Current status of liver transplantation in children.

There are two critical issues on opposite ends of the timeline for patients who are eligible for liver transplantation. On the one hand, the crisis in the cadaveric organ supply makes surviving to transplant ever more risky. On the other hand, patients who receive successful transplants face the consequences of long-term immunosuppression and its potentially life-threatening complications. The donor shortage is forcing difficult decisions that affect all patients who await liver transplantation. It is important to scrutinize carefully the results of all policies that govern allocation and the ethics of the solutions we advocate to ensure that no patient subgroup is being at a disadvantage. Current immunosuppression practices are being challenged by an increasing understanding of the immunologic events triggered by the allograft and the goal to free patients from consequences of a lifetime of immunosuppression. Clinicians can expect, and perhaps require, that new immunosuppressive protocols will address how the planned intervention might be expected to advance the understanding of tolerance mechanisms. As knowledge increases, clinicians can anticipate innovative new immunosuppressive proposals. Calcineurin and steroid-free induction, the use of donor-derived bone marrow infusion, recipient pretreatment, costimulatory blockade, and new antibody induction approaches are all being proposed--often in combination--for clinical trials. Researchers face additional challenges in defining endpoints if the goal is not just the short-term reduction in rejection but the minimization, and eventual discontinuation, of immunosuppressive drugs while maintaining excellent long-term graft function. How much "failure" will be accepted and how will it be defined? How will clinicians interpret liver biopsies if they begin to accept that some lymphocytic infiltrates may be beneficial mediators of the ongoing immune activation necessary for the maintenance of tolerance? How will they adjust immunosuppression practices to the dynamic processes in the immune response that maintain tolerance? Remarkable short-term successes in providing transplants for thousands of children with liver failure have brought these challenges into sharp focus. Clinicians must seek to move the life-giving science of transplantation toward a new goal: providing long lifetimes of excellent graft function with minimal toxicity from immunosuppressive drugs and the hope of freedom from immunosuppression altogether. Pediatric liver recipients, whose grafts have inherent tolerogenic potential and for whom we can anticipate decades of life after transplant, may prove to be an ideal study population to further these goals.