Medication Level Variability During First Year After Pediatric Kidney Transplantation

BACKGROUND: Variability in tacrolimus levels, measured with the Medication Level Variability Index (MLVI), and intrapatient variability (IPV) may be associated with graft outcomes in solid organ transplant recipients. However, the optimal method for measuring tacrolimus variability, the optimal timing for measurement, and intervention thresholds for pediatric kidney transplant recipients remain uncertain. METHODS: Our retrospective study included 149 pediatric kidney transplant recipients who received tacrolimus for maintenance immunosuppression. MLVI and IPV were assessed across 3 post-transplant intervals: 2-week to 3-month; 3- to 6-month; and 6- to 12-month. Associations between MLVI or IPV and graft outcomes were analyzed using landmark survival analysis, adjusting for age at transplant, donor type, and transplant year. We used survival trees to identify optimal thresholds. RESULTS: MLVI during 2-week to 3-month (aHR: 1.65; 95% CI: 1.08-2.52; p = 0.02) and 6-12-month intervals (aHR: 3.82; 95% CI: 1.39-10.5; p = 0.009) post-transplant was significantly associated with the risk of graft failure. Similarly, IPV during 2-week to 3-month (aHR: 1.63; 95% CI: 1.03-2.59; p = 0.04) and 6 to 12-month intervals (aHR: 2.22; 95% CI: 1.05-4.71; p = 0.04) was significantly associated with the risk of graft failure. IPV during a 2-week to 3-month interval was significantly associated with de novo donor-specific antibody (dnDSA) development (aHR: 1.38; 95% CI: 1.07-1.78; p = 0.02). We observed no significant associations between the 3- and 6-month interval and graft failure. Neither MLVI nor IPV during any interval predicted acute rejection. CONCLUSIONS: IPV during the first 3 months was associated with dnDSA development. Both MLVI and IPV during the first 3 months and at the 6- to 12-month interval post-transplant were associated with increased risk of graft failure.