Sirolimus in Combination With Tacrolimus
Cyclosporine (CsA) nephrotoxicity is enhanced by sirolimus (SRL). Tacrolimus is perceived to be less nephrotoxic than CsA, and therefore, CsA has been largely replaced by tacrolimus (TAC) when calcineurin inhibitors are used with SRL.

We analyzed 44 915 adult renal transplants in the Scientific Renal Transplant Registry (SRTR) from 2000 to 2004. Three thousand five hundred twenty-four (7.8%) patients received a baseline immunosuppressive regimen of TAC/SRL, with an inferior overall (log-rank p < 0.001) and death-censored graft survival (p < 0.001) as compared to TAC/MMF (N = 27 007). This effect was confirmed in multivariate Cox models; the adjusted hazard ratio (AHR) for overall graft loss with TAC/SRL was 1.47 (95% CI = 1.32, 1.63) and for CsA/SRL 1.38 (95% CI = 1.20, 1.59) relative to TAC/MMF. These effects were most apparent in high-risk transplants. Six-month acute rejection rates were low (11.5–12.6%) and not different between groups.

In summary, national data indicate that TAC/SRL as compared to TAC/MMF is associated with significantly worse renal allograft survival in all subgroups of patients and, in particular, higher-risk transplants. These Results have to be interpreted in the context of the inherent limitations of any retrospective database analysis and evaluated in context with data from prospective clinical trials.

Early studies by Andoh et al. in animals did not show any effects of sirolimus (SRL) alone on glomerular function or on interstitial fibrosis; however, subtle morphologic and functional tubular changes could be observed. However, as SRL in combination with cyclosporine (CsA) was being investigated in kidney transplantation in the United States, Andoh et al. reported a rapid communication that rapamycin could potentiate CsA-induced interstitial scarring in their well-described rat model. This was shortly followed by the phase III studies that led to the approval of SRL in the United States for kidney transplantation, where impaired renal function in patients on SRL and CsA was reported as compared to the control group. This finding was felt to be due to SRL potentiating CsA nephrotoxicity and led to the conception of the Rapamune Maintenance Regimen (RMR) study, where CsA was withdrawn at 2 months post-transplantation and patients remaining on full dose SRL and CsA were compared. The subjects in the RMR study experienced renal function improvements when taken off CsA and in the longer follow-up, achieved better graft survival despite a statistically nonsignificant increase in acute rejection during CsA withdrawal. This finding in the RMR study led to the labeling change suggesting withdrawal of CsA from regimens containing Rapamycin at 34 months post-transplantation in low-risk subjects. Subsequently, a large population study confirmed the original concerns raised in the phase III trials of the potential for worse graft survival in patients treated with the combination of CsA and SRL.

Given the overall perception of reduced nephrotoxicity with tacrolimus (TAC) compared to CsA, and the preliminary observations by MacDonald et al., TAC-SRL in combination with corticosteroids became increasingly accepted as a regimen that was both efficacious and afforded stable renal function. However, the best renal function with this combination was most evident in studies utilizing TAC in low doses. It is important to note that none of these studies compared renal function to a control group of TAC and MMF. Given the reciprocal nature of serum creatinine and GFR, it is possible that at the low values of serum creatinine seen with TAC, small increments in serum creatinine that might translate into important differences in GFR, could easily be overlooked. In fact, the only randomized prospective trial comparing SRL and MMF in combination with TAC, showed significantly worse renal function, and a trend toward inferior graft survival at 1 year in the patients treated with SRL and TAC versus MMF and TAC.

The latest released update of U.S. transplant data provided by the Scientific Renal Transplant Registry (SRTR), affords sufficient follow-up to retrospectively analyze Results with the combination of TAC and SRL versus the current most prevalent combination of TAC and MMF, and put the Results of accumulating prospective evidence in the context of the national usage of these drug regimens.