Tacrolimus- versus Sirolimus-based immunosuppression after simultaneous pancreas and kidney transplantation: 5 years results of a randomised trial

American Journal of Transplantation. 2020;[record in progress]
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Tacrolimus, the cornerstone immunosuppression after simultaneous pancreas and kidney transplantation, may exert nephrotoxic and diabetogenic effects. We therefore prospectively compared in an open-label, randomised, monocentric, 5-year follow-up study, a tacrolimus- and a sirolimus-based immunosuppressive regimen. Randomisation using the block method allowing a blind allocation was done at the time of surgery. All patients received anti-thymocyte globulin and maintenance therapy with tacrolimus, mycophenolate mofetil and steroids. At month 3, tacrolimus was continued or replaced by sirolimus. The primary endpoint was kidney and pancreas graft survival at one and five years. Fifty patients were included in final analysis in each group. At one year, difference for kidney and pancreas graft survival between sirolimus and tacrolimus were 0 % (CI 90 % [-4.61 %, 4.61 %]) and 6 % (CI 90 % [-6.32 %, 18.32 %]) respectively. There was neither difference in renal and pancreas graft survival at 5 years. Thirty-four patients (68 %) in the sirolimus group versus 3 (6 %) in the tacrolimus group needed definitive withdrawal of the study drug. Despite non-inferiority of sirolimus compared to tacrolimus for kidney and pancreas graft survival, the high rate of sirolimus discontinuation does not favour its use as cornerstone therapy after SPK. NCT00693446.

CET Conclusion

Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
This is a good quality study of immune suppression for Simultaneous Pancreas and Kidney (SPK) transplantation. The study used a centralised, block randomisation, with intention to treat analysis, but no blinding to treatment of the patients or clinicians. The report does use the slightly misleading term “blind allocation”, which the authors use for allocation concealment, and not true blinding, as this was an open-label study. The conclusion of this study is that sirolimus was non-inferior to tacrolimus for SPK graft survival. This may be true in the intention to treat analysis, however the huge proportion (68%) that had to be converted off sirolimus due to complications make a non-inferiority conclusion slightly meaningless. There were also 2 protocol amendments mandated to delay sirolimus introduction because of complications. All 7 patients who were randomised to sirolimus and started from day 1 after surgery had to change treatment. The first protocol amendment meant that immune suppression drugs did not start until day 7 after surgery, but 4/5 starting on sirolimus had to change treatment, making a second protocol change necessary. After this point sirolimus was not initiated until 90 days after surgery and tacrolimus was used in both arms up until this point. Overall the study amendments and results mean that sirolimus cannot be supported as standard immune suppression after SPK.

Methodological quality

Jadad score : 3
Allocation concealment : YES
Data analysis : PER PROTOCOL

Study details

Aims : The aim of this study was to compare a tacrolimus (TAC)-based immunosuppressive regimen with a sirolimus (SRL)-based immunosuppressive regimen after simultaneous pancreas and kidney (SPK) transplantation during a follow-up period of 5 years.
Interventions : Patients were randomised to either the tacrolimus group or the sirolimus group.
Participants : Simultaneous pancreas and kidney transplant recipients
Outcomes : The primary outcome of this study was pancreas and kidney graft survival at 12 and 60 months post-transplant. The secondary outcomes were acute rejection rate, patient survival, kidney and pancreas graft survival, renal function, histology of renal graft, pancreas graft function, and safety and tolerablility (accrording to pre-defined variables).
Follow up : 5 years


Funding : Industry funding
Publication type : Randomised Controlled Trial
Trial registration : ClinicalTrials.gov - NCT00693446
Language : English
Author email : diego.cantarovich@chu-nantes.fr