Kim H Piburn1, Vaka K Sigurjonsdottir2,3,4, Olafur S Indridason3, Lynn Maestretti5, Mary Victoria Patton5, Anne McGrath5, Runolfur Palsson3,4, Amy Gallo6, Abanti Chaudhuri1, Paul C Grimm1. 1. Division of Nephrology, Department of Pediatrics, Stanford University, Palo Alto, California. 2. Division of Nephrology, Department of Pediatrics, Stanford University, Palo Alto, California vakaks@gmail.com. 3. Division of Nephrology, Internal Medicine and Emergency Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland. 4. Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 5. Pediatric Kidney Transplant Program, Division of Nephrology, Department of Pediatrics, Lucile Packard Children's Hospital Stanford, Palo Alto, California. 6. Division of Abdominal Transplantation, Department of Surgery, Stanford University, Palo Alto, California.
Abstract
BACKGROUND AND OBJECTIVES: High 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, & MEASUREMENTS: All 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. RESULTS: Tacrolimus 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). CONCLUSIONS: High tacrolimus intrapatient variability was strongly associated with de novo donor-specific antibody formation.
BACKGROUND AND OBJECTIVES: High 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, & MEASUREMENTS: All 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. RESULTS: Tacrolimus 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). CONCLUSIONS: High tacrolimus intrapatient variability was strongly associated with de novo donor-specific antibody formation.
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