Everolimus with cyclosporine withdrawal or low-exposure cyclosporine in kidney transplantation from Month 3: a multicentre, randomized trial

Nephrol Dial Transplant. 2017 Jun 1;32(6):1060-1070. doi: 10.1093/ndt/gfx075.


Background.: Randomized trials have shown that early adoption of everolimus-based immunosuppressive regimens without a calcineurin inhibitor (CNI) improves long-term kidney graft function, but the optimal strategy for CNI minimization remains uncertain.

Methods.: In a prospective, randomized, multicentre, 12-month trial, 499 de novo kidney transplant patients were randomized at Month 3 to (i) remain on standard CNI (cyclosporine) therapy with mycophenolic acid, (ii) convert to everolimus with mycophenolic acid or (iii) start everolimus with reduced CNI and no mycophenolic acid (clinical trials registry: ClinicalTrials.gov-NCT00514514).

Results.: The primary endpoint, change in estimated glomerular filtration rate (eGFR) (Nankivell) from randomization to Month 12, was significantly greater in the CNI-free arm versus standard CNI therapy: mean difference 5.6 mL/min/1.73 m 2 [95% confidence interval (CI) 2.8-8.3 mL/min/1.73 m 2 , P < 0.001]. The improvement in eGFR in the CNI-free arm was also higher than in the low-CNI group (mean difference 5.5 mL/min/1.73 m 2 , 95% CI 2.8-8.2 mL/min/1.73 m 2 , P < 0.001), while results were similar in the low-CNI and standard CNI arms. The post-randomization incidence of biopsy-proven acute rejection was 11.7%, 8.1% and 7.9% in the CNI-free, low-CNI and standard CNI groups, respectively (CNI-free versus standard CNI, P = 0.27; low-CNI versus standard CNI, P = 1.00). Adverse events led to study drug discontinuation in 28.7%, 15.5% and 15.2% of CNI-free, low-CNI and standard CNI patients, respectively.

Conclusions.: Everolimus initiation with CNI withdrawal at Month 3 after kidney transplantation achieves a significant improvement in renal function at 12 months, with a similar rate of acute rejection.

Keywords: CNI-free; elimination; everolimus; kidney transplantation; withdrawal.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Calcineurin Inhibitors / therapeutic use
  • Cyclosporine / therapeutic use*
  • Drug Therapy, Combination
  • Everolimus / therapeutic use*
  • Female
  • Glomerular Filtration Rate
  • Graft Rejection / prevention & control*
  • Humans
  • Immunosuppressive Agents / therapeutic use*
  • Kidney / physiopathology
  • Kidney Failure, Chronic / therapy*
  • Kidney Transplantation
  • Male
  • Middle Aged
  • Mycophenolic Acid / therapeutic use
  • Prospective Studies
  • Treatment Outcome


  • Calcineurin Inhibitors
  • Immunosuppressive Agents
  • Cyclosporine
  • Everolimus
  • Mycophenolic Acid

Associated data

  • ClinicalTrials.gov/NCT00514514