A randomized 2x2 factorial trial, part 1: single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes.
Stevens RB, Foster KW, Miles CD, et al.Transplantation [record in progress].
Aims
To investigate the long term safety and efficacy of an induction arm comparing single dose versus divided dose rabbit antithymocyte globulin (rATG), and a maintenance arm comparing low dose tacrolimus versus withdrawal.
Interventions
Part one, patients were administered rATG and methylprednisolone (6mg/kg and 12mg/kg respectively) followed by either single dose rATG (6mg/kg over 24 hours) or divided dose rATG (1.5mg/kg x 4 doses) and steroid withdrawal and tacrolimus or sirolimus maintenance. In part two, patients were maintained on tacrolimus (2-4ng/mL) and sirolimus (4-6ng/mL), or sirolimus (8-12ng/mL) and mycophenolate mofetil (2g x twice a day).
Participants
180 adult primary or previous renal transplant recipients.
Outcomes
The primary outcomes included renal function and protocol biopsy histopathology. The secondary outcomes included patient, graft and rejection free survival, and infectious and non-infectious complications.
Follow-up
4 years.
CET Conclusions
This interesting trial employs a 2x2 factorial design to test two components of an immunosuppressive regimen. This first report compares kidney transplant recipients randomised to single dose (6 mg/kg) rATG to standard dosing (1.5mg/kg in 4 alternate-day doses). A subsequent report will detail the second part of the trial, where patients were randomised to calcineurin inhibitor (CNI) minimisation or withdrawal. The authors conclude from this first stage that single dose rATG results in less infective complications, reduced mortality and improved renal function at an average follow-up of over 4 years, with no increase in rejection rates. The authors ascribe the improved function to the increase in rATG concentrations present at the time of reperfusion, and the potential effects on the early post-reperfusion inflammatory response that this brings. The complex design and fact that only the first part of the trial is reported here makes the manuscript quite difficult to follow. Baseline immunosuppression was a combination of sirolimus and low-dose tacrolimus, with MMF only used if sirolimus introduction was delayed or CNI withdrawn. It is worth noting that mean tacrolimus levels were persistently higher than target throughout the trial. We will await the results of part 2 to see if there is any benefit to substitution of tacrolimus with MMF after 6 months in this regimen.
Data analysis
Modified intention-to-treat analysis
Quality notes
Previously assessed in Stevens RB, Mercer DF, Grant WJ, et al. Randomized trial of single-dose versus divided-dose rabbit anti-thymocyte globulin induction in renal transplantation: an interim report. Transplantation 2008; 85: 1391.
Trial registration
ClinicalTrials.gov – NCT00556933