Research Agenda for Pediatric Gastroenterology, Hepatology and Nutrition: Transplantation: Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation

RATIONALE In 1998, a total of 522 liver transplants, or approximately 12% of such operations in the US, were performed in patients younger than 18 years of age (1). For these children as for adults who underwent liver transplantation, 1-year survival rates approached 85%, the result of improvements in surgical technique, immunosuppression and antiviral therapy. The findings of studies in adult populations cannot be generalized to children because of differences in the indications for transplantation, as well as differences in surgical, infectious and developmental complications. A number of factors hamper pediatric studies. Even at the largest centers, only 30 to 40 children undergo transplantation each year and the population is heterogeneous. Consequently, individual transplant centers do not care for populations of sufficient size to identify interventions that improve outcome. Furthermore, with pharmacotherapeutic and surgical advances, the standard of care has evolved. The interpretation of studies performed over time at any single center is subject to the biases introduced by changes in care practices. Three major areas of research are considered of primary importance: tolerance induction, evaluation of outcome after liver transplantation, and post-transplant lymphoproliferative disease. In addition, there are three major research areas that may be considered a rank below: nonimmune graft injury, intestinal graft rejection and hepatocyte transplantation. AREAS OF EMPHASIS Evaluate Strategies to Induce Tolerance Research Goals Tolerance is classically defined as donor-specific immuno-nonresponsiveness and is manifest by long-term allograft function, without evidence of immunologic injury, maintained in the absence of immunosuppression (2). Full immunoresponsiveness to non-donor-derived antigens is preserved: animal studies have demonstrated the ability to fully reject a graft from a different donor as well as acceptance, without immunosuppression, of a second graft from the original donor. To date, true tolerance has been achieved in some small rodent models, but it is proving difficult to achieve consistently in large primate models. Current immunosuppressive strategies are nonspecific and, as such, associated with significant long-term risks of malignancy and infection. The nonimmunologic toxicities of current therapeutic modalities are substantial. With prolonged use, debilitating and life-threatening complications, including nephrotoxicity, neurotoxicity, bone disorders and cardiovascular disease, may occur. This has spurred research efforts to explore the mechanisms and clinical applications of tolerance induction. Furthermore, the problem of chronic rejection, which most likely is mediated by immune pathways different from those of acute rejection, has not been prevented by current immunosuppressive regimens (3). With successful tolerance induction strategies, long-term immunosuppressive drugs can be avoided. Such avoidance is of particular urgency in pediatric transplant recipients, who currently face the prospect of many decades of immunosuppressive drug use. Efforts to decrease long-term immunosuppression, or even consider discontinuation of immunosuppressive agents, are severely handicapped by lack of a reliable test to measure the recipient's degree of immunoresponsiveness to the graft. Without such a tolerance assay, random discontinuation of immunosuppressive therapy in stable patients is fraught with uncertainties. Research Goals The principal mechanisms of tolerance—anergy or depletion of alloreactive T cells, immuno-regulation and chimerism—are now providing promising strategies for clinical application. T cells are an absolute requirement for the rejection response. Cell surface markers that are capable of initiating co-stimulation are prime targets for new blockade approaches to modulate the immune response. Monoclonal antibodies to these targets are being developed, many of which are humanized to avoid induction of a neutralizing human antibody response. To advance this critically important field, the following areas of research must be targeted and supported: Increased application of immunomodulatory strategies to induce tolerance in large primate models Clinical trials in pediatric populations. Even early human trials of tolerance-inducing strategies must include pediatric recipients, while recognizing that the immune response and its regulation may be different in children Development of biologic markers to measure donor-specific immune response. Such markers will not only assess outcome in studies designed to induce tolerance but also, in the short term, provide important information for the tailoring of current immunosuppressive regimens to individual patients, to avoid over- and under-immunosuppression Research Strategies Critical to these efforts are basic science investigations that will further our understanding of T-cell signaling and activation. Clinical trials will require the participation of multiple transplant centers. Projected Timetable and Funding Requirements Basic science and clinical research initiatives to achieve tolerance will require a substantial and ongoing financial commitment. These initiatives provide an ideal opportunity for partnering between federal agencies and private groups, including the pharmaceutical industry. This research area is an extremely important frontier for young investigators. The infrastructure needed to support such studies includes data-gathering and analysis mechanisms to allow multicenter trials to be conducted. Funding for such collaborative multicenter databases, specific to the special outcomes and requirements of pediatric liver and intestinal transplant recipients, is critical. Prospectively Evaluate Outcome Measures After Pediatric Liver Transplantation Advances in immunosuppressive therapy and surgical techniques have improved graft and patient survival rates as well as expanded access to donor organs for pediatric liver transplant recipients. The improved rates have, in turn, resulted in greater acceptance of the procedure by patients, parents and physicians. The number of centers performing pediatric liver transplantation has increased as a direct result of greater patient and physician enthusiasm for the procedure, while the number of pediatric transplants has remained constant. Although the increased number of transplant centers likely has improved access to the procedure and proved convenient for patients and their families, the experience at each center has been substantially diluted. Increasing donor demand adversely affects donor availability for pediatric recipients. In addition, there is increasing pressure at present from public and private payers to raise efficiencies and cut costs. These factors provide a substantial impetus for pediatric transplant centers to examine the outcomes achieved in order to provide adequate stewardship for scarce donor resources and utilize dwindling financial resources most effectively (4). Unfortunately, the steady dilution in pediatric transplant experience precludes all but the crudest analysis of transplant outcomes. Research Goals It is recommended that a large multicenter transplant registry be developed that would prospectively collect data from all pediatric transplant centers. Such a database is essential for the accurate analysis of patient outcomes and for the development of innovations that might improve these outcomes in the future. Data from the multicenter pediatric transplant registry would be analyzed to determine the: A) Long-term graft and patient survival for pediatric transplantation, stratified by disease. Data on survival are currently available only for a few pediatric liver diseases. However, less common liver diseases that are considered potential indications, such as metabolic diseases, collectively account for about 30% of pediatric transplants. For many of these disorders, only anecdotal experience of short-term outcomes at a single center has been published. Establishment of a registry detailing the results of transplantation would allow for a more accurate assessment of the effectiveness of transplantation. These data, for example, would help determine the optimal timing of transplantation and the appropriateness of transplantation as a treatment option. B) Best methods of surgical and medical management. With dispersion of the pediatric transplant experience, local variations have developed in both the surgical procedure and postoperative care, including the use of immunosuppression. Some of these local idiosyncrasies may add to the overall cost of the procedure. Since there is currently no method to track the outcome of these various approaches, their effectiveness cannot be determined. The analysis of outcomes resulting from these management strategies, with comparison to outcomes in the entire data set, would be a first step in determining whether there is an optimal approach to operative and postoperative management. C) Long-term growth potential and long-term development potential of patients undergoing liver transplantation. Information regarding these issues is currently lacking and requires the collection of data to track somatic growth, reproductive capabilities, and educational and occupational achievements relative to the clinical characteristics of patients undergoing transplantation. Acquisition of this information would help to determine the optimal timing of the transplant procedure, and would allow for comparison of transplantation with other management strategies (5). For example, if it were shown that otherwise stable patients with cholestatic liver disease suffered irreversible compromise of growth or intellectual achievement over time, early transplantation would be justified. D) Long-term effects of immunosuppressive therapy. Several complications of standard immunosuppressive medications have been documented in children and adults. These include increased lipid levels, hypertension, decreased renal clearance, altered glucose metabolism, compromised growth and diminished bone accretion (6–8). The impact of these adverse effects is substantially greater in children than in adults because of the longer period of exposure to the drugs. The incidence of severe injury leading to potentially life-threatening conditions such as renal failure, heart disease or osteoporosis is not known. A determination of the incidence of these adverse effects, and the factors that predispose to their development, would be an important initial effort in devising strategies to reduce drug-induced organ damage. E) Long-term quality of life of children and their families after liver transplantation. The goal of transplantation is to improve the quality, as well as the quantity, of the patient's life. Recently, accurate, validated tools have been developed to assess pediatric quality of life. A large multicenter study utilizing these tools to evaluate the effectiveness of liver transplantation in reaching this goal is essential. As part of this study, children and their families would be followed over the long term, data would be stratified by specific diseases, and management strategies could be identified that yield the best outcomes. F) Long-term costs of transplantation. Anticipated costs for individual liver transplant recipients are currently difficult, if not impossible, to assess. Factors influencing cost include regional differences in overall cost of medical care, the United Network for Organ Sharing (UNOS) status of the patient at the time of transplantation, the number of comorbid conditions, and the type of graft. A database that tracks expenditures in addition to medical variables would be a first step in developing an accurate projection of costs for individual patients. Long-term follow-up of patient outcomes and cumulative associated costs would enable development of realistic cost-benefit analyses for pediatric transplantation. Research Strategies To achieve the above goals, a registry encompassing the majority of North American pediatric liver transplant recipients needs to be developed. Data must be collected in a prospective, standardized manner and analyzed in a timely and statistically valid fashion. Individual patients must be followed until adulthood. The ultimate goal of such a registry would be to determine the expected outcomes of liver transplantation for specific recipients and to identify factors that would influence the likelihood of achieving these outcomes. Validated tools need to be utilized or developed to assess some of these outcomes. Comparable experience in the pediatric oncology community has demonstrated the value of such a registry for determining therapeutic outcomes and developing new strategies to improve outcomes. An industry-funded pediatric liver transplant registry called SPLIT (S tudies in P ediatric L iver T ransplantation) currently collects data from 34 centers in Canada and the US, representing approximately 25% of the procedures performed annually. We propose expanded funding of the existing database to enable recruitment of additional centers to capture a minimum of 75% of the transplants performed each year. In addition, prospective studies evaluating specific outcomes are recommended. It is only through acquisition and analysis of these data that true measurements of the long-term effectiveness of liver transplantation will be achieved. Projected Timetable and Funding Requirements Funding for individual centers is needed to expand the existing SPLIT database to encompass the majority of pediatric liver transplant centers. Funding would largely be directed at support for transplant coordinators who gather the large amount of data required and for data entry personnel responsible for inputting the data. A small part of the funds would be allocated to a central data collection agency. Evaluate Interventions to Prevent and Treat Post-Transplant Lymphoproliferative Disease Post-transplant lymphoproliferative disease (PTLD) occurs in up to 11% of pediatric liver transplant recipients and up to 25% of pediatric intestinal transplant recipients. The associated mortality rate can be as high as 20% to 60%. In pediatric patients, more than 85% of PTLD is related to Epstein-Barr virus (EBV) infection and PTLD presents as a spectrum of disease ranging from benign B-cell hyperplasia to malignant lymphomas (9). Patients who are EBV naive and receive an organ from an EBV-positive donor, especially those being treated with increased levels of immunosuppressive agents for resistant rejection, are at high risk of developing PTLD (10). Infants and toddlers, who constitute 50% of the pediatric liver transplant population, are usually EBV naive. Up to 15% of high-risk liver transplant recipients will develop PTLD. More than 75% of high-risk patients acquire the virus within the first year of life. For children, especially those younger than 2 years of age, PTLD not only can be lethal but also can critically affect quality of life and graft function. It has been hypothesized that the outcome of EBV infection in pediatric transplant recipients reflects a balance between EBV-driven B-cell proliferation and the activity of EBV-specific cytotoxic T cells. If this hypothesis is true, then therapy that enhances the EBV-specific T-cell response or decreases B-cell proliferation should prevent PTLD. Prevention and preemptive treatment strategies include polymerase chain reaction (PCR) monitoring of the peripheral blood for the EBV genome, combined with antiviral therapy and reduction of immunosuppression with the first evidence of EBV infection. Treatment requires stopping T cell-directed immunosuppression so that immune surveillance by EBV-specific cytotoxic T cells is restored. Transplant physicians also use medications that inhibit viral replication and high-titer cytomegalovirus (CMV) globulin to prevent and treat PTLD. The efficacy of antivirals and immunoglobulin is difficult to assess because reduction of immunosuppressive therapy is almost always initiated simultaneously. However, the enhanced immune response that results from reduced immunosuppression is nonspecific and may precipitate allograft rejection. Research Goals Interventions need to be tested that can prevent or treat PTLD in pediatric liver transplant recipients by shifting the balance between B-cell proliferation and activation of EBV-specific cytotoxic T cells. Basic research is needed to develop: A reproducible method to measure EBV-specific cytotoxic T-cell activity; and A method for in vitro activation of recipient-derived EBV-specific T cells, including T cells from EBV-naïve recipients. The T cells can then be reinjected into the recipient at the time of diagnosis of PTLD to restore EBV-specific cytotoxic T cell competence (11). Clinical trials are needed to: Evaluate preemptive therapy that enhances EBV-specific cytotoxic T-cell activity and prevents development of PTLD Study the role of serial EBV PCR monitoring of the peripheral blood in preemptive therapy Determine the efficacy of standard treatment approaches (reduced immunosuppression, antivirals, hyperimmune globulin) in patients with PTLD Determine the efficacy of treatment with monoclonal antibodies directed cells or in the balance between B-cell proliferation and EBV-specific T-cell response in patients who to to preemptive or standard therapy. Research Strategies An analysis of the SPLIT registry that children the for entry into the It is that up to of high-risk patients are with EBV each year and that as many as 12% develop PTLD. We that 50% of patients with PTLD will not to standard therapy. A multicenter to determine optimal treatment is because the number of patients at even the largest transplant centers is small to achieve adequate Projected Timetable and Funding Requirements or will be required to each basic research The clinical research will be by of a clinical trials multiple centers. Evaluate Treatment Strategies for Liver are a demand To use existing resources initial graft must be the graft not function, or initial is to injury, there is an increased risk of and graft as well as greater It is that nonimmune injury to the allograft is associated with significant short-term and long-term graft injury results from the effects on the donor organ of injury and injury in the graft. With a understanding of the strategies can be are in this area of research is or the injury by and is likely to improve early graft and reduce the need for to primary or initial function. In of the ongoing donor in this area are of particular In addition, improved graft may allow the successful use of more which would further expand the donor it is now that the nonspecific response by nonimmune injury the immune response to the graft The risk of acute rejection may be but of greater is evidence that chronic rejection may be to early nonimmune an understanding of the response of the liver after injury is critically important with the increasing use in children of liver those from This research is also to liver donor is a in such as and which hepatocyte cell Current immunosuppressive drugs may be to some of these for example, inhibit liver Research Goals Research efforts are needed to develop strategies for nonimmune injury and early graft function. Such efforts will improve the donor by more organs to be It is also important to the response of the liver graft for a successful outcome after pediatric transplantation. and for Transplantation Research Goals intestinal constitute about of the to intestinal transplants that are performed each year in the have that acute rejection of the graft is and an important of graft The incidence and of rejection, less in of combined transplantation, is greater than occurs with liver are also to chronic rejection, which occurs with liver of intestinal is difficult to and with liver and transplantation, there is no blood test to the small the of rejection. diagnosis is difficult as the can be A diagnosis results in of an intestinal graft. are needed to: Evaluate markers for rejection. techniques may be on an understanding of the mechanisms rejection. to assess changes in intestinal that well with rejection. studies have been for this but results were nonspecific and other markers that might be early the of rejection Research Strategies Several approaches may be can be only at centers large of intestinal transplant procedures are Projected Timetable and Funding Requirements These studies are likely to be an ongoing The cost of support for clinical of the and data analysis may be immunologic if could raise of the total the Clinical of Transplantation transplantation to as a potential therapeutic to liver transplantation. providing to patients with a metabolic can improve can also as a in liver patients liver transplantation, providing a sufficient to metabolic The development of as a treatment after decades of basic research in liver cell issues the of and needed to be With successful can be and centers for use in the treatment of patients with liver Research Goals To the applications of further studies are to methods of of a number of cells needed for successful a single or are is the optimal of or for patient patients with metabolic disease for In do for patients with acute chronic liver time of in to a patient's clinical might of liver early In addition, studies are needed to the of availability of methods must be developed that enable to in that has been the number of available for transplantation will of the availability of new Research Strategies To achieve these research goals, multicenter clinical trials as well as basic research are It is important to support the of regional centers for the of research will also be enhanced by the development of animal models of liver cell transplantation. The population of long-term of liver transplantation has by the number of transplant procedures performed each year. In the cost of the liver transplant procedure and associated is at about For each year after a successful liver transplantation, direct care costs are to to of the cost of transplantation and Consequently, after the cumulative cost of graft and in a population of long-term is to the cost of the liver transplantation procedure. on these it is that is each year on liver transplantation in the pediatric for the procedures and an amount to graft and in the impact of pediatric transplant on total care costs will the potential for years of life for a undergoing transplantation is greater than that for a The and cost to the is more difficult to is of patients care for their children through long of and follow-up may their and while the medical needs of children the studies are in children and parents after liver or intestinal transplantation. The of children who undergo transplant procedures will affect their ability to and of the impact of liver and intestinal transplantation has not been

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