Retrospective Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Mar 27, 2021; 13(3): 362-374
Published online Mar 27, 2021. doi: 10.4254/wjh.v13.i3.362
Early tacrolimus exposure does not impact long-term outcomes after liver transplantation
Mikel Gastaca, Patricia Ruiz, Javier Bustamante, Lorea Martinez-Indart, Alberto Ventoso, José Ramón Fernandez, Ibone Palomares, Mikel Prieto, Milagros Testillano, Patricia Salvador, Maria Senosiain, Maria Jesus Suárez, Andres Valdivieso
Mikel Gastaca, Patricia Ruiz, Alberto Ventoso, Ibone Palomares, Mikel Prieto, Andres Valdivieso, Department of HPB Surgery and Liver Transplantation Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
Javier Bustamante, José Ramón Fernandez, Milagros Testillano, Patricia Salvador, Maria Senosiain, Maria Jesus Suárez, Department of Hepatology Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
Lorea Martinez-Indart, Department of Bioinformatics and Statistics Platform, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Bilbao 48903, Spain
Author contributions: Gastaca M designed and performed the research and wrote the paper; Ruiz P and Bustamante J designed the research and supervised the report; Martinez-Indart L provided the statistical analysis; Ventoso A, Palomares I, Prieto M, Salvador P, and Senosiain M acquired and analyzed the data; Testillano M, and Suárez MJ and Valdivieso A supervised the report; all authors approved the final version of the article.
Institutional review board statement: This study was reviewed and approved by the Research Ethics Committee of the Hospital Universitario Cruces, No. CEIC E13/08.
Informed consent statement: Patients gave written consent to be included in the liver transplantation prospective data base. The requirement for specific informed consent for this study was waived because of the retrospective nature of the study.
Conflict-of-interest statement: MG is a member of advisory boards and has received honoraria from Astellas, Novartis and Chiesi. JB has received honoraria from Astellas and Novartis. AV has received honoraria from Astellas and Novartis. All other authors have no conflicts to declare.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Mikel Gastaca, MD, Associate Professor, Surgeon, Department of HPB Surgery and Liver Transplantation Unit, Hospital Universitario Cruces, PLaza de Cruces s/n, Bilbao 48903, Spain.
Received: August 14, 2020
Peer-review started: August 14, 2020
First decision: December 11, 2020
Revised: December 27, 2020
Accepted: March 12, 2021
Article in press: March 12, 2021
Published online: March 27, 2021
Research background

Immunosuppression is a cornerstone in liver transplantation (LT) and current immunosuppressive regimens are mostly based on tacrolimus. At present, side effects relating anticalcineurin inhibitors are one of the main concerns for long-term outcomes after LT. Side effects are commonly related with drug dose and trough levels.

Research motivation

Tacrolimus trough levels (TTL) above 10 ng/mL during the first weeks after liver transplant have been related with mid and long-term outcomes including impairment of renal function and an increased rate of hepatocellular recurrence, de novo tumors and new-onset diabetes.

Research objectives

The aim of this study was to assess the influence of the TTL during the early post-transplant period in the long-term outcomes of LT.

Research methods

This was a retrospective study of 155 consecutive liver transplants treated with an immunosuppressive regimen based on de novo once-daily tacrolimus. Patients were classified into 2 groups according to their mean TTL within the first month after transplantation: ≤ 10 ng/mL (n = 98) and > 10 ng/mL (n = 57). All TTL obtained during the first month were used to define the mean values. Multivariate analyses were performed to assess risk factors for patient mortality.

Research results

TTL were significantly different among groups only during the first month after transplantation, but not during the rest of the follow-up After a median follow-up of 52.8 mo (range 2.8-81.1), no significant differences were observed in the evolution of the mean estimated glomerular filtration rate, hepatocellular carcinoma recurrence, development of de novo tumors, new-onset diabetes, new-onset arterial hypertension or biopsy-proven acute rejection rate. Five-year patient and graft survival were comparable. Early tacrolimus trough level was not an independent factor for patient mortality in multivariate analyses.

Research conclusions

Differences in tacrolimus levels restricted to the first month after transplantation did not result in significant differences in long-term outcomes of liver transplant recipients.

Research perspectives

Mid and long-term calcineurin inhibitors-related side effects after LT should be studied considering the cumulative exposure to tacrolimus along the follow-up and not only the trough levels observed during the early post-transplant period.