Comparison of sirolimus alone with sirolimus plus tacrolimus in type 1 diabetic recipients of cultured islet cell grafts.
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.
Gillard
Pieter
P
Academisch Ziekenhuis and Diabetes Research Center, Brussels Free University, Brussels, Belgium.
Ling
Zhidong
Z
Mathieu
Chantal
C
Crenier
Laurent
L
Lannoo
Matthias
M
Maes
Bart
B
Roep
Bart
B
Gorus
Frans
F
Pipeleers
Daniel
D
Keymeulen
Bart
B
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*
D001323:Autoantibodies; D002096:C-Peptide; D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus