Early elimination of exposure to calcineurin inhibitors through the use of the mammalian target of rapamycin (mTOR) inhibitor everolimus might help to improve long-term outcomes in some renal transplant recipients, according to results from the ZEUS study recently published in The Lancet.

Calcineurin inhibitors such as tacrolimus and ciclosporin are widely used as immunosuppressants in renal transplantation, but are associated with nephrotoxic effects and gradual deterioration of renal function. Some studies have indicated that the early conversion from calcineurin inhibitors to mTOR inhibitors might be associated with improved renal function; however, results from other studies have been conflicting, and adverse events associated with mTOR inhibitors have been a concern. The ZEUS investigators note that many of the adverse events associated with mTOR inhibitor use are at least partly dose-dependent and that an important challenge is to achieve sufficient efficacy while ensuring good tolerability. Their study was designed to investigate whether elimination of calcineurin inhibitors 4.5 months after renal transplantation, by switching to everolimus plus mycophenolate sodium, was associated with equivalent safety and efficacy but improved renal function as compared with continuation on ciclosporin and mycophenolate sodium.

Between June 2005 and September 2007 the researchers enrolled 503 patients (aged 18–65 years) who had received de novo kidney transplants at one of 17 transplant centers in Germany and Switzerland. Initially, patients received basiliximab induction treatment, ciclosporin, enteric-coated mycophenolate sodium, and corticosteroids. About 4.5 months after transplantation, 300 patients were randomly assigned to either continue on ciclosporin or to undergo stepwise elimination of calcineurin inhibitors by introduction of everolimus (0.75 mg twice daily). All patients remained on corticosteroids and mycophenolate sodium and were followed up for 12 months after transplantation.

In total, 118 of 155 patients (76%) in the everolimus group and 117 of 145 patients (81%) in the ciclosporin group completed treatment with the study drug up to 12 months after transplantation. The most common reason for study drug discontinuation was an adverse event (6% of the everolimus group and 2% of the ciclosporin group).

At the time of randomization, renal function was similar in the two groups, but 12 months after transplantation, adjusted mean calculated glomerular filtration rate was significantly higher in the everolimus group than in the ciclosporin group (71.8 ml/min/1.73 m2 versus 61.9 ml/min/1.73 m2; P <0.0001). No graft losses were reported. Over the entire study period, biopsy-proven acute rejection rate was 15% in both groups; however, during the randomized period of the trial, biopsy-proven acute rejection rate was significantly higher in the everolimus group than in the ciclosporin group (10% versus 3%). Among patients on everolimus who experienced acute rejection, mean dose and trough concentration of everolimus and mean dose of mycophenolate sodium at the time of rejection were similar to these measurements in the whole everolimus group.

The ZEUS researchers found that diarrhea, herpes virus infections, thrombocytopenia, aphthous stomatitis and back pain occurred more frequently in the everolimus group, and that hyperuricemia, asthenia and hypotension were more common in the ciclosporin group. Everolimus-treated patients had higher mean lipid concentrations than the ciclosporin group and also showed a small but significant increase in urinary protein excretion and lower hemoglobin levels.

A commentary published alongside the ZEUS study report notes that the early conversion from a calcineurin inhibitor to an mTOR inhibitor might result in improved renal function either by removing the preglomerular vasospastic effects of calcineurin inhibitors or through (as yet unproven) long-term beneficial effects of mTOR inhibitors.

An ongoing 5-year follow-up of the ZEUS study aims to determine whether the improved 1-year renal function shown with everolimus-based immunosuppression translates into improved long-term graft function and survival.