title: Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results.
abstract: BACKGROUND
  Comparison studies of calcineurin inhibitors as cornerstone immunosuppressants in renal transplantation have demonstrated that tacrolimus consistently reduces acute rejection rates and, in some studies, also improves long-term renal outcome in comparison to cyclosporin A (CsA). The aim of the present 2 year follow-up of the European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was to investigate long-term clinical outcome in terms of rate of acute rejection, graft and patient survival and graft function.
  
  
  METHODS
  The European Tacrolimus vs Cyclosporin A Microemulsion Renal Transplantation Study was a randomized, comparative 6 month trial of the calcineurin inhibitors tacrolimus and CsA in combination with both azathioprine and steroids. The intent-to-treat population (ITT) consisted of 286 patients in the tacrolimus arm and 271 in the CsA microemulsion (CsA-ME) arm. Whereas whole blood level targets were 10-20 and 5-15 ng/ml for tacrolimus and 100-400 and 100-200 ng/ml for CsA during months 0-3 and 4-6, respectively, during the investigator-driven follow-up after termination of the main study (months 7-24) no specific calcineurin inhibitor target levels were required. Follow-up data were collected at 2 years post-transplantation from 237 (82.9% of the ITT population) patients who received tacrolimus and 222 (81.9% of the ITT population) patients who received CsA-ME.
  
  
  RESULTS
  Calculated on ITT populations, mortality (2.0% vs 3.3%; P<0.05 in Kaplan-Meier analysis) was lower, but rate of graft loss (9.3% vs 11.2%; P = 0.12 in Kaplan-Meier analysis) was not significantly different after 2 years with tacrolimus- vs CsA-ME-based immunosuppression. Biopsy-proven acute rejection was significantly lower (19.6%) with tacrolimus than with CsA-ME (37.3%) during months 0-6 (P<0.0001), but was not significantly different during months 7-12 and 13-24 of follow-up (1.7% and 0.8% with tacrolimus and 4.7% and 0.9% with CsA-ME, respectively). A composite endpoint consisting of graft loss, patient death and biopsy-proven acute rejection occurred significantly more frequently in CsA-ME patients than in tacrolimus patients (42.8% vs 25.9%; P<0.001) during 24 months follow-up. Renal function 2 years post-transplant, measured by serum creatinine concentrations, was significantly better in tacrolimus-based compared with CsA-ME-based immunosuppression (136.9 vs 161.6 micromol/l; P<0.01). Cornerstone immunosuppression remained unchanged in 82.5% and 66.2% of patients treated with tacrolimus and CsA-ME, respectively. At 2 years, more patients in the tacrolimus arm were off steroids and received calcineurin inhibitor monotherapy, and fewer tacrolimus patients remained on a triple immunosuppressive regimen. The cardiovascular risk profile was affected favourably in the tacrolimus arm, with lower cholesterol and triglyceride concentrations (despite less use of cholesterol-lowering drugs); no significant difference in requirement for antidiabetic medication was noted.
  
  
  CONCLUSIONS
  The 2 year study results confirm that tacrolimus is a highly efficacious cornerstone immunosuppressant in kidney transplantation. Tacrolimus-based immunosuppression may induce long-term benefits with regard to graft function and graft survival. The overall side-effect profile is considered to be favourable.
authors.affiliation: Klinik und Poliklinik für Innere Medizin II - Nephrologie, Klinikum der Universität Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. bernhard.kraemer@klinik.uni-regensburg.de
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Krämer
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Montagnino
authors.forename: Domingo
authors.initials: D
authors.lastname: Del Castillo
authors.forename: Raimund
authors.initials: R
authors.lastname: Margreiter
authors.forename: Heide
authors.initials: H
authors.lastname: Sperschneider
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Olbricht
authors.forename: Bernd
authors.initials: B
authors.lastname: Krüger
authors.forename: Joaquín
authors.initials: J
authors.lastname: Ortuño
authors.forename: Hans
authors.initials: H
authors.lastname: Köhler
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kunzendorf
authors.forename: Hans-Krister
authors.initials: HK
authors.lastname: Stummvoll
authors.forename: Jose M
authors.initials: JM
authors.lastname: Tabernero
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Mühlbacher
authors.forename: Manuel
authors.initials: M
authors.lastname: Rivero
authors.forename: Manuel
authors.initials: M
authors.lastname: Arias
mesh_terms: D000293:Adolescent; D000328:Adult; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004655:Emulsions; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016030:Kidney Transplantation; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D004655:Emulsions; D007166:Immunosuppressive Agents; D008055:Lipids; D016572:Cyclosporine; D003404:Creatinine; D016559:Tacrolimus