Rainer Ganschow

Is There Still a Need for Living-related Liver Transplantation in Children?

ObjectiveTo assess and compare the value of split-liver transplantation (SLT) and living-related liver transplantation (LRT). Summary Background DataThe 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. MethodsOutcomes 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. ResultsAfter 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. ConclusionsThe 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.

One Hundred Thirty-Two Consecutive Pediatric Liver Transplants Without Hospital Mortality: Lessons Learned and Outlook for the Future

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.

Th2 cytokine profile in infants predisposes to improved graft acceptance after liver transplantation

BACKGROUND 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 aged <1 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. METHODS 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. RESULTS The incidence of acute graft rejection was as follows: 0 to 12 months, 26.8%; 1 to 3 years, 40.0%; and >3 years, 71.8%. There was a significantly lower incidence of acute rejection in infants 0 to 12 months of age compared with children >1 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. CONCLUSIONS 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.

Intensive care management after pediatric liver transplantation: A single‐center experience

Abstract: A retrospective study was conducted to determine the significance of intensive care management on outcome after liver transplantation (LTx) in children. Of 195 transplants performed in 162 children, factors affecting morbidity and mortality were documented during the post‐operative intensive care unit (ICU) stay. To assess the gain in experience of ICU management, we compared mean ventilation time and stay in the ICU as well as mortality, incidence of surgical complications, infections, and rejection episodes, during three different time‐periods (October 1991–August 1994, September 1994–July 1996, and August 1996–February 1998). The time spent by patients in the ICU (9.7 days vs. 7.9 days vs. 4.7 days, p < 0.001) and time on ventilation (5.2 days vs. 3.1 days vs. 1.2 days, p < 0.001) were significantly reduced over the duration of the study. The overall mortality was 18.0% (n = 30) and 76.7% (n = 23) of these deaths occured during the early post‐operative period in the ICU. The incidence of severe surgical complications decreased significantly over time, and the application of intra‐operative Doppler ultrasound since 1994 led to detection of 27 correctable vascular complications. The overall incidence of acute cellular rejection episodes in our center was 64.1%: 43.5% of the infectious episodes occured in the ICU (bacterial 70.2%, viral 12.3%, and fungal 17.5%). The main side‐effect from immunosuppressive drugs was arterial hypertension in 29% of the patients. We conclude that our efforts to improve intensive care management and monitoring were the key elements in reducing morbidity and mortality after pediatric LTx.

Liver Transplantation in Children With Progressive Familial Intrahepatic Cholestasis

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.

Pediatric transplantation: the Hamburg experience.

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 1 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.

Neonatal hemochromatosis: long-term experience with favorable outcome.

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.

Transplantation procedures in children with primary hyperoxaluria type 1: outcome and longitudinal growth.

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.

First experience with basiliximab in pediatric liver graft recipients

Abstract: Several studies have shown a significant reduction of acute cellular graft rejection in adult liver and kidney graft recipients treated with monoclonal anti‐interleukin‐2 (IL‐2)‐receptor antibodies. The mechanism was inhibition of activated T‐helper cells by blocking the α‐chain (CD25) of the IL‐2 receptor. The pilot study described here evaluated the use of basiliximab in pediatric liver transplantation (LTx), which is the first report on its use in children. Fifty‐two liver‐transplanted children were analyzed in this study. A matched‐pair historical control group (n = 26) received cyclosporin A (CsA) and prednisolone, and patients in the basiliximab group (n = 26) were treated with low‐dose CsA and basiliximab (after reperfusion and on day 4 post‐transplant). The incidences were compared of acute graft rejections, infectious complications, and the adverse effects of immunosuppressive medication within the first 6 months post‐transplant. The incidence of acute rejection was significantly higher in the control group (61.5% vs. 11.5%, p = 0.0004). The frequency of infectious complications was similar (46.1% vs. 53.8%). Patients in the basiliximab group showed less arterial hypertension; however, the differences were not statistically significant (30.7% vs. 7.7%, p = 0.07). Nephrotoxicity, hepatotoxicity or neurotoxicity were only seen in the control group (7.7%; 3.8%; 3.8%, respectively). Hence, the use of basiliximab in combination with CsA and steroids in pediatric liver transplant recipients is safe and reduces the incidence of acute graft rejection. Further studies are needed to confirm our preliminary results and to analyze long‐term effects on post‐transplant lymphoproliferative disease, chronic rejection, and patient survival.

Low-dose immunosuppression reduces the incidence of post-transplant lymphoproliferative disease in pediatric liver graft recipients

Objectives In pediatric solid organ transplantation, the Epstein-Barr virus (EBV)-related lymphoproliferative disorders (PTLD) still play a major role in post-transplant morbidity and mortality. The aim of the study was to determine the incidence of PTLD in pediatric patients with liver transplant who receive low-dose immunosuppression protocols. Methods All pediatric patients (n = 269) received a dual immunosuppression therapy consisting of cyclosporine A (initial trough levels, 170–200 &mgr;g/L; trough levels for maintenance immunosuppression after 1 year, 80–100 &mgr;g/L) and prednisolone (starting dose, 60 mg/m2). Steroids were reduced to 30 mg/m2 after 1 week, followed by a weekly tapering to 5 mg/m2. Seventy-seven of 269 patients were switched to tacrolimus therapy. The authors evaluated the significance of EBV-DNA monitoring by quantitative polymerase chain reaction in identifying patients at risk for PTLD. Results Patient survival was 90.3%; graft survival was 85.9%. Eight patients lost their grafts because of chronic rejection. The incidence of PTLD was low (0.7%), although a significant EBV viral load was found in 42.4% of the patients. One third of the patients with a viral load of 3,000 genomes/105 cells or greater had clinical signs of EBV infection. Conclusions The authors conclude that low-dose immunosuppressive protocols significantly reduce the incidence of PTLD. In patients treated with that regimen, the monitoring of EBV viral load seems not to be helpful. It can be assumed that low-dose immunosuppression does not suppress EBV-specific cytotoxic CD8+ T cells, thus allowing the host to control EBV infection without the risk of PTLD. Our low-dose immunosuppression protocol did not increase the risk of chronic rejection.