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Background and aims Tolerance is transplantation's holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance. Approach and results We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48 weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3-4). For-cause biopsies were done at investigators' discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100 U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1 year after stopping immunosuppression. Among 88 subjects (median age 11 years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval [CI] 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n = 32) occurred at ≤32% of the trial-entry immunosuppression dose and was treated with corticosteroids (n = 32) and/or tacrolimus (n = 38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4 years for either tolerant or nontolerant subjects. Conclusions Immunosuppression withdrawal showed that 37.5% of selected pediatric liver-transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.

Simultaneous liver-kidney transplantation (SLKT) is increasingly common in the United States. However, little is known about the renal-related outcomes following SLKT, which are essential to maximize the health of these allografts. We examined the factors impacting renal function following SLKT. This is an observational multicenter cohort study from the US Multicenter SLKT Consortium consisting of recipients of SLKT aged ≥18years of transplantations performed between February 2002 and June 2017 at 6 large US centers in 6 different United Network for Organ Sharing regions. The primary outcome was incident post-SLKT stage 4-5 chronic kidney disease (CKD) defined as

We aimed to understand the contemporary changes in the characteristics and the determinants of outcomes among simultaneous liver-kidney transplantation (SLKT) recipients at 6 liver transplantation centers in the United States. We retrospectively enrolled SLKT recipients between 2002 and 2017 in the US Multicenter SLKT Consortium. We analyzed time-related trends in recipient characteristics and outcomes with linear regression and nonparametric methods. Clustered Cox regression determined the factors associated with 1-year and overall survival. We enrolled 572 patients. We found significant changes in the clinical characteristics of SLKT recipients: as compared with 2002, recipients in 2017 were older (59 versus 52years; P&nbsp

Biliary atresia is a progressive fibroinflammatory cholangiopathy of infancy that is associated with activation of innate and adaptive immune responses targeting bile ducts. A recently completed multicenter phase I/IIA trial of intravenous immunoglobulin in biliary atresia did not improve serum total bilirubin levels at 90 days after hepatoportoenterostomy or survival with the native liver at 1 year. A mechanistic aim of this trial was to determine if the peripheral blood immunophenotype was associated with clinical outcomes. Flow cytometry of peripheral blood cell markers (natural killer [NK], macrophage subsets, T‐ and B‐cell subsets, regulatory T cells), neutrophils, and activation markers (clusters of differentiation [CD]38, CD69, CD86, human leukocyte antigen‐DR isotype [HLA‐DR]) was performed on 29 patients with biliary atresia at baseline and at 60, 90, 180, and 360 days after hepatoportoenterostomy. Plasma cytokines and neutrophil products were also measured. Spearman correlations of change of an immune marker from baseline to day 90 with change in serum bilirubin revealed that an increase in total bilirubin correlated with 1) increased percentage of HLA‐DR+CD38+ NK cells and expression of NK cell activation markers CD69 and HLA‐DR, 2) decreased percentage of regulatory T cells, and 3) increased interleukin (IL)‐8 and associated neutrophil products (elastase and neutrophil extracellular traps). Cox modeling revealed that the change from baseline to day 60 of the percentage of HLA‐DR+CD38+ NK cells and plasma IL‐8 levels was associated with an increased risk of transplant or death by day 360. Conclusion: Poor outcomes in biliary atresia correlated with higher peripheral blood NK cells and IL‐8 and lower regulatory T cells. Future studies should include immunotherapies targeting these pathways in order to protect the biliary tree from ongoing damage.

Biliary atresia (BA) is the most common cause of end-stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations-a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole-exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient-parent trios, from the National Institute of Diabetes and Digestive and Kidney Diseases-supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a prespecified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious biallelic variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice, and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other noncholestatic diseases. Conclusion: WES identified biallelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN data set; the dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a biologically plausible, cholangiocyte-expressed candidate gene for the BASM syndrome.

Becoming a transplant surgeon requires mastering both operative procedures and management of the patient before and after the operation. Along with the ability to make wise decisions under pressure, a solid foundation in all areas is necessary. In this issue, Khan et al. analyzed their experience training 11 fellows focusing specifically on the liver transplant operation (1). To evaluate for evidence of a learning curve, they divided fellow experience into two cohorts: Transplants 1 to 45, and 45 to 90. The break point matches the current American Society of Transplant Surgery (ASTS) minimum requirement of 45 liver transplants for fellows completing training in liver transplantation.

Published histologic studies of the hilar plate or entire biliary remnant at the time of Kasai portoenterostomy (KHPE) have not provided deep insight into the pathogenesis of biliary atresia, relation to age at surgery, prognosis or the basis for successful drainage. We report detailed histologic findings in 172 centrally reviewed biliary remnants with an average of 6 sections per subject. Active lesions were classified as either necroinflammatory (rare/clustered in a few subjects) or active concentric fibroplasia with or without inflammation (common). Inactive lesions showed bland replacement by collagen and fibrous cords with little or no inflammation. Heterogeneity was common within a given remnant; however, relatively homogenous histologic patterns, defined as 3 or more inactive or active levels in the hepatic ducts levels, characterized most remnants. Homogeneity did not correlate with age at KHPE, presence/absence of congenital anomalies at laparotomy indicative of heterotaxy and outcome. Remnants from youngest subjects were more likely than older subjects to be homogenously inactive suggesting significantly earlier onset in the youngest subset. Conversely remnants from the oldest subjects were often homogenously active suggesting later onset or slower progression. More data are needed in remnants from subjects

Long-term survival for children who undergo LT is now the rule rather than the exception. However, a focus on the outcome of patient or graft survival rates alone provides an incomplete and limited view of life for patients who undergo LT as an infant, child, or teen. The paradigm has now appropriately shifted to opportunities focused on our overarching goals of "surviving and thriving" with long-term allograft health, freedom of complications from long-term immunosuppression, self-reported well-being, and global functional health. Experts within the liver transplant community highlight clinical gaps and potential barriers at each of the pretransplant, intra-operative, early-, medium-, and long-term post-transplant stages toward these broader mandates. Strategies including clinical research, innovation, and quality improvement targeting both traditional as well as PRO are outlined and, if successfully leveraged and conducted, would improve outcomes for recipients of pediatric LT.

BACKGROUND SPLIT was founded in 1995 in order to collect comprehensive prospective data on pediatric liver transplantation, including waiting list data, transplant, and early and late outcomes. Since 2011, data collection of the current registry has been refined to focus on prospective data and outcomes only after transplant to serve as a foundation for the future development of targeted clinical studies. OBJECTIVE To report the outcomes of the SPLIT registry from 2011 to 2018. METHODS This is a multicenter, cross-sectional analysis characterizing patients transplanted and enrolled in the SPLIT registry between 2011 and 2018. All patients

Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe, feasible, acceptable, and efficacious for the treatment of BA. The primary objective of this study was to establish the feasibility, acceptability, and safety profile of IVIg administration after hepatoportoenterostomy (HPE) in BA. The secondary objective was to determine the treatment efficacy of IVIg based on good bile drainage and survival with the native liver.A multicenter, prospective, open-labeled, phase I/IIA trial of IVIg was conducted, with 1 g/kg/dose of IVIg infused at 3-5, 30, and 60 days post-HPE, and subjects followed for 360 days post-HPE. Twenty-nine participants completed the study.Administration of IVIg infusions was feasible and acceptable in 79%. None of the serious adverse events (SAEs) were directly related to IVIg infusions; however, 90% of participants had an SAE. Compared with a historical placebo-arm group, there was no significant increase in the proportion of IVIg participants with a serum total bilirubin1.5 mg/dL at 90, 180, or 360 days post-HPE. Survival with the native liver in the IVIg participants showed no significant benefit over the historical placebo arm, with a difference at 360 days of -11.9% (IVIg: 58.6%, placebo: 70.5%; 90% UCB: 2.1%; P 0.05).Although IVIg infusions in infants with BA post-HPE were feasible, acceptable and safe, there was no trend to lower bilirubin levels or improved 360-day survival with the native liver.Safety Study of Intravenous Immunoglobulin Post-Portoenterostomy in Biliary Atresia; #NCT01854827.

Objectives To identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere. Study design The Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected. Results We enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score. Conclusions Portal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.

Simultaneous kidney and pancreas (SPK) transplantation is an attractive option for patients with type 1 diabetes and end-stage renal disease. The incremental benefit of the pancreas transplant includes: freedom from insulin, normal glycemic control, freedom from hypoglycemic events, improvement or delay in secondary complications of diabetes, and potentially longer kidney graft survival. Because the immunosuppressive burden is similar to recipients of kidney transplantation alone (KTA), the incremental risks are largely secondary to the perioperative risks of the pancreas transplant procedure itself, which can be substantial. Advising kidney and pancreas transplant candidates as to the best transplant option has proven to be challenging. This is due to the variety of available choices and, in part, to the multitude of factors that may influence outcomes: availability of a living donor, waiting time for deceased donor kidneys and pancreas, local allocation algorithms and, most importantly, differences in recipients and donor organ quality between SPK versus KTA. Although all kidney or kidney-pancreas transplants provide a survival advantage compared with remaining on dialysis, analyses examining the incremental survival benefit of the pancreas have yielded mixed results. In these registry-based, observational studies, a number of methods are used to address differences between SPK and KTA recipients, which reflect more restrictive SPK selection criteria for both donors and recipients. Regression modeling, restrictions on donor and recipient inclusion criteria, matched kidney analyses, and comparative benefit models have been used but fail to completely eliminate this selection bias. The majority of existing studies either compared Kaplan-Meier survival curves or estimated hazard ratios (HRs) based on Cox regression. Kaplan-Meier curves are not risk-adjusted and, hence, may yield biased results. Hazard ratios based on Cox regression are suboptimal for guiding clinical decision making when the baseline risks are low (because the HR will overstate the actual effect on absolute survival) or if the hazards are not proportional. We restricted the KTA group based on covariate patterns present in SPK recipients. We adjust for treatment group-specific imbalances using Cox regression. Survival probabilities for SPK and KTA are then compared by taking the difference between the 2 treatment-specific average survival curves over a 0- to 10-year follow-up period. The resulting contrast has factored out differences between SPK and KTA case mixes because the SPK and KTA average survival curves are computed across the same set of subjects (the entire study population, regardless of the transplant actually received). This novel analytic construct then generate results that would be obtained through a randomized clinical trial, in the sense that survival curves are compared in a manner which factors out case mix differences.

Pediatric kidney transplant recipients experience a high-risk age window of increased graft loss during late adolescence and early adulthood that has been attributed primarily to sociobehavioral mechanisms such as nonadherence. An examination of how this age window affects recipients of other organs may inform the extent to which sociobehavioral mechanisms are to blame or whether kidney-specific biologic mechanisms may also exist. Graft loss risk across current recipient age was compared between pediatric kidney (n = 17,446), liver (n = 12,161) and simultaneous liver-kidney (n = 224) transplants using piecewise-constant hazard rate models. Kidney graft loss during late adolescence and early adulthood (ages 17-24 years) was significantly greater than during ages17 (aHR = 1.79, 95%CI = 1.69-1.90, p 0.001) and ages24 (aHR = 1.11, 95%CI = 1.03-1.20, p = 0.005). In contrast, liver graft loss during ages 17-24 was no different than during ages17 (aHR = 1.03, 95%CI = 0.92-1.16, p = 0.6) or ages24 (aHR = 1.18, 95%CI = 0.98-1.42, p = 0.1). In simultaneous liver-kidney recipients, a trend towards increased kidney compared to liver graft loss was observed during ages 17-24 years. Late adolescence and early adulthood are less detrimental to pediatric liver grafts compared to kidney grafts, suggesting that sociobehavioral mechanisms alone may be insufficient to create the high-risk age window and that additional biologic mechanisms may also be required.

Cirrhosis occurs in 5% to 10% of cystic fibrosis (CF) patients, often accompanied by portal hypertension. We analyzed 3 adverse liver outcomes, variceal bleeding (VB), liver transplant (LT), and liver-related death (LD), and risk factors for these in CF Foundation Patient Registry subjects with reported cirrhosis.We determined 10-year incidence rates for VB, LT, LD, and all-cause mortality (ACM), and examined risk factors using competing risk models and Cox-proportional hazard regression.From 2003 to 2012, 943 participants (41% females, mean age 18.1 years) had newly reported cirrhosis; 24.7% required insulin, 85% had previous pseudomonas. Seventy-three subjects had reported VB: 38 with first VB and new cirrhosis reported simultaneously and 35 with VB after cirrhosis report. Ten-year cumulative VB, LT, and LD rates were 6.6% (95% confidence interval [CI]: 4.0, 9.1%), 9.9% (95% CI: 6.6%, 13.2%), and 6.9% (95% CI: 4.0%, 9.8%), respectively, with an ACM of 39.2% (95% CI: 30.8, 36.6%). ACM was not increased in subjects with VB compared to those without (hazard ratio [HR] 1.10, 95% CI: 0.59, 2.08). CF-related diabetes (HR: 3.141, 95% CI:1.56, 6.34) and VB (HR: 4.837, 95% CI: 2.33, 10.0) were associated with higher LT risk, whereas only worse lung function was associated with increased LD in multivariate analysis. Death rate among subjects with VB was 24% with LT and 20.4% with native liver.VB is an uncommon complication of CF cirrhosis and can herald the diagnosis, but does not affect ACM. Adverse liver outcomes and ACM are frequent by 10 years after cirrhosis report.

To assess neurodevelopmental outcomes among participants with biliary atresia with their native liver at ages 12 months (group 1) and 24 months (group 2), and to evaluate variables predictive of neurodevelopmental impairment.Participants enrolled in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with either the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition. Scores (normative mean = 100 ± 15) were categorized as ≥100, 85-99, and85 for χThere were 148 children who completed 217 Bayley Scales of Infant and Toddler Development, 3rd edition, examinations (group 1, n = 132; group 2, n = 85). Neurodevelopmental score distributions significantly shifted downward compared with test norms at 1 and 2 years of age. Multivariate analysis identified ascites (OR, 3.17; P = .01) and low length z-scores at time of testing (OR, 0.70; P .04) as risk factors for physical/motor impairment; low weight z-score (OR, 0.57; P = .001) and ascites (OR, 2.89; P = .01) for mental/cognitive/language impairment at 1 year of age. An unsuccessful hepatoportoenterostomy was predictive of both physical/motor (OR, 4.88; P .02) and mental/cognitive/language impairment (OR, 4.76; P = .02) at 2 years of age.Participants with biliary atresia surviving with native livers after hepatoportoenterostomy are at increased risk for neurodevelopmental delays at 12 and 24 months of age. Those with unsuccessful hepatoportoenterostomy are4 times more likely to have neurodevelopmental impairment compared with those with successful hepatoportoenterostomy. Growth delays and/or complications indicating advanced liver disease should alert clinicians to the risk for neurodevelopmental delays, and expedite appropriate interventions.Clinicaltrials.gov: NCT00061828 and NCT00294684.

Introduction. Almost all pediatric orthotopic liver transplant (OLT) recipients require mechanical ventilation in the early postoperative period. Prolonged postoperative mechanical ventilation (PPMV) may be a marker of severe disease and may be associated with morbidity and mortality. We determined the incidence and risk factors for PPMV in children who underwent OLT. Methods. This was a retrospective analysis of data collected on 128 pediatric OLT recipients. PPMV was defined as postoperative ventilation ≥ 4 days. Perioperative characteristics were compared between cases and control groups. Multivariable logistic regression analysis was used to calculate odds ratios for PPMV after controlling for relevant cofactors. Results. An estimated 25% (95% CI, 17.4%–32.6%) required PPMV. The overall incidence of PPMV varied significantly by age group with the highest incidence among infants. PPMV was associated with higher postoperative mortality (p=0.004) and longer intensive care unit (p<0.001) and hospital length of stay (p<0.001). Multivariable analysis identified young patient age, preoperative hypocalcemia, and increasing duration of surgery as independent predictors of PPMV following OLT. Conclusion. The incidence of PPMV is high and it was associated with prolonged ICU and hospital LOS and higher posttransplant mortality. Surgery duration appears to be the only modifiable predictor of PPMV.

Fat-soluble vitamin (FSV) deficiency is a well-recognized consequence of cholestatic liver disease and reduced intestinal intraluminal bile acid. We hypothesized that serum bile acid (SBA) would predict biochemical FSV deficiency better than serum total bilirubin (TB) level in infants with biliary atresia.Infants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia after hepatoportoenterostomy were the subjects of this investigation. Infants received standardized FSV supplementation and monitoring of TB, SBA, and vitamin levels at 1, 3, and 6 months. A logistic regression model was used with the binary indicator variable insufficient/sufficient as the outcome variable. Linear and nonparametric correlations were made between specific vitamin measurement levels and either TB or SBA.The degree of correlation for any particular vitamin at a specific time point was higher with TB than with SBA (higher for TB in 31 circumstances vs 3 circumstances for SBA). Receiver operating characteristic curve shows that TB performed better than SBA (area under the curve 0.998 vs 0.821). Including both TB and SBA did not perform better than TB alone (area under the curve 0.998).We found that TB was a better predictor of FSV deficiency than SBA in infants with biliary atresia. The role of SBA as a surrogate marker of FSV deficiency in other cholestatic liver diseases, such as progressive familial intrahepatic cholestasis, α-1-antitrypsin deficiency, and Alagille syndrome in which the pathophysiology is dominated by intrahepatic cholestasis, warrants further study.

ObjectivesSteroids are a mainstay of treatment in orthotopic liver transplantation (OLT) and are associated with significant morbidity. This trial was conducted to assess the efficacy of steroids avoidance.MethodsPatients undergoing OLT between June 2002 and April 2005 were entered into a prospective, randomized trial of complete steroids avoidance and followed until November 2011. Recipients received either standard therapy (n = 50) or complete steroids avoidance (n = 50). Analyses were performed on an intention‐to‐treat basis. The mean follow‐up of all recipients was 2095 ± 117 days. Sixteen (32%) recipients randomized to the steroids avoidance group ultimately received steroids for clinical indications.ResultsIncidences of diabetes and hypertension prior to or after OLT were similar in both groups, as was the incidence of rejection. Patient and graft survival rates at 1, 3 and 5 years were lower in the steroids avoidance group than in the standard therapy group (patient survival: 1‐year, 80% versus 86%; 3‐year, 68% versus 76%; 5‐year, 60% versus 72%; graft survival: 1‐year, 76% versus 76%; 3‐year, 64% versus 74%; 5‐year, 56% versus 72%), but the differences were not statistically different.conclusionsComplete steroids avoidance provides liver transplant recipients with minimal benefit and appears to result in a concerning trend towards decreased graft and recipient survival. The present data support the use of at least a short course of steroids after liver transplantation.

The liver biopsy guides diagnostic investigation and therapy in infants with undiagnosed cholestasis. Histologic features in the liver may also have prognostic value in the patient with biliary atresia (BA). We assessed the relative value of histologic features in 227 liver needle biopsies in discriminating between BA and other cholestatic disorders in infants enrolled in a prospective Childhood Liver Disease Research Network (ChiLDReN) cohort study by correlating histology with clinical findings in infants with and without BA. In addition, we reviewed 316 liver biopsies from clinically proven BA cases and correlated histologic features with total serum bilirubin 6 months after hepatoportoenterostomy (the Kasai procedure, HPE) and transplant-free survival up to 6 years. Review pathologists were blinded to clinical information except age. Semiquantitative scoring of 26 discrete histologic features was based on consensus. Bile plugs in portal bile ducts/ductules, moderate to marked ductular reaction, and portal stromal edema had the largest odds ratio for predicting BA versus non-BA by logistic regression analysis. The diagnostic accuracy of the needle biopsy was estimated to be 90.1% (95% confidence interval [CI]: 85.2%, 94.9%), whereas sensitivity and specificity for a diagnosis of BA are 88.4% (95% CI: 81.4, 93.5) and 92.7% (95% CI: 84.8, 97.3), respectively. No histologic features were associated with an elevated serum bilirubin 6 months after HPE, although it (an elevated serum bilirubin) was associated with an older age at HPE. Higher stages of fibrosis, a ductal plate configuration, moderate to marked bile duct injury, an older age at HPE, and an elevated international normalized ratio were independently associated with a higher risk of transplantation.

BACKGROUND Significant intercenter variation exists in mortality and death-censored graft loss (DCGL) after transplantation. Failure to rescue (FTR, death after a major complication) is an emerging tool in quality improvement and may underlie this variation. This study is the first effort to investigate the relationship between FTR and outcomes in transplantation to assess its utility in care improvement. METHODS Using the Studies of Pediatric Liver Transplantation database, we identified 2330 children undergoing primary liver transplants at 21 centers. Centers were ranked by risk-adjusted mortality and sorted into tertiles. We then compared mortality, complications, and FTR across tertiles. RESULTS Overall mortality was 4.9%, ranging from 1.4% to 8.1% in the low and high mortality tertiles (P < 0.01). The low mortality tertile had significantly lower rates of complications (30.9% vs 38.5% and 40.4%, P < 0.01) as well as FTR (4.6% vs 9.9% and 14.3%, P < 0.01). A similar trend was seen in the DCGL analysis. CONCLUSIONS Our results demonstrate that although centers with higher mortality and DCGL have more frequent major complications, they exhibit 3-fold the rate of FTR. Efforts to standardize perioperative care, and thus minimize FTR, will have value to pediatric liver transplantation recipients. This preliminary study indicates that FTR may provide a useful quality improvement tool for the field of transplantation and warrants further investigation.

Portal hypertension (PHT) is a common consequence of biliary atresia (BA) and can lead to significant morbidity and mortality (1). Elevated portal pressure has been demonstrated as early as the time of hepatoportoenterostomy (2). The rate of development of complications of PHT is dependent in part upon whether bile flow is restored, with relatively rapid progression in infants with poor bile flow whose serum bilirubin levels remain elevated (i.e. “failed Kasai”) (3, 4). Despite good bile flow as demonstrated by normalization of serum bilirubin levels, the majority of children with BA still develop biliary cirrhosis with typical complications of PHT. Most published analyses of PHT are single center studies and focus on either the development of, or intervention for, clinical complications of PHT (5–12). Some are part of general surveys of BA and not focused on issues related to PHT. Many reports emanate from time periods when the development of complications of PHT was an indication for proceeding with liver transplantation. In the current era, many centers proceed with liver transplantation in infants and toddlers with BA who have evidence of poor bile flow after hepatoportoenterostomy, which is in effect pre-emptive for complications of PHT (1). Thus earlier reports may not necessarily be representative of the current clinical spectrum of PHT in BA. Unlike the practice in adults, portal pressures are not typically measured in children. Moreover, hepatic venous pressure gradients, when performed in BA, have the potential to underestimate actual portal pressure, both because of the primarily presinusoidal nature of the lesion in BA, but also because of the unexpected finding of intrahepatic venovenous collaterals (13). Defining PHT simply by the presence or absence of complications of PHT would underestimate its prevalence, since elevated portal pressure preceeds the development of both varices and ascites. In addition, reliance on endoscopic findings of portal hypertension depends upon surveillance endoscopy in at-risk children, which is not used by many clinicians in North America (14–16). A broader clinical definition of PHT would be of great value in pediatric hepatology given the invasive nature associated with direct measurement of portal pressure in children, as well as problems associated with and the limited availability of direct or indirect measurement of portal pressure in children. The purpose of the present study was to carefully examine a large well-characterized multi-center cross-sectional cohort of children with BA for the presence of PHT. This cohort was designed to reflect what one might encounter in the follow-up of children who survived with their native liver. The analysis used readily available non-invasive and practical clinical and laboratory objective measurable criteria. Both the nature and type of complications of PHT as well as laboratory correlates of PHT were investigated. In addition, the analysis was intended to set a baseline framework for potential future clinical investigations of PHT in children with BA (16)

Though robust clinical data are available within transplantation, these data are not used for broad-based, multicentered quality improvement initiates. This article describes a targeted quality improvement initiative within the Studies of Pediatric Liver Transplantation (SPLIT) Registry. Using standard statistical techniques and clinical expertise to adjust for data and statistical reliability, we identified the pediatric liver transplant centers in North America with the lowest hepatic artery thrombosis rate and biliary complication rates. A survey was completed to establish current practices within the entire SPLIT group. Surgeons from the highest performing centers presented a detailed, technically oriented overview of their current practices. The presentations and discussion that followed were recorded and form the basis of the best practices described herein. We frame this work as a unique six-step approach roadmap that may serve as an efficient and cost effective model for novel broad-based quality improvement initiatives within transplantation.

OBJECTIVE: Cholestasis predisposes to fat-soluble vitamin (FSV) deficiencies. A liquid multiple FSV preparation made with tocopheryl polyethylene glycol-1000 succinate (TPGS) is frequently used in infants with biliary atresia (BA) because of ease of administration and presumed efficacy. In this prospective multicenter study, we assessed the prevalence of FSV deficiency in infants with BA who received this FSV/TPGS preparation. METHODS: Infants received FSV/TPGS coadministered with additional vitamin K as routine clinical care in a randomized double-blinded, placebo-controlled trial of corticosteroid therapy after hepatoportoenterostomy (HPE) for BA (identifier NCT 00294684). Levels of FSV, retinol binding protein, total serum lipids, and total bilirubin (TB) were measured 1, 3, and 6 months after HPE. RESULTS: Ninety-two infants with BA were enrolled in this study. Biochemical evidence of FSV insufficiency was common at all time points for vitamin A (29%–36% of patients), vitamin D (21%–37%), vitamin K (10%–22%), and vitamin E (16%–18%). Vitamin levels were inversely correlated with serum TB levels. Biochemical FSV insufficiency was much more common (15%–100% for the different vitamins) in infants whose TB was ≥2 mg/dL. At 3 and 6 months post HPE, only 3 of 24 and 0 of 23 infants, respectively, with TB >2 mg/dL were sufficient in all FSV. CONCLUSIONS: Biochemical FSV insufficiency is commonly observed in infants with BA and persistent cholestasis despite administration of a TPGS containing liquid multiple FSV preparation. Individual vitamin supplementation and careful monitoring are warranted in infants with BA, especially those with TB >2 mg/dL.

The American Society of Transplant Surgeons (ASTS) sought whether the right number of abdominal organ transplant surgeons are being trained in the United States. Data regarding fellowship training and the ensuing job market were obtained by surveying program directors and fellowship graduates from 2003 to 2005. Sixty-four ASTS-approved programs were surveyed, representing 139 fellowship positions in kidney, pancreas and/or liver transplantation. One-quarter of programs did not fill their positions. Forty-five fellows graduated annually. Most were male (86%), aged 31-35 years (57%), married (75%) and parents (62%). Upon graduation, 12% did not find transplant jobs (including 8% of Americans/Canadians), 14% did not get jobs for transplanting their preferred organ(s), 11% wished they focused more on transplantation and 27% changed jobs early. Half fellows were international medical graduates; 45% found US/Canadian transplant jobs, particularly 73% with US/Canadian residency training. Fellows reported adequate exposure to training volume, candidate selection, pre/postoperative care and organ procurement, but not to donor management/selection, outpatient care and core didactics. One-sixth noted insufficient 'mentoring/preparation for a transplantation career'. Currently, there seem to be enough trainees to fill entry-level positions. One-third program directors believe that there are too many trainees, given the current and foreseeable job market. ASTS is assessing the total workforce of transplant surgeons and evolving manpower needs.

Background & aimsA substantial proportion of pediatric liver transplant recipients develop subclinical chronic allograft injury. We studied whether there are distinct patterns of injury based on histopathologic features and identified associated immunologic profiles.MethodsWe conducted a cross-sectional study of 157 stable, long-term pediatric recipients of transplanted livers (70 boys; > 6 years old at time of transplantation; mean, 8.9 ± 3.46 years after liver transplantation) who underwent liver biopsy analysis from August 13, 2012, through May 1, 2014. Participants had received livers from a living or deceased donor and had consistently normal results from liver tests. Liver biopsy specimens were scored by a central pathologist; anunsupervised hierarchical cluster analysis of histologic features was used to sort biopsy samples into 3 clusters. We conducted transcriptional and cytometric analyses of liver tissue samples and performed a systems biology analysis that incorporated clinical, serologic, histologic, and transcriptional data.ResultsThe mean level of alanine aminotransferase in participants was 27.6 ± 14.57 U/L, and the mean level of γ-glutamyl transferase was 17.4 ± 7.93 U/L. Cluster 1 was characterized by interface activity (n= 34), cluster 2 was characterized by periportal or perivenular fibrosis without interface activity (n= 45), and cluster 3 had neither feature (n=78). We identified a module of genes whose expression correlated with levels of alanine aminotransferase, class II donor-specific antibody, portal inflammation, interface activity, perivenular inflammation, portal and perivenular fibrosis, and cluster assignment. The module was enriched in genes that regulate T-cell-mediated rejection (TCMR) of liver and other transplanted organs. Functional pathway analysis showed overrepresentation of TCMR gene sets for cluster 1 but not clusters 2 or3.ConclusionIn an analysis of biopsies froman apparently homogeneous group of stable, long-termpediatric liver transplant recipients with consistently normalliver test results, we found evidence of chronic graft injury (inflammation and/or fibrosis). Biopsy samples with interface activity had a gene expression pattern associated withTCMR.

Impaired kidney function is a well-recognized complication following liver transplantation (LT). Studies of this complication in children have been limited by small numbers and insensitive outcome measures. Our aim was to define the prevalence of, and identify risk factors for, post-LT kidney dysfunction in a multicenter pediatric cohort using measured glomerular filtration rate (mGFR). We conducted a cross-sectional study of 397 patients enrolled in the Studies in Pediatric Liver Transplantation (SPLIT) registry, using mGFR90 mL/min/1.73 m(2) as the primary outcome measure. Median age at LT was 2.2 years. Primary diagnoses were biliary atresia (44.6%), fulminant liver failure (9.8%), metabolic liver disease (16.4%), chronic cholestatic liver disease (13.1%), cryptogenic cirrhosis (4.3%) and other (11.8%). At a mean of 5.2 years post-LT, 17.6% of patients had a mGFR90 mL/min/1.73 m(2) . In univariate analysis, factors associated with this outcome were transplant center, age at LT, primary diagnosis, calculated GFR (cGFR) at LT and 12 months post-LT, primary immunosuppression, early post-LT kidney complications, age at mGFR, height and weight Z-scores at 12 months post-LT. In multivariate analysis, independent variables associated with a mGFR90 mL/min/1.73 m(2) were primary immunosuppression, age at LT, cGFR at LT and height Z-score at 12 months post-LT.

To examine transition readiness, adherence, and health out- comes in pediatric liver transplant recipients using a clinically admin- istered screening measure. Seventy-one pediatric liver transplant recipients (11-20 yr) and 58 parents completed a clinic-based TRS measuring perceived and demonstrated self-management skills, AoR for health-related tasks, regimen knowledge, and psychosocial adjustment. Adherence was measured using s.d. of immunosuppressants, proportion of immunosuppressant blood levels out of target range, and clinic attendance. Health outcomes included liver test panels, biopsies, rejec- tion episodes, and hospitalizations. Results indicate that all domains of transition readiness, with the exception of demonstrated skills, and non- adherence were positively correlated with age. Proportion of immuno- suppressant blood levels below target range was positively correlated with self-management skills and increased responsibility for medication tasks. Parent regimen knowledge was associated with clinic attendance. Health outcomes were significantly related to medication non-adher- ence, but not to transition readiness domains. Medication adherence is considered to be a key factor in the transition from pediatric to adult- centered transplant care. Non-adherence is associated with an increased risk for medical complications and is potentially modifiable. Interven- tions to promote self-management skills and adherence should be an essential component of transition planning.

Note on sources: The articles in this report are based on the reference tables in the 2009 OPTN/SRTR Annual Report, which are not included in this publication. Many relevant data appear in the figures and tables included here. All of the tables may be found online at: http://www.ustransplant.org. Improving short-term results with intestine transplantation have allowed more patients to benefit with nearly 700 patients alive in the United States with a functioning allograft at the end of 2007. This success has led to an increase in demand. Time to transplant and waiting list mortality have significantly improved over the decade, but mortality remains high, especially for infants and adults with concomitant liver failure. The approximately 200 intestines recovered annually from deceased donors represent less than 3% of donors who have at least one organ recovered. Consent practice varies widely by OPTN region. Opportunities for improving intestine recovery and utilization include improving consent rates and standardizing donor selection criteria. One-year patient and intestine graft survival is 89% and 79% for intestineonly recipients and 72% and 69% for liver-intestine recipients, respectively. By 10 years, patient and intestine survival falls to 46% and 29% for intestine-only recipients, and 42% and 39% for liver-intestine, respectively. Immunosuppression practice employs peri-operative antibody induction therapy in 60% of cases; acute rejection is reported in 30%–40% of recipients at one year. Data on long-term nutritional outcomes and morbidities are limited, while the cause and therapy for late graft loss from chronic rejection are areas of ongoing investigation.

Single-center studies have shown acceptable long-term outcomes following orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) when tumors are within the Milan criteria. However, the overall survival and waiting list removal rates have not been described at a national level with pooled registry data. To evaluate this, a retrospective cohort of patients listed for OLT with a diagnosis of HCC between January 1998 and March 2006 was identified from Organ Procurement Transplant Network data. Analysis was performed from the time of listing. Adjusted Cox models were used to assess the relative effect of potential confounders on removal from the waiting list as well as survival from the time of wait listing. A total of 4482 patients with HCC were placed on the liver waiting list during the study period. Of these, 65% underwent transplantation, and 18% were removed from the list because of tumor progression or death. The overall 1- and 5-year intent-to-treat survival for all patients listed was 81% and 51%, respectively. The 1- and 5-year survival was 89% and 61% for those listed with tumors meeting the Milan criteria versus 70% and 32% for those exceeding the Milan criteria (P 0.0001). On multivariate analysis, advanced liver failure manifested by Child-Pugh class B or C increased the risk of death, while age 55 years, meeting the Milan criteria, and obtaining a liver transplant were associated with better survival. The current criteria for liver transplantation of candidates with HCC lead to acceptable 5-year survival while limiting the dropout rate. Liver Transpl 15:859-868, 2009. © 2009 AASLD.

The objective was to review the current state of knowledge and recommend future research directions related to long-term outcomes for pediatric liver transplant recipients. A 1-day Clinical Research Workshop on Improving Long-Term Outcomes for Pediatric Liver Transplant Recipients was held on February 12, 2007, in Washington, DC. The speaker topics were germane to research priorities delineated in the chapters on Pediatric Liver Diseases and on Liver Transplantation in the Trans-NIH Action Plan for Liver Disease Research. Issues that compromise long-term well-being and survival but are amenable to existing and new research efforts were presented and discussed. Areas of research that further enhanced the research priorities in the Action Plan for Liver Disease Research included collection of longitudinal data to define emerging trends of clinical challenges; identification of risk factors associated with long-term immunosuppression complications; development of tolerance-inducing regimens; definition of biomarkers that reflect the level of clinical immunosuppression; development of instruments for the measurement of health wellness; identification of risk factors that impede growth and intellectual development before and after liver transplantation and identification of barriers and facilitators that impact nonadherence and transition of care for adolescents.

Hepatopulmonary syndrome is an uncommon complication of nonacute liver failure, and in rare cases, hypoxia may be the presenting sign of liver dysfunction. The condition, once thought to be a contraindication, is improved in most cases by transplantation. There is a significant risk of postoperative, hypoxia-related morbidity and mortality in patients with hepatopulmonary syndrome. We present a case of life-threatening hypoxia following liver transplantation for liver failure and associated hepatopulmonary syndrome, with successful management using extracorporeal membrane oxygenation.

This article represents the sixth annual review of the current state of pediatric transplantation in the United States from the Scientific Registry of Transplant Recipients (SRTR). It presents updated trends, discussion of analyses presented during the year by the SRTR to the committees of the Organ Procurement and Transplantation Network (OPTN) and discussion of important issues currently facing pediatric organ transplantation. Unless otherwise stated, the statistics in this article are drawn from the reference tables of the 2007 OPTN/SRTR Annual Report. In this article, pediatric patients are defined as candidates, recipients or donors aged 17 years or less. Data for both graft and patient survival are reported as unadjusted survival, unless otherwise stated (adjusted patient and graft survival are available in the reference tables). Short-term survival (3 month and 1 year) reflects outcomes for transplants performed in 2004 and 2005; 3-year survival reflects transplants from 2002 to 2005; and 5-year survival reports on transplants performed from 2000 to 2005. Details on the methods of analysis employed may be found in the reference tables themselves or in the technical notes of the 2007 OTPN/SRTR Annual Report, both available online at http://www.ustransplant.org.

Surgical complications following pediatric liver transplantation are common and expensive. We examined the incremental costs of surgical complications and determined who pays for these complications (center or payer). We reviewed the records of 36 pediatric liver transplant patients aged

Malnutrition is a significant clinical problem in infants with biliary atresia. The natural history of poor growth and its potential association with early transplantation or death in children with biliary atresia was determined. Serial weight- and length-for-age z-scores were computed as part of a retrospective study of 100 infants who underwent hepatoportoenterostomy (HPE) for biliary atresia at 9 U.S. pediatric centers between 1997 and 2000. Poor outcome was defined as transplantation or death by 24 months of age (n = 46) and good outcome was defined as survival with native liver at 24 months of age with total serum bilirubin less than 6 mg/dL (n = 54). Growth velocity was significantly slower in the poor outcome group compared to the good outcome group (P < 0.001 for both weight and length). Mean weight z-scores were significantly lower by 6 months after HPE in the poor outcome group (−2.1 ± 1.4) compared to the good outcome group (−1.2 ± 1.4) (P < 0.001). In a subgroup with total bilirubin between 2 and 6 mg/dL at 3 months after HPE (n = 28), the weight z-scores at 3 months after HPE were significantly lower in the poor outcome group (−2.0 ±1.2) compared to the good outcome group (−1.0 ± 1.2) (P = 0.04) despite similar bilirubin concentrations. Conclusion: Growth failure after HPE was associated with transplantation or death by 24 months of age. The combination of intermediate bilirubin concentrations and poor mean weight z-scores 3 months after HPE was also associated with poor clinical outcome. (HEPATOLOGY 2007.)

Late graft loss (LGL) and late mortality (LM) following liver transplantation (LT) in children were analyzed from the studies of pediatric liver transplantation (SPLIT) database. Univariate and multivariate associations between pre- and postoperative factors and LGL and LM in 872 patients alive with their primary allografts 1 year after LT were reviewed. Thirty-four patients subsequently died (LM) and 35 patients underwent re-LT (LGL). Patients who survive the first posttransplant year had 5-year patient and graft survival rates of 94.2% and 89.2%, respectively. Graft loss after the first year was caused by rejection in 49% of the cases with sequelae of technical complications accounting for an additional 20% of LGL. LT for tumor, steroid resistant rejection, reoperation in the first 30 days and >5 admissions during the first posttransplant year were independently associated with LGL in multivariate analysis. Malignancy, infection, multiple system organ failure and posttransplant lymphoproliferative disease accounted for 61.8% of all late deaths after LT. LT performed for FHF and tumor were associated with LM. Patients who are at or below the mean for weight at the time of transplant were also at an increased risk of dying. Frequent readmission was also found to be associated with LM.

To examine the outcome of technical variant liver transplant techniques relative to whole organ liver transplantation in pediatric liver transplant recipients.Technical variant liver transplant techniques comprising split, reduced, and live-donor liver transplantation evolved to address the need for timely and size appropriate grafts for pediatric recipients.Analysis of data from the Studies of Pediatric Liver Transplantation (SPLIT) registry, a multicenter database of 44 North American pediatric liver transplant programs. The outcome (morbidity and mortality) of each of the technical variants were compared with that of whole organ recipients.Data were available on 2192 transplant recipients (1183 whole, 261 split, 388 reduced, and 360 live donor). Recipients of all technical variant graft type were significantly younger than whole organ recipients, but on average spent 2.3 months less on the waiting list. Thirty-day post-transplant morbidity was increased for each type of technical variant relative to whole organ (45.1% whole, 66.7% split, 65.5% reduced, 51.9% live-donor). Biliary complications (30 day: 7.5% whole, 18.8% split, 16% reduced, 17.5% live-donor) and portal vein thrombosis (30 day: 3.6% whole, 8% split, 8% reduced, 7.5% live-donor) were more common in all technical variant types. Graft type was an independent predictor of graft loss (death or retransplantation) in a multivariate analysis. Split and reduced (relative risk = 1.74 and 1.77, respectively) grafts had a worse outcome when compared with whole organ recipients.Technical variant techniques expand the pediatric donor pool and reduce time from listing to transplant, but they are associated with increased morbidity and mortality.

We quantified the financial implications of surgical complications following pancreas transplantation. We reviewed medical and financial records of 49 pancreas transplant recipients at the University of Michigan Health System (UMHS) between 1/6/2002 and 11/22/2004. The association of donor, transplant recipient and financial variables was assessed. The median costs to UMHS of procedures and follow-up were $92,917 for recipients without surgical complications versus $108,431 when a surgical complication occurred, a difference of $15,514 (p = 0.03). Median reimbursement by the payer was $17,363 higher in patients with a surgical complication (p = 0.001). Similar trends (higher insurer costs) were noted when stratifying by payer (public and private) and specific procedure (SPK and PAK). All parties (patient, physician, payer and medical center) should benefit from quality improvement, with payers having a financial interest in pancreas transplant surgical quality initiatives.

Solid organ transplantation is accepted as a standard lifesaving therapy for end-stage organ failure in children. This article reviews trends in pediatric transplantation from 1996 to 2005 using OPTN data analyzed by the Scientific Registry of Transplant Recipients. Over this period, children have contributed significantly to the donor pool, and although the number of pediatric donors has fallen from 1062 to 900, this still accounts for 12% of all deceased donors. In 2005, 2% of 89,884 candidates listed for transplantation were less than 18 years old; in 2005, 1955 children, or 7% of 28,105 recipients, received a transplant. Improvement in waiting list mortality is documented for most organs, but pretransplant mortality, especially among the youngest children, remains a concern. Posttransplant survival for both patients and allografts similarly has shown improvement throughout the period; in most cases, survival is as good as or better than that seen in adults. Examination of immunosuppressive practices shows an increasing tendency across organs toward tacrolimus-based regimens. In addition, use of induction immunotherapy in the form of anti-lymphocyte antibody preparations, especially the interleukin-2 receptor antagonists, has increased steadily. Despite documented advances in care and outcomes for children undergoing transplantation, several considerations remain that require attention as we attempt to optimize transplant management.

The prospect of graft loss is a problem faced by all transplant recipients, and retransplantation is often an option when loss occurs. To assess current trends in retransplantation, we analyzed data for retransplant candidates and recipients over the last 10 years, as well as current outcomes. During 2005, retransplant candidates represented 13.5%, 7.9%, 4.1% and 5.5% of all newly registered kidney, liver, heart and lung candidates, respectively. At the end of 2005, candidates for retransplantation accounted for 15.3% of kidney transplant candidates, and lower proportions of liver (5.1%), heart (5.3%) and lung (3.3%) candidates. Retransplants represented 12.4% of kidney, 9.0% of liver, 4.7% of heart and 5.3% of lung transplants performed in 2005. The absolute number of retransplants has grown most notably in kidney transplantation, increasing 40% over the last 10 years; the relative growth of retransplantation was most marked in heart and lung transplantation, increasing 66% and 217%, respectively. The growth of liver retransplantation was only 11%. Unadjusted graft survival remains significantly lower after retransplantation in the most recent cohorts analyzed. Even with careful case mix adjustments, the risk of graft failure following retransplantation is significantly higher than that observed for primary transplants.

Chronic renal dysfunction may develop after pediatric heart transplantation (PHTx). We examined the incidence of end-stage renal disease (ESRD) and chronic renal insufficiency (CRI) after PHTx, the associated pre-transplant patient characteristics, and impact of renal disease on survival.Data sources included the Scientific Registry of Transplant Recipients, Centers for Medicare and Medicaid Services and the Social Security Death Master File. All PHTx recipients (age18 years) in the USA from 1990 to 1999 who survived1 year were included. ESRD was defined as long-term dialysis and/or kidney transplant. CRI was defined as creatinine2.5 mg/dl, including those with ESRD. Relationships between pre-transplant characteristics and time to ESRD and CRI were analyzed using Cox proportional hazards models. The effect of renal disease on survival was analyzed using time-dependent Cox models.During the mean follow-up of 7 years (range 1 to 14 years), 61 of 2,032 (3%) PHTxs developed ESRD. Ten-year actuarial risks for ESRD and CRI were 4.3% and 11.8%, respectively. In a multivariate analysis, significant risk factors for ESRD were: hypertrophic cardiomyopathy; African-American race; intensive care unit (ICU) stay or extracorporeal membrane oxygenation (ECMO) at time of transplant; and pre-transplant diabetes. Risk factors for CRI were: pre-transplant dialysis; hypertrophic cardiomyopathy; African-American race; and previous transplant. Adjusted risk of death in those who developed CRI was 9-fold higher than in those who did not (p0.0001).After PHTx there is an increasing risk for CRI and ESRD over time. Recipients with the characteristics identified in this study may be at greater risk. Development of renal disease significantly increases the risk of post-transplant mortality.

The transition from pediatric to adult transplant care is a high risk period for non-adherence and poor health outcomes. This article describes a quality improvement initiative integrated into a pediatric liver transplant program that focused on improving outcomes following the transfer from pediatric to adult liver transplant care. Using improvement science methodology, we evaluated the impact of our center’s transition readiness skills (TRS) program by conducting a chart review of 45 pediatric liver transplant recipients who transferred to adult transplant care. Medication adherence, clinic attendance, and health status variables were examined for the year pre-transfer and first year post-transfer. 19 recipients transferred without participating in the TRS program (control group) and 26 recipients participated in the program prior to transferring to the adult clinic (TRS group). The TRS group was significantly older at the time of transfer, more adherent with medications, and more likely to attend their first adult clinic visit compared to the control group. Among the TRS group, better adolescent and parent regimen knowledge were associated with greater adherence to post-transfer clinic appointments. Transition planning should focus on the gradual shift in responsibility for health management tasks, including clinic attendance, from parent to adolescent. There may be support for extending transition support for at least 1 year post-transfer to promote adherence.

Given the increased risk for nonadherence and poor health outcomes in late adolescence, there is a need for better methods to evaluate and improve the transition process as adolescent patients are prepared to be independent adults. This study assessed the psychometrics and concurrent validity of a newly developed measure of the allocation of responsibility for health management in pediatric liver transplant patients. 48 patients and 37 parents completed a 13-item measure of allocation of responsibility. We performed an exploratory principal components analysis on survey results and used component scores to assess the relationship between allocation of responsibility and age, age at transplant, adherence, and health outcomes. Two primary components were identified: Communication with the Health Care System, and Self-Management Tasks. Parent perception of adolescent responsibility for tasks related to communicating with the healthcare system was correlated, in younger patients, with increased nonadherence while responsibility for tasks related to self-management was correlated, in older patients, with decreased nonadherence. These results support allocation of responsibility as a two-domain construct, and they provide targets for monitoring and intervention as adolescent patients advance towards transfer.

This article reviews trends in pediatric solid organ transplantation over the last decade, as reflected in OPTN/SRTR data. In 2004, children younger than 18 years made up nearly 3% of the 86,378 candidates for organ transplantation and nearly 7% of the 27,031 organ transplant recipients. Children accounted for nearly 14% of the 7152 deceased organ donors. The transplant community recognizes important differences between pediatric and adult organ transplant recipients, including different etiologies of organ failure, surgical procedures that are more complex or technically challenging, effects of development on the pharmacokinetic properties of common immunosuppressants, unique immunological aspects of transplant in the developing immune system and increased susceptibility to posttransplant complications, particularly infectious diseases. For these reasons, and because of the impact of end-stage organ failure on growth and development, the transplant community has generally provided pediatric candidates with special consideration in the allocation of deceased donor organs. Outcomes following kidney, liver and heart transplantation in children often rank among the best. This article emphasizes that the prospects for solid organ transplantation in children, especially those aged 1-10 years are excellent. It also identifies themes warranting further consideration, including organ availability, adolescent survival and challenges facing pediatric transplant clinical research.

The 2005 American Society of Transplant Surgeons (ASTS) Winter Symposium entitled ‘The Art and Science of Immunosuppression’ explored ways to maximize existing immunosuppressive protocols and to develop new strategies incorporating novel agents and emerging diagnostic technologies to customize immunosuppression and reduce side effects. Several presentations evaluated steroid withdrawal or avoidance protocols reflecting the significant difficulties of bone loss, glucose control and growth retardation in children associated with long-term steroid use. Calcineurin-inhibitor related renal dysfunction of both native and transplanted kidneys was identified as significant, but no consensus was reached concerning effective prevention. Similarly, recurrence of Hepatitis C following liver transplantation was identified as problematic without identifying a preferred immunosuppressive regimen in this setting. Control of T-cell mediated rejection was found to be excellent, but recognition and treatment of non-T cell causes of allograft damage (i.e. B- or NK-cell mediated) was identified as an area of current interest. Immunosuppressive agents under development, such as those blocking co-stimulation or cytokine signals, and JAK-3 inhibitors were discussed. Finally, the available technologies for molecular and genetic diagnostics and the clinical correlation in the post-transplant setting were discussed.

Introduction: It is unclear how to manage high risk hemodialysis patients who present with an indwelling catheter. The National Kidney Foundation Practice Guidelines urge prompt removal of the catheter, but the guidelines do not specifically address the problem of patients whose only option is a femoral arteriovenous (AV) graft. Methods: This study was a retrospective review of all patients who underwent femoral AV graft placement for hemodialysis access between January 1, 1996 and January 1, 2003 at the University of Michigan Health System (UMHS). Graft patency is reported according to the standards developed by the Society of Vascular Surgery and the American Association of Vascular Surgeons. Results: Thirty patients were identified who had undergone femoral AV graft placement. The mean follow-up was 23 months (range 1‐75 months). The patients had had significant medical comorbidities and multiple previous access operations (mean 3; interquartile range 1‐5). The 1-year secondary graft patency rate was 41%, the 2-year rate was 26%, and the 3-year rate was 21%. Infection was the cause of final graft loss in eight patients (50% of the grafts losses, 27% of the total grafts placed.) Among those who died (n = 14), the mean time from femoral graft placement to death was 31.2 – 27.5 months. The patient survival was quite low: at 1 year 81%, at 2 years 68%, and at 3 years 54%. Conclusions: These complex patients who have exhausted their upper extremity hemodialysis options do poorly following femoral AV graft placement. Consideration should be given to longterm catheter-based access in some of these patients.

Background Vancomycin-resistant enterococcal (VRE) infections cause significant morbidity and mortality among patients undergoing liver transplantation. We performed a prospective study among patients awaiting transplantation to assess rates, risk factors, and outcomes associated with VRE colonization before and after transplantation. Methods All adults on the transplantation waiting list from 2000-2003 were eligible. Demographic, historical, and laboratory data, as well as stool samples to be analyzed for VRE, were collected at enrollment and every 4-6 months thereafter until transplantation. After transplantation, samples were obtained every 3 days during hospitalization and were analyzed for VRE; outcomes were assessed at 90 days. Results Overall, 375 patients were enrolled in our study, and 142 received transplants. VRE colonization occurred in 50 (13%) of 375 patients before transplantation and was independently associated with treatment with antianaerobic antimicrobials, third-generation cephalosporins, proton pump inhibitors, or neomycin; having a recent endoscopic retrograde cholangiopancreatogram or paracentesis procedure; and admission to the liver unit. Of these 50 patients, 22 (44%) received a transplant, and 7 (32%) of 22 developed a VRE infection after transplantation. An additional 22 patients (18%) who were not colonized before transplantation acquired VRE after transplantation; VRE infection developed in 5 (23%) of these patients. Patients colonized with VRE either before or after transplantation had longer stays in the intensive care unit and the hospital. Mortality at 90 days was significantly greater among those who acquired VRE after transplantation (5 [23%] of 22), compared with those who had VRE colonization before transplantation (2 [9%] of 22). Conclusions Liver transplantation candidates with VRE colonization before transplantation experience greater morbidity but not greater mortality, compared with noncolonized candidates. Transplant recipients who acquire VRE after transplantation have a higher mortality rate than noncolonized recipients. Strategies should be implemented to reduce nosocomial VRE acquisition after transplantation among this vulnerable group.

CD4(+) T cells that respond to indirectly presented alloantigen have been shown to mediate chronic rejection, however, the role of the indirect pathway in acute rejection has yet to be completely elucidated. To this end, BALB/c or C57BL/6 mice were depleted of CD8(+) T cells and transplanted with class II transactivator (CIITA)-deficient cardiac allografts, which cannot directly present class II alloantigens to CD4(+) T cells. In this manner, the rejection response by CD4(+) cells was forced to rely upon the indirect recognition pathway. When not depleted of CD8(+) cells, both BALB/c and C57BL/6 mice rejected CIITA-/- allografts and a polarized Th1 response was observed. In contrast, when BALB/c recipients of CIITA-/- allografts were depleted of CD8(+) T cells, the grafts were acutely rejected and a strong Th2 response characterized by eosinophil influx into the graft was observed. Interestingly, CD8-depleted C57BL/6 recipients of CIITA-/- allografts did not acutely reject their transplants and a Th2 response was not mounted. These findings indicate that CD4(+) T cells responding to indirectly presented alloantigens mediate graft rejection in a Th2-dominant manner, and provide further evidence for the role of Th2 responses in acute graft rejection.

Background. This study evaluated the efficacy of a protocol of initial balloon dilation for biliary strictures after liver transplantation. Methods. Complete records from 96 patients with biliary strictures were retrospectively reviewed. Seventy-six patients received percutaneous transhepatic balloon cholangioplasty (PTBC) after initial placement of biliary drainage (percutaneous transluminal cholangiography [PTC]) tube. In most cases, three dilations were performed with a 4 to 8 week interval between procedures. Follow-up ranged from 6 months to 10 years. Results. PTBC successfully treated strictures in 39 of 76 (51.3%) cases. Factors favoring successful PTBC included older age at transplant, shorter cold ischemic time, and single strictures. There were nine recurrent strictures after PTBC, all of which were successfully treated by nonoperative measures. The number of dilations performed affected both the likelihood of success and the long-term risk of stricture recurrence. Of the 37 PTBC failures, 14 underwent subsequent surgical revision. When both angiographic and surgical modalities were considered, treatment success was associated with first transplants, shorter cold ischemic time and operative time, and less intraoperative transfusion requirements. Factors associated with treatment failure included multiple, central hepatic duct, and intrahepatic strictures. PTC-tube independence was achieved in 51 of 76 (67%) patients using the combined approach of PTBC and surgery for PTBC failures. Conclusions. PTBC is an effective initial modality for treating posttransplant biliary strictures. Prolonged cold ischemic and operative times and multiple or peripheral strictures predispose to treatment failure. Solitary extrahepatic strictures that fail PTBC are salvageable with surgical revision with excellent results.

The survival benefit of simultaneous liver-kidney transplantation (SLKT) over liver transplantation alone (LTA) is unclear from the current literature. Additionally, the role of donor kidney quality, measured by the kidney donor risk index (KDRI), in survival benefit of SLKT is not studied. We compared survival benefit after SLKT and LTA among recipients with similar pretransplant renal dysfunction using novel methodology, specifically with respect to survival probability and area under the survival curve by dialysis status and KDRI. Data were obtained from the Scientific Registry of Transplant Recipients. The study cohort included patients with pre-liver transplantation (LT) renal dysfunction who were wait-listed and received either a SLKT (n = 1326) or a LTA (n = 4283) between March 1, 2002 and December 31, 2009. Inverse Probability of Treatment Weighting-SLKT and LTA survival curves, along with the 5-year area under the survival curve, were computed by dialysis status at transplant. The difference in the area under the curve represents the average additional survival time gained via SLKT over LTA. For patients not on dialysis, SLKT resulted in a significant 3.7-month gain in 5-year mean posttransplant survival time. The decrease in mortality rate differs significantly by KDRI, and an estimated 76% of SLKT recipients received a kidney with KDRI sufficiently low for mortality. The mortality decrease for SLKT was concentrated in the first year after transplant. The difference between SLKT and LTA 5-year mean posttransplant survival time was 1.4 months and was nonsignificant for patients on dialysis. In conclusion, the propensity score-adjusted survival among SLKT and LTA recipients was similar for those who were on dialysis at LT. Although statistically significant, the survival advantage of SLKT over LTA was of marginal clinical significance among patients not on dialysis and occurred only if the donor kidney was of sufficient quality. These results should be considered in the ongoing debate regarding the allocation of kidneys to extra-renal transplant candidates.

Objectives To examine the medical status of children with biliary atresia (BA) with their native livers after hepato- portoenterostomy (HPE) surgery. Study design The Childhood Liver Disease Research and Education Network database was utilized to examine subjects with BA living with their native livers 5 or more years after HPE and to describe the prevalence of subjects with BA with an “ideal” outcome, defined as no clinical evidence of chronic liver disease, normal liver biochemical indices (aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, platelet count, total bilirubin, international normalized ratio, and albumin), and normal health-related quality of life 5 or more years after HPE. Results Children with BA (n = 219; 43% male) with median age 9.7 years were studied. Median age at HPE was 56 (range 7-125) days. Median age- and sex-adjusted height and weight z-scores at 5-year follow-up were 0.487 (IQR −0.27 to 1.02) and 0.00 (IQR −0.74 to 0.70), respectively. During the 12 preceding months, cholangitis and bone fractures occurred in 17% and 5.5%, respectively. Health-related quality of life was reported normal by 53% of patients. However, only 1.8% met the study definition of “ideal” outcome. Individual tests of liver synthetic function (total bilirubin, albumin, and international normalized ratio) were normal in 75%, 85%, and 73% of the study cohort. Conclusion Cholangitis and fractures in long-term survivors underscore the importance of ongoing medical surveillance. Over 98% of this North American cohort of subjects with BA living with native livers 5 or more years after HPE have clinical or biochemical evidence of chronic liver disease.