Pediatric Liver Transplant Patients Research Articles

Acute Kidney Injury After Pediatric Liver Transplantation

BackgroundThe aim of the present study is to assess acute kidney injury (AKI) incidence according to the pRIFLE and AKIN criteria and to evaluate the risk factors for early developing AKI in postoperative intensive care unit after pediatric liver transplantation (LT). MaterialsAfter exclusion of retransplantations, 7 cadaveric and 44 living donors, totaling 51 pediatric LT patients that were performed between 2005 and 2017, were reviewed retrospectively. AKI was defined according to both pediatric RIFLE (Risk for renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal disease) and Acute Kidney Injury Network (AKIN) criteria. Documented data were compared between AKI and non-AKI patients. ResultsAKI incidences were 17.6% by AKIN and 37.8% by pRIFLE criteria. AKIN-defined AKI group had statistically lower serum albumin level, higher serum sodium level, higher furosemide dose, and higher rate of red blood cell (RBC) transfusion than the non-AKI group (P = .02, P = .02, P = .01 and P = .04, respectively). AKI patients had significantly prolonged mechanical ventilation (P = .01) and hospital LOS (P = .02). The pRIFLE-defined AKI group had significantly lower serum albumin level, higher blood urea nitrogen (BUN) level, and higher ascites drained and also showed higher requirement for RBC and 20% human albumin transfusions than the non-AKI group (P = .02, P = .04, P: =.007, P = .02 and P = .05, respectively). ConclusionWe evaluated that hypoalbuminemia, high requirement for RBC and 20% human albumin transfusions, high serum sodium, high furosemide use, and high flow of ascites are risk factors for AKI and high BUN levels can be predictive for AKI in pediatric LT patients. The effect of AKI on outcome variables were prolonged mechanical ventilation and hospital LOS.

Pharmacogenomics analysis in Chinese pediatric liver transplantation patients with renal toxicity induced by tacrolimus

Survival for pediatric liver transplantation patients is limited by nephrotoxicity of calcineurin inhibitors tacrolimus. The present study was to explore the association of genetic factors with nephrotoxicity of pediatric liver transplantation patients treated with tacrolimus.Chinese pediatric liver transplantation patients under tacrolimus therapy between March 2014 and August 2018 from Children’s Hospital of Fudan University were retrospectively analyzed. A total of 15 patients, including 6 patients with nephrotoxicity induced by tacrolimus and 9 patients without nephrotoxicity, were detected by pharmacogenomics (PGxOne®160). Demographic characteristics and laboratory testing were collected from medical logs. Tacrolimus blood concentrations were extracted from therapeutic drug monitoring (TDM) documents.The risk of renal toxicity induced by tacrolimus in Chinese pediatric liver transplantation patients were positively associated with T allele of cytochrome P450 1A2 (CYP1A2) rs2470890 (RR = 2.857, 95% confidence interval = [1.392–5.863]), A allele of dopamine D2 (DRD2) rs1076560 (RR = 4.375, 95% confidence interval = [1.148–16.676]), T allele of paraoxonase-1 (PON1) rs662 (RR = 2.800, 95% confidence interval= [1.184–6.622]), respectively.Pharmacogenomics analysis in Chinese pediatric liver transplantation patients with renal toxicity induced by tacrolimus was firstly reported. The SNPs in 3 genes (CYP1A2, DRD2, and PON1) were associated with risk of tacrolimus-induced nephrotoxicity

Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: A retrospective study

BackgroundAcute kidney injury (AKI) may contribute to high mortality rates after liver transplantation. Few studies have investigated AKI in pediatric liver transplantation. This retrospective study was conducted to investigate the risk factors for and associated outcomes of AKI in pediatric liver transplant recipients. MethodsEighty pediatric liver transplant patients were included. The occurrence of AKI was defined by the KDIGO Clinical Practice Guidelines for Acute Kidney Injury. A multivariate regression analysis model was used to investigate risk factors for AKI in the pediatric liver recipients. ResultsThe final multivariable regression model showed that biliary atresia (odds ratio [OR] = 0.097, p = 0.03), increased time of the anhepatic phase (OR = 0.871, p = 0.005) and lower postoperative jaundice clearance (OR = 13.936, p = 0.02) were independently associated with the development of AKI in pediatric patients. Additionally, cumulative 3-year patient (p = 0.15) and graft (p = 0.26) survival rates between the non-acute kidney injury (NAKI) and AKI groups were 95.2% vs 86.8% and 90.5% vs 84.2%, respectively. ConclusionPediatric liver transplant recipients with a presence of biliary atresia, increased time of anhepatic phase, and a lower postoperative jaundice clearance had an increased risk of AKI. The long-term outcomes of patients who developed AKI appears to be worse compared with those having NAKI. Type of StudyPrognosis study. Level of EvidenceLevel III.

Endoscopic treatment of biliary complications after duct-to-duct biliary anastomosis in pediatric liver transplantation.

Studies reporting outcomes of endoscopic treatment methods in children who underwent liver transplantation (LT) is very limited. We present our outcomes, as a high-volume transplant center where endoscopic methods are preferred as the first choice in the treatment of biliary complications in children. Patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) as the first treatment approach for biliary complications after LT between 2005 and 2017 were included. Clinical data included patient demographics, ERCP indications (stricture or leak), and treatment outcomes, including the need for percutaneous and surgical intervention. ERCP was performed in 49 patients who had a duct-to-duct anastomosis (38 living donor liver transplantation (LDLT), 11 deceased donor liver transplantation (DDLT)). The most common biliary complication was stricture. Our endoscopic success rate was 66.7% (18/27) and 75% (6/8) in LDLT and DDLT patients with stricture (p > 0.05), respectively. While our endoscopic success rate was 75% (3/4) in patients with leak alone after LDLT, it was 25% (1/4) in patients with leak and stricture in this group. The endoscopic success rate was 50% in two patients who had leak alone after DDLT. ERCP should be considered as a preferential treatment option for the management of biliary complications in pediatric liver transplant patients with duct-to-duct anastomosis, as in adults.

Scoring Systems and Postoperative Outcomes in Pediatric Liver Transplantation

PurposeThe aim of this study is to investigate the effects of risk scores (Pediatric End-stage Liver Disease [PELD], Child-Turcotte-Pugh [CTP], and Pediatric Risk of Mortality [PRISM-III]) of pediatric liver transplant patients on the postoperative period. MethodSeven cadaveric and 45 living donors, totaling 52 pediatric liver transplantation (LT) patients, were reviewed retrospectively. PELD and CTP scores were calculated based on data at hospital admission. PRISM-III score was calculated from data during the first 24 hours of intensive care unit (ICU) admission. Hospital length of stay (LOS), ICU LOS, patients who developed acute kidney injury (AKI), requirement for inotropic-vasopressor therapy, hospital mortality, long-term mortality, duration of mechanical ventilation, metabolic disease, and demographic features were documented.For CTP score, class C was defined as high, and A and B as low. Cutoff values of PELD and PRISM-III scores were detected by using receiver operating characteristic curves. According to these cutoff values, patients were divided into 2 groups as high and low for each score. Documented data was analyzed and compared in groups for each score. ResultsHospital LOS was significantly longer in the high-PELD (P = .01) and high-CTP (P = .01) groups. ICU LOS was significantly longer in the high-PRISM-III group (P = .01). Requirement for inotropic-vasopressor therapy was significantly higher in the high-PELD (P = .04) and high-CTP (P = .04) groups. ConclusionHemodynamic instability and long hospital LOS can be expected in pediatric post-LT patients with high PELD or CTP scores; there is also the risk that AKI maybe higher for high-PELD score patients. Unexpectedly, the PRISM-III score did not have any correlation with the severity of physiological condition and mortality.

Model extrapolation to a real-world dataset: evaluation of tacrolimus population pharmacokinetics and drug interaction in pediatric liver transplantation patients

1. Numerous tacrolimus population pharmacokinetic (PPK) models in pediatric liver transplantation patients have been established to define an optimal dose schedule. However, the applicability of extrapolating these PPK models to our clinical center remains unknown. The goals of the present study was to evaluate model external predictiveness and establish a new model applicable to traditional therapeutic drug monitoring data.2. Published PPK models were collected from the literature and assessed using our real-world dataset including 41 pediatric liver transplantation patients via the individual prediction error method. The establishment of a new model was characterized using non-linear mixed-effects modeling.3. Nine published pediatric liver transplantation PPK models were identified, three of which could be applied to our real-world dataset. However, these models were dissatisfactory in terms of individual prediction error and hence, inadequate for extrapolation. Finally, a new model applicable to our real-world dataset was established as follows: CL/F = 22.9 × (WT/70)0.75 × (1 − WZ × 0.264) × (1 − FCZ × 0.338) × (1 + ASPI × 0.281) × (POD/41)0.0486 L/h; V/F = 906 × (WT/70) L. Where WT, WZ, FCZ, ASPI and POD were weight, Wuzhi capsule, fluconazole, aspirin and post-transplantation day, respectively. In conclusion, published models were inadequate for application to our real-world dataset. The present study produced a new model applicable to our real-world study data.

Severe Sepsis in Pediatric Liver Transplant Patients: The Emergence of Multidrug-Resistant Organisms.

To describe characteristics of liver transplant patients with severe sepsis in the PICU. Retrospective descriptive analysis. Tertiary children's hospital PICU. Liver transplant recipients admitted January 2010 to July 2016 for pediatric severe sepsis. None. Between January 2010 and July 2016, 173 liver transplants were performed, and 36 of these patients (21%) were admitted with severe sepsis (54 episodes total). Median age at admission was 2 years (1-6.5 yr), 47.2% were male. Bacterial infections were the most common (77.8%), followed by culture negative (12.9%) and viral infections (7.4%). Fungal infections accounted for only 1.9%. Median time from transplant for viral and culture negative infections was 18 days (8.25-39.75 d) and 25 days (9-41 d), whereas 54.5 days (17-131.25 d) for bacterial infections. Bloodstream and intra-abdominal were the most common bacterial sites (45% and 22.5%, respectively). Multidrug-resistant organisms accounted for 47.6% of bacterial sepsis. Vancomycin-resistant Enterococcus and extended-spectrum beta-lactamase producers were the most frequently identified multidrug-resistant organisms. Patients with multidrug-resistant organism sepsis demonstrated higher admission Pediatric Logistic Organ Dysfunction scores (p = 0.043) and were noted to have an odds ratio of 3.8 and 3.6 for mechanical ventilation and multiple organ dysfunction syndrome, respectively (p = 0.047 and p = 0.044). Overall mortality was 5.5% (n = 2 patients), with both deaths occurring in multidrug-resistant organism episodes. We report that multidrug-resistant organisms are increasingly being identified as causative pathogens for sepsis in pediatric liver transplant recipients and are associated with significantly higher odds for mechanical ventilation and higher organ failure. The emergence of multidrug-resistant organism infections in pediatric liver transplant patients has implications for patient outcomes, antibiotic stewardship, and infection prevention strategies.

Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients.

Tacrolimus is the cornerstone in pediatric liver transplant immunosuppression. Despite close monitoring, fluctuations in tacrolimus blood levels affect safety and efficacy of immunosuppressive treatments. Identifying the factors related to the variability in tacrolimus exposure may be helpful in tailoring the dose. The aim of the present study was to characterize the clinical, pharmacological, and genetic variables associated with systemic tacrolimus exposure in pediatric liver transplant patients. De novo transplant patients with a survival of more than 1month were considered for inclusion and were genotyped for cytochrome P450 3A5 (CYP3A5). Peritransplant clinical factors and laboratory covariates were recorded retrospectively between 1month and 2years after transplant, including alanine aminotransferase (ALT), aspartate aminotransferase, hematocrit, and tacrolimus predose steady-state blood concentrations collected 12hours after tacrolimus dosing. A linear mixed effect (LME) model was used to assess the association of these factors and the log-transformed tacrolimus dose-normalized trough concentration (logC0/D) levels. Bootstrapping was used to internally validate the final model. External validation was performed in an independent group of patients who matched the original population. The developed LME model described that logC0/D increases with increases in time after transplant (β=0.019, 95% confidence interval [CI], 0.010-0.028) and ALT values (β=0.00030, 95% CI, 0.00002-0.00056), whereas logC0/D is significantly lower in graft CYP3A5 expressers compared with nonexpressers (β=-0.349, 95% CI, -0.631 to -0.062). In conclusion, donor CYP3A5 genotype, time after transplant, and ALT values are associated with tacrolimus disposition between 1month and 2years after transplant. A better understanding of tacrolimus exposure is essential to minimize the occurrence of an out-of-range therapeutic window that may lead to adverse drug reactions or acute rejection.

Population pharmacokinetics of immediate- and prolonged-release tacrolimus formulations in liver, kidney and heart transplant recipients.

AimsDevelop a population pharmacokinetics model of tacrolimus in organ transplant recipients receiving twice‐daily, immediate‐release (IR‐T; Prograf) and/or once‐daily, prolonged‐release (PR‐T; Advagraf or Astagraf XL) tacrolimus.MethodsTacrolimus concentration–time profiles were analysed from 8 Phase II studies in adult and paediatric liver, kidney and heart transplant patients receiving IR‐T and/or PR‐T. A tacrolimus population pharmacokinetic model, including identification of significant covariates, was developed using NONMEM.ResultsOverall, 23,176 tacrolimus concentration records were obtained from 408 patients. A 2‐compartment model with first‐order absorption and elimination described the concentration–time profiles. Tacrolimus absorption rate was 50% slower with PR‐T vs IR‐T. Tacrolimus apparent oral clearance was 44.3 L/h in Whites and 59% higher in Asians. Tacrolimus central volume of distribution was 108 L in males and 55% lower in females; trough concentrations were similar between formulations. Tacrolimus relative bioavailability was similar between formulations (geometric mean ratio PR‐T:IR‐T 95%, 90% confidence intervals: 89%, 101%). Asians had 83% and 51% higher relative bioavailability than Whites and Blacks, respectively, for IR‐T and PR‐T. Whites had 49% and 77% higher relative bioavailability than Blacks for PR‐T and IR‐T, respectively. Blacks had 52% lower relative bioavailability than Whites and Asians for IR‐T and PR‐T. Type of organ transplanted and patient population (adult/paediatric) did not have a significant effect on tacrolimus pharmacokinetics.ConclusionsThis population pharmacokinetic model described data from transplant recipients who received IR‐T and/or PR‐T. Tacrolimus trough concentrations and relative bioavailability were similar between formulations, supporting 1 mg:1 mg conversion from Prograf to Advagraf/Astagraf XL in clinical practice.

Incidence, clinical features, and outcomes of food allergy in children who underwent liver transplant: 16-year experience.

Food allergies often develop after liver transplant, especially in young children. However, data are scarce on clinical characteristics and patient outcomes. When we evaluated our pediatric liver transplant patients over a 16-year period, food allergy incidence was 8% (19/236 patients). All patients with food allergies were <18months old, with incidence in this age group of 19.2% (19/99). Two patients had a single food and 17 had multiple food allergies. Five patients showed only non-IgE-mediated food allergies. Eggs, milk, nuts, and wheat were the most common allergens. Presenting symptoms included diarrhea, flushing, angioedema attacks, wheezing/chronic cough, and vomiting. Seven patients had EBV, and two patients had CMV infections at time of food allergy diagnosis. Twelve patients had eosinophilia. Seven patients (36.8%) were able to regain tolerance to all food allergens. However, one patient with single nut allergy and three with multiple food allergies were still on allergen-eliminated diets. Eight patients with multiple food allergies gained tolerance to some of the food allergens. In conclusion, food allergies in our patients were mainly against multiple foods and IgE mediated. Infections like EBV and CMV may play a role in food allergies after liver transplant, especially in pretransplant-naive patients.

Cardiovascular Risk Assessment in Pediatric Liver Transplant Patients.

Cardiovascular (CV) diseases play a leading role in the mortality of adult liver transplant (LT) recipients. However, data regarding CV risk factors in children after LT remain sparse. The present study assessed the presence of CV risk factors and signs of CV impairment in LT children. A total of 42 LT recipients (21 men, age 9.93 ± 3.57 years) were studied. Body composition [body mass index standard deviation score, percentage of body fat (by bioimpedance analysis)], lipid profiles, glycemic control, blood pressure, and arterial stiffness [assessed by aortic pulse wave velocity (PWV)] were evaluated. The effect of different treatment modalities [tacrolimus (TAC) (n = 30) or cyclosporine (CyA) (n = 11)] was also analyzed. Almost 18% of children were overweight or obese. Patients on TAC had a significantly higher body fat mass and percentage of body fat compared with the CyA group (P < 0.02). Borderline to high lipid values were present in 40% of patients. Children on CyA had higher serum cholesterol levels compared to TAC (P < 0.004). Nineteen percent of patients had hypertension. Half of the patients had glomerular filtration rate values <90 mL/min/1.73 m, whereas PWV values were above the 95th percentile in 12%. Increased body fat, chronic kidney disease, high lipid content, hypertension, and increased arterial stiffness are already present and are in part related to the type of immunosuppression regimen in LT children >5 years following transplantation. Long-term follow-up is needed to evaluate their impact on CV health and survival.

Recanalization of Chronic Portal Vein Occlusion in Pediatric Liver Transplant Patients

PurposeTo evaluate technical and clinical success and report long-term outcomes of portal vein (PV) recanalization in pediatric orthotopic liver transplant (OLT) patients with chronic PV occlusion. Materials and MethodsThis is a retrospective review of 15 OLT patients (5 males) with chronic PV occlusion who underwent PV recanalization (33 procedures) between October 2011 and February 2018. Median age was 4.5 years (range, 1–16 years); median weight was 16.6 kg (range, 11.5–57.3 kg). Median time interval from OLT to first intervention was 3.25 years (range, 0.6–15.7 years). Clinical presentations included hypersplenism (n = 12), gastrointestinal bleeding (n = 9), and ascites (n = 3). One patient had incidental diagnosis of PV occlusion. Primary, primary-assisted, and secondary patency at 3, 6, 12, and 24 months were evaluated. ResultsTechnically successful PV recanalization and reduction of PV pressure gradient to ≤ 5 mm Hg was performed in 13/15 patients (87%). Ten of 15 (67%) patients had successful recanalization with the first attempt. Clinical success, defined as improvement in signs and symptoms of portal hypertension, was achieved in 12/13 (92%) patients. Five of 33 (15%) major complications (Society of Interventional Radiology class C), including perisplenic hematoma (n = 2), hemoperitoneum (n = 2), and hepatic artery pseudo aneurysm (n = 1), were managed with pain medication and blood product replacement. Median follow-up was 22 months (range, 1–77 months). Median primary patency was 5 months. Primary patency at 3, 6, 12, and 24 months was 53.8%, 46.2%, 38.5%, and 30.8%, respectively. Primary-assisted patency was 84.6%, 76.9%, 53.8%, and 46.2%, respectively. Secondary patency was 92.3%, 84.6%, 53.8%, and 46.2%, respectively. ConclusionsPV recanalization is a safe and effective minimally invasive option in the management of chronic PV occlusion after pediatric OLT.

Roles of Epstein–Barr virus viral load monitoring in the prediction of posttransplant lymphoproliferative disorder in pediatric liver transplantation

This study is aimed to investigate the risk factors and clinical characteristics of posttransplant lymphoproliferative disorder (PTLD) after conducting Epstein-Barr virus (EBV) viral load monitoring in pediatric liver transplant (LT) patients in Taiwan, where EBV infection is endemic. From 2007 to 2013, pediatric LT recipients who underwent EBV viral load monitoring within 3 months after LT were recruited in this study. The impact of clinical parameters-including age at LT, sex, peak EBV viral load and immunosuppressant levels after LT-on the risk of PTLD were assessed. A total 39 patients underwent LT at a median age of 1.3 years (range: 0.6-14.0 years), and 5 patients developed PTLD during follow-up. Cox's proportional-hazards model identified two predictors of PTLD: peak EBV viral load within 3 months of LT >4100copies/μg peripheral blood mononuclear cells (PBMC) DNA and peak tacrolimus level within 3 months of LT>14.8ng/mL (Hazard ratio=17.14 and 11.54, P=0.02 and 0.03, respectively). Kaplan-Meier survival analysis revealed significant higher cumulative incidence rates of PTLD (27.3% and 41.8% at 0.3 and 1.2 years after LT) in subjects with peak EBV viral load >4100copies/μg PBMC DNA within 3 months after LT. (P=0.001, log-rank test). Close monitoring of EBV viral load within 3 months after LT is helpful to predict a high risk of PTLD. Tapering of immunosuppressants is suggested if the EBV viral load is >4100copies/μg PBMC DNA in LT children.

Predictable and Unusual Adverse Effects of Immunosuppression in Pediatric Liver Transplant Patients.

Our aim was to determine potentially adverse effects of immunosuppressive protocols after liver transplantation in children. The medical records of 60 children who underwent liver transplant retrospectively analyzed. Corticosteroid, tacrolimus, and mycophenolate mofetil were the primary immunosuppressive agents used in our center. The mean age of children was 6.1 years, ranging from 3 months to 17 years (34 boys, 26 girls). The most common indication for liver transplant was biliary atresia (26.7%). Thirty-nine patients (65%) received livers from living donors, and 21 patients (35%) received from livers from deceased donors. The main complications of immunosuppressive therapy were diarrhea associated with mycophenolate mofetil, hyperglycemia and hypertension associated with corticosteroid, and seizures and tremors associated with tacrolimus. Two patients developed post transplant lymphoproliferative disorder. The diagnosis was based on histologic findings of cervical lymphadenopathy and duodenal biopsy. One patient was diagnosed with acute lymphoblastic lymphoma. In addition to these predictable adverse effects, unusual adverse effects of immunosuppression were also observed. Hemolytic anemia (n = 3) (one was also diagnosed with Evans syndrome), eosinophilic gastroenteritis (n = 2), de novo food allergy (n = 2), posttransplant lymphoproliferative disorder (n = 2), Burkitt lymphoma (n = 1), and renal tubular acidosis (n = 1) were thought to be related to tacrolimus therapy. Adverse effects of immunosuppression represent a major cause of postoperative morbidity. The common effects of immunosuppression are recognized easily by clinicians. It should be kept in mind that unexpected symptoms and signs may be related to immunosuppression in pediatric liver transplant patients.

Oral Health Status of Kuwaiti Children with a History of Chronic Liver Disease

Objective: To investigate the oral health status and dental manifestations of children with a history of chronic liver disease (CLD) compared to healthy children.Subjects and Methods: Twenty children (15 boys and 5 girls) with a history of CLD were compared to 20 healthy controls matched for age and gender. The clinical examination was carried out by the same dentist. Caries prevalence, using the decayed, missing, and filled primary and permanent teeth indices (dmft/DMFT), was recorded. Developmental enamel defects, plaque scores, and gingival overgrowth were also investigated. Results: No statistically significant differences were found in mean dmft scores for children with a history of CLD (4.9 ± 5.4) and for healthy individuals (3.9 ± 4.5). However, the mean DMFT score was significantly higher (p =0.025) in children with CLD (4.2 ± 4.6) compared to controls (1.7 ± 1.6). The mean decayed teeth parameter (DT) was also significantly higher in children with CLD (p =0.004). All patients with CLD exhibited enamel defects compared to only 33% in the control group (p< 0.05). A higher mean plaque index was observed in children with a history of CLD (p< 0.001). Also, a positive correlation for gingival overgrowth was noted in patients with a history of CLD (p< 0.05). Green staining was evident only in the permanent dentition of 1 child with CLD. Conclusion: Children with a history of CLD exhibited a high caries prevalence, high plaque scores, and more enamel defects compared to healthy subjects. Gingival overgrowth is less prevalent among pediatric liver transplant patients on tacrolimus therapy.

Factors associated with the need for intraoperative packed red cells transfusion in pediatric liver transplant patients

Factors associated with the need for intraoperative packed red cells transfusion in pediatric liver transplant patients

Nutritional Management for Infants and Children Pre and Post-Liver Transplant

Background: Infants and children undergoing liver transplant require ongoing nutritional evaluation throughout the pre and post-transplant period. The pathophysiologic causes of chronic liver disease and acute liver failure are varied, and each present different and unique nutritional challenges. Methods: A review of the literature and Seattle Children's established guidelines for nutritional management of pediatric liver transplant patients was conducted. Results: We present guidelines of care to optimize nutrition status of infants and children in the pre and post-transplant phases. Conclusion: While malnutrition is common in the child with liver failure, it is also treatable when approached with a multidisciplinary focus on identification of clinical symptoms.

1580. Characteristics of Early vs. Late Onset Post-transplant Lymphoproliferative Disorder After Liver Transplant:– A Descriptive Study of the United Network of Organ Sharing (UNOS) Database

BackgroundPost-transplant lymphoproliferative disorder (PTLD) is a devastating complication of solid-organ transplant. In liver transplant, studies comparing the risk factors for early vs. late onset PTLD have been limited to single centers. Using a national database, we sought to compare early and late onset PTLD in adult and pediatric liver transplant patients in terms of patient characteristics, immunosuppressive regimens, and mortality.MethodsWe conducted a retrospective analysis of the UNOS database to compare early (<1 year) and late (1+ year) onset PTLD in pediatric (<18) and adult (18+) liver transplant patients. We compared patient demographics, co-morbid conditions, immunosuppressive regimens, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) risk status, reason for transplant, and mortality. We categorized EBV and CMV risk status into high, intermediate, and low based on donor and recipient serostatus. Categorical variables were analyzed using Fisher’s exact test. The Kaplan–Meier method, log-rank test, and multivariable Cox regression were used to examine mortality.ResultsNinety-two pediatric patients and 807 adult patients met study criteria. Overall mortality was 35.87 and 53.78% for pediatric and adult patients, respectively. In adults, unadjusted survival was significantly different for early vs. late onset PTLD (P < 0.001; Figure 1); the latter was associated with a 64.33% decreased mortality risk (95% CI: 51.17–73.95%; P < 0.001). There was no difference in mortality in pediatric patients (P = 0.549). In neither population was EBV risk status associated with early vs. late onset PTLD. In adults, tacrolimus, mycophenolate mofetil (MMF), and steroid maintenance therapy were associated with late onset PTLD (P < 0.001; 0.006; <0.001).Figure 1.ConclusionWe conclude the following: (1) Mortality is greater for early vs. late onset PTLD in adult patients; the converse has been shown previously. (2) Tacrolimus, MMF, and steroids are associated with late onset PTLD in adult patients. (3) EBV risk status did not differ between early and late onset PTLD in both the adult and pediatric populations. This contradicts established reports that EBV negative serostatus of the recipient at the time of transplant is a risk factor for early onset PTLD.Disclosures All authors: No reported disclosures.

Cancer After Liver Transplantation in Children and Young Adults: A Population-Based Study From 4 Nordic Countries.

Cancer after liver transplantation (LT) constitutes a threat also for young recipients, but cancer risk factors are usually absent in children and large studies on the cancer risk profile in young LT recipients are scarce. Data of patients younger than 30 years who underwent LT during the period 1982-2013 in the Nordic countries were linked with respective national cancer registries to calculate standardized incidence ratios (SIRs). A total of 37 cancer cases were observed in 923 patients with 7846 person-years of follow-up. The SIR for all cancer types, compared with the matched general population, was 9.8 (12.4 for males and 7.8 for females). Cumulative incidence of cancer adjusted for the competing risk of death was 2% at 10 years, 6% at 20 years, and 22% at 25 years after LT. Non-Hodgkin lymphoma was the most common cancer type (n = 14) followed by colorectal (n = 4) and hepatocellular cancer (n = 4). Age was a significant risk factor for cancer, and the absolute risk of most cancers (except for lymphoma) increased considerably in young adults older than 20 years. The cancer risk pattern is different in pediatric and young LT patients compared with adult recipients. The striking increase in cancer incidence in young adulthood after the second decade of life deserves further consideration in transition programs.

Survival Time to Biopsy-Proven Acute Rejection and Tacrolimus Adverse Drug Reactions in Pediatric Liver Transplantation.

Despite advances in surgical procedures and the optimization of immunosuppressive therapies in pediatric liver transplantation, acute rejection (AR) and serious adverse drug reaction (ADR) to tacrolimus still contribute to morbidity and mortality. Identifying risk factors of safety and efficacy parameters may help in optimizing individual immunosuppressive therapies. This study aimed to identify peritransplant predictors of AR and factors related to the risk of ADR to tacrolimus in a large Latin American cohort of pediatric liver transplant patients. We performed a retrospective cohort study in a pediatric liver transplant population (n = 72). Peritransplant variables were collected retrospectively including demographic, clinical, laboratory parameters, genomic (CYP3A5 donor and recipients polymorphism), and tacrolimus trough concentrations (C0) over a 2-year follow-up period. Variability in tacrolimus C0 was calculated using percent coefficient of variation and tortuosity. ADR- and AR-free survival rates were calculated using the Kaplan-Meier method, and risk factors were identified by multivariate Cox regression models. Cox-proportional hazard models identified that high tortuosity in tacrolimus C0 was associated with an 80% increased risk of AR [hazard ratio (HR), 1.80; 95% confidence interval (CI), 1.01-3.22; P < 0.05], whereas steroid in maintenance doses decreased this risk (HR, 0.56; 95% CI, 0.31-0.99; P < 0.05). Forty-six patients experienced at least one ADR including hypomagnesemia, nephrotoxicity, hypertension, malignancies, and tremor as a first event. Multivariate analysis showed that C0 values 10 days before the event (HR, 1.25; 95% CI, 1.21-1.39; P < 0.0001) and CYP3A5 expresser recipients (HR, 2.05; 95% CI, 1.03-4.06; P < 0.05) were independent predictors of ADR. Tacrolimus C0 values, its variability, and CYP3A5 polymorphisms were identified as risk factors of AR and tacrolimus ADR. This knowledge may help to control and reduce their incidence in pediatric liver transplant patients. Prospective studies are important to validate these results.