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To compare the incidence of acute histologically proven rejection in children who have had a liver transplant for hepatoblastoma with a control group of children transplanted for biliary atresia (EHBA). A retrospective case notes based study was performed. Twenty patients were identified with hepatoblastoma who were transplanted at a single unit between 1991 and 2008. These were matched as closely as possible for age, gender, year of transplant and type of immunosuppression used to the control group transplanted for biliary atresia (n = 60). There was a significant decrease in rate of acute rejection as assessed by the rejection activity index (RAI) in the hepatoblastoma group (75% vs. 50%, respectively, p < 0.04). Chronic rejection was rare in both groups, but twice as common in the biliary atresia group. Equal levels of immunosuppression were achieved in both groups. Renal function was noted to be reduced one yr post-transplant in both groups, as previously reported. A modified immunosuppression regimen could be considered in children with hepatoblastoma undergoing liver transplantation., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A male infant was diagnosed with atypical hemolytic uremic syndrome (aHUS) at the age of 5.5 months. Sequencing of the gene (CFH) encoding complement factor H revealed a heterozygous mutation (c.3644G>A, p.Arg1215Gln). Despite maintenance plasmapheresis he developed recurrent episodes of aHUS and vascular access complications while maintaining stable renal function. At the age of 5 years he received an isolated split liver graft following a previously established protocol using pretransplant plasma exchange (PE) and intratransplant plasma infusion. Graft function, renal function and disease remission are preserved 2 years after transplantation. Preemptive liver transplantation prior to the development of end stage renal disease is a valuable option in the management of aHUS associated with CFH mutations.

Orthotopic liver transplantation (OLT) is effective therapy for end-stage liver disease but immunosuppression with calcineurin inhibitors (CNI) leads to significant nephrotoxicity, resulting in either a reduction of dosage to below the therapeutic level or omission of the drug altogether. Basiliximab (Bx) is a human/mouse chimeric monoclonal antibody that inhibits binding of interleukin-2 (IL-2) to IL-2 receptors and thus prevents proliferation of T cells, which is the main step in the development of acute cellular rejection. The aim of this study was to identify the role of Bx in the prevention of acute cellular rejection and in the reduction of nephrotoxicity in children post-liver transplantation. We evaluated three children (19 months, 22 months, and 11 yr of age; one male, two female) who were treated with Bx post-OLT on compassionate grounds. The indications were: nephrotoxicity in two children, requiring re-transplantation for hepatic artery thrombosis and recurrent giant cell hepatitis, respectively; and nephrotoxicity secondary to chemotherapy for hepatoblastoma in the third child. All patients received 10 mg of Bx, at OLT and on Day 4. Tacrolimus (0.15 mg/kg/day) was started at 48 h (n = 2) and cyclosporin (5 mg/kg/day) at 2 weeks (n = 1). Trough levels of tacrolimus were maintained at 5-8 ng/mL and trough levels of cyclosporin at 100-150 mg/L for the first 3 months. All patients received methylprednisolone (2 mg/kg) with azathioprine (1.5 mg/kg) (n = 2) and/or mycophenolate mofetil (20 mg/kg) (n = 1). The glomerular filtration rate (cGFR) was calculated using the Schwartz formula before and 10 weeks after transplant. Bx was found to be easy to administer and no major side-effects were reported. One child had two episodes of mild acute rejection at 5 and 9 weeks post-OLT and one developed chronic rejection requiring re-transplantation at 9 weeks post-OLT. One child did not develop rejection. The mean pretransplant cGFR was 58.1 (54.6-64.1) mL/min/m2. Within 10 weeks of transplantation, the cGFR had improved by 69% to a mean of 116 (88-157.6) mL/min/m2. To conclude, Bx was well tolerated in all children and had a renal sparing effect. It was effective in preventing early acute rejection, but the combination of Bx and low-dose CNI drugs did not prevent late acute or chronic rejection. Further studies to evaluate the appropriate levels of CNI immunosuppression with Bx are required.

It is believed that liver transplantation may improve the outcome of early onset methylmalonic acidemia. We report a case of methylmalonic acidemia in which successful liver transplantation in infancy failed to prevent neurologic damage caused by a metabolic stroke.

Background: Neonates and small infants represent less than 5% of paediatric candidates for liver replacement. Most cases present under urgent conditions and receive grafts from large donors. Surgical techniques must be adapted for adequate graft preparation, vascular reconstruction, and abdominal closure., Methods: Technical aspects and outcome of 15 liver transplantations in infants weighing less than 5 kg performed at our unit were analysed retrospectively., Results: Liver transplantation was performed under urgent or highly urgent condition in 13 cases. Reduced or split liver grafts were used in all cases (median donor to recipient weight ratio, 9), including a monosegmental graft in 2 cases. In 10 cases, vascular reconstruction was done using a vascular conduit (5, 4, and 1 for artery, portal, and hepatic veins, respectively) and a delayed closure of the abdomen was necessary in 7 children. Postoperative complications were as follows: thrombosis of hepatic artery (n = 1) or portal vein (n = 1), gastrointestinal haemorrhage (n = 2), intraperitoneal bleeding (n = 1), biliary stricture (n = 2), septicaemia (n = 1). Two infants died of brain damage with a functioning graft. One child underwent retransplant for chronic rejection., Conclusions: Overall, survival rate is 60% (median follow-up, 34 months), which compares favourably with older patient groups when case mix is comparable.

Background: Adoptive immunotherapy with autologous and donor-derived cytotoxic T lymphocytes (CTL) has recently been used to treat Epstein Barr virus (EBV)-positive posttransplant lymphoproliferative disease (PTLD)., Methods and Results: We report complete regression of EBV-positive PTLD in an 18-month-old small bowel and liver transplant recipient after one infusion of partially human leukocyte antigen (HLA)-matched EBV-specific CTL grown ex vivo from an EBV seropositive unrelated blood donor. No infusion-related toxicity or evidence of graft-versus-host disease was observed. The tumor showed signs of regression within 1 week and EBV load in peripheral blood dropped to undetectable levels. Limiting dilution analyses (LDA) detected no EBV-specific CTL precursor (CTLp) cells before the infusion, and high numbers of CTLp at 4 hr and 24 hr post-CTL infusion. There was a reversal of the CD4/8 ratio in peripheral blood and an increase in HLA-DR positive CD8 cells. The patient has been in complete remission for 24 months., Conclusion: If this success is repeated in more PTLD patients, then stored CTL could be used for antiviral and antitumor therapies in immunocompromised patients.

Background: Primary hyperoxaluria type 1 (PH1) is a rare condition in which deficiency of the liver enzyme alanine:glyoxylate aminotransferase leads to renal failure and systemic oxalosis. Combined liver-kidney transplantation (LKT) is recommended for end-stage renal failure (ESRF) in adults, but management of infants and young children is controversial. We retrospectively reviewed six children who underwent LKT for PH1., Methods: The median age at diagnosis was 1.8 years (range 3 weeks to 7 years). Two children presented with severe infantile oxalosis at 3 and 9 weeks, five patients had ESRF with nephrocalcinosis and systemic oxalosis, (median duration of dialysis 1.3 years), and one had progressive chronic renal failure. Four children underwent combined LKT, one child staged liver then kidney, and one infant had an isolated liver transplant. The median age at transplantation was 8.9 years (range 1.7-15 years)., Results: Overall patient survival was four out of six. The two infants with PH1 and severe systemic oxalosis died (2 and 3 weeks post-transplant) due to cardiovascular oxalosis and sepsis. The other four children are well at median follow-up of 10 months (range 6 months to 7.4 years). No child developed hepatic rejection and all have normal liver function. Renal rejection occurred in three patients. Despite maximal medical management, oxalate deposits recurred in all renal grafts, contributing to graft loss in one (one of the infants who died), and significant dysfunction requiring haemodialysis post-transplant for 6 months., Conclusions: LKT is effective therapy for primary oxalosis with ESRF but has a high morbidity and mortality rate in children who present in infancy with nephrocalcinosis and systemic oxalosis. We feel that earlier LKT, or pre-emptive liver transplantation, may be a better therapeutic strategy to improve the outlook for these patients.

Background: The critical shortage of size-matched donor organs for infants and small children in need of combined liver and intestinal transplantation has lead to long waiting times and a high risk of dying before transplantation. Utilizing grafts from larger donors could alleviate this problem, but using larger composite grafts in small children has been challenging and unsuccessful in the past., Methods: We conducted a pilot study for evaluating the results of transplanting into small recipients a composite graft (reduced-size liver and whole small bowel, including duodenum and pancreas head) procured from large donors. Liver size reduction was performed ex situ using the extrahilar approach, which leaves the liver hilum untouched. Straightforward implantation of the graft was performed by simple, two-step vascular anastomoses. The preservation of the donor duodenum in continuity with the combined graft avoided the need for biliary reconstruction, thus preserving maximal bowel length for gut continuity restoration in the recipient., Results: Two children, weighing 7.6 and 9.8 kg, respectively, underwent transplantation of a composite graft procured from donors weighing 35 kg. Their waiting time (68 and 97 days, respectively) was shorter compared with our previous experience with conventional techniques. Both are currently alive and well, at home and on full enteral feeds, 15 and 11 months after transplantation, respectively., Conclusion: This new technique has extended the range of possible donors for small candidates waiting for combined grafts and was successful in two patients. It should be considered for small recipients in the future.

Background: Biliary atresia is an obliterative cholangiopathy of infancy that is fatal if untreated. Surgical treatment, the Kasai portoenterostomy, may restore bile flow and clear jaundice, and, if successful, achieve a 10-year survival of 90% with a native liver. The outcome of a 2-year cohort of children with biliary atresia in the UK and Ireland was assessed to find the current frequency, the factors influencing outcome, and the medium-term need for liver transplantation., Methods: Cases diagnosed between March, 1993, and February, 1995, were notified by paediatricians to the British Paediatric Surveillance Unit via a monthly reporting system. Confirmed cases were followed up by postal questionnaires to notifying paediatricians., Findings: 93 cases were confirmed, a frequency of 1/16700 livebirths. Primary surgery was done in 91 children in 15 surgical centres with an early success rate for clearing jaundice of 55% overall. Centres were grouped according to caseload; group A had more than 5 cases/year and group B fewer than 5 cases/year. Early success was higher in group-A centres, odds ratio 2.02 (95% CI 0.86-4.73), but this did not reach statistical significance. Of 41 children in whom surgery was unsuccessful in clearing jaundice 9 (22%) died and 30 (73%) underwent liver transplantation. Survival without liver transplantation and overall survival were both significantly greater in group-A centres, rate ratios 0.48 (95% CI 0.27-0.86) and 0.32 (0.11-0.94). Actuarial 5-year survival without transplantation was 61.3% in group-A centres and 13.7% in groupB centres. Actuarial 5-year overall survival was 91.2% in group A and 75% in group B. Once centre size was taken into account, no other factor, including age at surgery, was predictive of survival without transplantation or overall survival., Interpretation: The outcome of children with biliary atresia is related to the caseload of the surgical centre where they have their primary surgery. Children with biliary atresia should be managed in surgical centres with a caseload of more than five cases annually.

Unlabelled: The outcome for children with severe forms of methylmalonic acidaemia remains poor. Patients have recurrent episodes of metabolic decompensation; many have neurodevelopmental complications and the mortality is high. Long-term survivors develop chronic renal failure. Because of the poor prognosis, transplantation has been considered. In young patients with early onset disease, liver transplantation might prevent complications and, for those in end-stage renal failure, kidney transplantation could be combined with that of the liver. The results of liver transplantation in the early onset patients have generally been disappointing. In particular there appears to be a high risk of neurological complications. The optimal management of those in end-stage renal failure has not yet been determined although combined liver and kidney transplantation has been successful., Conclusion: The role of transplantation in methylmalonic acidaemia has yet to be established and follow up of all patients who are considered for transplantation is essential.

Background Nitisinone has transformed the management of hereditary tyrosinaemia type 1 (HT1). However, the risk of developing hepatocellular carcinoma is related to the age at which treatment is commenced. Little data on the outcome of children treated preemptively exist. Aim To describe the outcome of children with HT1 treated with nitisinone following selective newborn screening (NBS) and to compare their outcome with index siblings who had presented clinically. Subjects 12 children with HT1 were detected by NBS. Seven children were screened for HT1 because of an affected sibling (n=5). Four children were detected due to raised tyrosine concentrations on routine NBS and one child was born in a country with universal NBS for HT1. Outcome Nitisinone was commenced at 4 (1-52) days old. 6 children had an initial coagulopathy which resolved after 4 (1-7) days treatment. Currently at median age 8.5 (3-12.5) years all are clinically normal, with normal liver function tests and imaging. Those of school age are in normal classes but four have reported learning difficulties. Five index siblings presented clinically with acute liver failure (four) and chronic liver disease (one) at median 4 (1.5-17) months. One died of liver failure prior to nitisinone's availability. Four were treated with nitisinone; one failed to respond and underwent liver transplantation and three responded. One responder died from complications of prematurity and the remaining two have compensated liver disease. Summary Children with HT1 treated with nitisinone following NBS have an excellent outcome. Conclusions Universal NBS for HT1 should be introduced in the UK. [ABSTRACT FROM AUTHOR]

Aim: To identify the clinical and biochemical risk factors associated with outcome of paracetamol induced significant hepatotoxicity in children. Methods: Retrospective case notes review of those with paracetamol overdose admitted from 1992 to 2002. Patients were analysed in two groups: group I recovered after conservative treatment and group II developed progressive liver dysfunction and were listed for liver transplantation. Results: Of 51 patients (6 moles, 45 females, aged 0.8-16.1 years), 6 (aged <7 years) received cumulative multiple doses, and 45 a single large overdose (median 345 mg/kg, range 91-645). The median (range) interval to hospital at presentation post-ingestion was 24 hours (4-65) and 44 hours (24-96) respectively in groups I and II. Patients received standard supportive treatment including N- acetylcysteine. All children in group I survived. In group II, 6/11 underwent orthotopic liver transplantation (OLT) and 2/6 survived; 5/11 died awaiting OLT. Cerebral oedema was the main cause of death. Children who presented Late to hospital for treatment and those with progressive hepatotoxicity with prothrombin time >100 seconds, hypoglycaemia, serum creatinine >200 µmol/l, ocidosis (pH <7.3), and who developed encephalopathy grade III, had a poor prognosis or died. Although hepatic transaminase levels were markedly raised in both groups, there was no correlation with necessity for liver transplantation or death. Conclusion: Accidental or incidental paracetamol overdose in children may be associated with toxic liver damage leading to fulminant liver failure. Delayed presentation and/or delay in treatment, and hepatic encephalopathy ⩾grade III were significant risk factors, implying poor prognosis and need for OLT. Prompt identification of high risk patients, referral to a specialised unit for management, and consideration for liver transplantation is essential. [ABSTRACT FROM AUTHOR]

Abstract: Combination of cyclosporine (CsA) and tacrolimus immunosuppression post-liver transplantation (LT) and the chemotherapeutic drugs used to treat hepatoblastoma (HB), are nephrotoxic. We aimed to determine the severity and duration of nephrotoxicity in children following LT for unresectable HB. We reviewed all children undergoing LT for unresectable HB at the Liver Unit, Birmingham Children's Hospital, UK, from 1991 to July 2000. Thirty-six children undergoing LT for biliary atresia, matched for age and sex, were selected as controls to compare pre- and post-LT renal function. Renal function was determined by estimation of glomerular filtration rate (eGFR) derived from plasma creatinine using Schwartz's formula. Twelve children with HB (mean age of diagnosis 33 months) who underwent LT (mean age 47 months) and 36 controls (mean age of LT 34 months) were studied. CsA was the main immunosuppressive drug used in each group. The median eGFR before, and at 3, 6, 12, 24 and 36 months after LT in HB group was significantly lower than controls (93 vs. 152, 66 vs. 79, 62 vs. 86, 66 vs. 87, 64 vs. 94, 53 vs. 90 mL/min/1.73 m2 , respectively; 0.01 < p < 0.03). The reductions in the median eGFR of both the HB group and controls before and at 36 months after LT were 49 and 41%, respectively. At 36 months after LT, there was a trend for partial recovery of the eGFR in the controls but not in the HB group. Children who underwent LT for unresectable HB had renal dysfunction before transplantation that persisted for 36 months after LT. [ABSTRACT FROM AUTHOR]