Improved Renal Function After Early Conversion From a Calcineurin Inhibitor to Everolimus: a Randomized Trial in Kidney Transplantation

Abstract

In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids. The primary endpoint, change in measured GFR (mGFR) from week 7 to month 12, was significantly greater with everolimus than controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; analysis of covariance [ANCOVA]). Per protocol analysis demonstrated a more marked difference: an increase of 8.7 (11.2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p < 0.001; ANCOVA). There were no differences in graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All but two episodes of BPAR in each group were mild. Adverse events occurred in 95.1% of everolimus patients and 90.0% controls (p = 0.19), with serious adverse events in 53.9% and 38.0%, respectively (p = 0.025). Discontinuation because of adverse events was more frequent with everolimus (25.5%) than controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNItreated controls but discontinuations and BPAR were more frequent.

Five-Year Outcomes in Kidney Transplant Patients Converted From Cyclosporine to Everolimus: The Randomized ZEUS Study

“…It should be borne in mind, however, that patients at high immunological risk were not randomized in the current study. Other randomized trials of early switch from CNI to mTOR inhibitor therapy have also applied exclusion criteria of varying stringency, but generally excluding patients with PRA >30% or those with previous rejection based on differing criteria (19)(20)(21)30). The efficacy of early conversion from a CNI agent to an mTOR inhibitor in patients at high immunological risk, for example in those with steroid-resistant acute rejection, has not been examined.…”

“…In common with other randomized studies of early conversion from CNI-to mTOR inhibitor-based immunosuppression (19)(20)(21)30), the eligibility criteria for the current study included minimum graft function parameters at time of randomization (serum creatinine not greater than 265 mmol/L and proteinuria no higher than 1 g/day). No trial has yet investigated the renal effect of early CNI withdrawal regardless of baseline graft function and proteinuria status.…”

“…Other, smaller randomized trials have examined the effect of early conversion to everolimus (21) or sirolimus (19,20,30), some of which have provided longer-term follow-up data. The Post-CONCEPT Study monitored a subset of patients to 5 years posttransplant (31) after completion of the 1-year CONCEPT trial (20) in which conversion from CsA to sirolimus took place at 3 months after transplantation.…”

“…Results have demonstrated that immunosuppressive efficacy is maintained, but although an improvement in graft function has been observed (13) a significant difference may not be sustained (17). Evidence from a series of randomized studies indicates that longer-term renal benefit may be achieved if an mTOR inhibitor is introduced and CNI therapy is withdrawn during the first 6 months after kidney transplantation (18)(19)(20)(21), before extensive, irreversible CNI-related nephrotoxicity develops (2).…”

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model

“…The method of random allocation, 71,86,128 including the method of sequence generation, was clearly stated and adequate in only two induction studies 71,128 and 18 maintenance studies, 86,103,110,112,119,122,124,126,127,[129][130][131][132][133][134][135][136]150 whereas 65 studies (nine induction studies [72][73][74]87,95,98,137 and 54 maintenance studies 51,58,59,75-85,88,89,91-94,99-102, 104-109,111,113-118,120,121,125,138-147,152-155 ) and both of the studies of induction and maintenance treatment 123,148 did not clearly specify the method used. The remaining maintenance study 149 used a minimisation technique that included a random element.…”