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The long-term goal of this project is to improve outcomes for pediatric liver transplant recipients by discoveries to guide clinical decision-making related to immunosuppression management, specifically safe withdrawal of immunosuppression.
A 2007 consensus conference on long-term outcomes in pediatric liver transplantation sponsored by the NIH concluded that (1) long-term immunosuppression precipitates substantial non-immune and immune-related complications and that (2) identification of biomarkers that inform immunologic mechanisms of tolerance would lessen the risk for complications and lead to intervention studies to individualize, minimize, and/or withdraw immunosuppression. The conclusion of the consensus conference is strongly aligned with NIAID mission in transplant immunology to “conduct clinical trials to evaluate approaches that include tolerogenic, anti-inflammatory, and immunomodulatory strategies to treat and prevent immune-mediated diseases and to explore the mechanisms of action of such approaches. To directly address the challenges put forth at the consensus conference, we will conduct a multi-center, longitudinal study using a single arm design to test the hypothesis that a defined subset of pediatric liver tx recipients can safely and durably withdraw from immunosuppression.
The current study provides an innovative and comprehensive approach, bringing together clinical experts, leaders in transplant pathology and leaders in transplant immunology to address the critical gaps in knowledge. The expected outcome of the study will be the identification of clinical, histologic, transcriptional, and immunologic phenotype(s) that predict safe and successful immunosuppression and in doing so, substantially alter the long-term immunosuppression management of stable pediatric liver transplantation. If we could reliably identify the patients who can withdraw from immunosuppression, it would have a significant impact on health care costs and morbidity.
Dr. Bucuvalas serves as the study co-PI and clinical protocol chair. His principal collaborator and the overall study PI is Sandy Feng MD, PhD ; UCSF and The study is funded by NIAID and by NIDDK.
During the course of their illness as many as 50% of children who had a liver transplant stop taking their medications. Non-adherence is the most important reason for late organ rejection in long term survivors of pediatric liver transplantation. If we can use variation in tacrolimus levels as a marker of non-adherence, then we could target patients at risk In order to address this important risk-factor effectively, the first step is to evaluate a method that would identify non-adherence in these children. This multi-center study tests the ability of an objective measure of adherence to immunosuppressant medications to predict organ rejection and loss in children who had a liver transplant.
Dr. Bucuvalas is a site PI and serves on the steering committee. The principal collaborator and the overall study PI is Eyal Shemesh MD; Mt Sinai. The study is funded by NIDDK.
The overriding goal of the Acute Liver Failure study is to improve short- and long-term outcomes for pediatric acute liver failure (PALF), a devastating, complex disease.
The Pediatric Acute Liver Failure Study Group (PALFSG) is the first and only multi-center, multi-national collaboration to examine PALF. The uncertainty of diagnosis, disease severity, treatment strategies, and expected clinical trajectory likely leads to LT. Reducing uncertainty by focusing the diagnostic strategy, better characterizing disease severity, identifying cohorts amenable to targeted therapies, and recognizing the factors that drive outcome may reduce the need for LT and enhance organ availability for others.
We are conducting serial clinical, biochemical, genomic, proteomic, metabolomic, immunologic, and cytokine analyses in PALF to accurately identify patient characteristics that will reliably predict disease progression, neurocognitive sequelae, potential for spontaneous recovery, and risk of death, as well as identify cohorts that respond favorably to directed therapy (e.g., immunomodulation). By doing so, we might develop new therapeutic approaches and decrease LTX.
The principal collaborator and the overall study PI is Robert Squires MD; Childrens Hospital of Pittsburgh. The study is funded by NIDDK.
As the UNOS registry pares down its data requirements we are left with a gap: that is a mechanism to address long term outcomes in children who undergo liver transplantation. The impetus and rationale to conduct such research is outlined in a recent report of the NIDDK symposium on long- term outcomes in pediatric liver transplant recipients1. In the report, areas were identified as potential areas of focus for patient-based research. Listed below are those areas that would require observational research as might be accomplished through a collaborative registry effort.
We have established a consortium of more than 20 pediatric liver transplant centers to address these issues.
The aim of this study is to determine if (1) surgical techniques and perioperative procedures change as a result of the demonstrated variation in outcome and identification of best practice (2) the rate of HAT changes over time. The primary objective is to determine if the rate of HAT at pediatric liver transplant centers is decreased with implementation of a consensus developed bundle of best surgical and perioperative practice. The secondary objectives is to determine if variation in practice pattern decreases as a result of formation of a learning collaborative.
The principal collaborators are Michael Englesbe MD (U of Michigan) and Beau Kelly (Vanderbilt University)
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