*Purpose: Accumulating data indicates that sub-therapeutic levels of calcineurin inhibitors are associated with long-term graft loss. However, while widely used tacrolimus (TAC) was shown to provide adequate immunosuppression with lower acute rejection rate, its optimal maintenance dose for long term graft survival is still unknown. The aim of our study was to determine the minimal TAC trough level, which is associated with improved kidney graft survival.

*Methods: We conducted a retrospective cohort study based on the Rabin Medical Center transplantation registry. We defined five TAC trough level intervals: 3-(4), 4-(5), 5-(6), 6-(7) and 7-(8) ng/ml. We calculated the exposure time for each drug level interval during the first year following transplantation, defined as the cumulative number of days at each interval. This measure was adjusted to the exposure time below a given interval-level, allowing us to define the threshold for optimal TAC trough level as the upper limit of the interval. We then determined the association between the adjusted exposure time at each TAC level-interval and our primary outcome – death-censored graft survival.

*Results: We included 1417 patients with a median follow up of 5.3 years (IQR 2.9-8.5 years). TAC through level interval of 5-6 ng/ml was the highest interval which demonstrated a statistically significant association between exposure time and increased risk of graft loss, even after adjustment to the exposure time below 5ng/ml (HR 1.59 per log days, 95% CI 1.25-2.01, p<0.001). These results remained consistent in an extensive multivariate analysis including TAC level variability and were not significantly changed when we analyzed the first three months and the subsequent nine months separately.

*Conclusions: Prolonged exposure time to TAC trough level between 5-6ng/ml within the first- year post transplantation was independently associated with increased risk of long- term graft loss. These results imply that keeping TAC trough levels above 6ng/ml during the first year might improve kidney transplantation outcome

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