Tacrolimus Exposure After Liver Transplantation in Randomized Controlled Trials: Too Much for Too Long

Abstract

To the Editor: We read with great interest the randomized controlled trial (RCT) by De Simone et al. 1, which evaluated the combination of tacrolimus and everolimus after liver transplantation (LT). They demonstrated that glomerular filtration rate decreased less at 12 months with everolimus and reduced tacrolimus, compared to a conventional tacrolimus based regimen, while rejection rates were similar. Although these results are promising we are very concerned about what is meant by “conventional exposure to tacrolimus” in RCT, and its potential implications on clinical practice and patients' safety. Although acute cellular rejection (ACR) rates are similar in LT compared to other solid organs such as kidney, the response to steroid boluses is better, and graft function is usually preserved. Furthermore a certain grade of immune activation may be beneficial in terms of graft tolerance, considering the improved long-term survival in patients who have one episode of ACR, at least for patients without hepatitis C 2. Despite this evidence, RCT evaluating tacrolimus based immunosuppression after LT continue to use systematically high trough concentrations (TC) in the “conventional arm,” similar to those used in kidney transplantation. This high exposure pertains especially to the first 4–6 weeks after LT, where target tacrolimus TC are >10–12 ng/mL even in recent RCT 3. De Simone et al. continue this trend of high tacrolimus exposure: mean TC at randomization (day 30 ± 5) was 10–12 ng/mL in the overall trial population, and was >8 ng/mL during the first 12 months in the conventional arm. The consequences of over-exposure to tacrolimus in RCT are not surprising: the most important pertains to the kidney, as LT recipients have the highest rates of chronic renal failure among non-renal transplants, second only to intestinal transplantation 4. Indeed our recent systematic review showed increased renal impairment rates at 1 year after LT, in the most recent RCT using tacrolimus (Figure 1) 3. De Simone et al. also have some data suggesting over-exposure to tacrolimus in the conventional tacrolimus arm: a pronounced decrease in glomerular filtration rate between randomization and month 12, of nearly 8 ml/min/1.73 m2; frequent serious adverse events (43.2%) and infections (43.6%); and very low rate of biopsy proven ACR (18.9%). Many LT centers consider LT patients to be over immunosuppressed and have empirically reduced TC of tacrolimus. Indeed, we recently published our experience with 493 consecutive LT patients receiving tacrolimus based immunosuppression protocols 2. Patients with mean tacrolimus TC 7–10 ng/mL early after LT had similar ACR rates, and independently better graft survival (RR = 0.46; p = 0.014), compared to patients with TC > 10 ng/mL, whether additional immunosuppressive drugs were used or not. Thus, reduced tacrolimus is sufficient to prevent most ACR 5, and additional drugs such as everolimus or antimetabolites can be used to increase immunopotency in selected cases. We feel, as do others, that this new evidence should impact on the design of future RCT, to make results more applicable to current clinical practice. We hope that in the future “conventional tacrolimus” will change to “reduced tacrolimus” as the standard of care arm for RCT. Patients and clinicians will both benefit. M. Rodríguez-Perálvarez1,2, G. Germani1, T. Darius3, J. Lerut3, E. Tsochatzis1, M. De la Mata2 and A. K. Burroughs1* 1The Royal Free Sheila Sherlock Liver Centre and UCL Institute of Digestive and Liver Health, Royal Free Hospital, London, UK 2Gastroenterology and Hepatology Unit. CIBERehd. IMIBIC. Reina Sofía University Hospital, Córdoba, Spain 3Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint Luc, Université Catholique de Louvain (UCL), Brussels, Belgium *Corresponding author: Andrew K. Burroughs, andrew.burroughs@nhs.net The author of this manuscript has no conflicts of interest to disclose as described by the American Journal of Transplantation.