes mellitus and dyslipidemia, and cardiovascular complications such as hypertension and arrhythmias. Mycophenolate, a reversible inhibitor of inosine monophosphate dehydrogenase, frequently causes gastrointestinal disturbances, including diarrhea and colitis, as well as hematologic side effects like anemia and leukopenia, which increase infection risk. Therapeutic drug monitoring (TDM) and pharmacogenomics have emerged as essential strategies for mitigating these toxicities. TDM ensures tacrolimus trough levels are maintained within a therapeutic range, minimizing the risks of nephrotoxicity and rejection. Pharmacogenomic insights, such as CYP3A5 polymorphisms, allow for personalized tacrolimus dosing based on individual metabolic profiles. For mycophenolate, monitoring inosine monophosphate dehydrogenase activity provides a pharmacodynamic approach to dose optimization, reducing gastrointestinal and hematologic toxicities. Emerging tools, including dried blood spot sampling and pharmacokinetic modeling, offer innovative methods to simplify monitoring and enhance precision in outpatient settings. Despite their utility, the toxicity profiles of these drugs, including those of early immunosuppressants such as cyclosporine and azathioprine, necessitate further consideration of alternative immunosuppressants like sirolimus, everolimus, and belatacept. Although promising, these newer agents require careful patient selection and further research. Future directions in immunosuppressive therapy include integrating individual pharmacogenetic data to refine dosing, minimize side effects, and improve long-term graft outcomes. This narrative review underscores the importance of personalized medicine and advanced monitoring in optimizing post-transplant care.

T cells are key mediators of alloresponse during liver transplantation (LTx). However, the dynamics of donor-reactive T-cell clones in peripheral blood during a clinical T-cell-mediated rejection (TCMR) episode remain unknown. Here, we collected serial peripheral blood mononuclear cell samples spanning from pre-LTx to 1 year after LTx and available biopsies during the TCMR episodes from 26 rejecting patients, and serial peripheral blood mononuclear cell samples were collected from 96 nonrejectors. Immunophenotypic and repertoire analyses were integrated on T cells from rejectors, and they were longitudinally compared to nonrejected patients. Donor-reactive T-cell clone was identified and tracked by cross-matching with the mappable donor-reactive T-cell receptor repertoire of each donor-recipient pair in 9 rejectors and 5 nonrejectors. Before transplantation, the naive T-cell percentage and T-cell receptor repertoire diversity of rejectors was comparable to that of healthy control, but it was reduced in nonrejectors. After transplantation, the naïve T-cell percentages decreased, and T-cell receptor repertoires were skewed in rejectors; the phenomenon was not observed in nonrejectors. Alloreactive clones increased in proportion in the peripheral blood of rejectors before TCMR for weeks. The increase was accompanied by the naïve T-cell decline and memory T-cell increase and acquired an activated phenotype. Intragraft alloreactive clone tracking in pre-LTx and post-LTx peripheral blood mononuclear cell samples revealed that the pretransplant naïve T cells were significant contributors to the donor-reactive clones, and they temporarily increased in proportion and subsequently reduced in blood at the beginning of TCMR. Together, our findings offer an insight into the dynamic and origin of alloreactive T cells in clinical LTx TCMR cases and may facilitate disease prediction and management.

The consequences of unintended pregnancy in recipients of liver transplants (LTs), a growing part of the high-risk obstetric population, remain unknown. To fill this gap, we conducted a retrospective registry cohort study to describe the risk factors, obstetric and neonatal morbidity, and graft outcomes associated with unintended pregnancy after LT. This study utilized the Transplant Pregnancy Registry International and included 565 pregnancies of recipients of LT between 1967 and 2019 from 289 hospitals, primarily in North America. The primary outcome of acute cellular rejection and secondary outcomes of graft loss, severe maternal morbidity, and neonatal composite morbidity were compared by pregnancy intention. The study population included 60.9% with intended pregnancies and 39.1% with unintended pregnancies. Recipients with unintended pregnancy were more likely to self-report as Black race, to be younger, nulliparous, and to have exposure to teratogenic immunosuppression. Acute cellular rejection was more common with unintended pregnancy (3.7% vs. 1.2%, p =0.047). Unintended pregnancies had lower median birth weight (2806.6 vs. 2948.4 g, p =0.033). Unintended pregnancy was not associated with increased neonatal morbidity or severe maternal morbidity. These findings underscore the importance of family planning counseling, access to safe and effective contraceptive options, as well as multidisciplinary prenatal care in the growing population of recipients of reproductive-aged LT.

Advances in surgical procedures and immunosuppressive therapies have considerably improved the outcomes of patients who have undergone liver transplantation in the past few decades. In 2020, the Italian Liver Transplant Working Group published practice-oriented algorithms for immunosuppressive therapy (IT) in adult liver transplant (LT) recipients. Due to the rapidly evolving LT field, regular updates to the recommendations are required. This review presents a consensus- and evidence-based update of the 2020 recommendations.

The Italian Liver Transplant Working Group set out to address new IT issues, which were discussed based on supporting literature and the specialists' personal experiences. The panel deliberated on and graded each statement before consensus was reached.

A series of consensus statements were formulated and finalized on: (i) oncologic indications for LT; (ii) management of chronic LT rejection; (iii) combined liver-kidney transplantation; (iv) immunosuppression for transplantation with an organ donated after circulatory death; (v) transplantation in the presence of frailty and sarcopenia; and (vi) ABO blood group incompatibility between donor and recipient. Algorithms were updated in the following LT groups: standard patients, critical patients, oncology patients, patients with specific etiology, and patients at high immunologic risk. A steroid-free approach was generally recommended, except for patients with autoimmune liver disease and those at high immunologic risk.

The updated consensus- and evidence-based 2024 recommendations for immunosuppression regimens in adult patients with ABO-compatible LT address a range of clinical variables that should be considered to optimize the choice of the immunosuppression treatment in clinical practice in Italy.

Prevention and management of allograft rejection urgently require more effective therapeutic solutions. Current immunosuppressive therapies used in solid organ transplantation, while effective in reducing the risk of acute rejection, are associated with substantial adverse effects. There is, therefore, a need for agents that can provide immunomodulation, supporting graft tolerance, while minimizing the need for immunosuppression. Extracorporeal photopheresis (ECP) is an immunomodulatory therapy currently recommended in international guidelines as an adjunctive treatment for the prevention and management of organ rejection in heart and lung transplantations. This article reviews clinical experience and ongoing research with ECP for organ rejection in heart and lung transplantations, as well as emerging findings in kidney and liver transplantation. ECP, due to its immunomodulatory and immunosuppressive-sparing effects, offers a potential therapeutic option in these settings, particularly in high-risk patients with comorbidities, infectious complications, or malignancies.

Donor-derived cell-free DNA (dd-cfDNA) has emerged as a reliable, noninvasive method for the surveillance of allograft rejection in heart transplantation (HT) patients, but its utility in multi-organ transplants (MOT) is unknown. We describe our experience using dd-cfDNA in simultaneous MOT recipients.

A single-center retrospective review of all HT recipients between 2018 and 2022 that had at least one measurement of dd-cfDNA collected. Patients who had simultaneous MOT were identified and included in this study. Levels of dd-cfDNA were paired with endomyocardial biopsies (EMB) performed within 1 month of blood testing if available. Acute cellular rejection (ACR) was defined as ISHLT (International Society for Heart and Lung Transplantation) grade ≥ 2R. and antibody-mediated rejection (AMR) was defined as pAMR grade > 0. The within-patient variability score of the dd-cfDNA was calculated by the variance/average.

The study included 25 multiorgan transplant recipients: 13 heart-kidney (H-K), 8 heart-liver (H-Li), and 4 heart-lung (H-Lu). The median age was 55 years, 44% were female; the median time from HT until the first dd-cfDNA measurement was 4.5 months (IQR 2, 10.5). The median dd-cfDNA level was 0.18% (IQR 0.15%, 0.27%) for H-K, 1.15% (IQR 0.77%, 2.33%) for H-Li, and 0.69% (IQR 0.62%, 1.07%) for H-Lu patients (p < 0.001). Prevalence of positive dd-cfDNA tests (threshold of 0.20%) were 42.2%, 97.3%, and 92.3% in the H-K, H-Li, and H-Lu groups, respectively. The within-patient variability score was highest in the H-Li group (median of 0.45 [IQR 0.29, 0.94]) and lowest in the H-K group (median of 0.09 [IQR 0.06, 0.12]); p = 0.002. No evidence of cardiac ACR or AMR was found. Three patients experienced renal allograft ACR and/or AMR, two patients experienced rejection of the liver allograft, and one patient experienced an episode of AMR-mediated lung rejection. One person in the H-K group experienced an episode of cardiac allograft dysfunction that was not associated with biopsy-confirmed rejection.

Dd-cfDNA is chronically elevated in most MOT recipients. There is a high degree of within-patient variability in levels (particularly for H-Li and H-Lu recipients), which may limit the utility of this assay in monitoring MOT recipients.

Basiliximab is a high-cost induction agent typically given as two doses in liver transplant recipients. This study evaluated renal outcomes in live-donor liver transplant recipients (LDLTRs) with stable renal function at the time of transplant receiving one versus two doses of basiliximab.

We retrospectively identified 231 adult LDLTR with a serum creatinine (SCr) <1.5 mg/dL on post-transplant Day 5. The primary endpoint was a change in SCr from post-transplant Days 5 to 30 between the groups. Secondary endpoints included incidence of acute kidney injury (AKI), liver rejection, and culture-positive infections within 3 and 6 months of transplant. Basiliximab-related cost savings were also evaluated.

Median change in SCr from post-transplant Days 5 to 30 was no different between the single-dose or two-dose groups (0.1 [IQR: -0.1-0.3] vs. 0.2 [IQR: -0.1-0.4], p = 0.08). Incidence of AKI was 56.9% in the two-dose group versus 39.0% in the single-dose group (p = 0.01). There was no difference in bacterial (p = 0.40), fungal (p = 0.59), or viral (p = 0.78) infections. Acute cellular rejection through 6 months post-transplant was noted in 9.7% of patients receiving two doses and 6.3% in the single-dose arm (p = 0.42). Basiliximab-related cost savings in the single-dose arm was ∼$697 863.72 over 159 transplants.

Single-dose basiliximab appears to be safe and effective in place of two doses in LDLTR with stable renal function on post-transplant Day 5. Utilization of a single basiliximab dose significantly reduced medication-related costs.

T cell-targeted therapies are commonly used to manage T cell hyperactivity in autoimmune disorders, graft-versus-host diseases (GVHD), and transplant rejections. However, many patients experience significant side effects or inadequate responses to current treatments, highlighting the urgent need for alternative strategies. In this study, we searched for regulators of T cells through proximity labeling with APEX2 to detect proteins interacting with CD8α, a coreceptor of the T-cell receptor (TCR). This screen revealed TMX1, an ER resident transmembrane disulfide oxidoreductase, is essential for T cell cytotoxicity and NFAT, NFκB, and AP1 signaling but not cell proliferation. TMX1 deletion decreases surface TCR expression and destabilizes CD3ζ, a subunit of TCR complex; however, overexpression of CD3ζ rescues the phenotype, suggesting that TMX1 is not required for CD3ζ function. Mechanistically, TMX1 was found to directly engage the CxxC motif of CD3δ, which has been reported to be essential for proper TCR assembly and function. We hypothesize that the loss of TMX1 interaction with CD3δ leads to impaired TCR assembly and subsequent CD3ζ destabilization. These findings identify TMX1 as a novel regulator of T-cell receptor assembly and a potential target for immunosuppressive therapy.

The diagnosis of liver antibody-mediated rejection (AMR) is challenging and likely under-recognized. The association of AMR with donor-specific antibodies (DSA), and its clinical course in relation to pathologic findings and treatment are ill defined. We identified cases of liver AMR by following the criteria outlined by the 2016 Banff Working Group. Patient demographics, native liver disease, histopathologic findings, treatment type, clinical outcome, and transaminase levels during AMR diagnosis, treatment, and resolution were determined. Patients (n = 8) with AMR average age was 55.2 years (range: 19-68). Seven of eight cases met the Banff criteria for AMR. Personalized treatment regimens consisted of optimization of immunosuppression, intravenous pulse steroids, plasmapheresis, IVIG, rituximab, and bortezomib. Five patients experienced complete resolution of AMR, return of transaminases to baseline, and decreased DSA at long-term follow-up. One patient developed chronic AMR and two patients required re-transplantation. Follow-up after AMR diagnosis ranged from one to 11 years. Because AMR can present at any time, crossmatch, early biopsy, and routine monitoring of DSA levels should be implemented following transaminase elevation to recognize AMR. Furthermore, treatment should be immediately implemented to reverse AMR and prevent graft failure, chronic damage, re-transplantation, and possibly mortality.

Titrating tacrolimus concentration in liver transplantation recipients remains a challenge in the early post-transplant period. This multicenter retrospective cohort study aimed to develop and validate a machine-learning algorithm to predict tacrolimus concentration. Data from 443 patients undergoing liver transplantation between 2017 and 2020 at an academic hospital in South Korea were collected to train machine-learning models. Long short-term memory (LSTM) and gradient-boosted regression tree (GBRT) models were developed using time-series doses and concentrations of tacrolimus with covariates of age, sex, weight, height, liver enzymes, total bilirubin, international normalized ratio, albumin, serum creatinine, and hematocrit. We conducted performance comparisons with linear regression and populational pharmacokinetic models, followed by external validation using the eICU Collaborative Research Database collected in the United States between 2014 and 2015. In the external validation, the LSTM outperformed the GBRT, linear regression, and populational pharmacokinetic models with median performance error (8.8%, 25.3%, 13.9%, and - 11.4%, respectively; P < 0.001) and median absolute performance error (22.3%, 33.1%, 26.8%, and 23.4%, respectively; P < 0.001). Dosing based on the LSTM model's suggestions achieved therapeutic concentrations more frequently on the chi-square test (P < 0.001). Patients who received doses outside the suggested range were associated with longer ICU stays by an average of 2.5 days (P = 0.042). In conclusion, machine learning models showed excellent performance in predicting tacrolimus concentration in liver transplantation recipients and can be useful for concentration titration in these patients.

In this report, we describe the case of a patient with concomitant maple syrup urine disease (MSUD) and type I diabetes mellitus (T1DM) who underwent domino liver transplantation (DLT) , and the associated perioperative management. To the best of our knowledge, a DLT in an adult with both MSUD and T1DM has not been previously reported in the literature. Intensive care admission with multidisciplinary oversight is necessary for metabolic preconditioning prior to surgery. The complex interplay between these two disease processes presented with grossly elevated baseline insulin requirements and refractory intraoperative hyperglycemia. Following the successful procedure, the patient maintained excellent glycemic control on a normal diet. Four months post transplant, the patient presented with mild to moderate cellular graft rejection.

Rejection following liver transplantation continues to impact transplant recipients although rates have decreased over time with advances in immunosuppression management. The diagnosis of rejection remains challenging with liver biopsy remaining the reference standard for diagnosis. Proper classification of rejection type and severity is imperative as this guides management and ultimately graft preservation. Future areas of promise include non-invasive testing for detection of rejection to reduce the morbidity associated with invasive testing and further advances in immunosuppression management to reduce toxicities associated with immunosuppression while minimizing rejection related morbidity.

Liver transplant (LT) recipients require close follow-up with regular monitoring of the liver function tests (LFTs). Evaluation of deranged LFT should be individualized depending upon the time since LT, peri-operative events, clinical course, and any complications. These derangements can range from mild and asymptomatic to severe and symptomatic elevations requiring expedited personalized assessment and management. Pattern of LFT derangement (hepatocellular, cholestatic, or mixed), donor-recipient risk factors, timing after LT (post-operative, 1-12 months, and >12 months since LT) along with clinical context and symptomatology are important considerations before proceeding with the initial evaluation. Compliance to immunosuppression and drug interactions should be ascertained along with local epidemiology of infections. Essential initial evaluation must include an ultrasound abdomen with Doppler to rule out any structural causes such as biliary or vascular complications apart from focussed laboratory evaluation. Early allograft dysfunction, ischemia reperfusion injury, small-for-size syndrome, biliary leaks, hepatic artery, and portal vein thrombosis are usual culprits in the early post-operative period whereas viral hepatitis (acute or reactivation), opportunistic infections, and recurrence of the primary disease are more frequent in the later period. Graft rejection, biliary strictures, sepsis, and drug induced liver injury remain possible etiologies at all times points after LT. Initial evaluation algorithm must be customized based on history, clinical examination, risk factors, and pattern and severity of deranged LFT. Allograft rejection is a diagnosis of exclusion and requires liver biopsy to confirm and assess severity. Empirical treatment of rejection sans liver biopsy is discouraged.

Liver transplantation is one of the most challenging areas in the medical field. Despite that, it has already been established as a standard treatment option, especially in decompensated cirrhosis and selected cases of hepatocellular carcinoma and acute liver failure. Complications due to graft rejection, including mortality and morbidity, have greatly improved over time due to better immunosuppressive agents and management protocols. Currently, immunosuppression in liver transplant patients makes use of the best possible combinations of effective agents to achieve optimal immunosuppression for long-term graft survival. Induction agents are no longer used routinely, and the aim is to provide minimal immunosuppression in the maintenance phase. Currently available immunosuppressive agents are mainly classified as biological and pharmacological agents. Though the protocols may vary among the centers and over time, the basics of effective use usually remain similar. Most protocols use the combination of multiple agents with different mechanisms of action to reduce the dose and minimize the side effects. Along with the improvement in operative and perioperative techniques, this art of immunosuppression has contributed to the recent progress made in the outcomes of liver transplants. In this review, we will discuss the various types of immunosuppressive agents currently in use, the different protocols of immunosuppression used, and the art of optimal use for achieving maximum immunosuppression without increasing toxicity. We will also discuss the practical aspects of various immunosuppression regimens, including drug monitoring, and briefly discuss the concepts of immunosuppression minimization and withdrawal.

Acute cellular rejection (ACR) is a significant immune issue among recipients following liver transplantation. Although diffusion-weighted magnetic resonance imaging (DWI) is widely used for diagnosing liver disease, it has not yet been utilized for monitoring ACR in patients after liver transplantation. Therefore, the aim of this study was to evaluate the efficacy of DWI in monitoring treatment response among recipients with ACR. This study enrolled 25 recipients with highly suspected ACR rejection, and all subjects underwent both biochemistry and DWI scans before and after treatment. A pathological biopsy was performed 4 to 24 h after the first MRI examination to confirm ACR and degree of rejection. All patients were followed up and underwent a repeated MRI scan when their liver function returned to the normal range. After data acquisition, the DWI data were post-processed to obtain the apparent diffusion coefficient (ADC) map on a voxel-by-voxel basis. Five regions of interest were identified on the liver parenchyma to measure the mean ADC values from each patient. Finally, the mean ADC values and biochemical markers were statistically compared between ACR and non-ACR groups. A receiver operating characteristic (ROC) curve was constructed to evaluate the performance of the ADC and biochemical data in detecting ACR, and correlation analysis was used to understand the relationship between the ADC values, biochemical markers, and the degree of rejection. The histopathologic results revealed that 20 recipients had ACR, including 10 mild, 9 moderate, and 1 severe rejection. The results demonstrated that the ACR patients had significantly lower hepatic ADC values than those in patients without ACR. After treatment, the hepatic ADC values in ACR patients significantly increased to levels similar to those in non-ACR patients with treatment. The ROC analysis showed that the sensitivity and specificity for detecting ACR were 80% and 95%, respectively. Furthermore, the correlation analysis revealed that the mean ADC value and alanine aminotransferase level had strong and moderate negative correlation with the degree of rejection, respectively (r = -0.72 and -0.47). The ADC values were useful for detecting hepatic ACR and monitoring treatment response after immunosuppressive therapy.

Acute rejection is a life-threatening complication after liver transplantation. Immunosuppressants such as tacrolimus are used to inhibit acute rejection of liver grafts in clinic. However, inefficient intragraft accumulation may reduce the therapeutic outcomes of tacrolimus. Here, an enzyme-responsive nanoparticle is developed to selectively enhance the accumulation of tacrolimus in liver allograft through enzyme-induced aggregation to refine immunotherapeutic efficacy of tacrolimus. The nanoparticles are composed of amphiphilic tacrolimus prodrugs synthesized by covalently conjugating tacrolimus and matrix metalloproteinase 9 (MMP9)-cleavable peptide-containing methoxy poly (ethylene glycol) to poly (l-glutamic acid). Upon exposure to MMP9, which is overexpressed in rejected liver allografts, the nanoparticles undergo a morphological transition from spherical micellar nanoparticles to microscale aggregate-like scaffolds. Intravenous administration of MMP9-responsive nanoparticles into a rat model of acute liver graft rejection results in enhanced nanoparticle accumulation in allograft as compared to nonresponsive nanoparticles. Consequently, the MMP9-responsive nanoparticles significantly inhibit intragraft inflammatory cell infiltration and proliferation, maintain intragraft immunosuppressive environment, alleviate graft damage, improve liver allograft function, abate weight loss and prolong recipient survival. This work proves that morphology-switchable enzyme-responsive nanoparticles represent an innovative strategy for selectively enhancing intragraft accumulation of immunosuppressive agents to improve treatment of liver allograft rejection.