Corticosteroid elimination in renal transplantation: pro

CLINICAL MANIFESTATION of corticosteroid-related morbidities are protean in scope, and there remains little argument among transplant professionals that their elimination is a worthy goal in managing solid organ transplant recipients. Unequivocal proof that elimination of corticosteroids is superior to long-term corticosteroid therapy has remained a difficult goal to achieve due to a number of barriers. The most salient of these barriers include: (1) lack of accepted, objective parameters for measuring salutary effects of corticosteroid elimination; (2) misinterpretations and misleading conclusions regarding risk of late allograft loss in patients in whom maintenance corticosteroid therapy has been eliminated; (3) design flaws in randomized trials of corticosteroid elimination; (4) failure to assure inadequate maintenance immunosuppression in patients in whom corticosteroids are eliminated; (5) obfuscation of the benefits of elimination of maintenance corticosteroid therapy by treatment of rejection with high-dose corticosteroid therapy; and (6) elimination of corticosteroid therapy at relatively late points in the posttransplant period, beyond which the morbid effects of corticosteroid therapy have already been incurred. An outstanding example of how previous, outdated trials can lead to erroneous conclusions has recently been provided in a published meta-analysis of corticosteroid withdrawal (CSWD) trials. This study actually constituted a rigorous, exhaustive analysis of published corticosteroid withdrawal trials. A total of 10 trials were analyzed, and statistical analysis of risk for graft loss after CSWD was estimated to be 1.38. However, analysis of these studies indicated that the risk of graft loss was not statistically significant in any of these studies, and that the underlying immunosuppression in two of the trials was an inadequately dosed sandimmune version of cyclosporine Neoral. Moreover, the risk in the third study, the CCTAT randomized trial, was largely incurred in African American patients. The inclusion of several trials in which CSWD was performed under outdated immunosuppression obviates the current clinical significance of the author’s conclusions that the risk of graft loss is increased after CSWD. Over the past few years, a number of new, more potent immunosuppressive agents have received regulatory approval including tacrolimus, mycophenolate mofetil, sirolimus, anti-IL-2 receptor antibodies, and thymoglobulin. Data from randomized and nonrandomized trials with these agents has provided cogent evidence that corticosteroid withdrawal is now more easily achieved, and with substantially reduced risks of acute rejection. Moreover, combination therapy with these agents has allowed complete avoidance of maintenance corticosteroid therapy, or, alternatively, elimination at early time points in the posttransplant period (viz, within the first posttransplant month). Finally, recent data has indicated that induction antibody therapy in combination with these new agents may allow complete abrogation of the risk of acute rejection in patients in whom maintenance corticosteroid therapy is eliminated. To date, several trials have been reported where corticosteroid withdrawal or corticosteroid avoidance (CSAV) has been conducted under modern immunosuppressive therapy that includes at least one of the following agents: mycophenolate mofetil, tacrolimus, or sirolimus. These studies have each shown that the risk of moderate acute rejection in primary renal allograft recipients in whom CSWD or CSAV has been been performed has been less than 5%. These data argue strongly that the risk of acute rejection in CSWD is substantially less under modern immunosuppressive therapy, and that older experiences under cyclosporine/ Azathioprine therapy are outdated. In conclusion, a new era has dawned for elimination of corticosteroid therapy from maintenance immunosuppressive regimens in renal transplant recipients. Their use in maintenance anti-rejection therapy is being reduced or eliminated in an increasing number of transplant programs.