Calcineurin Inhibitor Minimization in the Symphony Study: Observational Results 3 Years after Transplantation

ArticleinAmerican Journal of Transplantation 9(8):1876-85 · July 2009with81 Reads
DOI: 10.1111/j.1600-6143.2009.02726.x · Source: PubMed
Abstract
The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow-up, renal function remained stable (mean change: -0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low-dose tacrolimus arm continued to have the highest GFR (68.6 +/- 23.8 ml/min vs. 65.9 +/- 26.2 ml/min in the standard-dose cyclosporine, 64.0 +/- 23.1 ml/min in the low-dose cyclosporine and 65.3 +/- 26.2 ml/min in the low-dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair-wise tests). The MMF and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low-dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.

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  • ... Therapeutic ranges developed for Tac have not generally been based on statistical approaches, but rather on a mixture of empirical observations, in quite small samples of patients. In the past 20 years, there has been a substantial change in the target Tac concentration after kidney transplantation, with target concentrations as high as 20 ng/mL in the early 1990s, and with targets as low as 3-7 ng/mL after the publication of the Symphony-Elite study [3]. However, only few studies have compared different Tac concentration ranges and there is little support to promote the use of a specific therapeutic window and aim for certain target concentrations [21]. ...
  • ... the induction regimen between the two countries may be due to different donor types (proportion of deceased donor) and immunologic risk (proportion of sensitized patients). An initial ISx therapy containing biologics induction plus low-dose TAC-based triple therapy has been broadly accepted based on the Symphony study[10,11]. Most recipients in ourstudy (81.4%) also received the initial maintenance therapy with a CNI-based triple regimen, and TAC was used seven times more frequently than CSA was (87.7% vs. 12.3%). ...
  • ... It prevents or delays the rejection of the donor tissue by the host, but it is also potentially toxic to other organs and increases risks for infection and cancer [52,53]. The calcineurin-inhibitor (CNI; cyclosporin or tacrolimus) used as a component of immunosuppression regimens has been implicated in renal dysfunction and beta-cell toxicity, enough so to have been studied in a clinical trial to minimize their use [73]. The use of current immunosuppression regimens also complicates the justifications for islet transplantation, considered a nonlife-saving treatment, in paediatric patients to minimize risks associated with immunosuppression [74]. ...
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