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

• Published in: European journal of clinical pharmacology Vol. 75; no. 7; pp. 951 - 958
• Main Authors: Rahamimov, Ruth, Tifti-Orbach, Hagit, Zingerman, Boris, Green, Hefziba, Schneider, Shira, Chagnac, Avry, Mor, Eytan, Fox, Benjamin D., Rozen-Zvi, Benaya
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2019; Springer Nature B.V
• Subjects: Adult; Biomedical and Life Sciences; Biomedicine; Biopsy; Exposure; Female; Gender; Graft Survival; Grafting; Hemodialysis; Hospitals; Humans; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - therapeutic use; Kidney Transplantation; Kidney transplants; Kidneys; Male; Middle Aged; Nephrology; Patients; Pharmacoepidemiology and Prescription; Pharmacology/Toxicology; Risk groups; Statistical models; Survival; Tacrolimus; Tacrolimus - blood; Tacrolimus - pharmacokinetics; Tacrolimus - therapeutic use; Transplantation; Variability; Variables; Graft survival; Trough levels; Tacrolimus; Variability; Kidney transplantation
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-019-02643-y

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.