A Randomized 2x2 Factorial Clinical Trial of Renal Transplantation: Steroid-Free Maintenance Immunosuppression with Calcineurin Inhibitor Withdrawal after Six Months Associates with Improved Renal Function and Reduced Chronic Histopathology.
Stevens RB, Foster KW, et al.PLoS ONE 2015 [Electronic Resource] 10(10): e0139247.
Aims
To determine whether complete discontinuation of calcineurin inhibitor (CNI) would improve renal function.
Interventions
All recipients received 6 mg/kg intravenous rATG beginning at transplantation with either a single infusion over 24 hours, or four 1.5 mg/kg infusions on alternate days. Initial maintenance immunosuppression consisted of sirolimus and tacrolimus. After 6 months, patients were randomized and converted either to CNI minimization or to CNI withdrawal.
Participants
180 primary and selected previous renal transplant recipients aged 18- 65 years
Outcomes
Primary outcomes measured were renal function, and acute and chronic renal histopathology. Secondary outcomes included patient survival, graft survival, biopsy-proven rejection, and infectious and non-infectious complications.
Follow-up
Follow-up averaged 51.8 ± 15.1 months after transplantation and 45.8 ± 14.9 months after CNI withd
CET Conclusions
This is an interesting report of a 2x2 factorial RCT in 180 kidney transplant recipients. Firstly, participants were randomized between single infusion of rATG versus 4 divided infusions of rATG with maintenance immunosuppression being tacrolimus and sirolimus. A second randomisation after 6 months allocated participants to CNI withdrawal (tacrolimus replaced with MMF) or CNI minimisation. 73% of the participants in the CNI withdrawal group could be withdrawn from CNIs with 74% of these patients remaining CNI free for 2 years. Multivariate logistic regression analysis showed that there was no synergistic interaction between the interventions of the first and second randomisation for renal function or chronic graft histopathology. Both the intention to treat and per protocol analyses showed improved renal function for the CNI withdrawal group. Intention to treat analysis showed lower chronic histopathology composite scores for the CNI withdrawal group at 12 months but not at 24 months. There were no differences in patient and death-censored graft survival rates up to 6 years posttransplant. Protocol biopsies at 12 and 24 months did not show a difference in the frequency or severity of rejection between groups.
Data analysis
Modified intention-to-treat analysis
Trial registration
ClinicalTrials.gov - NCT00556933