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

The longevity of renal transplantation (RT) rests on the delicate balance of adequate immunosuppression to minimize immunologic allograft insult through rejection and donor-specific antibody (DSA) formation, as well as excess immunosuppression potentially leading to toxicities such as malignancy and infection.1 Tacrolimus, a calcineurin inhibitor, is the mainstay of immunosuppression following RT. It is classified as a narrow therapeutic index medication, displaying wide interpatient variability and intrapatient variability (IPV) and requiring frequent therapeutic drug monitoring of trough levels.2-5 Therefore, it is critical to maintain therapeutic levels to preserve allograft function. In addition to assessing adequate trough levels, tacrolimus IPV is another important consideration for allograft longevity.5 Increased tacrolimus IPV, as measured by coefficient of variation (CV%) or SD, is associated with deleterious outcomes in RT recipients, including increased allograft fibrosis, rejection, development of DSA, and decreased allograft survival.5-14 Several studies assessing time in therapeutic range (TTR) with tacrolimus have demonstrated that patients with lower TTR values have been associated with de novo DSA (dnDSA) development and inferior allograft outcomes.15-17 However, many of these aforementioned studies were in the setting of triple immunosuppression therapy with immediate-release tacrolimus, antimetabolite, and long-term corticosteroid therapy. Patients on early corticosteroid withdrawal (ECSWD) protocol rely solely on tacrolimus and mycophenolate for maintenance immunosuppression, with mycophenolate doses being generally standardized and tacrolimus trough levels being titrated on the basis of targeted trough concentrations. Theoretically, the importance of tacrolimus TTR may be more critical within this population, as clinical efficacy in the prevention of rejection and DSA could depend more heavily on these tacrolimus concentrations and TTR compared with prior studies in the setting of triple immunosuppression. Therefore, the purpose of this study was to evaluate the impact of tacrolimus TTR and IPV on renal allograft outcomes in the setting of an ECSWD protocol.