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Area Under Trough Concentrations of Tacrolimus as a Predictor of Progressive Renal Impairment After Liver Transplantation

Rodríguez-Perálvarez, Manuel PhD1; Guerrero, Marta MD1,2; De Luca, Laura MD2,3; Gros, Beatriz MD1; Thorburn, Douglas MD2,3; Patch, David MD2,3; Aumente, María D. PharmD4; Westbrook, Rachel MD2,3; Fernández, Rocío MD1; Amado, Víctor MD1; Aguilar, Patricia PhD1; Montero, Jose Luis PhD1; O’Beirne, James MD2,3; Briceño, Javier PhD1; Tsochatzis, Emmanuel PhD2,3; De la Mata, Manuel PhD1

doi: 10.1097/TP.0000000000002760
Original Clinical Science—Liver

Background. Tacrolimus minimization is usually restricted to patients with pretransplant renal impairment, and this strategy could result into worse renal outcomes after liver transplantation (LT).

Methods. A consecutive cohort of 455 LT patients receiving tacrolimus-based immunosuppression was studied (2008–2013). Cumulative exposure to tacrolimus was calculated as the area under curve of trough concentrations (AUCtc). Patients were stratified as tacrolimus minimization, conventional, or high exposure, according to the thresholds based in the COMMIT consensus. Estimated glomerular filtration rates (eGFR) were assessed by the Modification of Diet in Renal Disease formula (MDRD-4) up to 5 years after LT.

Results. Seventy patients (15.4%) had pretransplant eGFR < 60 mL/min, which was associated with increased mortality rates, particularly within the first 5 years post-LT (31.4% versus 17.5%; Breslow P = 0.010). After LT, there was an abrupt eGFR decline within the first 3 months (median 18.6 mL/min; P < 0.001), further decreasing up to 12 months (additional 3 mL/min), without any improvement thereafter. According to AUCtc, 33.7% of patients received tacrolimus minimization, 44.8% conventional exposure, and 21.5% high exposure. Conventional/high exposure to tacrolimus resulted in a more pronounced eGFR decline within the first 3 months when compared with minimization (23.3 mL/min versus 9.5 mL/min; P < 0.001). This gap was even higher in patients with initially preserved renal function. Tacrolimus AUCtc was an independent predictor of eGFR decline within the first 3 months after controlling for potential confounders.

Conclusions. AUCtc is a surrogate of cumulative exposure to tacrolimus and may be helpful for routine dose adjustments. Tacrolimus minimization should be universally attempted after LT to preserve renal function.

1 Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain.

2 Sheila Sherlock Liver Unit, Royal Free Hospital, London, United Kingdom.

3 UCL Institute for Liver and Digestive Health, Royal Free Campus, London, United Kingdom.

4 Department of Clinical Pharmacokinetics, Reina Sofía University Hospital, Córdoba, Spain.

Received 10 January 2019. Revision received 5 March 2019.

Accepted 31 March 2019.

This work was investigator-driven and it is free from any industry sponsorship. M.G. is a recipient of a research grant awarded by the Asociación Española para el Estudio del Hígado (AEEH). The other authors declare no conflicts of interest.

M.R.-P., E.T., and M.M. participated in conception and design. M.G., L.D., B.G., M.D.A, R.F., V.A., and P.A. participated in data acquisition. M.G., M.R-P., and P.A. calculated area under curve of trough concentrations. M.R.-P. and M.G. performed the statistical analysis. M.R-P, M.G., D.T., D.P., and J.B. performed the interpretation of data. M.R.-P. and M.G. wrote the original draft. L.D., B.G., D.T., D.P., M.D.A., R.W., R.F., V.A., P.A., J.L.M, J.O., J.B., E.T., and M.M. performed the critical revision for important intellectual content. E.T. and M.M. performed the study supervision. All authors have approved the final version of the article. E.T. and M.M. equally contributed to the article and are joint senior authors.

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Correspondence: Manuel Rodríguez-Perálvarez, MD, PhD, Hospital Universitario Reina Sofía, Avda/Menéndez Pidal s/n, Postal Code 14004, Córdoba, Spain. (

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