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

  • Ruth RahamimovEmail author
  • Hagit Tifti-Orbach
  • Boris Zingerman
  • Hefziba Green
  • Shira Schneider
  • Avry Chagnac
  • Eytan Mor
  • Benjamin D. Fox
  • Benaya Rozen-Zvi
Pharmacoepidemiology and Prescription



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.


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.


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.


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.


Kidney transplantation Tacrolimus Trough levels Variability Graft survival 


Authors’ 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.

Compliance with ethical standards

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

Supplementary material

228_2019_2643_MOESM1_ESM.docx (119 kb)
ESM 1 (DOCX 119 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Nephrology and HypertensionRabin Medical CenterPetah TikvaIsrael
  2. 2.Department of TransplantationRabin Medical CenterPetah TikvaIsrael
  3. 3.Sackler Faculty of MedicineTel-Aviv UniversityTel-AvivIsrael
  4. 4.Department of Nephrology and HypertensionRabin Medical CenterPetah TikvaIsrael
  5. 5.Department of PulmonologyAssaf Harofeh (Yitzhak Shamir) Medical CenterZrifinIsrael

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