High Intrapatient Variability of Tacrolimus Concentrations Predicts Accelerated Progression of Chronic Histologic Lesions in Renal Recipients

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High intrapatient variability (IPV) of tacrolimus concentrations is increasingly recognized as a predictor of poor outcome in solid organ recipients. How it relates to evolution of histology has not been explored. We analyzed tacrolimus IPV using the coefficient of variability (CV) from months 6–12 after transplantation in a cohort of 220 renal recipients for whom paired protocol biopsies at 3 mo and 2 years were available. Recipients in the highest CV tertile had an increased risk of moderate to severe fibrosis and tubular atrophy by 2 years compared with the low-IPV tertile (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.09–5.60, p = 0.031; and OR 2.40, 95% CI 1.03–5.60, p = 0.043, respectively). Other predictors were donor age, severity of chronic lesions at 3 mo, and presence of borderline or subclinical rejection at 3 mo. Chronicity score increased significantly more in the high CV tertile group than in the middle and low tertiles (mean increase 1.97 ± 2.03 vs. 1.18 ± 2.44 and 1.12 ± 1.80, respectively; p < 0.05). CV did not predict evolution of renal function, which did not deteriorate within the 2-year follow-up period. These results indicate that high IPV is related to accelerated progression of chronic histologic lesions before any evidence of renal dysfunction.

Key words

clinical research/practice
immunosuppression/immune modulation
kidney transplantation/nephrology
pharmacology
fibrosis
immunosuppressant
calcineurin inhibitor: tacrolimus
kidney (allograft) function/dysfunction
pharmacokinetics/pharmacodynamics

Abbreviations

C0/D
dose-corrected concentration
CI
confidence interval
CV
coefficient of variability
DBD
donation after brain death
DCD
donation after cardiac death
DSA
donor-specific antibody
eGFR
estimated GFR
IPV
intrapatient variability
MMF
mycophenolate mofetil
MVI
microvascular inflammation
OR
odds ratio
PRA
panel reactive antibody
SD
standard deviation

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Both authors contributed equally to this article.