Mosaicism and the taxonomy of human disease

Two papers in this special issue of Cold Spring Harbor Molecular Case Studies on Mosaicism throw light on an interesting conundrum in mosaic disorders. This conundrum centers on thresholds for the definition of mosaic disorders and how to reconcile the incredible inter- and intrapatient variability of mosaic disorders with the clinical imperative to have clear and distinct categorical diagnoses.

Intrapatient Variability in Tacrolimus Trough Levels Over 2 Years Affects Long-Term Allograft Outcomes of Kidney Transplantation

This study aimed to determine the impact of tacrolimus (TAC) trough level (C0) intrapatient variability (IPV) over a period of 2 years after kidney transplantation (KT) on allograft outcomes. In total, 1,143 patients with low immunologic risk were enrolled. The time-weighted coefficient variability (TWCV) of TAC-C0 was calculated, and patients were divided into tertile groups (T1: < 24.6%, T2: 24.6%–33.7%, T3: ≥ 33.7%) according to TAC-C0-TWCV up to post-transplant 1st year. They were classified into the low/low, low/high, high/low, and high/high groups based on a TAC-C0-TWCV value of 33.7% during post-transplant 0–1st and 1st–2nd years. The allograft outcomes among the three tertile and four TAC-C0-TWCV groups were compared. The T3 group had the highest rate of death-censored allograft loss (DCGL), and T3 was considered an independent risk factor for DCGL. The low/low group had the lowest and the high/high group had the highest risk for DCGL. Moreover, patients with a mean TAC-C0 of ≥5 ng/ml in the high/high group were at the highest risk for DCGL. Thus, TAC-IPV can significantly affect allograft outcomes even with a high mean TAC-C0. Furthermore, to improve allograft outcomes, a low TAC-IPV should be maintained even after the first year of KT.

Association between medication adherence and intrapatient variability in tacrolimus concentration among stable kidney transplant recipients

This study analyzed the association between medication adherence and the intrapatient variability (IPV) of tacrolimus concentrations among kidney transplant recipients through a post hoc analysis of the dataset from a recently conducted randomized controlled trial. Among 138 patients enrolled in the original trial, 92 patients with ≥ 5 months of medication event monitoring system (MEMS) use and ≥ 4 tacrolimus trough values were included in this post hoc analysis. The variability of tacrolimus trough levels was calculated using coefficient variation (CV) and mean absolute deviation. Adherence was assessed using MEMS and self-report via the Basal Assessment of Adherence to Immunosuppressive Medication Scale. There were no statistically significant differences in the CV [median 16.5% [interquartile range 11.6–25.5%] and 16.0% [11.5–23.5%], respectively, P = .602] between the nonadherent (n = 59) and adherent groups (n = 33). There was also no significant correlation between the CV and adherence detected by MEMS (taking adherence, ρ = − 0.067, P = .527; dosing adherence, ρ = − 0.098, P = .352; timing adherence, ρ = − 0.113, P = .284). Similarly, adherence measured by self-report did not significantly affect the IPV (P = .452). In this post hoc analysis, nonadherent behavior, measured through electronic monitoring or self-report, did not affect the IPV.

Retrospective Analysis of Tacrolimus Intrapatient Variability as a Measure of Medication Adherence

Background: Increased intrapatient variability (IPV) in tacrolimus levels is associated with graft rejection, de novo donor-specific antibodies, and graft loss. Medication nonadherence may be a significant contributor to high IPV. Objective: The objective of this study is to determine the utility of tacrolimus IPV in detecting nonadherence by examining the relationship between self-reported adherence and tacrolimus coefficient of variability (COV), a measure of IPV. Design: Retrospective cohort study. Setting: St. Michael’s Hospital, Toronto, Ontario. Patients: All patients who were at least 1-year post-kidney transplant as of March 31, 2019, prescribed tacrolimus as an immunosuppressant and had a self-reported adherence status. Patients were excluded from the primary analysis of examining the correlation between COV and self-reported adherence if they lacked a calculatable COV. Measurements: Self-reported adherence, COV, demographic data, transplant, and medication history. Methods: A modified Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) administered by healthcare professionals to assess self-reported adherence was used. The COV of tacrolimus trough levels was calculated and its correlation to BAASIS response was noted. The median COV was used as a cutoff to examine the characteristics of patients deemed “high COV” and “low COV.” Results: A total of 591 patients fit the initial criteria; however, only 525 had a recent calculatable COV. Overall, 92.38% of the population were adherent by self-report. Primary analysis identified a COV of 25.2% and 29.6% in self-reported adherent and nonadherent patients, respectively, though the result was not significant ( P = .2). Secondary analyses showed a significant correlation between younger age at transplant and at the time of adherence self-reporting with nonadherence ( P = .01). In addition, there was a strong correlation between those nonadherent with routine post-transplant blood work and younger age ( P < .01). Limitations: The limitations included modified nonvalidated BAASIS questionnaire, social desirability bias, BAASIS only administered in English, and patients with graft failure not active in clinic not being captured. Conclusions: The COV should not be used as the sole method for determining medication adherence. However, COV may have some utility in capturing individuals who are not adherent to their blood work or patients who are having a poor response to tacrolimus and should be switched to another medication.