Patterns in Tacrolimus Variability and Association with De Novo Donor-Specific Antibody Formation in Pediatric Kidney Transplant Recipients

Abstract

Background and objectivesHigh tacrolimus intrapatient variability has been associated with inferior graft outcomes in patients with kidney transplants. We studied baseline patterns of tacrolimus intrapatient variability in pediatric patients with kidney transplants and examined these patterns in relation to C1q-binding de novo donor-specific antibodies.Design, setting, participants, & measurementsAll tacrolimus levels in participants who underwent kidney-only transplantation at a single pediatric center from 2004 to 2018 (with at least 12-month follow-up, followed until 2019) were analyzed to determine baseline variability. Intrapatient variability was defined using the coefficient of variation (SD/mean ×100%) of all samples in a 6-month moving window. Routine de novo donor-specific antibody measurements were available for a subgroup of patients transplanted in 2010–2018. Cox proportional hazards models using tacrolimus intrapatient variability as a time-varying variable were used to examine the association between intrapatient variability and graft outcomes. The primary outcome of interest was C1q-binding de novo donor-specific antibody formation.ResultsTacrolimus intrapatient variability developed a steady-state baseline of 30% at 10 months post-transplant in 426 patients with a combined 31,125 tacrolimus levels. Included in the outcomes study were 220 patients, of whom 51 developed C1q-binding de novo donor-specific antibodies. De novo donor-specific antibody formers had higher intrapatient variability, with a median of 38% (interquartile range, 28%–48%) compared with 28% (interquartile range, 20%–38%) for nondonor-specific antibody formers (P<0.001). Patients with high tacrolimus intrapatient variability (coefficient of variation >30%) had higher risk of de novo donor-specific antibody formation (hazard ratio, 5.35; 95% confidence interval, 2.45 to 11.68). Patients in the top quartile of tacrolimus intrapatient variability (coefficient of variation >41%) had the strongest association with C1q-binding de novo donor-specific antibody formation (hazard ratio, 11.81; 95% confidence interval, 4.76 to 29.27).ConclusionsHigh tacrolimus intrapatient variability was strongly associated with de novo donor-specific antibody formation.

Effect of Voriconazole on Tacrolimus Blood Concentration in Renal Transplant Recipients after Voriconazole Discontinuation

“…Tis retrospective study of 46 kidney transplant recipients demonstrated that patients with high TAC intrapatient variability (coefcient of variation >30%) had a higher risk of de novo donor-specifc antibody formation (hazard ratio, 5.35; 95% confdence interval, 2.45 to 11.68), which was associated with poor graft outcomes [4]. Te Consensus on Modifable Risk Management in Transplantation expert panel also recommended that large fuctuations in TAC levels and high exposure levels in the early posttransplant period should be avoided because they increase mortality caused by events related to excessive immunosuppression such as infections, cardiovascular events, and malignancies [19].…”

“…In triple therapy regimens with TAC, mycophenolate mofetil, and glucocorticoid, maintaining TAC C 0 at 8-15 ng/ml is recommended for 0-3 months postsurgery [3]. Intrapatient variability refects fuctuations in trough levels over a specifc time interval [4]. Intrapatient variability of TAC C0 increases the risk of poor prognosis after transplantation [5,6].…”

HLA (emphasis on DQ) compatibility for longer allograft survival in pediatric transplantation: Modern evidence and challenges

“…Unfortunately, long‐term graft and patient survival rates are still suboptimal, 7–9 and the lifelong requirement for immunosuppression in children is associated with complications and mortality 10 . Immunosuppression minimization and non‐adherence, that is especially prevalent among pediatric patients, 11 can lead to increased risk of generating de‐novo donor‐specific HLA antibodies (dnDSA) and inferior graft outcomes 12 . Allosensitization, in turn, can cause chronic rejection, which is a leading cause of graft loss 13 .…”

“…10 Immunosuppression minimization and non-adherence, that is especially prevalent among pediatric patients, 11 can lead to increased risk of generating de-novo donor-specific HLA antibodies (dnDSA) and inferior graft outcomes. 12 Allosensitization, in turn, can cause chronic rejection, which is a leading cause of graft loss. 13 Lastly, allosensitization after graft loss leads to increased sensitization as measured by degree of calculated panel reactive antibodies (cPRA), reducing access to compatible retransplantation and increasing waiting time at relisting.…”

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

“…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).…”