High Tacrolimus Intrapatient Variability and Subtherapeutic Immunosuppression are Associated With Adverse Kidney Transplant Outcomes

Abstract

Background: Kidney transplant recipients with high intrapatient variability (IPV) in tacrolimus (Tac) exposure experience more rejection and reduced graft survival. To understand the underlying pathophysiology of this association, the authors investigated whether patients with high tacrolimus IPV have a more activated immune system than patients with low IPV. In addition, exposure to tacrolimus and mycophenolic acid (MPA) was studied in relation to rejection and graft survival.Conclusions: This study verifies the relationship between high tacrolimus IPV and impaired kidney allograft survival in long-term follow-up. DSA was also found to be more prevalent in patients with subtherapeutic concentrations of tacrolimus and MPA. An increased prevalence of donor-specific alloreactivity is yet to be demonstrated in patients with high IPV.

Tacrolimus—why pharmacokinetics matter in the clinic

“…As a reaction to the high variability in intrapatient trough levels, which are associated with worse outcomes (124)(125)(126)(127)(128)(129), once-daily administered Tac formulations with prolonged drug release have been developed to improve bioavailability and adherence as well as lower intraday fluctuation and peak concentrations (Cmax), as illustrated in Figure 1. In addition to the widely established IR-Tac, granulate formulation extended release (ER)-Tac (Advagraf ® ) with a prolonged drug release (90% absorption after 6-12 h) and LCP-Tac (Envarsus ® ) with an additional improved bioavailability have been established in clinical practice, reviewed in detail by Piotti et al (130).…”

Pathophysiological Implications of Variability in Blood Tacrolimus Levels in Pediatric and Adolescent Kidney Transplant Recipients

“…In one pediatric study, the intrapatient variability of MPA was higher than that of tacrolimus (8). However, data are mixed as to the effect of MPA levels and intrapatient variability on DSA formation and donorreactive T lymphocytes (9). The study by Piburn et al (2) was not equipped to evaluate whether corticosteroids modified the effect of tacrolimus on de novo DSA formation, as only patients with a high immunologic risk were prescribed prednisone (2).…”