title: Conversion of long-term kidney transplant recipients from calcineurin inhibitor therapy to everolimus: a randomized, multicenter, 24-month study.
abstract: BACKGROUND
  Benefits of conversion from calcineurin inhibitor (CNI) to mammalian target of rapamycin inhibitor-based immunosuppression in long-term kidney transplant patients remain uncertain.
  
  
  METHODS
  ASCERTAIN was a 24-month, open-label, multicenter study. Kidney transplant patients more than 6 months posttransplant receiving CNI (baseline glomerular filtration rate [GFR] 30-70 mL/min/1.73 m) were randomized to everolimus with CNI elimination (n=127) or CNI minimization (n=144), or continued CNI unchanged (controls, n=123) to assess the effect on measured GFR at month 24 after randomization.
  
  
  RESULTS
  Renal function was stable in all groups to month 24. Mean measured GFR at month 24, the primary endpoint, was 48.0±22.0 mL/min/1.73 m, 46.6±21.1 mL/min/1.73 m, and 46.0±20.4 mL/min/1.73 m in the CNI elimination, CNI minimization, and control groups, respectively. Differences between CNI elimination (1.12 mL/min/1.73 m, 95% confidence interval [CI] -3.51 to 5.76, P=0.63) and CNI minimization (0.59 mL/min/1.73 m, 95% CI -3.88 to 5.07, P=0.79) versus controls at month 24 were nonsignificant that is, the primary endpoint was not met. No efficacy endpoint differed significantly between groups. Post hoc analyses showed that patients with baseline creatinine clearance (CrCl) more than 50 mL/min had a significantly greater increase in measured GFR after CNI elimination versus controls (difference 11.4 mL/min/1.73 m, 95% CI 2.1 to 20.8 mL/min/1.73 m, P=0.017). Adverse events resulted in discontinuation in 36 (28.3%) CNI elimination patients, 24 (16.7%) CNI minimization patients, and 5 (4.1%) controls (P<0.001 vs. CNI elimination; P=0.020 vs. CNI minimization).
  
  
  CONCLUSIONS
  Conversion to everolimus with CNI elimination or minimization a mean of 5.6 years after kidney transplantation had no overall renal benefit and was associated with more frequent adverse events and discontinuations. Patients with CrCl more than 50 mL/min may benefit from a change in therapy more than 6 months after renal transplantation.
authors.affiliation: Medical Department, Rikshospitalet, University of Oslo, Oslo, Norway. hallvard.holdaas@rikshospitalet.no
authors.forename: Hallvard
authors.initials: H
authors.lastname: Holdaas
authors.forename: Lionel
authors.initials: L
authors.lastname: Rostaing
authors.forename: Daniel
authors.initials: D
authors.lastname: Serón
authors.forename: Edward
authors.initials: E
authors.lastname: Cole
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chapman
authors.forename: Bengt
authors.initials: B
authors.lastname: Fellstrøm
authors.forename: Erik H
authors.initials: EH
authors.lastname: Strom
authors.forename: Alan
authors.initials: A
authors.lastname: Jardine
authors.forename: Karsten
authors.initials: K
authors.lastname: Midtvedt
authors.forename: Uwe
authors.initials: U
authors.lastname: Machein
authors.forename: Bettina
authors.initials: B
authors.lastname: Ulbricht
authors.forename: Alexander
authors.initials: A
authors.lastname: Karpov
authors.forename: Philip J
authors.initials: PJ
authors.lastname: O'Connell
mesh_terms: D000328:Adult; D065095:Calcineurin Inhibitors; D003404:Creatinine / Q000097:blood / Q000652:urine; D000068338:Everolimus; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D000068338:Everolimus; D003404:Creatinine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus