title: Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients: long-term follow-up of the SHIRAKISS randomized, prospective study.
abstract: BACKGROUND
  Cyclosporine nephrotoxicity negatively impacts long-term outcome after heart transplantation (HT). We previously reported 1-year results from a randomized study showing that cyclosporine-lowering strategies based on everolimus or mycophenolate mofetil (MMF) are equally effective for reducing progression of renal dysfunction. It is unknown whether this efficacy could be maintained over the long term.
  
  
  METHODS
  Thirty-four recipients 1 to 4 years after HT and with 25 to 60 ml/min of creatinine clearance (CrCl) were randomized to everolimus with a very low dose (C(0): 50 to 90 ng/ml, n = 17) or MMF with low dose of cyclosporine (C(0): 100 to 150 ng/ml, n = 17). Follow-up was prolonged up to 3 years, and calculated CrCl was the main efficacy measure.
  
  
  RESULTS
  Cyclosporine was maintained at 70% and 30% lower than baseline in the everolimus and MMF arms, respectively, throughout the 3-year study period. CrCl remained stable in the everolimus patients (+7% from baseline; p = 0.7), but improved in the MMF patients (+20% from baseline; p < 0.01), with a trend toward improved values compared with everolimus patients (46 ± 12 vs 56 ± 15 ml/min; p = 0.06). Subgroup analysis revealed that baseline proteinuria markedly influenced the renal function response to everolimus: whereas in patients with baseline proteinuria CrCl significantly worsened (-20%; p = 0.04), it improved in those without (+15%; p = 0.03). Safety was comparable between the two study arms.
  
  
  CONCLUSIONS
  Cyclosporine nephrotoxicity improved after a prolonged dose reduction in patients receiving MMF. The everolimus-based strategy provided a similar benefit only to patients without baseline proteinuria. While raising caution against the universal use of everolimus for kidney protection, our long-term results support the need for customized approaches in the management of drug toxicities in maintenance HT recipients.
authors.affiliation: Cardiovascular Department, University of Bologna, Academic Hospital S. Orsola-Malpighi, via Massarenti 9, Bologna, Italy. luciano.potena2@unibo.it
authors.forename: Luciano
authors.initials: L
authors.lastname: Potena
authors.forename: Paola
authors.initials: P
authors.lastname: Prestinenzi
authors.forename: Isidoro G
authors.initials: IG
authors.lastname: Bianchi
authors.forename: Marco
authors.initials: M
authors.lastname: Masetti
authors.forename: Paolo
authors.initials: P
authors.lastname: Romani
authors.forename: Gaia
authors.initials: G
authors.lastname: Magnani
authors.forename: Francesco
authors.initials: F
authors.lastname: Fallani
authors.forename: Fabio
authors.initials: F
authors.lastname: Coccolo
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.forename: Claudio
authors.initials: C
authors.lastname: Ponticelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Rapezzi
authors.forename: Francesco
authors.initials: F
authors.lastname: Grigioni
authors.forename: Angelo
authors.initials: A
authors.lastname: Branzi
mesh_terms: D000368:Aged; D003404:Creatinine / Q000652:urine; D016572:Cyclosporine / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011446:Prospective Studies; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors; D014180:Transplantation; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D003404:Creatinine; D009173:Mycophenolic Acid; D020123:Sirolimus