title: 15-year follow-up of a multicenter, randomized, calcineurin inhibitor withdrawal study in kidney transplantation.
abstract: BACKGROUND
  Calcineurin inhibitors (CNIs) are essential immunosuppressive drugs after renal transplantation. Because of nephrotoxicity, withdrawal has been a challenge since their introduction.
  
  
  METHODS
  A randomized multicenter trial included 212 kidney patients transplanted between 1997 and 1999. All patients were initially treated with mycophenolate mofetil (MMF), cyclosporine A (CsA), and prednisone (pred). At 6 months after transplantation, 63 patients were randomized for MMF/pred, 76 for MMF/CsA, and 73 for MMF/CsA/pred. Within 18 months after randomization 23 patients experienced a rejection episode: MMF/pred (27.0%), MMF/CsA (6.8%) and MMF/CsA/pred (1.4%) (P<0.001).
  
  
  RESULTS
  During 15 years of follow-up, 73 patients died with a functioning graft, and 43 patients lost their graft. Ninety-six were alive with a functioning graft. Intention-to-treat analysis did not show a significant difference in patient and graft survival. In multivariate analysis, death-censored graft survival was significantly associated with serum creatinine at 6 months after transplantation and maximum PRA but not with the randomization group. CNI withdrawal did not result in a reduced incidence of or death by malignancy or cardiovascular disease. Death-censored graft survival was significantly worse in those patients randomized for CNI withdrawal that had to be reverted to CNI. Independent of randomization group, compared with no rejection, death-censored graft survival was significantly worse in 23 patients with acute rejection after randomization.
  
  
  CONCLUSIONS
  Fifteen years after conversion to a CNI free regimen, there was no benefit regarding graft and patient survival or regarding prevalence of or death by comorbidities. However, rejection shortly after CNI withdrawal was associated with decreased graft survival.
authors: 1 Department of Internal Medicine, Erasmus Medical Centre Rotterdam, The Netherlands. 2 Department of Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands. 3 Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands. 4 Dutch Transplantation Foundation, Leiden, The Netherlands. 5 Department of Nephrology University Medical Centre, Utrecht, The Netherlands. 6 Address correspondence to: J. I. Roodnat, M.D., Ph.D., Erasmus Medical Centre, Room D427, PO box 2040, 3000CA Rotterdam, The Netherlands.
authors: Joke I
authors: JI
authors: Roodnat
authors: Luuk B
authors: LB
authors: Hilbrands
authors: Ronald J
authors: RJ
authors: Hené
authors: Ruud G L
authors: RG
authors: de Sévaux
authors: Peter J H
authors: PJ
authors: Smak Gregoor
authors: Judith A
authors: JA
authors: Kal-van Gestel
authors: Cynthia
authors: C
authors: Konijn
authors: Arjan
authors: A
authors: van Zuilen
authors: Teun
authors: T
authors: van Gelder
authors: Andries J
authors: AJ
authors: Hoitsma
authors: Willem
authors: W
authors: Weimar
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D065095:Calcineurin Inhibitors; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000097:blood / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D009426:Netherlands; D011241:Prednisone / Q000008:administration & dosage; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012042:Registries; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine; D009173:Mycophenolic Acid; D011241:Prednisone