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

Abstract

Tacrolimus (Tac) is widely used to prevent rejection and graft loss in solid organ transplantation. A limiting characteristic of Tac is the high intra and interpatient variability associated with its use. Routine therapeutic drug monitoring (TDM) is necessary to facilitate Tac management and to avoid undesirable clinical outcomes. However, whole blood trough concentrations commonly utilized in TDM are not strong predictors of the detrimental clinical outcomes of interest. Recently, researchers have focused on Tac intrapatient variability (Tac IPV) as a novel marker to better assess patient risk. Higher Tac IPV has been associated with a number of mechanisms leading to shortened graft survival. Medication nonadherence (MNA) is considered to be the primary determinant of high Tac IPV and perhaps the most modifiable risk factor. An understanding of the methodology behind Tac IPV is imperative to its recognition as an important prognostic measure and integration into clinical practice. Therapeutic interventions targeting MNA and reducing Tac IPV are crucial to improving long-term graft survival.

Keywords: graft survival; health services and outcomes research; immunosuppressant - calcineurin inhibitor: tacrolimus; kidney transplantation/nephrology.

FIGURE 1

Conceptual model of high tacrolimus (Tac) intrapatient variability (IPV) and graft loss in kidney transplant recipients. The key determinants of high Tac variability are food and drug interactions, including herbal supplements, genetic factors, medication nonadherence, and concomitant illness. High Tac variability leads to an increased incidence of acute rejection, de novo donor-specific antibody (dnDSA) development, and histologic lesions. Ultimately, there is an increased risk of graft loss in recipients with high Tac IPV