Tacrolimus Intrapatient Variability, Time in Therapeutic Range, and Risk of De Novo Donor–Specific Antibodies

Abstract

Background. Tacrolimus (TAC) is the most important agent for maintenance immunosuppression and prevention of immunologic injury to the renal allograft, yet there remains no consensus on how best to monitor drug therapy. Both high TAC intrapatient variability and low TAC time in therapeutic range (TTR) have been associated with risk of de novo donor–specific antibodies (dnDSA). In this study, we hypothesized that the risk associated with high TAC coefficient of variation (CV) is a result of low TAC TTR rather than the variability itself. Methods. We analyzed the risk of dnDSA, acute rejection, or death-censored graft loss by non–dosed-corrected TAC CV and TAC TTR during the first posttransplant year in a cohort of 538 patients with a median follow-up period of 4.1 years. Results. Patients with CV >44.2% and TTR <40% (high intrapatient variability and low TTR) had a high risk of dnDSA (adjusted OR = 4.93, 95% confidence interval = 2.02-12.06, P < 0.001) and death-censored graft loss by 5 years (adjusted HR = 4.00, 95% confidence interval = 1.31-12.24, P = 0.015) when compared with patients with CV >44.2% and TTR ≥40% (high intrapatient variability and optimal TTR), while the latter patients had similar risk to patients with CV <44.2% (lower intrapatient variability). Conclusions. These data suggest that previously reported immunologic risk associated with high TAC intrapatient variability is due to time outside of therapeutic range rather than variability in and of itself when evaluating absolute non–dose-corrected TAC levels irrespective of reason or indication.

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

“…Among patients with high CV, those with low TTR had significantly higher risk for dnDSA, acute rejection, and death‐censored graft loss compared with high TTR. Among patients with high TTR, outcomes were not significantly different when comparing those with low and high CV 61 . These results suggest combining IPV measures may offer stronger predictive value, however, further studies in this area are necessary.…”

“…A recent study in adult kidney transplant recipients also identified an association between TTR less than 78% and risk of rejection, graft loss, mortality, and infection 59 . Davis et al conducted two analyses within a single group of adult kidney transplant recipients utilizing TTR and CV 60,61 . The first analysis used a cutoff of TTR less than 60% to identify high‐risk patients based on warfarin literature.…”

A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation

“…More recent studies have further investigated the role that high Tac IPV plays in dnDSA development. Davis et al reported that immunologic risk associated with high Tac IPV can be attributed to time spent outside of therapeutic range 20 . Using mean Tac IPV alone may overlook individuals at higher immunologic risk.…”

Clinical Implications of Tacrolimus Time in Therapeutic Range and Intrapatient Variability in Urban Renal Transplant Recipients Undergoing Early Corticosteroid Withdrawal

“…In a subsequent evaluation by the same study group, it was reported that patients with CV% >44.2% and TTR <40% had an increased risk of dnDSA (OR, 4.93; 95% CI, 2.02-12.06; P < 0.001). 16 Additionally, patients with CV% >44.2% and TTR <40% had an increased association with death-censored graft loss at 5 years (HR, 4.00; 95% CI, 1.31-12.24; P = 0.015). This study identified their CV% and TTR thresholds based on ROC curve analysis.…”

“…This study identified their CV% and TTR thresholds based on ROC curve analysis. 16 However, this study cohort also included both kidney and pancreas transplant recipients with various tacrolimus off-protocol trough goals, which increased the potential for lower TTR compared with a more homogenous immunosuppression cohort.…”