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In this review, we focused on CLKT with regard to indication, results, outcome, and future developments. PH1 is one of the most common diagnoses for adult and pediatric patients qualifying for CLKT. The other major indication for combined transplantation is ARPKD. CLKT appears to be superior to sequential liver and kidney transplantation in the majority of patients and overall results following CLKT are now good, even in small children. Clinical observations suggest that there is an immunological advantage of CLKT in comparison with isolated liver or kidney transplantation. More clinical studies are necessary to identify the best candidates for CLKT while the availability of donor organs is low.

Anti-HLA antibodies and especially donor-specific antibodies (DSA) play a significant role in graft survival after solid organ transplantation. Their impact on long-term survival in adult liver transplantation (LT) is controversial, but they may be a risk factor. The effects of DSA after pediatric LT are still unclear.We performed a retrospective evaluation of DSA in sera from 43 children who had received transplants at our tertiary center. Twenty-four patients had good long-term clinical and laboratory graft function (group 1), whereas 19 LT recipients suffered from histologically confirmed and clinically relevant chronic allograft rejection (group 2); 16 of these have already undergone retransplantation due to graft dysfunction. Inclusion criteria were availability of sera before the first LT to identify preformed antibodies in case of DSA positivity after LT and long-term follow-up at our institution. Sera were analyzed for anti-HLA antibodies using Luminex single antigen beads, where a mean fluorescence intensity value of more than 1500 was considered positive.The prevalence of DSA was 33% for group 1 and 68% for group 2. Antibodies were predominantly HLA class II. Values of mean fluorescence intensity were comparable in both groups. Only one of the DSA+ ve patients from group 1 exhibited preformed antibodies. In conclusion, pediatric patients with chronic rejection revealed a higher rate of de novo DSA, especially of HLA-class II DSA. Further studies are necessary to confirm these data with a larger pediatric cohort.

In a 24-month, multicenter, single-arm, prospective study, 56 pediatric liver transplant patients with or without basiliximab induction were converted at 1-6 months post-transplant from standard calcineurin inhibitor (CN) therapy (± mycophenolic acid), to everolimus with reduced exposure to CNI (tacrolimus n=50, cyclosporine n=6). Steroid therapy was optional. Recruitment was stopped prematurely due to high rates of PTLD, treatment-related serious infections leading to hospitalization and premature study drug discontinuation. Subsequently, patients aged

Deoxyguanosine kinase (DGUOK) deficiency is a well-known cause of hepatocerebral mitochondrial DNA depletion syndromes, which include a broad spectrum of clinical presentations. Affected patients often develop life-threatening liver failure, but the benefits of liver transplantation (LT) are controversial because of the frequently severe neurological involvement due to the underlying mitochondrial disease. We describe the long-term clinical course of 2 patients from our institution and provide an update on their outcomes after LT with this condition. Another 12 pediatric patients were identified through a systematic search of the literature. All 14 reported patients underwent transplantation in infancy despite mild to moderate neurological impairment in some cases. The 2 DGUOK-deficient patients from our center displayed liver failure and mild to moderate neurological involvement. At the time of this writing, they had been followed for 5 and 8 years after LT, both patients were alive, and they had only mild neurological symptoms. Three of the 12 patients identified through the literature review survived for a long time (17, 12, and 23 years); 8 died during early follow-up; and for 1 patient, no follow-up information was available. The 1-year survival rate was 64%; 36% survived for more than 5 years. The long-term survivors had good quality of life. In conclusion, although survival after LT for DGUOK deficiency is lower than survival after LT for other indications, a significant proportion of patients benefit from LT with long-term survival and a stable neurological situation despite initial neurological abnormalities. Nevertheless, a decision to carry out LT for patients with DGUOK deficiency remains difficult because neurological symptoms may occur and worsen after LT despite their absence before transplantation.

To date, the course of cognitive development in children after liver transplantation (Ltx) is poorly understood. Cognitive performance, however, is crucial in all developmental stages and for educational achievement. This cross-sectional single-center study examined the prevalence of long-term cognitive impairment in a cohort of 64 pediatric patients after Ltx. Median age at Ltx was 12 months. The revised Wechsler Intelligence Scale IV was administered to assess cognitive performance. Patients were compared with an age- and gender-matched group of children without a chronic health condition. Liver transplanted children performed significantly worse in three of four cognitive domains as well as in the Total Intelligence Quotient (Total IQ) (p = 0.017 to p = 0.005). Liver transplant recipients showed substantially more "serious delays" (IQ 70) compared to the reference group (9.4% vs. 4.7%). Children with a genetic-metabolic disease performed worse than the other groups in three of the four WISC Indices and in the Total IQ (p = 0.05 to p = 0.01). The strongest association was revealed between height at Ltx and Verbal Comprehension (R(2) = 0.21), Perceptual Reasoning (R(2) = 0.30), Working Memory (R(2) = 0.23) and Total IQ (R(2) = 0.25). Our results indicate a high impact of primary diagnosis and height percentile at Ltx even on children's long-term cognitive performance.

Individualization of immunosuppressive medications is an important objective in transplantation medicine. Reliable biomarkers to distinguish between patients dependent from intensive immunosuppressive therapy and those where therapy can be minimized among pediatric transplant recipients receiving immunosuppressive medications are still not established. We evaluated the potential of cross-sectional quantification of regulatory T cells, lymphocyte subsets, and cytokine concentrations as biomarkers in 60 pediatric liver transplant recipients with AR, CR, or normal graft function and in 11 non-transplanted patients. Transplant recipients presenting with AR had significantly higher CD8+ T-cell counts, significantly higher concentrations of IL-2, and increased levels of IFN-γ compared with asymptomatic patients or controls. Regulatory T-cell numbers did not differ between children with rejection and children with good graft function. A tendency toward increased concentrations of IL-4 and TGF-β was detected in transplant recipients with good graft function. Cross-sectional parameters of peripheral regulatory T cells in pediatric liver transplant recipients do not seem to be valuable biomarkers for individualizing immunosuppressive therapy prior to the weaning process. Lymphocyte subsets, IL-2, IFN-γ, IL-4, and TGF-β serum concentrations may be helpful to identify children in whom immunosuppression can be reduced or discontinued.

Liver transplantation offers excellent results for children with end-stage liver disease, and efforts should be directed toward maintaining long-term graft health. We evaluate graft pathology in healthy pediatric transplant recipients with low-maintenance immunosuppressive medications to assess whether protocol biopsies are helpful for adapting immunosuppression and protecting long-term graft function. Liver biopsies were performed on 60 healthy pediatric liver transplant recipients, and histological findings were correlated with laboratory, serological, and radiological results. Fourteen patients (23%) were diagnosed with acute or early chronic rejection, and immunosuppressive medications were increased in these children. Liver function tests did not correlate with histological findings. The incidence of fibrosis was 36% in transplant recipients five or more years after liver transplantation. We observed an unexpectedly high prevalence of rejection and fibrosis in children with no laboratory abnormalities, which led to changes in their immunosuppressive medications. Scheduled biopsies appear to be useful in pediatric transplant recipients with low immunosuppressive medications for early detection of morphological changes in liver transplants. Further studies are needed to evaluate whether adaption of immunosuppression helps to reduce tissue damage and the incidence of allograft dysfunction in the long term.

The use of everolimus has recently emerged for solid-organ transplantation in children. This review gives an overview of the relevant studies and clinical trials involving the immunosuppressive effects of everolimus in child organ transplant.The use of everolimus in pediatric organ transplantation is associated with a decrease in calcineurin inhibitor-related toxicity, better renal function, a low number of acute rejections, and an acceptable side-effect profile. Particularly, the use of everolimus reduces the incidence of virus infection and the risk of posttransplant lymphoproliferative disease.Everolimus is an effective agent with several advantages for pediatric solid-organ transplantation. Future prospective, randomized controlled trials will have to be performed in order to validate the findings of these pilot trials.

The role of mTOR inhibitors, such as EVL, has not been established for pediatric liver transplant recipients up to now, although data from adult solid organ graft transplantation are very promising. Major complications following pediatric liver transplantation in the long-term course include chronic graft rejection and CNI-derived nephrotoxicity. The purpose of our study was to report first results using EVL as a rescue therapy in pediatric liver transplant recipients for the following indications: chronic graft dysfunction n=12, suspected CNI toxicity n=3, hepatoblastoma n=2, and recurrence of primary sclerosing cholangitis post-Ltx n=1. Four patients with chronic graft dysfunction developed completely normal liver function tests using EVL, six patients showed partial improvement, and two patients did not respond at all. One patient with CNI-induced nephropathy showed a slightly improved GFR. Both patients with hepatoblastoma did not develop any metastasis post-Ltx. First experience with EVL in pediatric liver transplant recipients shows promising results in patients with chronic graft failure when standard immunosuppression has failed. The future role of EVL in immunosuppressive protocols for children post-Ltx has to be proven by controlled clinical trials.

Background Studies reporting the immediate pediatric intensive care unit (PICU) treatment after combined liver-kidney transplantation (CLKT) are scarce, although this period is pivotal for survival and long-term outcome. Methods We retrospectively analyzed all pediatric CLKT performed in our center between 1998 and 2010. Results Sixteen patients underwent 17 CLKT at a median age of 5.3 years (range, 1.3-15.9 years). Median body weight at CLKT was 17.7 kg (range, 9.2-55 kg). Underlying diagnosis was primary hyperoxaluria type 1 in nine patients and autosomal recessive polycystic kidney disease in seven patients. Median time on PICU was 8.5 days (range, 3-68 days); however, patients with primary hyperoxaluria type 1 had a significantly longer stay (P=0.031). Median duration of ventilation was 1 day; however, five patients required ventilation for 25 to 52 days. Continuous veno-venous hemofiltration was applied in nine patients due to delayed kidney graft function, volume overload, or high plasma oxalate. Overall, the survival rate after CLKT was 100% and long-term outcome was very good at a mean follow-up of 3.6 years (range, 0.5-12.2 years). Waiting time, donor age, and donor-to-recipient weight ratio were found to be significant risk factors for an extended PICU stay (P=0.02, 0.0031, and 0.014, respectively). Conclusions Immediate postoperative course after CLKT may be challenging and complex. However, excellent results can be achieved, even in small children.

Summary In children with renal insufficiency and accompanying or underlying liver disease, combined liver and kidney transplantations (CLKT) are indicated. However, because of the rare indications, the number of paediatric CLKT is low. Our aim was to analyse CLKT in children with special regard to surgical aspects and outcome. All paediatric CLKT performed at our institution between 1998 and 2009 were retrospectively analysed. Between 1998 and 2009, 15 CLKT were performed in 14 paediatric patients (median age 8 years, range 1–16 years). The indications for CLKT were autosomal recessive polycystic kidney disease (n = 7), primary hyperoxaluria type 1 (n = 7) and retransplantation because of primary liver nonfunction (n = 1). In the postoperative course, six patients showed bleeding complications, thereof three patients needed operative revision for intra-abdominal bleeding. Eight of 15 patients (53%) needed dialysis. The 1- and 5-year patient survival was 100%; and 1- and 5-year graft survival was 80% for the liver and 93% for the kidney allograft. A number of different complications, especially secondary haemorrhage have to be anticipated after CLKT, requiring a timely and interdisciplinary treatment approach. With this management, our patients showed an excellent graft and patient survival.

Summary Nowadays, most paediatric liver transplant recipients receive a split or other technical variant graft from adult deceased or live donors, because of a lack of available age- and size matched paediatric donors. Few data are available, especially for liver grafts obtained from very young children (

Kaller T, Boeck A, Sander K, Richterich A, Burdelski M, Ganschow R, Schulz KH. Cognitive abilities, behaviour and quality of life in children after liver transplantation. Pediatr Transplantation 2010: 14:496–503. © 2010 John Wiley & Sons A/S. Abstract: Aims: We investigated interrelations between cognitive abilities, behavioural problems, quality of life and disease-related variables of children after LTX. Methods: Our sample consisted of 25 children. They were 8.5/2.8 (M/SD) years old and had received the transplant 5.5/3.1 years previously. For assessment we used well-established instruments. Results: Liver transplanted children scored below the population mean on the cognitive as well as on the behavioural instrument and showed scores below average in the scales Self-esteem, Friends and Total Score regarding QoL. Behavioural problems were associated with poorer cognitive performance (r=−0.38 to −0.63). QoL regarding physical well-being was correlated with sequential processing (r=0.41). Lower sequential processing scores were associated with lower QoL. Also between behavioural parameters and QoL correlations could be determined. Children with more behavioural problems experienced lower QoL (r=−0.40 to r=−0.76). Age at onset of disease showed correlations with behavioural and QoL parameters (r=−0.49 resp. r=0.44). Cognitive functioning was associated with medical complications (r=−0.44). Conclusions: High interrelations between cognitive functioning, behavioural deficits and QoL were obtained. Especially noticeable are correlations between sequential processing and internalized behavioural functions as both are associated with left lateralized brain functioning. This relationship could indicate differential effects on brain development during the preoperative phase.

Little is known about the role of platelets in relation to ischemia/reperfusion injury (IRI) of the liver graft especially in children. Thrombocyte function was prospectively analysed in 21 consecutive pediatric liver transplantation (pLT) patients by platelet aggregometry secondary to adenosine diphosphate (ADP), collagen, and the von Willebrand factor activator ristocetin (VWF:rco). Post-OP serum levels of ALT were used to divide patients into groups with high (highHD, n = 8) and low (lowHD, n = 13) hepatocellular damage. Clinically, highHD-patients showed impaired plasmatic coagulation and elevated serum bilirubin levels early after pLT when compared with lowHD-patients. Further, platelet counts markedly decreased between pre-OP and postreperfusion (postrep.) in the highHD group (P = 0.003) and did not recuperate by POD6. In lowHD individuals thrombocytopenia improved from both pre-OP (P < 0.05) and postrep. (P < 0.001) respectively towards POD6. Experimental thrombocyte testing revealed that before graft reperfusion only ADP-dependent platelet aggregation correlated with reperfusion injury, thrombocytopenia and early graft function. During the first 48 h after graft reperfusion, all inducers tested demonstrated elevated platelet aggregation levels in the highHD group. Our data suggest a possible role of platelets and their aggregative status in liver IRI subsequent to clinical pLT. Reperfusion-independent ADP-triggered platelet function may be a determinant for IRI in the pediatric hepatic graft recipient.

Krampe K, Briem-Richter A, Fischer L, Nashan B, Ganschow R. The value of immunoprophylaxis for cytomegalovirus infection with intravenous immunoglobulin in pediatric liver transplant recipients receiving a low-dose immunosupressive regimen. Pediatr Transplantation 2010: 14: 67–71. © 2009 Wiley Periodicals, Inc. Abstract: The incidence of CMV infection following pediatric Ltx is particularly high, which can be attributed to the increased number of patients at high risk for primary infection (donor CMV+, recipient CMV−). Current approaches to cope with this complication producing post-operative morbidity include prophylactic or preemptive ganciclovir therapy. As the risk for symptomatic CMV infection is directly correlated with the intensity of immunosuppression, the aim of our study was to assess the value of IVIG in order to protect children receiving low-dose immunosuppression from CMV disease. Twenty-eight consecutive children (median age 62.2 months) at high risk prospectively received three infusions of IVIG on days four, 14, and 28 post-transplant and were monitored for six months post-Ltx. Immunosuppression consisted of cyclosporine (initial trough levels 170–200 μg/L) and prednisolone (starting dose 15 mg/m2) as well as basiliximab induction therapy. Patient survival was 100% and graft survival was 92.9%. Two subjects developed laboratory findings of CMV infection (8%) and one child suffered from tissue invasive CMV disease (4%). Three patients were excluded from the study because of protocol violations. We conclude that there was a low incidence of CMV disease among a prospective cohort receiving low-dose immunosuppression and a standard IVIG product.

BKV infection is a potential cause of renal dysfunction in non-renal organ transplant recipients. JCV is the causative agent of PML. Furthermore, polyomaviruses are tumor inducing viruses and molecular data suggest an association with malignancies among solid organ transplant patients. So far, there are no studies analyzing polyomavirus viruria following Ltx in children. We performed a prospective prevalence study at a mean of 2187 (range 20-5671) days after transplantation in 100 consecutive children admitted for the routine follow-up examination post-Ltx. The urine was screened for BKV and JCV DNA by using PCR in each case. A plasma analysis by PCR was also done if more than 100,000 DNA copies/mL urine were detected. BKV or JCV viruria was found in 19% (n = 19) of our patients. All patients were free of clinical signs of viral infection, PML, or nephropathy. GFR was normal in 97% of patients and we found no statistical difference of kidney function between patients with and without BKV/JCV viruria. The extent of immunosuppressive therapy had no influence on the polyomavirus viruria. Overall, we found a higher prevalence of polyomavirus viruria in our pediatric liver transplant recipients than reported in adult patients.

Portal vein thrombosis can occur as a result of primary anomalies, after liver transplantation, and for other reasons. It may result in severe complications secondary to portal hypertension, such as bleeding from esophageal or gastric varices, hypersplenism, or impaired somatic growth. In this retrospective study, we analyzed the outcome of 25 children who underwent a Rex shunt procedure. The following venous grafts were used as the shunt: the autologous internal or external jugular vein (n = 17) or a cryopreserved graft (n = 5); in three patients the umbilical vein was recanalized. The median follow up time was 109 months (range 18 days-146 months). The best results were achieved in patients in whom an autologous jugular vein segment was used as a vascular graft for the Rex shunt (shunt patency of 88%). In patients with a functioning shunt no further lower or upper gastrointestinal bleeding occurred. And in the entire study population hypersplenism syndrome improved after surgery. In our large cohort of pediatric patients, the Rex shunt has shown to be an effective method to eliminate portal hypertension and to revascularize the liver and thereby prevents the possible consequences of long-term portosystemic shunting.

Background. Cure of the metabolic defect in primary hyperoxaluria type 1 (PH1) is possible with liver transplantation (LTx). Preemptive LTx (PLTx) was promoted to prevent chronic kidney disease due to nephrocalcinosis and urolithiasis. However, timing of this procedure is difficult in view of the heterogeneity of PH1 and effective conservative treatment. Combined liver-kidney transplantation (LKTx) is able to cure metabolic defect and replace renal function at the same time and is effective and indicated for patients with or approaching end-stage renal disease (ESRD). Sometimes a sequential approach for LKTx (first liver, then kidney) has been recommended. Methods. We report on 13 patients with PH1 since 1995 who underwent transplantation procedures in our center for PH1 at a median age of 4.7 (range 1.4–8.9) years. Results. The first two patients, planned for a sequential strategy, died early after LTx because of infectious complications. Four patients underwent PLTx at a median glomerular filtration rate of 65 (range 27–98) mL/min/1.73 m2/day (Hoppe et al., Pediatr Nephrol 1996; 10: 488), and three patients still have sufficient residual renal function after a follow-up of median 11.6 years. Seven patients with ESRD received a combined LKTx, including four with infantile oxalosis, and three weighing less than 10 kg. There was no mortality and catch-up growth was observed in most patients. Conclusion. In summary and conclusion, transplantation procedures are challenging in PH1, but our results including growth data are encouraging. PLTx remains an option despite the difficulties in timing the procedure. LKTx is indicated for patients with ESRD and is possible even in patients with infantile oxalosis and may improve longitudinal growth.

In adult liver graft recipients, it has been shown that certain chemokine polymorphisms (CCR5Delta32) may correspond to ischemic type biliary lesions leading to chronic graft dysfunction. The aim of our present study was to assess the importance of CCR5Delta32 polymorphism in a cohort of pediatric liver graft recipients with regard to acute or chronic graft dysfunction. A total of 137 children post-liver transplantation have been included for genetic analysis (CCR5Delta32 polymorphism), and the incidence of acute and chronic graft dysfunction was analyzed. The most common diagnosis leading to LTx was biliary atresia (56.2%), the median age was 14 months, and 33.5% of the patients received a living-related graft. In all, 110 of the subjects were found to have the CCR5 wild type, 25 children were heterozygous for CCR5Delta32, and two patients were homozygous. Of 137, 44 (32.1%) developed acute graft rejection, nine out of 137 (6.6%) chronic graft dysfunction (vanishing bile duct syndrome), and 84 (61.3%) children had neither acute nor chronic graft rejection. There was no significant correlation between acute graft rejection or chronic graft dysfunction and the CCR5Delta32 allele in the study population. We conclude that CCR5Delta32 polymorphism may not play a role in acute or chronic liver graft dysfunction in children.

Background. Acute neonatal liver failure is a rare condition that is often fatal. Liver transplantation (LTx) in affected neonates may be life saving, but there are only few data on the long-term outcome of neonatal LTx. Patients and Methods. We conducted a retrospective study of 11 LTx performed in 10 pediatric patients with acute liver failure in the first month of life. Median age at LTx was 15 days (range: 7-31 days) and median weight was 3.25 kg (range: 2-4 kg). The reasons for liver failure were neonatal hemochromatosis (n=5), hemangioendothelioma (n=2), infection caused by echovirus type 11 (n=1), mitochondrial disorder (n=1), unknown (n=1), and primary nonfunction after LTx (n= 1). In 10 patients, LTx organs of deceased donors were used (reduced size n = 5, split n = 5), and living donor LTx was performed in one neonate. The patients were evaluated with respect to survival, graft function, perioperative complications, and neurodevelopmental outcome. Results. After a median follow-up time of 5 years (range: 1-14 years), 8 of 10 patients (80%) were alive. Seven of them were in good clinical condition and had normal liver function tests. One patient had to undergo retransplantation , because of primary nonfunction and another is currently listed for retransplantation because of chronic graft dysfunction. Neurodevelopment was normal in 75% of the surviving patients. Conclusions. Liver transplantation provides good short- and medium-term results in neonatal acute liver failure.

Both calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, are widely used in pediatric liver transplant recipients and currently data are limited with regards to long-term results using the one drug or the other in comparable low doses. We conducted the present study to assess the advantages and disadvantages of both drugs in children at least five yr post-liver transplantation. A total of 129 children were enrolled in the study. Thirty-eight of the children were switched to tacrolimus monotherapy for different reasons [steroid resistant graft rejection (n = 15), chronic rejection (n = 5), severe acute rejection (n = 4), repetitive acute graft rejection (n = 5), dysfunction of the transplant (n = 3), insufficient CsA metabolism (n = 3), hypertrichosis (n = 2), and CsA toxicity (n = 1)], four patients had primary tacrolimus therapy, and 87 patients are receiving cyclosporine. Mean trough levels were 5.3 +/- 2.3 ng/mL (tacrolimus) and 73.6 +/- 44.5 micro/L (cyclosporine), respectively at least five yr post-orthotopic liver transplantation (OLT). There was no significant difference in the calculated glomerular filtration rate between children on cyclosporine and tacrolimus (142.7 + 39.5 mL/min/1.73 m(2) vs. 151.1 +/- 44.1 mL/min/1.73 m(2)). The incidence of arterial hypertension was 7.1% vs. 9.2%, that of hepatotoxicity was 0% vs. 2.3%. Cosmetic changes were found in more than one-third of the patients on cyclosporine and in 4.8% of the patients receiving tacrolimus. Quality of life was excellent in both groups (self assessment). The impact of CNIs on chronic graft dysfunction cannot be assessed by our present study. We conclude from the results that cyclosporine and tacrolimus are both excellent drugs for maintenance immunosuppression in the long-term course following pediatric liver transplantation. However, this retrospective analysis is limited by the bias between children on CsA as compared with patients receiving tacrolimus. A prospective randomized controlled trial is needed in order to assess which CNI is the best for children following OLT.

An AGS is a dominant inherited multisystem disorder caused by mutations in the Notch signaling pathway (JAG1). In our center, 5.3% of liver transplantations (OLT) are performed in children with AGS. Some of the affected children fulfilled criteria for OLT, despite the absence of liver cirrhosis. The aim of our present study was to evaluate the indications and outcome for OLT in children with this complex disorder as clear criteria are difficult to establish in clinical practice. A total of 37 patients were included in a retrospective analysis. Twenty-four children underwent OLT for chronic end-stage liver failure (n = 8) or symptomatic liver disease (n = 16). Patient survival post-OLT was 91.7% after 1 yr, that of graft survival was 87.5%, respectively. Significant post-transplant vascular complications included a mid-aortic syndrome (n = 1) and severe lethal bleeding due to suspected vascular malformation (n = 1). Severe hypercholesterolemia (>800 mg/dL) and xanthomata resolved completely in affected patients. We conclude from our data that indications for OLT in AGS should be extended to patients with severe symptomatic liver disease, even in the absence of liver cirrhosis because of the significantly improved outcome after pediatric OLT in the last decade. Future studies must identify underlying mechanisms of hypercholesterolemia and vascular malformation.

It has been shown that an induction therapy with the monoclonal anti-interleukin-2 receptor antibody basiliximab (Simulect) is capable to reduce the incidence of acute graft rejection in adult and pediatric liver transplantation (Ltx). However, data on long-term results using basiliximab in children post-Ltx are still pending. Therefore, the objective of our study was to report on the long-term results of basiliximab induction therapy in pediatric liver transplant recipients. A total of 54 children received two single doses of basiliximab in addition to cyclosporine and prednisolone following Ltx. We analyzed the incidence of acute and chronic graft rejection that of post-transplant lymphoproliferative disease (PTLD), and patient and graft survival. The follow-up was 22-46 months. The historical control group (matched controls) consisted of 54 patients treated with a cyclosporine and prednisolone dual therapy. Patient survival was 53 of 54 in the treatment group and 51 of 54 in the controls. One patient was retransplanted in the treatment group vs. three patients in the control group. The incidence of acute graft rejection was 16.6% compared with 53.7% in the control group (p < 0.001), that of chronic rejection was comparable in both groups (one of 54 vs. one of 54). The incidence of steroid resistant rejection was four of 54 vs. six of 54 that of PTLD were one of 54 vs. zero of 54. There were no adverse effects observed, which could be related to the antibody treatment. We conclude that basiliximab provides safe and effective induction immunosuppression in pediatric liver graft recipients. Short- and even long-term results are excellent.

Background. Since starting our program in 1989, 455 pediatric orthotopic liver transplantations have been performed using all techniques. In April 2001, we experienced our last in-hospital death of a pediatric liver-transplant recipient. Since then, all our liver-transplant children (n = 170) were able to be discharged from the hospital. The aim of this study is to analyze the actual status of pediatric liver transplantation at the University of Hamburg and to find future perspectives to improve the results after pediatric liver transplantation. Methods. From May 4, 2001 until September 8, 2004, 22 (13%) whole organs, 18 (11%) reduced-size organs, 79 (47%) split organs, and 51 (30%) organs from living donors were transplanted into 142 patients. One hundred forty-one were primary liver transplants, 25 retransplants, 3 third, and I fourth liver transplants. Of the 170 orthotopic liver transplantations (OLT), 31 (18%) were highly urgent (United Network of Organ Sharing [UNOS] I). Results. After 170 consecutive pediatric liver transplants, no patients died during the hospital course (100% patient survival < 3 months), but overall, 5 (2.9%) recipients died during further follow-up. The 3-month and actual graft survival rates are 93% and 85%, respectively. Twenty (11.8%) children had to undergo retransplantation. However, patient survival was not sustained by longer graft survival. Analyzing our series, we see that graft survival after reduced-size liver transplantation showed a significantly lower rate versus living-donor liver transplantation. Conclusion. The learning curve in pediatric liver transplantation has reached a turning point where immediate patient survival is considered the rule. The challenge is to increase graft survival to the same level. The long-term management of the transplant patients, with the aim of avoiding late graft loss and achieving excellent quality of life, will become the center of the debate.

Hypogammaglobulinemia has been reported after solid organ transplantation in adults, however immunoglobulin replacement [intravenous immunoglobulins (IVIG)] is only necessary in a minority of affected patients. We here present three pediatric patients with severe post-transplant hypogammaglobulinemia following liver transplantation (LTx) receiving a cyclosporine-based standard immunosuppression. Patient 1 was transplanted at the age of 10 months for biliary atresia. Eight weeks post-Ltx the serum IgG was 1.7 g/L. Patient 2 was transplanted at the age of 12 yr for acute liver failure. Four weeks post-Ltx the IgG dropped to 2.6 g/L. Patient 3 was transplanted at the age of 4 months for biliary atresia. Ten weeks post-Ltx severe hypogammaglobulinemia (IgG < 1.48 g/L) was diagnosed during a severe infectious complication. Patients 1 and 3 received a steroid bolus therapy for acute graft rejection. All patients had normal IgG concentrations prior to Ltx and lymphocyte subsets were post-operatively in the normal range. There was no extensive loss of protein by ascites. IGIV were replaced in the three patients monthly without further complications. In two of the patients (1 and 3) IVIG therapy was discontinued 8 and 10 months after Ltx when the immunosuppression has been reduced and serum IgG concentrations were found in the normal range without further immunoglobulin replacement. Severe hypogammaglobulinemia is a rare phenomenon following pediatric LTx and seems to be mainly caused by immunosuppressive drugs, however, the exact underlying mechanisms are unclear. A screening for hypogammaglobulinemia is useful after pediatric LTx, especially in patients with an intensified immunosuppression. Moreover, further immunologic research in affected patients is necessary.

Objective: Orthotopic liver transplantation (OLT) has become an established procedure for the treatment of pediatric patients with end-stage liver disease. Since starting our program in 1989, 422 pediatric OLTs have been performed using all techniques presently available. Analyzing our series, we have concluded that the year of transplantation is the most important prognostic factor in patient and graft survival in a multivariate analysis. Methods: From April 2001 to December 1, 2003, 18 whole organs (14%), 17 reduced-size organs (13%), 53 split organs (42%; 46 ex situ, 7 in situ), and 44 organs from living donors (33%) were transplanted into 115 patients (62 male and 53 female). One hundred twelve were primary liver transplants, 18 were retransplants, one third and one fourth liver transplants. Of the 132 OLTs, 26 were highly urgent (19.7%). The outcome of these 132 OLTs was retrospectively analyzed. Results: Of 132 consecutive pediatric liver transplants, no patients died within the 6 months posttransplantation. Overall, 3 recipients (2%) died during further follow-up, 1 child because of severe pneumonia 13 months after transplantation and the second recipient with unknown cause 7 months postoperatively, both with good functioning grafts after uneventful transplantation. The third had a recurrence of an unknown liver disease 9 months after transplantation. The 3-month and actual graft survival rates are 92% and 86%, respectively. Sixteen children (12%) had to undergo retransplantation, the causes of which were chronic rejection (3.8%), primary nonfunction (3.8%), primary poor function (PPF; 1.5%), and arterial thrombosis (3%). The biliary complication rate was 6%; arterial complications occurred in 8.3%; intestinal perforation was observed in 3%; and in 5%, postoperative bleeding required reoperation. The portal vein complication rate was 2%. Conclusions: Progress during the past 15 years has enabled us to perform pediatric liver transplantation with near perfect patient survival. Advances in posttransplant care of the recipients, technical refinements, standardization of surgery and monitoring, and adequate choice of the donor organ and transplantation technique enable these results, which mark a turning point at which immediate survival after transplantation will be considered the norm. The long-term treatment of the transplanted patient, with the aim of avoiding late graft loss and achieving optimal quality of life, will become the center of debate.

The chimeric, monoclonal antibody basiliximab inhibits the proliferation and clonal expansion of activated T cells. To date basiliximab has been used only in combination with other immunosuppressive agents for rejection prophylaxis after solid organ transplantation. An infant underwent liver transplantion (LTx) at the age of 5 months because of biliary atresia. The primary immunosuppression consisted of cyclosporine and prednisolone. As a result of a steroid resistant rejection episode on day 26 post-LTx we had to switch the initial immunosuppressive regiment to tacrolimus and steroids. Because of severe cholestasis and assumed impaired enteral resorption we were forced to administer an unusually high dosage (2 mg/kg/day) of tacrolimus. Four months after LTx an intestinal B-cell lymphoma was diagnosed when the patient suffered from a small bowel perforation. After stopping the immunosuppressive medication we started treatment with the anti-CD20 monoclonal antibody rituximab for B-cell depletion. During the 12 wk no B cells were detectable in the peripheral blood by flow cytometry. In this setting we started a monotherapy with repetitive doses of basiliximab for immunosuppression. During the following course there was no further rejection and no recurrence of the tumor. From this experience we conclude that monotherapy with basiliximab after LTx and anti-CD20 treatment for B-cell lymphoma is efficient and safe.

Englert C, Ganschow R. Liver transplantation in a child with liver failure due to chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation from the same unrelated living donor. Abstract: We report a case of a six-yr-old boy who developed chronic GVHD of the liver, intestines, and skin following allogeneic hematopoietic SCT. The boy received an allogeneic hematopoietic stem cell transplant at the age of two yr because of early recurrence of ALL. Chimerism analysis showed complete chimerism. In the following year, he developed GVHD despite adequate immunosuppressive therapy. Liver biopsy showed liver GVHD resulting in liver cirrhosis by the age of five yr. LTx was performed with a left liver lobe from the unrelated donor from whom the stem cells had been taken. Immunosuppressive therapy consisted of low-dose steroids and low-dose cyclosporine. The postoperative course was uneventful. Graft function was excellent, and we performed protocol biopsies at seven days and three wk as well as three, six, and nine months after transplantation; none of these showed any signs of rejection or GVHD. Immunosuppressive therapy was discontinued nine months after LTx. Three yr after transplantation, the boy is in good condition with normal graft function. To our knowledge, this is the first report on LTx following allogeneic hematopoietic SCT from the same unrelated living donor.

Background: Data on the oxidative metabolism of polymorphonuclear neutrophils (PMN) after solid organ transplantation are very limited. We hypothesized that immunosuppressive agents reduce the capacity of PMN to produce reactive oxygen species, such as O2−, H2O2, OH, and OCL− leading to an increased susceptibility to infectious complications after liver transplantation. Methods: A lucigenin-enhanced chemiluminescence (CL) assay was used with soluble and particulate stimuli to study the oxidative metabolism of PMN in pediatric liver graft recipients. Sixteen patients (median age: 2.4 yr) were enrolled in a prospective study and integrated CL response was compared with the CL activity of 29 healthy controls. Results: In the second week post-transplant, we found a significantly reduced CL activity. Pre-operatively, and after lowering steroids and cyclosporin A (CsA) the oxidative burst was normal. Conclusions: Our data suggest that CsA and steroids may not only influence T and B cells but also PMN, which may be a relevant factor for the incidence of infectious complications in pediatric liver graft recipients.

Liver allocation in the Eurotransplant (ET) region has changed from a waiting time to an urgency-based system using the model of end-stage liver disease (MELD) score in 2006. To allow timely transplantation, pediatric recipients are allocated by an assigned pediatric MELD independent of severity of illness. Consequences for children listed at our center were evaluated by retrospective analysis of all primary pediatric liver transplantation (LTX) from deceased donors between 2002 and 2010 (110 LTX before/50 LTX after new allocation). Of 50 children transplanted in the MELD era, 17 (34%) underwent LTX with a high-urgent status that was real in five patients (median lab MELD 22, waiting time five d) and assigned in 12 patients (lab MELD 7, waiting time 35 d). Thirty-three children received a liver by their assigned pediatric MELD (lab MELD 15, waiting time 255 d). Waiting time in the two periods was similar, whereas the wait-list mortality decreased (from about four children/yr to about one child/yr). One- and three-yr patient survival showed no significant difference (94.5/97.7%; p = 0.385) as did one- and three-yr graft survival (80.7/75.2%; and 86.5/82%; p = 0.436 before/after). Introduction of a MELD-based allocation system in ET with assignment of a granted score for pediatric recipients has led to a clear priorization of children resulting in a low wait-list mortality and good clinical outcome.

In case of graft failure, re-LTX is the only life-saving option but it has been associated with inferior results. This study analyzes the outcome following pediatric re-LTX with a main focus on the timely relation between initial transplant and re-LTX. All pediatric LTX at our institution between 2000 and 2010 divided into patients with primary LTX and patients undergoing re-LTX early (≤30 days) or late (>30 days) after previous LTX were analyzed. Two hundred and ninety-eight primary LTX(79%), 33 early (9%), and 46 late (12%) re-LTX were performed. Patient/graft survival was significantly worse for children undergoing early re-LTX compared to primary LTX and late re-LTX (p = 0.024/0.001 and p = 0.015/0.03). One-/five-yr graft survival rates were 66%/49% for early re-LTX compared to 86%/76% for late re-LTX and 90%/74% for primary LTX. The inferior results in children undergoing early re-LTX were due to events occurring in the first six months with similar survival thereafter. No difference in outcome was evident after adjustment of the groups for high-urgency status. Outcome was excellent for primary LTX and late re-LTX, supporting late re-LTX in children. Early re-LTX takes an elevated risk of early graft loss and patient death; however, beyond the early postoperative period, the outcome was comparable.

Living-related liver transplantation (LRT) and split-liver transplantation (SLT) are surgical strategies that have led to a reduction in the pretransplant death rate in children from 20% to nearly 0%. 1–5 LRT provides a graft of excellent quality by minimizing the cold ischemic time. Primary nonfunction (PNF) after LRT is rare. In addition, this procedure is elective and thus allows flexibility in choosing the optimal time for transplantation with regard to the recipient’s clinical status. Because of these advantages, worldwide long-term results of LRT are equal or even superior to those obtained with cadaveric full-size or reduced-size techniques. The actual 1-year graft and patient survival rate after LRT exceeds 80%. 6–10 The expansion of LRT for adult recipients reflects the great expectations of this procedure despite the higher risks for the donor associated with major hepatectomy. Split-liver transplantation (SLT) is technically comparable to LRT. However, as in other cadaveric procedures, it is theoretically susceptible to potential negative effects resulting from logistical and clinical circumstances related to donor condition, organ transportation, and cold ischemic time. SLT is divided into the ex situ approach, which means back-table division of the flushed and cooled graft under preservation conditions, and the in situ split, which is performed by partitioning the liver within the heart-beating donor before flushing and explantation of the divided organ, thus saving the time needed for back-table partitioning under cold ischemic conditions. 11 Initial reports from split-liver programs from Europe and the United States indicate that SLT has acceptable results, 5,12 although initial results were not as encouraging as after the introduction of LRT. Growing surgical experience has resulted in improved outcomes, comparable to those of cadaveric liver trans-plantation. 11,13–17 Whether LRT should generally be preferred over SLT is a matter of debate. 18 LRT might be recommended as the method of choice in pediatric liver transplantation, arguing that it provides grafts of best quality. However, it carries potential risks for the donor that can be avoided by performing SLT. This led Azoulay et al 16 to state that “given the improving results of split-liver transplantation we believe that, whenever possible, this technique should be offered before living-related liver transplantation.” This study aims at providing objective arguments for the choice of procedure in pediatric liver transplantation. Given this aim, the results after LRT and SLT, with regard to postoperative liver function parameters, complications, and survival rates are compared. This study was performed to answer the following questions: Does SLT provide results equal to LRT? Are there still indications in which the decision in favor of LRT over SLT is justified?

The T helper cell type 1 (Th1) cytokines interleukin (IL)-2 and interferon (IFN)-gamma are mediators of acute graft rejection after liver transplantation and Th2 cytokines, such as IL-4 and IL-10, may have a protective role and correlate with graft acceptance. To test the hypothesis that infants aged1 year have an immunological advantage with regard to graft acceptance because of a partially immature immune system with a physiological balance toward a Th2 cytokine profile, we conducted the present study.We compared the T helper serum cytokine profiles in 105 infants and children after liver transplantation with or without acute graft rejection and analyzed the normal age-distributed concentrations of T helper cytokines in 51 healthy controls.The incidence of acute graft rejection was as follows: 0 to 12 months, 26.8%; 1 to 3 years, 40.0%; and3 years, 71.8%. There was a significantly lower incidence of acute rejection in infants 0 to 12 months of age compared with children1 year (11/41 vs. 38/64; P=0.001). In healthy infants, significant increasing Th1 cytokine concentrations and decreasing Th2 cytokine concentrations were found with increasing age. Patients with acute rejection had significantly higher values of Th1 cytokines compared with nonrejecting subjects, who had significantly higher concentrations of Th2 cytokines. A longitudinal analysis of serum cytokines from patients showed that changes of the cytokine patterns in the follow-up did not differ significantly from preoperative values, except in the 4 weeks posttransplant.We conclude from the data that the physiological balance toward a Th2 cytokine profile of infants in the first months of life predisposes to improved graft acceptance. Transplantation of children with biliary atresia as early as possible, avoiding Th1 stimulation by recurrent infections and vaccinations, may have a positive impact on overall tolerance.

In primary hyperoxaluria type 1 (PH 1), deficiency or mistargeting of hepatic alanine glyoxylate aminotransferase (AGT) results in over-production of oxalate and hyperoxaluria, leading to nephrocalcinosis and development of end-stage renal disease (ESRD) in the majority of patients. Renal transplantation (Tx) alone carries a high risk of disease recurrence as the metabolic defect is not cured. Therefore, combined liver/kidney Tx is recommended for patients with ESRD. An alternative approach is to cure PH 1 by pre-emptive isolated liver Tx (PLTx) before ESRD has occurred, but this approach has been carried out only occasionally and there are no uniformly accepted recommendations concerning the timing of this procedure. We report follow-up 3-5.7 yr after performing successful PLTx in four children (at the age of 3-9 yrs) with PH 1 prior to the occurrence of ESRD (glomerular filtration rate [GFR] range 27-98 mL/min/1.73 m 2 ). There was no mortality or long-term morbidity associated with the Tx procedure. Plasma and urinary oxalate levels normalized rapidly within 4 weeks, and renal function did not deteriorate under immunosuppression, even in one patient with advanced chronic renal failure (GFR 27 mL/min/1.73 m 2 ) who showed a stable course for more than 5.7 yrs. Although treatment must be individualized in this severe metabolic disorder, and PLTx has to be regarded as an invasive procedure, we consider that PLTx should be offered and considered early in the course of PH 1. PLTx cures the metabolic defect in PH 1 and can help to prevent, or at least delay, the progression to ESRD and systemic oxalosis.

Progressive familial intrahepatic cholestasis (PFIC) is caused by mutations of the bile salt export pump or the multidrug resistance P-glycoprotein, resulting in chronic hepatic failure. Partial external diversion of bile or ileal bypass is effective in some cases and, in others, liver transplantation (OLT) is necessary. Forty-two children were included in this study. Twenty-six children suffered from PFIC type 2 and 16 from PFIC type 3. Symptoms included pruritus, cholestasis, liver cirrhosis, and growth retardation. Seventeen patients received external biliary diversion. Ten had to undergo OLT in the following course. As of this report, three of the remaining patients were on the wait list for OLT. Twenty-three children received a liver graft primarily with excellent outcome. Our data show that OLT is the option of choice in symptomatic PFIC and whenever liver cirrhosis is present. We suggest a very restrictive recommendation of external biliary diversion. However, gene therapy may be a future option for children with PFIC.

Controlled trials of mTOR inhibitors in children following solid organ transplantation are scarce, although evidence from prospective single-arm studies is growing. Everolimus with reduced CNI therapy has been shown to be efficacious and safe in de novo pediatric kidney transplant patients in prospective trials. Prospective and retrospective data in children converted from CNI therapy to mTOR inhibition following kidney, liver, or heart transplantation suggest preservation of immunosuppressive efficacy. Good renal function has been maintained when mTOR inhibitors are used de novo in children following kidney transplantation or after conversion to mTOR inhibition with CNI minimization. mTOR inhibition with reduced CNI exposure is associated with a low risk for developing infection in children. Growth and development do not appear to be impaired during low-dose mTOR inhibition, but more studies are required. No firm conclusions can be drawn as to whether mTOR inhibitors should be discontinued in children requiring surgical intervention or whether mTOR inhibition delays progression of hepatic fibrosis after pediatric liver transplantation. In conclusion, current evidence suggests that use of mTOR inhibitors in children undergoing solid organ transplantation is efficacious and safe, but a number of issues remain unresolved and further studies are required.

Amanita phalloides intoxication can lead to FHF with high mortality, especially in children. There is still ongoing discussion about the optimal treatment and decision criteria for emergency liver transplantation (LTx). Here, we summarize our experience with outcomes in five children. Five children with severe A. phalloides intoxication were treated at our tertiary center from 1995 to 2010 and studied retrospectively with respect to clinical and laboratory aspects that might help to decide between LTx or conservative therapy only. The findings are discussed with regard to recommended treatment and transplantation criteria for adults. All patients survived, of whom two of five received emergency LTx. Three patients survived with conservative treatment consisting of intravenous silibinin, NAC, detoxification measures, and intensive care. Indications for LTx in two children were progressive brain edema and cardiovascular failure. Children with FHF due to A. phalloides intoxication should be considered early for emergency LTx but should be monitored closely for the necessity of definite LTx. Early detoxification with active charcoal as well as silibinin and NAC seems to improve the outcome. Late recovery of liver function after day 4 post-ingestion is possible.

Due to a lack of available size-matched liver grafts from children, most pediatric recipients are transplanted with technical variant grafts from adult donors. Size requirements for these grafts are not well defined, and consequences of mismatched graft sizes in pediatric liver transplantation are not known. Existing formulas for calculation of a standard liver volume are mostly derived from adults disregarding the age-related percentual liver weight changes in children. In this study, we aimed to establish a formula for general use in children to calculate the standard liver volume. In a second step, the formula was applied in pediatric patients undergoing liver transplantation at our institution between 2000 and 2010 (n = 377). Analysis of a large number (n = 388) of autopsy data from children by regression analysis revealed a best fit for two formulas: "Formula 1," children 0 to ≤1 year (n = 246): standard liver volume [ml] = -143.062973 +4.274603051 * body length [cm] + 14.78817631 * body weight [kg]; "Formula 2," children >1 to

In ARPKD, mutations in the PKHD1 gene lead to remodeling of the kidneys and liver. These may result in progressive liver fibrosis with portal hypertension requiring combined liver and kidney transplantation (CLKT). There is currently no consensus on the indication for CLKT and data on long-term outcomes are scarce. We analyzed in detail the pretransplant liver symptomatology, laboratory and ultrasound data, histological studies, and genotypes in eight patients undergoing CLKT. The median age was 10.1 years (range 1.7–16) and median follow-up was 4.6 years (range 1.1–8.9). All patients had clinical signs of portal hypertension and abnormal ultrasound findings. Congenital hepatic fibrosis was present in all pretransplant biopsies (6 out of 8 patients) and in all explanted livers. All patients survived; liver and kidney graft survival was 72% and 88%, respectively. Liver and kidney function were stable in all patients with a median eGFR of 70 ml/min/1.73 m² (range 45–108 ml/min/1.73 m²). Height-SDS improved significantly after 12, 24, and 36 months (P = 0.016, 0.022 and 0.018 respectively). The indication for CLKT remains challenging and controversial. A favorable outcome for patients with ARPKD can be achieved by using the degree of portal hypertension, longitudinal ultrasound examinations, and preoperative liver histology as parameters for CLKT.

Outcomes of pediatric liver transplantation have constantly improved in the last decade. Living-related liver transplantation does not seem to improve long-term outcomes following liver transplantation, but few studies have evaluated immunological parameters of the alloimmune response after living vs. deceased donor organ transplantation. We analyzed numbers of regulatory T cells, lymphocyte subsets, and serum cytokine concentrations in 12 pediatric recipients of living-related liver transplants and in 28 pediatric recipients of deceased donor organs during their annual follow-ups. Transplant recipients who underwent living donor organ transplantation had significantly higher numbers of regulatory T cells and IL-4 serum concentrations than recipients of deceased donor organs; both of these factors are associated with beneficial outcomes and transplantation tolerance. Living-related liver transplantation may have potentially beneficial immunological aspects, although long-term outcomes do not seem to be better in recipients of living donor organs than in recipients of deceased donor organs. Further studies are needed to compare immunological aspects of the two transplant procedures.

Aims. Liver-transplanted children have an increased risk for serious developmental problems. We examined attention and executive functioning and their relation to intelligence and several disease-related variables after transplantation. Methods. This is a monocentric, cross-sectional study with no reference group. Children's mean age at transplantation was 3.4±3.8 years (n=137, age 10.2±3.8 years). Assessment included attention and executive functioning (Test of Attentional Performance [TAP]/Test of Attentional Performance [children's version] [KITAP]) and intelligence (Wechsler Intelligence Scale for Children, 3rd edition/Kaufman Assessment Battery for Children). Results. In most TAP and KITAP Subscales, children scored in the lower normal range, but reaction times, errors, and omissions were significantly below the population mean. Most notable deficits became manifest in the subscales Sustained Attention and Working Memory where 47% respectively 38% of the present sample scored below the normal range. Most TAP and KITAP Subscales, particularly Alertness and Go/NoGo, were highly correlated with Wechsler Intelligence Scale for Children, 3rd edition and Kaufman Assessment Battery for Children Subscales indicating that liver-transplanted children with longer reaction times display lower intelligence scores. Regression analysis revealed that decelerated reaction times in the subscales TAP-Go/NoGo, Divided Attention (KITAP and TAP), and KITAP-Sustained Attention were associated with type of donation, duration of disease, age at transplantation, and sex (R 2 =0.14 to R 2 =0.25). Conclusion. Results provide evidence suggesting that liver-transplanted children are at risk of developmental deficits regarding attention and executive functioning. Especially intrinsic alertness and working memory performance seem to be insufficient. This might result in deficient initiating, sustaining, and controlling of action. In summary, results demonstrate the need for an early and comprehensive developmental screening after pediatric liver transplantation.

Objectives Pediatric liver transplant recipients often need to undergo liver biopsies for the detection and specification of complications such as acute or chronic graft rejection, infection, or drug toxicity. Complications resulting from liver biopsy are rare. The aim of our single-center retrospective study was to report on liver biopsy-related complications and, moreover, to assess the significance of histological findings in correlation with the suspected diagnosis. Patients and methods Overall, 120 liver biopsies from 67 children were performed and analyzed. All of the biopsies were performed with ultrasound guidance using midazolam and ketamine. Results The overall incidence of complications was 5.0%, but most of these complications were mild. In 2 cases, however, the complications were severe and required surgical intervention in addition to further medical treatment.In about 92% of the cases, liver histology confirmed the previously suspected diagnosis based on clinical and clinical laboratory indications. Conclusions We concluded that postliver transplantation liver biopsy in children seldom provides unexpected results and, even using ultrasound guidance, has led, albeit rarely, to serious complications. We therefore now accept potential delay in treatment and reserve liver biopsy for patients who fail to respond to therapy based on clinical judgment.

Chronic kidney disease (CKD) has been increasingly shown to be a negative prognostic factor after liver transplantation (Ltx). Creatinine-based glomerular filtration rate (GFR) formulas are notoriously insensitive. In children, non-invasive determination of GFR by measurement of serum cystatin C is feasible and repeatedly correlated to the gold standards of GFR measurements. The aim of our study was to determine GFR using cystatin C (GFR(cys)) in comparison with conventional calculated creatinine clearance (GFR(crea)) in the long-term follow-up after paediatric liver transplantation (pLtx) in a large number of patients.GFR of 168 children following liver transplantation was determined using cystatin C (GFR(cys)) and the Schwartz formula (GFR(crea)). In order to evaluate risk factors for CKD, a logistic regression analysis was performed. A multivariate model was applied to assess the impact of immunosuppressive treatment.The mean follow-up after transplantation was 7.8 (0.44-15.72) years. Due to a high overestimation of GFR as demonstrated in a Bland-Altman plot, only three patients with CKD stages 2-3 were detected with GFR(crea) compared with 34 with GFR(cys) (P0.001). Thus, prevalence of CKD with GFR((cys))90 mL/min/1.73 m2; was 30.4%, 7.6% and 27% in patients with 5, 10 and10 years of follow-up, respectively. Patients on cyclosporine had a significantly lower GFR than patients on tacrolimus. Logistic regression analysis did not show any significant risk factor for the development of CKD.The cystatin C equation is a non-invasive and sensitive diagnostic tool to detect renal dysfunction in children after Ltx at an early stage. The choice of first-line calcineurin inhibitor has an important impact on the development of CKD.

FHF is characterized by a high percentage of unknown causes leading to acute liver failure and furthermore by an increased morbidity and mortality prior to and post-Ltx. In different transplant centers, the reasons leading to FHF differ significantly as well as outcome. We report our single center experience with 30 pediatric patients receiving a liver transplant for FHF, out of a total of 83 children presenting with FHF. The time to transfer patients to the transplant center after the diagnosis of FHF was long, with a median of 14 days (Ltx group) and 12 days (controls), respectively. In nearly half of the patients (n = 14) in the Ltx group, we were not able to establish an exact diagnosis prior to Ltx: 50% suffered from encephalopathy, and 13 patients were treated in the intensive care unit prior to transplant. Because of the availability of different surgical techniques, all children received a timely transplant [split (n = 18), living donor (n = 9), whole organ (n = 2), and reduced liver (n = 1)]. Patient survival was 93.4%, and graft survival was 83.4% for at least one yr follow-up. Severe complications following Ltx included three cases with aplastic anemia and one child suffering from systemic mitochondrial depletion syndrome. The survival of patients treated medically was 83%. We conclude that a strong focus should be made on early referral to a specialized center and on improvement of diagnostic tools to timely detect the underlying reason for FHF. Results following Ltx for FHF are good.

IHHE as the most common vascular tumor of the liver in infancy can present with acute postnatal liver and congestive heart failure. LTx may be a lifesaving option, but can be complicated by extrahepatic involvement and bleeding complications, especially in neonates. Here we discuss the benefit of LTx in cases of acute postnatal deterioration and massive extent of the hepatic tumor. Three infants with IHHE were transplanted at our institution between 2005 and 2007. Two were neonates with acute postnatal decompensation and progressive liver and heart failure within days. Treatment with steroids and chemotherapy was ineffective; resection surgery and interventional treatment were not considered appropriate. LTx was performed at the age of 7 and 24 days, respectively. An additional infant with a bilobar tumor that evolved more slowly was transplanted on day-of-life 56. Patients 1 and 2 had to be resuscitated during the LTx procedure because of massive bleeding and both died during the procedure. Patient 3 had a complicated post-operative course but is doing well one-yr post-LTx. Neonates with extended hepatic and extrahepatic involvement of IHHE should be evaluated carefully prior to LTx. Whenever possible, alternative interventional treatment options should be considered.

Background The presence of autoantibodies and development of autoimmune hepatitis after liver transplantation has recently been reported as one of the causes for chronic graft dysfunction. The pathogenesis and clinical significance of this disease still remains unclear. Methods We evaluate 96 patients for the prevalence of autoantibodies and autoimmune hepatitis after pediatric liver transplantation and review their clinical follow-up including virus serologies, ultrasound examination and liver biopsies. Results Positive autoantibodies were detected in 74% of the patients after pediatric OLT. Graft dysfunction was observed in 46% of these children, and in 35% of the transplant recipients seronegative for autoantibodies. None of the patients showed histological signs or fulfilled clinical criteria for de novo autoimmune hepatitis. One child with negative autoantibodies was diagnosed to have a histologically proven de novo AIH two yr following OLT. Conclusions There is a high prevalence of autoantibodies after pediatric OLT, but the incidence of de novo AIH is very rare. In transplant recipients showing elevated liver function tests de novo autoimmune hepatitis has to be excluded by liver biopsy even if the patient is seronegative for autoantibodies.

OBJECTIVE. Neonatal hemochromatosis is a severe, often fatal multiorgan disorder of iron metabolism. Liver transplantation can be curative; the benefit of antioxidant treatment is discussed controversially. We summarize our experience with neonatal hemochromatosis over the past 13 years. METHODS. A retrospective study was performed of 16 patients with acute liver failure attributable to neonatal hemochromatosis between 1992 and 2004. RESULTS. Median age at the onset of neonatal hemochromatosis was 2 days (range: 0–21 days). Median weight at the time of diagnosis was 2900 g (range: 1520–4200 g). All patients had elevated ferritin levels (median: 4179 μg/L), and transferrin saturation (median: 99%). Fourteen patients (87.5%) showed significant hepatocyte siderosis in biopsies; 4 children had additional iron deposition in extrahepatic tissue. Four patients were diagnosed by MRI. Seven infants received liver transplants, 5 of them in combination with a preceding antioxidant treatment. Four children (25%) received antioxidants without the necessity of liver transplantation and were in good clinical condition at the time of this evaluation. Five patients (31.3%) died, 3 of them without any treatment because of initial fulminant multiorgan failure. In September 2005, 68.7% of the patients were still alive after a median follow-up of 5 years. CONCLUSIONS. Neonatal hemochromatosis is a severe metabolic disease, but early antioxidant treatment and liver transplantation in addition to optimal medical care can improve the outcome dramatically. Children with moderate liver failure can survive without liver transplantation, but should be monitored closely for deterioration.

Diaphragmatic hernia is a rare complication following solid organ transplantation. We here report three pediatric patients suffering from posttransplant enterothorax. One patient with biliary atresia presented with clinical signs of peritonitis without showing pulmonary symptoms four weeks following liver transplantation. The second patient was admitted with suspected pneumonia, whereas the third patient presented with recurrent abdominal pain over weeks and physical examination revealed the unexpected diagnosis of enterothorax. All patients received split liver transplants. Unspecific clinical signs mislead to suspected infectious complication under immunosuppression. No apparent risk factors for diaphragmatic hernia could be identified. Diaphragmatic hernia can present with a variety of atypical clinical symptoms. Severe or prolonged abdominal complains should lead to x-ray examination. We speculate that the split liver technique used in our center could lead to this rare complication due to the different anatomic position of the liver transplant in the abdomen.

End-stage liver cirrhosis because of metabolic or infectious diseases predisposes to hepatic malignancies like hepatocellular carcinoma. We report the first case of hepatoblastoma incidentally detected in the explanted liver of a 2-yr-old child undergoing liver transplantation for cirrhosis because of progressive familial intrahepatic cholestasis (PFIC). The diagnosis was difficult to obtain. The hepatoblastoma was not seen on ultrasound examination of the cirrhotic liver. As we could confirm retrospectively, alpha fetoprotein (AFP) was found elevated prior to transplantation. Two years after successful transplantation, there are no signs of malignancy detectable by clinical and radiological methods. We conclude from this case that PFIC may induce hepatoblastoma and that children with liver cirrhosis should undergo routine screening of serum AFP concentration.

Background. Despite major surgical and medical advances, it is still a challenge to perform transplantation in small infants. This study, focusing on short- and long-term outcomes, summarizes our 10-year experience with liver transplantation (LTx) in infants aged less than 6 months. Patients and Methods. We analyzed 43 patients aged 6 months or less (range: 12-184 days, median: 136 days) whose median weight at the time of LTx was 5.8 kg (range: 2.8-8.0 kg). The reasons for LTx were biliary atresia (n=27; 62.8%), neonatal hepatitis (n=6; 14%), neonatal cholestasis (n=4; 9.3%), and miscellaneous (n=6; 14%). The patients were followed up for a median time of 3 years and evaluated with respect to graft function, physical, and neurodevelopmental outcome. Results. The patient survival was 90.7% after 1 year and 87.2% after 2 years. The graft survival was 86% after 1 year and 82.1% after 2 years. Twelve patients (27.9%) experienced 15 surgical complications requiring intervention, two of whom demonstrated vascular thrombosis (4.7%). Acute early rejection occurred in 15 patients (34.9%), and chronic rejection occurred in 3 patients (7%); 83.3% of the patients had normal liver function test results at the time of evaluation. Complications such as posttransplant lymphoproliferative disease (4.7%) and persistent arterial hypertension (4.7%) were rarely seen. The physical and neurodevelopmental outcomes were good. Conclusions. LTx in infants aged less than 6 months provides excellent short- and long-term results. Low weight or young age of infants awaiting LTx should not be exclusion criteria for LTx.