Tacrolimus Trough Levels, Rejection and Renal Impairment in Liver Transplantation: A Systematic Review and Meta-Analysis

Authors

  • M. Rodríguez-Perálvarez,

    1. The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery. UCL, and Royal Free Hospital. Pond Street, London, UK
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  • G. Germani,

    1. The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery. UCL, and Royal Free Hospital. Pond Street, London, UK
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  • T. Darius,

    1. Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint Luc, Université Catholique de Louvain (UCL), Brussels, Belgium
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  • J. Lerut,

    1. Starzl Unit of Abdominal Transplantation, Cliniques Universitaires Saint Luc, Université Catholique de Louvain (UCL), Brussels, Belgium
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  • E. Tsochatzis,

    1. The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery. UCL, and Royal Free Hospital. Pond Street, London, UK
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  • A. K. Burroughs

    Corresponding author
    1. The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery. UCL, and Royal Free Hospital. Pond Street, London, UK
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Andrew K. Burroughs, andrew.burroughs@nhs.net

Abstract

We hypothesized that current trough concentrations of tacrolimus after liver transplantation are set too high, considering that clinical consequences of rejection are not severe while side effects are increased. We systematically reviewed 64 studies (32 randomized controlled trials and 32 observational studies) to determine how lower tacrolimus trough concentrations than currently recommended affect acute rejection rates and renal impairment. Among randomized trials the mean of tacrolimus trough concentration during the first month was positively correlated with renal impairment within 1 year (r = 0.73; p = 0.003), but not with acute rejection, either defined using protocol biopsies (r =−0.37; p = 0.32) or not (r = 0.11; p = 0.49). A meta-analysis of randomized trials directly comparing tacrolimus trough concentrations (five trials for acute rejection [n = 957] and two trials for renal impairment [n = 712]) showed that “reduced tacrolimus” trough concentrations (<10 ng/mL) within the first month after liver transplantation were associated with less renal impairment at 1 year (RR = 0.51 [0.38–0.69]), with no significant influence on acute rejection (RR = 0.92 [0.65–1.31]) compared to “conventional tacrolimus” trough levels (>10 ng/mL). Lower trough concentrations of tacrolimus (6–10 ng/mL during the first month) would be more appropriate after liver transplantation. Regulatory authorities and the pharmaceutical industry should allow changes of regulatory drug information.

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