Markers of operational immune tolerance after pediatric liver transplantation in patients under immunosuppression.

A prospective identification of the estimated 20-50% of pediatric LTX recipients developing operational tolerance would be of great clinical advantage. So far markers of immune tolerance - T-cell subpopulations or gene expression profiles - have been investigated only retrospectively in successfully weaned patients. Fifty children aged 8-265 months (median 89) were investigated 1-180 months (median 44) after LTX under ongoing immunosuppression. T-cell subpopulations were measured during regular post-transplant visits using FACS (Vδ1- vs. Vδ2-γδ-T cells and Tregs). A Vδ1/Vδ2-γδ-T-cell ratio ≥1.42 previously reported in operational tolerance was found in 12 of 50 (24%) patients. In analogy, a Treg count ≥44 per µL was found in 35 of 50 (70%) patients and a Treg proportion ≥2.23% of CD3(+) -T cells in 39 of 50 (78%) patients. Only 9 of 50 patients (18%) fulfilled both criteria. The parameters Vδ1/Vδ2-γδ-T-cell ratio and Tregs were not significantly correlated to each other or with donor type or immunosuppression. Vδ1/Vδ2-γδ-T-cell ratio was more stable in serial examinations compared with Treg analyses. The observed proportion of 18% pediatric LTX patients with potential operational tolerance is in accordance with previous reports. However, clinical experience shows that rejections may happen even after long-time weaning of immunosuppression. This suggests that operational tolerance is a dynamic process, with uncertain prediction by Vδ1/Vδ2-γδ-T-cell ratio and/or Tregs under immunosuppression.

[Living donation liver transplantation in children]. / Lebendspende-Lebertransplantation beim Kind.

Liver transplantation is the first-line therapy for children with acute and chronic hepatic failure, metabolic liver diseases and liver tumors. As most of the children with end-stage liver disease are very small in stature the resources of compatible organs of deceased donors are limited. Living liver donation was able to nearly eliminate waiting list mortality with excellent patient and graft survival. As 80% of the pediatric recipients have a body weight <25 kg donation of the left lateral lobe (segments II+III) is sufficient in most of the cases. According to a standardization of the surgical procedures as well as the preoperative, intraoperative and postoperative management donation of the left lateral lobe advanced to a procedure with very low donor morbidity and mortality rates. The complexity of hepatic disease patterns in pediatric patients which often affect other organ systems demand a close cooperation with an experienced pediatric team. Pediatric living donor liver transplantation requires high expertise in liver surgery and split liver transplantation and should therefore only be performed in transplant centers meeting these high qualifications.

Cognitive abilities, behaviour and quality of life in children after liver transplantation.

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.

Effectiveness of Rex shunt in children with portal hypertension following liver transplantation or with primary portal hypertension.

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.

Hepatoblastoma in a child with progressive familial intrahepatic cholestasis.

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.

Hypogammaglobulinemia in pediatric liver transplant recipients.

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.

Split liver transplantation: past, present and future.

The technique of liver splitting offers an effective way of increasing the donor pool and decreasing pediatric waiting list mortality. A donor liver is divided in such a way that the left lateral liver graft can be transplanted into a small child and the right extended liver graft into an adult. This innovative technique did not harm the adult recipient pool. Because of its technical complexity and the initial poor results after split liver transplantation (SLT) this procedure has slowly gained acceptance in the Transplantation Community after its first introduction in 1988 (4). Small children with end stage liver disease suffered the most from the extreme shortage of cadaveric donor organs due to the difficulty of finding size-matched donors. The successful surgical development of SLT and a better donor and recipient selection have led to a reduction of the pediatric pretransplant mortality to nearly zero and to results comparable with those after whole organ transplantation (WLT). By splitting a donor organ into two 'full' hemi-grafts and providing a small adult ( < 60 kg) or a big child ( > 30 kg) with the full left graft and a medium-sized adult (60-80 kg) with the full right graft, a small-for-size situation for adolescents or adults can be avoided and the total number of available grafts can be increased. It is the goal to provide each recipient with its customized graft in the near future. However, splitting for two adults requires high technical skills and profound knowledge of the anatomic variations and should be performed in centers with large transplantation experience.

C2 blood concentrations of orally administered cyclosporine in pediatric liver graft recipients with a body weight below 10 kg.

Pharmacokinetic studies in adult and pediatric liver transplant recipients have shown that the C(2) monitoring is superior to the traditional determination of CsA trough levels (C(0)) as an estimate of CsA exposure. However, target reference values for C(2) in very small infants have not been established yet. The objective of our study was to assess the distribution of C(2) levels in the first week following Ltx and to analyze enteral absorption of CsA for this group of patients. We documented CsA C(0) and C(2) levels in 25 infants with a body weight below 10 kg (median 6.8 kg; range 3.0-9.8 kg) in the first 7 days after Ltx. The infants had a median age at transplantation of 7 months (range 0.3-20.0 months). The underlying diagnoses were biliary atresia (n = 17), acute liver failure (n = 4), metabolic disease (n = 4). All children received CsA microemulsion (Neoral, initial 10 mg/kg/day), prednisolone, and two single doses of basiliximab as immunosuppressive drugs. The mean C(0) and C(2) levels were as follows: day 1: C(0) 77.0 +/- 39.6, C(2) 340.5 +/- 140.0 ng/mL; day 2: C(0) 135.5 +/- 53.2, C(2) 467.0 +/- 168.2 ng/mL; day 3: C(0) 146.5 +/- 70.8, C(2) 519.0 +/- 219.1 ng/mL; day 4: C(0) 168.5 +/- 55.1, C(2) 570.0 +/- 163.7 ng/mL; day 5: C(0) 156.5 +/- 38.0, C(2) 612.0 +/- 132.4 ng/mL; day 6: C(0) 177.0 +/- 41.1, C(2) 606.0 +/- 149.2 ng/mL; day 7: C(0) 174.0 +/- 27.2, C(2) 622.0 +/- 98.8 ng/mL (r = 0.82, p < 0.05). This analysis demonstrates that there is a good enteral absorption of CsA in very small children post-Ltx in the early post-operative period. Based on the C(2) levels achieved, we conclude that there is a good correlation between C(0) and C(2) levels even in very small infants.

The impact of cyclosporine on the development of immunosuppressive therapy for pediatric liver transplantation.

Since the introduction of cyclosporine into pediatric liver transplantation remarkable progress in patient and graft survival has been observed: survival rates 60%; acute (60%), steroid-resistant (22%) and chronic rejection (4%); infections (60%); and side effects (20%). Individualization of cyclosporine therapy complements the development of new immunosuppressive agents such as tacrolimus, mycophenolate mofetil, and sirolimus for specific indications. The ultimate goal of transplantation to achieve immunotolerance a waits future progress.

Basiliximab monotherapy following B-cell lymphoma after pediatric liver transplantation and anti-CD20 therapy.

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.

The oxidative metabolism of polymorphonuclear neutrophils in pediatric liver graft recipients.

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.

Is there still a need for living-related liver transplantation in children?

OBJECTIVE: To assess and compare the value of split-liver transplantation (SLT) and living-related liver transplantation (LRT). SUMMARY BACKGROUND DATA: The concept of SLT results from the development of reduced-size transplantation. A further development of SLT, the in situ split technique, is derived from LRT, which itself marks the optimized outcome in terms of postoperative graft function and survival. The combination of SLT and LRT has abolished deaths on the waiting list, thus raising the question whether living donor liver transplantation is still necessary. METHODS: Outcomes and postoperative liver function of 43 primary LRT patients were compared with those of 49 primary SLT patients (14 ex situ, 35 in situ) with known graft weight performed between April 1996 and December 2000. Survival rates were analyzed using the Kaplan-Meier method. RESULTS: After a median follow-up of 35 months, actual patient survival rates were 82% in the SLT group and 88% in the LRT group. Actual graft survival rates were 76% and 81%, respectively. The incidence of primary nonfunction was 12% in the SLT group and 2.3% in the LRT group. Liver function parameters (prothrombin time, factor V, bilirubin clearance) and surgical complication rates did not differ significantly. In the SLT group, mean cold ischemic time was longer than in the LRT group. Serum values of alanine aminotransferase during the first postoperative week were significantly higher in the SLT group. In the LRT group, there were more grafts with signs of fatty degeneration than in the SLT group. CONCLUSIONS: The short- and long-term outcomes after LRT and SLT did not differ significantly. To avoid the risk for the donor in LRT, SLT represents the first-line therapy in pediatric liver transplantation in countries where cadaveric organs are available. LRT provides a solution for urgent cases in which a cadaveric graft cannot be found in time or if the choice of the optimal time point for transplantation is vital.