Pediatric Liver Transplantation Research Articles

A blood-based PT-LIFE (Pediatric Liver Transplantation-LIver Fibrosis Evaluation) biomarker panel for noninvasive evaluation of pediatric liver fibrosis after liver transplantation: A prospective derivation and validation study

Allograft fibrosis is increasingly detected in graft biopsies as the postoperative period extends, potentially emerging as a pivotal determinant of long-term graft function and graft survival among pediatric recipients. Currently, there is a paucity of noninvasive diagnostic tools capable of identifying allograft fibrosis in pediatric recipients of liver transplants. This study involved 507 pediatric liver transplant patients and developed a novel blood-based diagnostic assay, Pediatric Liver Transplantation-Liver Fibrosis Evaluation (PT-LIFE), to noninvasively distinguish allograft fibrosis using blood samples, clinical data, and biopsy outcomes. The PT-LIFE assay was derived from a matrix of 23 variables and validated in 2 independent cohorts. It integrates 3 biomarkers (LECT2, YKL-40, FBLN3) with an area under the receiver operating characteristic curve of 0.91. In the pooled analysis, a PT-LIFE score lower than 0.12 identified liver allograft fibrosis semiquantitative scores 0 to 2 with a sensitivity of 91.9%, whereas scores above 0.29 indicated liver allograft fibrosis semiquantitative scores 3 to 6, with a specificity of 88.4%. The PT-LIFE assay presents as a promising noninvasive diagnostic tool for the detection of allograft fibrosis in pediatric liver transplant recipients.

Independent Risk Factors and Economic Burden Associated With Delayed Extubation Following Pediatric Liver Transplantation.

Successful early extubation (EE) after liver transplant (LT) has been shown to reduce intensive care unit (ICU) and hospital length of stay and infectious, vascular, and sedation-related complications in adults. EE may not always be feasible in children, and many may require prolonged mechanical ventilation. Limited data exists regarding the candidacy of EE, risk factors, consequences, and hospital costs of delayed extubation (DE) in pediatric LT. We conducted a retrospective review to investigate predictive factors and associated costs of EE and DE in infants and children after orthotopic LT at our institution between 2011 and 2021. Of 338 LT (median age 39 months, 54% females), 246 (73%) had EE (within 24 h of LT), while 27% had DE. Age < 1 year (p = 0.0019), diagnosis of biliary atresia (0.02), abnormal pre-LT echocardiogram (0.02), and patients with ongoing hospital admission before LT (0.0001) were independently associated with DE. Hospital costs were significantly (∼3-fold) higher (p < 0.0001) in the DE group. In addition, factors associated with increased total hospital costs were age < 1 year and hospitalization before LT. EE post-LT is feasible and merits a trial. The prevalence of DE though modest is associated with increased resource utilization and hospital costs. Children who can be extubated early and those at risk for DE can be identified pre-operatively for optimal planning and allocation of resources.

The Assessment and Management of Biliary Atresia in Hawai'i, 2009-2023.

Although biliary atresia (BA) is a rare neonatal disorder, it remains the leading cause of pediatric end-stage liver disease. Early diagnosis of BA and treatment with the Kasai procedure can significantly reduce the need for pediatric liver transplant. Current data suggests that performing the Kasai procedure at 30-45 days of life is associated with longer native liver survival rates and reduction of the need for liver transplant. The incidence rate of BA in the state of Hawai'i is nearly double the incidence rate in the continental US. International studies have demonstrated that screening programs for BA reduce the age at diagnosis and treatment. However, there has been no statewide analysis on the ages at diagnosis or at Kasai, nor does a statewide screening program for BA exist. The purpose of this study is to review the age of diagnosis and treatment of BA to determine if the current practice in Hawai'i is in line with the published data. A retrospective chart review of all patients diagnosed with BA at the state's primary children's hospital was performed (2009-2023) and 19 patients who underwent the Kasai procedure were identified. The mean age at diagnosis is 71.4 days (n=19) and the mean age at Kasai procedure is 72.0 days (n=19). Both the average age at diagnosis and treatment for BA in Hawai'i is significantly higher than published data suggesting best outcomes at 30-45 days of life. This review suggests that the implementation of a statewide screening program for BA in Hawai'i is warranted.

Key Aspects of Pediatric Liver Transplant Patient Visits to the Pediatric Emergency Department.

Patients with liver transplant can present to a pediatric emergency department with short- and long-term complications of transplant. Here, we described clinical features of pediatric liver transplant patients admitted to the pediatric emergency department and identified risk factors that may lead to pediatric intensive care unit admission. We retrospectively evaluated pediatric liver transplant patients admitted posttransplant to Baskent University Hospital's pediatric emergency department in 2023. We noted symptoms, laboratory tests, hospitalization status, and final diagnoses. We compared clinical and laboratory features of patients admitted or not admitted to the intensive care unit. In 2023, 108 presentations of 33 liver transplant patients presented to our pediatric emergency department: 46.3% were girls, mean age was 7.79 ± 4.40 years, and median posttransplant day at time of emergency department visit was 622 days. Common symptoms were vomiting (48%), fever (46%), and rhinorrhea and cough (34%). Forty-nine visits (45.4%) resulted in hospitalization; 5 visits (4.6%) resulted in PICU admission, with 2 mortalities (1.8%). Final diagnoses included acute gastroenteritis and upper respiratory tract infections (23 patients) and lower respiratory tract infections (13 patients). Seven patients had cholangitis, 6 had intra-abdominal infection, and 5 had sepsis. Seizures and sepsis were significantly correlated with intensive care unit admission (P <.001). Patients admitted to the intensive care unit had significantly shorter time posttransplant versus other patients (518 ± 324 vs 1498 ± 1658 days; P < .001). Half of patients who presented to the emergency department required hospitalization mainly for observation and supportive treatment, with a small number requiring intensive care unit admission. Nevertheless, physicians caring for liver transplant patients should be aware of serious complications and monitor patients closely, especially early posttransplant when intensive immunosuppressive treatment regimens are used.

Posttransplant Lymphoproliferative Disorder in Pediatric Solid-Organ Transplant Recipients: A 7-Year Single-Center Analysis.

Posttransplant lymphoproliferative disorder is a consequential complication following solid-organ transplant, particularly associated with the Epstein-Barr virus. We studied a single center's cases of pediatric posttransplant lymphoproliferative disorder for a 7-year period and focused on incidence rates, anatomic sites involved, and correlation with clinical outcomes. We explored clinical features and treatment outcomes in patients with pediatric posttransplant lymphoproliferative disorder, with emphasis on patient survival and associated clinical ramifications. This was a retrospective analysis of medical records from pediatric solid-organ transplant recipients (liver or kidney) at Baskent University Ankara Hospital Organ Transplantation Center between January 1, 2017, and January 1, 2024, approved by the Institutional Review Board (KA24/63). We identified cases based on pathology-confirmed persistent lymphadenopathy or tumorous lesions. Patient categorization distinguished between malignant and benign groups. Early posttransplant lymphoproliferative disorder was defined within the initial year after transplant. Epstein?Barr virus association was determined through in situ hybridization, and patient characteristics were reviewed comprehensively. In 7 years, 10 pediatric patients (9 liver transplants, 1 kidney transplant) were diagnosed with posttransplant lymphoproliferative disorder, with an incidence of 8.7% for pediatric liver transplants. Mean age at diagnosis was 46.4 months, and mean time from transplant to diagnosis was 21.2 months. The most common complaints at diagnosis included fever, lymphadenopathy, hepatosplenomegaly, dyspnea, and diarrhea. Treatment modalities included rituximab, immunosuppression reduction, intravenous immunoglobulin therapy, and chemotherapy (NHL Berlin-Frankfurt-Münster 90 protocols). All patients achieved remission (mean follow-up, 22.9 mo). Early diagnosis of posttransplant lymphoproliferative disorder is important, and rituximab with immunosuppression reduction is effective to achieve complete remission, particularly in early polymorphic cases. Despite challenges, all patients achieved remission, signaling improved outcomes in pediatric posttransplant lymphoproliferative disorder. Active monitoring of Epstein?Barr virus infection may further reduce posttransplant lymphoproliferative disorder complications in pediatric solid-organ transplant; hence, early diagnosis is crucial.

Effectiveness and Safety of Tacrolimus-Mycophenolate Combination Therapy vs. Tacrolimus Monotherapy in Pediatric Liver Transplantation

Effectiveness and Safety of Tacrolimus-Mycophenolate Combination Therapy vs. Tacrolimus Monotherapy in Pediatric Liver Transplantation

An innocent bystander or a predisposing culprit? Kidney injury following pediatric liver transplantation.

Survival after pediatric liver transplantation has increased dramatically over the years, revealing extra-hepatic complications including impaired kidney function. We conducted a large single-center retrospective study to evaluate kidney outcomes after pediatric liver transplantation. From electronic charts of 121 children who underwent liver transplantation during 2007-2020, we collected pre- and post-transplant data. We investigated the presence of post-transplant permanent kidney injury, including proteinuria, hypertension, and decreased estimated glomerular filtration rate (eGFR). We excluded children who died, underwent liver-kidney transplantation, or had less than 1year of follow-up. During a median follow-up of 5.1 (interquartile range 2.9-7.3) years, eGFR decreased, mostly in the first year post-transplant. In addition, 41% of the children presented with acute kidney injury. At their last follow-up, 35% showed permanent kidney injury (hypertension 13%, proteinuria 36%, and eGFR < 90mL/min per 1.73m2 7%). Kidney ultrasounds were abnormal for 44% of the children at the last visit, compared to 11% before transplant (p < 0.001). In multivariate analysis, abnormal kidney ultrasound before transplant (odds ratio = 4.53, 95% CI 1.1-18.7) and liver disease with potential risk of primary kidney involvement (odds ratio = 4.77, 95% CI 1.58-14.4) were predictors for hypertension or decreased eGFR at the last follow-up. The high prevalence of kidney injury after pediatric liver transplantation and the pretransplant predictors for kidney injury highlight the importance of a thorough kidney pretransplant evaluation and follow-up.

Optimizing Piperacillin Dosing in Pediatric Liver Transplant Recipients: A Case Series.

Pathophysiological changes post-liver transplantation impact the pharmacokinetics and pharmacodynamics of antibiotics. Piperacillin, often used in combination with tazobactam, is a key antibiotic after transplantation to its broad-spectrum activity, but there is a lack of specific pharmacokinetic data in this population. This study aims to describe the pharmacokinetic parameters and target attainment of piperacillin in pediatric liver transplant recipients. Patients with preserved renal function (estimated glomerular filtration rate > 50 mL/min/1.73 m2) receiving intravenous piperacillin-tazobactam at 112.5 mg/kg every 8 h (100 mg piperacillin/12.5 mg tazobactam), with a rapid infusion (0.5-1 h), were included. Two blood samples per child were collected during the same interval within 48 h of starting therapy. A Bayesian approach was applied to estimate individual pharmacokinetic parameters and perform dosing recommendations against Enterococcus spp., Enterobacterales and Pseudomonas aeruginosa. Eight patients with median age of 8 months were included. Median piperacillin clearance and central volume of distribution for the cohort were 11.11 L/h/70 kg and 9.80 L/70 kg, respectively. Seven patients (87.5%) presented with concentrations below the target of 100% fT > MIC. Simulations suggested that these patients required more frequent dosing and extended duration of infusion to ensure target attainment. One patient (12.5%) had trough concentrations that exceed 16 mg/L and could receive a lower daily dose. This case series highlights the importance of personalized therapy in pediatric liver transplant recipients due to the unpredictable and highly variable piperacillin pharmacokinetics in this population.

Incidence and risk factors for chronic rejection in pediatric liver transplantation.

Chronic rejection (CR) is a progressive immunological injury that frequently leads to long-term liver allograft dysfunction and loss. Although CR remains an important indication for retransplantation, as transplant immunosuppression has evolved, its prevalence in adults undergoing liver transplantation (LT) has declined. However, the incidence and factors that lead to CR in pediatric LT are poorly defined. Therefore, we sought to systematically measure CR's incidence and assess both the risk factors for developing CR and outcomes in a large cohort of pediatric recipients of LT. In this single-center study, we retrospectively analyzed and compared relevant recipient characteristics, surgical details, immunosuppression, graft, and patient survival in the CR and control groups over a 17-year period. After a median time of 1.9 years after LT, 19/356 recipients of LT (5.3%) developed CR in our cohort. Posttransplant lymphoproliferative disorder ( p = 0.01), infections ( p = 0.02), autoimmune liver diseases (HR = 7.3, p = <0.01), Black race (HR = 11.5, p = 0.01), and 2 or more episodes of T cell mediated rejection (HR = 5.1, p = <0.01) were associated with CR development. The retransplantation rate among CR cases was 15.8% at a median follow-up time of 4.1 years. Overall, patient survival was lower in the CR group (78.9%) versus controls (91.1%). While CR incidence in our pediatric cohort was lower than previously reported rates of >12%, the CR group had a higher graft failure rate that required retransplantation and lower overall patient survival. Thus, identifying risk factors may warrant specialized immunosuppression protocols and closer posttransplantation monitoring to reduce the risk of morbidity and mortality from CR.

A Predictive Model of Pressure Injury in Children Undergoing Living Donor Liver Transplantation Based on Machine Learning Algorithm.

The aim of our study was to formulate and validate a prediction model using machine learning algorithms to forecast the risk of pressure injuries (PIs) in children undergoing living donor liver transplantation (LDLT). A retrospective cohort study. The research was carried out at China's largest paediatric liver transplantation centre. A total of 438 children who underwent LDLT between June 2021 and December 2022 constituted the study cohort. The dataset was partitioned randomly into 70% for training datasets (306 cases) and 30% for testing datasets (132 cases). Utilising four machine learning algorithms-Decision Tree, Random Forest, Gradient Boosting Decision Tree and eXtreme Gradient Boosting-we identified risk factors and constructed predictive models. Out of 438 children, 42 developed PIs, yielding an incidence rate of 9.6%. Notably, 94% of these cases were categorised as Stage 1, and 54% were localised on the occiput. Upon evaluating the four prediction models, the Decision Tree model emerged as the most effective. The primary contributors to pressure injury in the Decision Tree model were identified as operation time, intraoperative corticosteroid administration, preoperative skin protection measures and preoperative skin conditions. A visualisation elucidating the logical inference process for the 10 variables within the Decision Tree model was presented. Ultimately, based on the Decision Tree model, a predictive system was developed. Machine learning algorithms facilitate the identification of crucial factors, enabling the creation of an effective Decision Tree model to forecast pressure injury development in children undergoing LDLT. With this predictive model at their disposal, nurses can assess the pressure injury risk level in children more intuitively. Subsequently, they can implement tailored preventive strategies to mitigate the occurrence of PIs. Paediatric patients contributed electronic health records datasets.

Role of mTOR Inhibitors in Pediatric Liver Transplant Recipients: A Systematic Review.

Immunosuppressive medications play a crucial role in determining both organ and patient survival following liver transplantation (LT). Typically, immunosuppressive protocols for pediatric LT patients rely on calcineurin inhibitors (CNIs). While inhibitors of mammalian target of rapamycin (mTOR) have demonstrated beneficial outcomes in adult recipients of liver allografts, such as improved renal function post-LT, their application in pediatric liver transplant recipients is a subject of debate due to uncertain efficacy and potential adverse effects. This review evaluates the potential roles of mTOR inhibitors in the context of pediatric LT patients. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol for conduct and reporting. Databases until 31 August 2023 were searched using specific terms and keywords. All clinical studies focusing on mTOR inhibitors in pediatric LT were included. Out of 888 identified articles, 30 studies, involving 386 children who had undergone liver transplantation and received mTOR-inhibitor-based immunosuppressive regimens, met the inclusion criteria. The beneficial impacts of switching from a CNI to an mTOR inhibitor or adding an mTOR inhibitor to CNI-reduced immunosuppression in LT pediatric patients with impaired kidney function are controversial, and high-powered clinical studies are need. It appears that enhancing immunosuppression by adding an mTOR inhibitor to CNI is helpful for pediatric LT recipients who are experiencing refractory acute rejection or chronic rejection. mTOR-inhibitor-containing regimens failed to reduce the occurrence of post-transplant lymphoproliferative disorders (PTLD) among children with LT that may be due to concomitant high CNI concentration among studied patients. The effectiveness of mTOR inhibitors in treating PTLD remains uncertain; however, in patients with PTLD who are at high risk of rejection, mTOR inhibitors may be administered. Conversion to or the addition of mTOR inhibitors to maintenance immunosuppression seems to be suitable for pediatric patients who received a transplant due to hepatic malignancies such as hepatoblastoma or hepatocellular carcinoma or for those with post-transplant primary or recurrent malignancies. Switching to an mTOR inhibitor may improve some CNI-related adverse effects such as gingival hyperplasia, neurotoxicity, nephropathy, hypertrophic cardiomyopathy, or thrombotic microangiopathy. Although the exact role of mTOR inhibitors among pediatric patients who have received a liver transplant needs further study, two algorithms are presented in this review to guide conversion from CNIs to mTOR inhibitors or the addition of mTOR inhibitor to a CNI-minimization immunosuppressive regimen for pediatric patients who may benefit from this class of drugs. This review mainly consisted of retrospective studies with inadequate sample sizes and lacked a control group, which represents the main limitation of this study.

Human leukocyte antigen compatibility and incidence of donor-specific antibodies in pediatric liver transplant recipients.

Antibody-mediated rejection following liver transplantation (LT) has been increasingly recognized, particularly with respect to the emergence of de novo donor-specific antibodies (DSAs) and their impact on graft longevity. While substantial evidence for adult populations exists, research focusing on pediatric LT outcomes remains limited. To investigate the prevalence of human leukocyte antigen (HLA) mismatches and DSA and evaluate their association with rejection episodes after pediatric LT. A cohort of pediatric LT recipients underwent HLA testing at Santa Casa de Porto Alegre, Brazil, between December 2013 and December 2023. Only patients who survived for > 30 days after LT with at least one DSA analysis were included. DSA classes I and II and cross-matches were analyzed. The presence of de novo DSA (dnDSA) was evaluated at least 3 months after LT using the Luminex® single antigen bead method, with a positive reaction threshold set at 1000 MFI. Rejection episodes were confirmed by liver biopsy. Overall, 67 transplanted children were analyzed; 61 received grafts from living donors, 85% of whom were related to recipients. Pre-transplant DSA (class I or II) was detected in 28.3% of patients, and dnDSA was detected in 48.4%. The median time to DSA detection after LT was 19.7 [interquartile range (IQR): 4.3-35.6] months. Biopsy-proven rejection occurred in 13 patients at follow-up, with C4d positivity observed in 5/13 Liver biopsies. The median time to rejection was 7.8 (IQR: 5.7-12.8) months. The presence of dnDSA was significantly associated with rejection (36% vs 3%, P < 0.001). The rejection-free survival rates at 12 and 24 months were 76% vs 100% and 58% vs 95% for patients with dnDSA anti-DQ vs those without, respectively. Our findings highlight the importance of incorporating DSA assessment into pre- and post-transplantation protocols for pediatric LT recipients. Future implications may include immunosuppression minimization strategies based on this analysis in pediatric LT recipients.

Mapping out a Medication Adherence Promotion System (MAPS): Can it reduce graft rejection in pediatric liver transplantation?

Mapping out a Medication Adherence Promotion System (MAPS): Can it reduce graft rejection in pediatric liver transplantation?

Postoperative Delirium Screening Characteristics in Pediatric Intestinal, Liver, and Renal Transplant Recipients: Single-Center Retrospective Cohort Study.

To describe and compare the results of delirium screening in the immediate post-transplant PICU admission for pediatric intestinal, liver, and renal transplant recipients. We also examined associations with known and suspected risk factors for pediatric delirium (PD). Retrospective analysis of a single-center cohort, 2016-2022. Twenty-four-bed PICU in a high-volume transplant center. All intestinal, liver, and renal transplant recipients under 23 years old admitted between July 2016 and August 2022. We identified 211 pediatric transplant recipients: intestinal ( n = 36), liver ( n = 78), and renal ( n = 97). Results of the Cornell Assessment for PD during the immediate post-transplant PICU admission were reviewed and patients were categorized into screen positive, screen negative, and unscreened. Corresponding data on known and suspected risk factors for PD were also collected. Data on delirium subtypes were not collected. Screens were available for 156 of 211 patients (74%) who were included in the final analysis. The prevalence of a positive screen by transplant category was: intestine 80% (24/30), liver 75% (47/63), and renal 14% (9/63). A positive screen was associated with younger age, greater duration of mechanical ventilation, and greater PICU length of stay (LOS) in bivariate analysis. In multivariable analysis, age and PICU LOS remained strongly correlated with a positive screen ( p < 0.05). Deep sedation and agitation as categorized by the State Behavioral Scale was associated with a positive screen, as was significant iatrogenic withdrawal symptoms ( p < 0.05). Most patients screened positive by post-transplant days 2 and 3 (58/80 [72%] and 64/80 [80%], respectively). In our 2016 to 2022 experience, we found a high prevalence of positive PD screens in pediatric intestinal and liver transplant recipients in the immediate post-transplant PICU admission. A positive screen was associated with younger age and greater PICU LOS.

223.5: Biodegradable stent for biliary reconstruction in pediatric liver transplantation, surgical approach.

223.5: Biodegradable stent for biliary reconstruction in pediatric liver transplantation, surgical approach.

364.3: Risk factors and outcomes of neutropenia following pediatric liver transplantation.

364.3: Risk factors and outcomes of neutropenia following pediatric liver transplantation.

204.1: Identification of patients with low likelihood of biopsy-proven acute rejection by donor-derived cell-free DNA and liver function tests in pediatric liver transplant.

204.1: Identification of patients with low likelihood of biopsy-proven acute rejection by donor-derived cell-free DNA and liver function tests in pediatric liver transplant.

301.4: Vacuum-assisted laparostomy for delayed abdominal closure in pediatric liver transplantation: A case series.

301.4: Vacuum-assisted laparostomy for delayed abdominal closure in pediatric liver transplantation: A case series.

V-212.3: Living donor versus deceased donor in pediatric liver transplantation: A systemic review.

V-212.3: Living donor versus deceased donor in pediatric liver transplantation: A systemic review.

P.487: Alloactivation has a key role in biopsy-proven acute rejection in pediatric liver transplant.

P.487: Alloactivation has a key role in biopsy-proven acute rejection in pediatric liver transplant.