MO1013: What is the Best Measure of Time in the Therapeutic Range of Tacrolimus for Kidney Transplantation?
Authors: Rodrigo Emilio , Barreda Paloma , Cañamero Lucía , Boya Marta , del Mar García Saiz María , Valero San Cecilio Rosalía , Belmar Vega Lara , Kislikova María , Angeles de Cos María , Carlos Ruiz San Millán Juan 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Tacrolimus is the main immunosuppressive drug in the vast majority of kidney transplants, but it is a drug with a narrow therapeutic margin. Each centre must establish therapeutic ranges to optimize its efficacy and minimize its toxic effects. Maintaining levels in the appropriate range is difficult due to its inherent inter- and intra-patient variability. In the monitoring of transplants, in addition to assessing the drug levels at each visit, the measurement of time in therapeutic range (TTR) allows us to measure how long the patient has been exposed to the appropriate doses. Currently, it is not known which are the optimal ranges of time or of blood levels that are better related to the subsequent evolution of kidney transplantation.

METHOD
We performed a single centre, observational study of 215 consecutive kidney transplant recipients performed in our centre from October/2014 to January/2020 who received uninterrupted treatment with tacrolimus during the first year, excluding hypersensitized recipients. TTR was calculated using the Rosendaal method between months 3 and 12 (TTR-M3-12) or 6 and 12 (TTR-M6-12) with a target for blood levels &gt;6 ng/mL (TTR-M3-12-T &gt; 6, TTR-M6-12-T &gt; 6) or between 6 and 10 ng/mL (TTR-M3-12-T6-10, TTR-M6-12-T6-10).

RESULTS
The mean follow-up time was 4.1 ± 2.0 years. The TTR that had a greater capacity to discriminate the risk of rejection {TTR-M3-12-T &gt; 6: AUC-ROC 0.614, [95% confidence interval (95% CI) 0.513–0.714]; P = .018; TTR-M6-12-T &gt; 6: AUC-ROC 0.607, 95% CI 0.502–0.713, P = .029; TTR-M3-12-T6-10: AUC-ROC 0.610, 95% CI 0.516–0.703, P = .023; TTR-M6-12-T6-10; AUC-ROC 0.596, 95% CI 0.495–0.696, P = .051} during the first year and of having a glomerular filtration rate of &lt;30 mL/min/1.73 m2 at the first year (TTR-M3-12-T &gt; 6: AUC-ROC 0.676, 95% CI 0.542–0.811; P = .014; TTR-M6-12-T &gt; 6: AUC-ROC 0.623, 95% CI 0.511–0.795; P = .037; TTR-M3-12-T6-10: AUC-ROC 0.566, 95% CI 0.429–0.703; P = .358; TTR-M6-12-T6-10: AUC-ROC 0.575, 95% CI 0.446–0.703; P = .310) was TTR-M3-12-T &gt; 6. By Cox regression, the TTR that was significantly related to death censored graft loss of the kidney graft censoring for death was TTR-M3-12-T &gt; 6 (TTR-M3-12-T &gt; 6: HR = 0.972, 95% CI 0.949–0.995; P = .079; TTR-M6-12-T &gt; 6: HR = 0.980, 95% CI 0.961–0.998; P = .033; TTR-M3-12-T6-10: HR = 0.985, 95% CI 0.962–1.009; P = .230; TTR-M6-12-T6-10: HR = 0.987, 95% CI 0.968–1.007; P = .199). By multivariate Cox regression analysis, patients in the lower tertile of TTR (HR = 10.027, 95% CI 1.244–81.447; P = .031) had worse survival than those in the upper tertiles, regardless of kidney function in the first year (Fig. 1).

CONCLUSION
The measurement of TTR after kidney transplantation makes possible to easily estimate the time of exposure to adequate levels of tacrolimus, relating it to the risk of acute rejection, kidney function in the first year, and death-censored graft survival. Among the possible TTR measures, the one that is best related to post-transplant outcome is taking into account tacrolimus blood levels between month 3 and 12 and those &gt;6 ng/mL (TTR-M3-12-T &gt; 6).