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Reduction of exposure to tacrolimus trough level variability is associated with better graft survival after kidney transplantation

  • Pharmacoepidemiology and Prescription
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Abstract

Purpose

High tacrolimus trough drug level variability was found to be associated with reduced graft survival. The primary goal of this study was to find whether reduction of exposure to high tacrolimus trough level variability in patients in which previously had high variability was associated with better graft survival.

Methods

All tacrolimus drug level values in patients that underwent kidney transplantation at our center between 2006 and 2015 were collected. Exposure to variability was calculated using a time-weighted coefficient of variability (TWCV). Time-dependent univariate and multivariate Cox proportional hazard models were used to analyze the primary outcome of graft survival and to determine a cutoff value for TWCV as a predictor of this outcome.

Results

A total of 878 patients were included in the study with a median follow-up of 1263 days. TWCV above 25% was significantly associated with reduced graft survival (HR3.66, 95% CI 2.3–5.8, p < 0.001). Of the 480 patients (54.7%) who had a cumulative TWCV of > 25% at a certain time during the follow-up, 110 (22.9%) later returned to a cumulative TWCV of less than 25%. Reduction of TWCV to values below 25% was associated with a hazard of graft loss that was not different from patients who had cumulative TWCV of less than 25% during the entire follow-up period (HR 1.81, 95% CI 0.71–4.62, p = 0.218 and HR 1.08, 95% CI 0.39–2.99, p = 0.780) in univariate and multivariate analyses, respectively.

Conclusions

Monitoring TWCV can help detect the high-risk patients. Interventions intended to reduce variability on long-term graft survival may have a positive effect on graft survival.

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Author information

Author notes

  1. Benjamin D. Fox and Benaya Rozen-Zvi contributed equally to this work.

Authors and Affiliations

  1. Department of Nephrology and Hypertension, Rabin Medical Center, Beilinson campus, 39, Jabutinsky st., Petah Tikva, Israel

    Ruth Rahamimov, Hefziba Green, Shira Schneider, Avry Chagnac & Benaya Rozen-Zvi

  2. Department of Transplantation, Rabin Medical Center, Beilinson campus, Petah Tikva, Israel

    Ruth Rahamimov & Eytan Mor

  3. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Ruth Rahamimov, Hagit Tifti-Orbach, Boris Zingerman, Hefziba Green, Avry Chagnac, Eytan Mor, Benjamin D. Fox & Benaya Rozen-Zvi

  4. Department of Nephrology and Hypertension, Rabin Medical Center, HaSharon campus, Petah Tikva, Israel

    Boris Zingerman & Avry Chagnac

  5. Department of Pulmonology, Assaf Harofeh (Yitzhak Shamir) Medical Center, Zrifin, Israel

    Benjamin D. Fox

Authors
  1. Ruth Rahamimov
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Contributions

Rahamimov Ruth: conceived the study, drafted the manuscript, provided intellectual content of critical importance to the work and approved the version to be published.

Tifti-Orbach Hagit: collected the data, provided intellectual content of critical importance to the work, and approved the version to be published.

Zingerman Boris: provided intellectual content of critical importance to the work and approved the version to be published.

Green Hefziba: provided intellectual content of critical importance to the work and approved the version to be published.

Schneider Shira: provided intellectual content of critical importance to the work and approved the version to be published.

Chagnac Avry: provided intellectual content of critical importance to the work, revised and approved the version to be published.

Mor Eytan: provided intellectual content of critical importance to the work, revised the manuscript, and approved the version to be published.

Fox Benjamin D: designed the study, provided intellectual content of critical importance to the work, revised the manuscript, and approved the version to be published.

Rozen-Zvi Benaya: designed the study, analyzed the data, revised the manuscript, provided intellectual content of critical importance to the work, and approved the version to be published.

Corresponding author

Correspondence to Ruth Rahamimov.

Ethics declarations

The study was approved by the RMC Institutional Review Board and was conducted according to the declaration of Helsinki and the declaration of Istanbul.

Conflict of interest

Ruth Rahamimov received a fee for participation in advisory boards from Novartis and Teva.

Benaya Rozen-Zvi received a consultation fee from Fresenius Medical and a Lecture fee from Novartis

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Rahamimov, R., Tifti-Orbach, H., Zingerman, B. et al. Reduction of exposure to tacrolimus trough level variability is associated with better graft survival after kidney transplantation. Eur J Clin Pharmacol 75, 951–958 (2019). https://doi.org/10.1007/s00228-019-02643-y

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  • DOI: https://doi.org/10.1007/s00228-019-02643-y

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