STEROIDS VERSUS STEROID-FREE TACROLIMUS BASED IMMUNOSUPPRESSION IN PEDIATRIC REN

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Successful renal transplantation offers the best hope to the child to restore normal growth, development and life style after ESRD. Over the last decade, advances in immunosuppression have improved graft survival and reduced the incidence of early immunological adverse events such as acute rejection in the first post-transplant year to about 27% in recipient of living donor kidneys. In the absence of tolerance to the graft, immunosuppressive medications have to be taken for the life of the organ. Morbidities associated with immunosuppressive drugs include undesirable cosmetic effects (which contribute to noncompliance) as well as conditions that increase cardiovascular risk such as hypertension, dyslipidemias, and diabetes mellitus. Corticosteroids have been the invariant drug in immunosuppressive protocols. Corticosteroids have been the cornerstone of immunosuppressive therapy for renal transplantation for 40 years, however corticosteroids have numerous undesirable side effects, including Cushingoid habitus, poor growth, infection, hypertension, hyperlipidemia, glucose intolerance, diabetes mellitus, bone loss, cataracts, acne and changes in mood and behavior. In children, the Cushingoid habitus greatly impacts compliance and growth retardation comes at a very unfortunate stage for children and adolescents who are going through their major growth periods. Elimination of steroid therapy in children with renal transplants would appear to be greatly beneficial. Nevertheless, it has proven difficult, if not impossible, to withdraw steroids in these patients without increased acute and chronic rejection. There are several theoretical reasons to believe that steroid use makes the recipient steroid dependent, including the numerous observations that subsequent steroid withdrawal has been associated with a detrimental outcome and that immunomodulatory effects of steroids, once reversed, may have untoward side effects. It is likely that steroid dependency cannot develop in a patient not previously exposed to steroids. If suppression of the immune response becomes conditioned to steroid exposure, then subsequent steroid withdrawal has the potential for a detrimental outcome, as has been demonstrated clinically. In addition, steroids appear to impact peripheral tolerance by a Fas mediated mechanism. Similarly, by blocking signaling through the T cell receptor, steroids may prevent the induction of apoptosis. Steroid withdrawal after previous steroid exposure can therefore theoretically increase the risk of acute graft rejection. In other words, steroid-adapted suppression of the immune response is destined to increase the risk of acute rejection on attempted steroid withdrawal. This is most pertinent in an immunogenic organ, like the kidney. It has been hypothesized that a completely steroid-free immunosuppressive protocol should avoid steroid dependent suppression of the immune response, which makes either steroid withdrawal or alternate dosing hazardous for rebound acute rejection. Late steroid withdrawal (after the first transplant year) has been successful in a small number of patients with stable graft function, but the small target population that can benefit from this approach may be difficult to predict and remains limited.