title: Comparison of sirolimus alone with sirolimus plus tacrolimus in type 1 diabetic recipients of cultured islet cell grafts.
abstract: BACKGROUND
  One year survival of islet cell grafts has been reproducibly achieved under combination immune therapy including tacrolimus (TAC). However, the use of TAC causes beta-cell and renal toxicity. Because sirolimus (SIR) monotherapy was successful in kidney transplantation under antithymocyte globulin (ATG), we undertook a pilot study comparing SIR monotherapy with SIR-TAC combination therapy.
  
  
  METHODS
  Nonuremic type 1 diabetics received a cultured beta-cell graft under ATG and were randomly assigned to SIR or SIR-TAC-maintenance therapy; a second graft was implanted during posttransplantation month 3 without ATG. The planned number of patients per group (n=10) was reduced to five in view of the observed side effects.
  
  
  RESULTS
  At posttransplant month 6, three SIR-patients had lost graft function and two presented marginal function; among SIR-TAC-patients, there were two early graft failures but three became insulin-independent. These three patients maintained metabolically relevant function (C-peptide >1 ng/ml and coefficient of variation fasting glycemia <25%) for more than 2 years but low-dose insulin therapy was needed from 8, 18, and 26 months posttransplant; this was still the case in two of them after reducing and stopping TAC dose. In both groups, incapacitating adverse events were attributed to sirolimus requiring its discontinuation in 4 of 10 patients; in the 3 patients with pretransplant microalbuminuria, macroalbuminuria developed which resolved when sirolimus was stopped.
  
  
  CONCLUSIONS
  SIR monotherapy is not sufficient to suppress rejection after transplantation under ATG, but it can maintain survival of established beta-cell grafts. However, the risk for a SIR-induced proteinuria remains a concern.
authors.affiliation: Academisch Ziekenhuis and Diabetes Research Center, Brussels Free University, Brussels, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Gillard
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Ling
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Laurent
authors.initials: L
authors.lastname: Crenier
authors.forename: Matthias
authors.initials: M
authors.lastname: Lannoo
authors.forename: Bart
authors.initials: B
authors.lastname: Maes
authors.forename: Bart
authors.initials: B
authors.lastname: Roep
authors.forename: Frans
authors.initials: F
authors.lastname: Gorus
authors.forename: Daniel
authors.initials: D
authors.lastname: Pipeleers
authors.forename: Bart
authors.initials: B
authors.lastname: Keymeulen
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000453:epidemiology; D001323:Autoantibodies / Q000097:blood; D002096:C-Peptide / Q000097:blood; D017690:Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D004359:Drug Therapy, Combination; D005260:Female; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000166:cytology* / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000473:pathology; D020123:Sirolimus / Q000627:therapeutic use*; D016559:Tacrolimus / Q000627:therapeutic use*
chemical_list: D001323:Autoantibodies; D002096:C-Peptide; D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus