BTS 2014 Report: Renal outcomes following transplantation: which immunosuppression regimen to use?

Maria Dalby reporting on the Oral Presentation by Lluís Guirado, Fundació Puigvert, Barcelona, Spain.  Renal function is a strong predictor of patient and graft survival after renal transplantation, and switching from a twice-daily to a once-daily immunosuppressive regimen can help preserve renal function by maintaining stable serum levels and helping adherence. In the opening session of Astellas’ satellite symposium, Professor Lluís Guirado shared the results of three years of follow-up of patients converted from a twice-daily to a once-daily tacrolimus regimen, which showed excellent preservation of renal function together with high levels of patient satisfaction with the conversion.

Professor Guirado’s centre in Barcelona has had extensive experience with the once-daily formulation of tacrolimus for immunosuppression following renal transplantation. The EVOLUTION study, which was published in 2011 and had Professor Guirado as principal investigator, included more than 1,800 patients converted from 2005 onwards from twice-daily to once-daily tacrolimus and followed under a randomised, prospective, observational protocol [1]. The results at 12 months showed that once-daily tacrolimus had maintained stable renal function with no significant change in creatinine clearance after conversion. Tacrolimus trough levels decreased by 9.1% and the mean tacrolimus dose was increased by 1.24% (p < 0.0001 for both). Only a very small number (8/1,832; 0.4%) of patients presented with a biopsy-proven acute rejection episode during the first 12 months post-conversion. A total of 34 patients (1.85%) discontinued their treatment during this period, predominantly due to neurological side effects (8 patients), low tacrolimus levels (8 patients) or neoplasia (5 patients). The protocol also included a patient satisfaction survey at 12 months which showed overwhelmingly that once-daily was the option favoured by patients – 99.4% of patients felt positive about the conversion to once-daily tacrolimus, because of the increased convenience of avoiding the evening dose and improved adherence [1].

Post-transplant renal function in the first 12 months post-transplantation is known to predict graft survival in the long term [2]. Follow-up studies have shown that the mean estimated glomerular filtration rate (eGFR) in renal transplant recipients declines by around 1.6 ml/min/1.73m² annually post-transplant [3], which is approximately twice the rate with which renal function declines in the health population. Based on the renal function outcomes observed in the EVOLUTION study, and the characteristic pharmacokinetic profile of once-daily tacrolimus with a lower C_max and thus lower overall exposure to drug than with the twice-daily formulation, a follow-up study was designed to monitor outcomes at three years post-conversion. A total of 1,456 patients from 18 centres participating in the original study were included in the R-EVOLUTION study. Only patients who had stable renal function at the time of conversion to once-daily tacrolimus were eligible for inclusion in this study. Patient survival at three years was 96.45%. Death-censored graft survival at three years was 96.16%, with the vast majority of grafts lost due to chronic allograft nephropathy. The mean tacrolimus dose remained almost unchanged after three years, and although mean tacrolimus trough levels had only decreased from 6.75 mg/ml to 6.31 mg/ml, confidence intervals had narrowed considerably over three years, indicating less variation in trough levels with once-daily administration. Renal function was preserved – at three years post-conversion, eGFR had improved by 1ml/min/1.73m² which is particularly important given the widespread use of extended-criteria donors in Spain. Professor Guirado concluded that once-daily tacrolimus provides a means of maintaining a satisfactory equilibrium between immunosuppression and nephrotoxicity which helps preserve renal function in the long term.

References

1.         Guirado, L., et al., Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients. Am J Transplant, 2011. 11(9): p. 1965-71.

2.         Hariharan, S., et al., Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int, 2002. 62(1): p. 311-8.

3.         Gill, J.S., et al., The change in allograft function among long-term kidney transplant recipients. J Am Soc Nephrol, 2003. 14(6): p. 1636-42.