Adherence in pediatric renal recipients and its effect on graft outcome, a single‐center, retrospective study

Feddersen, Nele; Pape, Lars; Beneke, Jan; Brand, Korbinian; Prüfe, Jenny

doi:10.1111/petr.13922

Cited by 5 publications

(4 citation statements)

References 30 publications

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“…Interestingly, we saw a clear trend towards a higher TacIPV in patients below the age of 6 years. This finding is in contrast to studies suggesting a higher TacIPV in adolescents due to lower therapy adherence [ 31 , 35 , 36 ], but is consistent with a study by Prytula et al [ 33 ]. Although our study does not allow any causal inferences, a possible explanation might be a generally higher susceptibility to infections, in particular gastrointestinal, at younger age, which is known to interfere with TacIPV [ 8 ] because diarrhea leads to increased Tac bioavailability.…”

Section: Discussionsupporting

confidence: 91%

Association of intraindividual tacrolimus variability with de novo donor-specific HLA antibody development and allograft rejection in pediatric kidney transplant recipients with low immunological risk

et al. 2022

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Background Tacrolimus (Tac) intraindividual variability (TacIPV) in pediatric kidney transplant patients is only poorly understood. We investigated the impact of TacIPV on de novo donor-specific HLA antibodies (dnDSA) development and allograft rejection in Caucasian pediatric recipients of a living or deceased donor kidney with low immunological risk. Methods This was a single-center retrospective study including 48 pediatric kidney transplant recipients. TacIPV was calculated based on coefficient of variation (CV%) 6–12 months posttransplant. TacIPV cutoff was set at the median (25%). Outcome parameters were dnDSA development and rejection episodes. Results In total, 566 Tac levels were measured with median 11.0 (6.0–17.0) measurements per patient. The cutoff of 25% corresponded to the median CV% in our study cohort (25%, IQR 18–35%) and was comparable to cutoffs determined by receiver operating characteristic (ROC) curve analysis. High TacIPV was associated with higher risk of dnDSA development (HR 3.4, 95% CI 1.0–11.1, P = 0.047; Kaplan–Meier analysis P = 0.018) and any kind of rejection episodes (HR 4.1, 95% CI 1.1–14.8, P = 0.033; Kaplan–Meier analysis P = 0.010). There was a clear trend towards higher TacIPV below the age of 6 years. TacIPV (CV%) was stable over time. A TacIPV (CV%) cutoff of 30% or IPV quantification by mean absolute deviation (MAD) showed comparable results. Conclusions High TacIPV is associated with an increased risk of dnDSA development and rejection episodes > year 1 posttransplant even in patients with low immunological risk profile. Therefore, in patients with high TacIPV, potential causes should be addressed, and if not resolved, changes in immunosuppressive therapy should be considered. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

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Section: Discussionsupporting

confidence: 91%

Association of intraindividual tacrolimus variability with de novo donor-specific HLA antibody development and allograft rejection in pediatric kidney transplant recipients with low immunological risk

et al. 2022

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“…Our data show that younger patients have lower tacrolimus trough levels, and higher TacIPV. This contrasts with other studies suggesting higher TacIPV in adolescents due to lower adherence to the immunosuppressive medication [9–11], but is consistent with our previous single-center study [12] and previous work by Prytula et al [13] showing higher TacIPV in younger patients. Although our study does not allow for causal inferences, potential factors leading to higher tacrolimus variability could be differences in metabolism [14], frequency of dose adjustments due to intercurrent infections [5, 15], especially diarrhea which is more common in infants and may lead to a paradoxical increase in tacrolimus exposure, infection-related inflammation [16], and gut microbiota composition between young children and adolescents [17, 18].…”

Section: Discussionsupporting

confidence: 87%

Age-related differences in rejection rates, infections and tacrolimus exposure in pediatric kidney transplant recipients – a benchmark study of the CERTAIN registry

Baghai Arassi,

Feißt,

Krupka

et al. 2024

Preprint

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Background. Data on age-related differences in rejection rates, infectious episodes and tacrolimus exposure in pediatric kidney transplant recipients (pKTR) on a uniform tacrolimus-based immunosuppressive regimen are scarce. Methods. We therefore performed a large-scale analysis of 802 pKTR from the CERTAIN registry from 40 centers in 14 countries. Inclusion criteria were a tacrolimus-based immunosuppressive regimen and at least two years of follow-up. The patient population was divided into three age groups (infants <6 years, school-aged children 6-12 years, and adolescents >12 years) to assess age-related differences in outcome. Results. Median follow-up was 48 months (IQR, 36-72). Within the first 2 years post-transplant, infants had a significantly higher incidence of infections (80.6% vs. 55.0% in adolescents, P<0.001) and a significantly higher number of cumulative hospital days (median 13 days vs. 7 days in adolescents, P < 0.001). Adolescents had a significantly higher rate of biopsy-proven acute rejection episodes in the first year post-transplant (21.7%) than infants (12.6%, P=0.007). Infants had significantly lower tacrolimus trough levels, lower concentration-to-dose ratios as an approximation for higher tacrolimus clearance, and higher intra-patient variability (all P < 0.01) than adolescents. Conclusions. This largest study to date in European pKTR on a tacrolimus-based immunosuppressive regimen shows important age-related differences in rejection rates, infection episodes, tacrolimus exposure and clearance. These data suggest that immunosuppressive therapy in pKTR should be tailored according to the age-specific risk profiles of this heterogeneous patient population.

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“…Intrapatient variability reflects the fluctuation in trough levels within an individual over a given time interval (9). Fluctuations in tacrolimus levels may occur for many reasons, including vomiting or feeding problems, dose adjustments in response to infection or malignancy, timing and fat content of meals, drug-drug interactions or genetic factors that affect its metabolism, and medication nonadherence (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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

Piburn

Sigurjonsdottir

Indridason

et al. 2022

CJASN

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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.

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Adherence in pediatric renal recipients and its effect on graft outcome, a single‐center, retrospective study

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 5 publications

References 30 publications

Association of intraindividual tacrolimus variability with de novo donor-specific HLA antibody development and allograft rejection in pediatric kidney transplant recipients with low immunological risk

Association of intraindividual tacrolimus variability with de novo donor-specific HLA antibody development and allograft rejection in pediatric kidney transplant recipients with low immunological risk

Age-related differences in rejection rates, infections and tacrolimus exposure in pediatric kidney transplant recipients – a benchmark study of the CERTAIN registry

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

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