Reducing Exposure to Calcineurin Inhibitors After Kidney Transplantation

What Does This Important Study Show? 

Focusing on protocols designed to minimize exposure to calcineurin inhibitors, collaborators from 83 centers in 15 countries participated in the Efficacy Limiting Toxicity Elimination (ELiTE)–Symphony study.7 Primary kidney transplant recipients (n = 1,645) were randomized either to a control group treated with standard-dose cyclosporine (based on target trough blood levels), mycophenolate mofetil (MMF) and corticosteroids, or to 1 of 3 experimental groups who received induction antibody therapy with daclizumab, maintenance therapy with MMF and steroids, and either (1) low-dose cyclosporine, (2) low-dose tacrolimus, or (3) low-dose sirolimus—the latter group essentially constituting a calcineurin inhibitor avoidance arm. Estimated glomerular filtration rate (GFR), calculated by the Cockcroft-Gault formula, was the primary end point. After 1 year of follow-up, patients receiving low-dose tacrolimus had the highest GFR (65.4 ± 27 mL/min/1.73 m2), the lowest rate of biopsy-proven acute rejection (12.3%), and highest rate of graft survival (94.2%). In this group, estimated GFR and the incidence of acute rejection were statistically superior to the control group. The worst outcomes occurred in the low-dose sirolimus, calcineurin inhibitor avoidance group, which exhibited the lowest GFR (56.7 ± 27 mL/min/1.73 m2), the lowest rate of graft survival (89.3%), and the highest rate of biopsy-proven acute rejection (37.2%). Diarrhea and new-onset of diabetes mellitus were more likely to occur in patients receiving low-dose tacrolimus. Serious adverse events, particularly delayed wound healing and lymphoceles, were most common in the low-dose sirolimus group, requiring discontinuation of the agent in 7.8% of study participants.

How Does This Study Compare With Prior Studies? 

Previous studies directly comparing the efficacies of cyclosporine and tacrolimus have had conflicting results.8 In the ELiTE-Symphony study, overall outcomes of patients in the low-dose tacrolimus arm were superior to those of the 2 groups treated with either standard-dose or low-dose cyclosporine. Although there have been a number of previous studies describing calcineurin inhibitor–sparing strategies, few large randomized studies have directly compared calcineurin inhibitor dose reduction to calcineurin inhibitor elimination. One such study was the Cyclosporine Avoidance Eliminates Serious Adverse Renal Toxicity (CAESAR) study, in which 500 patients were randomized to either continuous therapy with standard or low-dose cyclosporine, or to withdrawal of cyclosporine 6 months posttransplant, in a regimen that included maintenance therapy with MMF and prednisone.9 Despite induction therapy with daclizumab in the low-dose and cyclosporine withdrawal arms, at 12 months the cumulative incidence of biopsy-proven acute rejection was significantly higher in the cyclosporine withdrawal group (38%) compared to the low- and standard-dosage cyclosporine groups (25.4% and 27.5%, respectively; P < 0.05).

The ELiTE-Symphony study is unique in comparing calcineurin inhibitor reduction strategies to true calcineurin inhibitor avoidance. Previous trials of calcineurin inhibitor avoidance have yielded mixed results. One study comparing cyclosporine therapy to calcineurin inhibitor avoidance in patients treated with daclizumab, MMF, and corticosteroids resulted in excellent rates of graft and patient survival in both arms at 12 months, but patients in the calcineurin inhibitor avoidance arm had an unacceptably high rate of acute rejection (53%).10 More recent trials using sirolimus-based immunosuppression as the basis for calcineurin inhibitor avoidance have yielded lower rates of acute rejection.11, 12 However, only one11 of the latter 2 studies showed a beneficial association between calcineurin inhibitor avoidance and long-term allograft function. In the current study, the low GFR in the calcineurin inhibitor avoidance arm almost certainly reflected the high rates of acute rejection. Similar results have been reported in the calcineurin inhibitor–free arm of the Optimizing Renal Transplant Immunosuppression to Overcome Nephrotoxicity (ORION) trial which, to date, has been presented only in abstract form.13

What Should Clinicians and Researchers Do? 

The immunosuppressive regimen favored in the ELiTE-Symphony study bears striking resemblance to protocols already in common use in the United States. According to the most recent report of the Scientific Registry of Transplant Recipients (SRTR), approximately 75% of kidney transplant recipients receive induction therapy with antilymphocyte antibodies. Tacrolimus is the most commonly prescribed calcineurin inhibitor maintenance agent. Less than 10% of patients receive de novo sirolimus. While the tacrolimus levels achieved initially in the ELiTE-Symphony study were lower than those targeted in many US centers, maintenance levels were actually not different or even higher than those used in US centers. Thus, the results of this trial should be reassuring to most US transplant centers. Taken together with other recent experiences, the results suggest, however, that calcineurin inhibitor avoidance protocols should be attempted only with great caution, at least with currently available alternative immunosuppressants.

The ELiTE-Symphony study has several shortcomings including a relatively short duration of follow-up and lack of protocol biopsies that would have allowed correlations between allograft histology and function. In the calcineurin inhibitor avoidance arm, the target sirolimus blood levels (4 to 8 ng/mL) were lower than those known to be therapeutically effective in preventing rejection and may have accounted for the increased incidence of acute rejection. Dosing of MMF in this study was empirical and did not take into consideration some important pharmacokinetic and pharmacodynamic drug interactions. For example, MMF exposure is known to be greater in tacrolimus-treated patients, and might account for the decreased rates of rejection and higher incidence of diarrhea in the low-dose tacrolimus group.

Although the regimens studied in the ELiTE-Symphony were relevant to protocols used in the United States, the patient population was not. Only 8% of the study cohort had diabetes mellitus at the time of transplantation, while almost one-third of US kidney transplant recipients have kidney failure from diabetes mellitus. Fewer than 2% of the patients were African American, but African Americans make up approximately 24% of US kidney transplant recipients and generally require higher doses of immunosuppressants to achieve rates of acute rejection comparable to white recipients. Thus, results of the ELiTE-Symphony study may underestimate the incidence of acute rejection in US transplant recipients treated with similar protocols. African American ethnicity also is a risk factor for development of new-onset diabetes posttransplant, and this study probably underestimates the incidence of tacrolimus-induced diabetes expected in a US population.

Toxicities of immunosuppressants continue to accrue beyond the first transplant year. In fact, the incidence of calcineurin inhibitor–mediated interstitial fibrosis and new-onset diabetes mellitus increase with time, may continue to occur despite “low-dose” regimens, and may ultimately outweigh the negative effects of early acute rejection in the long-term. Thus, there is still a need to study the ELiTE-Symphony protocols in more ethnically heterogeneous populations over longer periods of time.