title: Everolimus with reduced calcineurin inhibitor in thoracic transplant recipients with renal dysfunction: a multicenter, randomized trial.
abstract: BACKGROUND
  The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking.
  
  
  METHODS
  In a 12-month, open-labeled, multicenter study, maintenance thoracic transplant patients (glomerular filtration rate > or =20 mL/min/1.73m and <90 mL/min/1.73 m) >1 year posttransplant were randomized to continue their current CNI-based immunosuppression or start everolimus with predefined CNI exposure reduction.
  
  
  RESULTS
  Two hundred eighty-two patients were randomized (140 everolimus, 142 controls; 190 heart, 92 lung transplants). From baseline to month 12, mean cyclosporine and tacrolimus trough levels in the everolimus cohort decreased by 57% and 56%, respectively. The primary endpoint, mean change in measured glomerular filtration rate from baseline to month 12, was 4.6 mL/min with everolimus and -0.5 mL/min in controls (P<0.0001). Everolimus-treated heart and lung transplant patients in the lowest tertile for time posttransplant exhibited mean increases of 7.8 mL/min and 4.9 mL/min, respectively. Biopsy-proven treated acute rejection occurred in six everolimus and four control heart transplant patients (P=0.54). In total, 138 everolimus patients (98.6%) and 127 control patients (89.4%) experienced one or more adverse event (P=0.002). Serious adverse events occurred in 66 everolimus patients (46.8%) and 44 controls (31.0%) (P=0.02).
  
  
  CONCLUSIONS
  Introduction of everolimus with CNI reduction offers a significant improvement in renal function in maintenance heart and lung transplant recipients. The greatest benefit is observed in patients with a shorter time since transplantation.
authors.affiliation: Department of Cardiology, Oslo University Hospital, Rikshospitalet, and Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Gullestad
authors.forename: Martin
authors.initials: M
authors.lastname: Iversen
authors.forename: Svend-Aage
authors.initials: SA
authors.lastname: Mortensen
authors.forename: Hans
authors.initials: H
authors.lastname: Eiskjaer
authors.forename: Gerdt C
authors.initials: GC
authors.lastname: Riise
authors.forename: Lena
authors.initials: L
authors.lastname: Mared
authors.forename: Oystein
authors.initials: O
authors.lastname: Bjørtuft
authors.forename: Björn
authors.initials: B
authors.lastname: Ekmehag
authors.forename: Kjell
authors.initials: K
authors.lastname: Jansson
authors.forename: Svein
authors.initials: S
authors.lastname: Simonsen
authors.forename: Einar
authors.initials: E
authors.lastname: Gude
authors.forename: Bengt
authors.initials: B
authors.lastname: Rundqvist
authors.forename: Hans E
authors.initials: HE
authors.lastname: Fagertun
authors.forename: Dag
authors.initials: D
authors.lastname: Solbu
authors.forename: Claes-Håkan
authors.initials: CH
authors.lastname: Bergh
mesh_terms: D000368:Aged; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007674:Kidney Diseases / Q000150:complications* / Q000503:physiopathology; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D012537:Scandinavian and Nordic Countries; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus; D016559:Tacrolimus