Comparison of sirolimus alone with sirolimus plus tacrolimus in type 1 diabetic recipients of cultured islet cell grafts

Transplantation. 2008 Jan 27;85(2):256-63. doi: 10.1097/TP.0b013e31815e8926.

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.

Trial registration: ClinicalTrials.gov NCT00409461.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Albuminuria / epidemiology
  • Autoantibodies / blood
  • C-Peptide / blood
  • Cell Transplantation / adverse effects
  • Cell Transplantation / methods*
  • Diabetes Mellitus, Type 1 / surgery*
  • Drug Therapy, Combination
  • Female
  • Graft Survival / immunology
  • Humans
  • Immunosuppressive Agents / therapeutic use
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / immunology
  • Islets of Langerhans Transplantation / adverse effects
  • Islets of Langerhans Transplantation / immunology*
  • Lymphocyte Count
  • Male
  • Middle Aged
  • Postoperative Complications / pathology
  • Sirolimus / therapeutic use*
  • Tacrolimus / therapeutic use*

Substances

  • Autoantibodies
  • C-Peptide
  • Immunosuppressive Agents
  • Sirolimus
  • Tacrolimus

Associated data

  • ClinicalTrials.gov/NCT00409461