Dynamic kinetics of graft-derived cell-free DNA and personalized tacrolimus target ranges for acute rejection monitoring in pediatric liver transplantation
4 affiliations
- 1Department of Science and Education, Tianjin First Central Hospital , ,
- 2Department of Pharmacy, Tianjin Chest Hospital , ,
- 3Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital , ,
- 4S&KM Biotechnology Co., Ltd. , , ,
Abstract
Introduction: Acute rejection remains the most common complication during the early post-transplantation period for pediatric patients. Given the limitations of current diagnostic strategies, there is an urgent need to develop accurate and noninvasive biomarkers for allograft monitoring. Tacrolimus-based immunosuppression represents the cornerstone regimen following liver transplantation. However, for pediatric patients, current evidence remains insufficient to establish well-defined therapeutic target ranges for personalized tacrolimus therapy in pediatric patients. We investigated perioperative graft-derived cell-free DNA (GcfDNA) kinetics in pediatric recipients to establish the utility of GcfDNA for monitoring acute rejection and to explore the tacrolimus target concentration range in this population.
Methods: Forty children (age ≤ 3 years) with biliary atresia who underwent liver transplantation were enrolled. All received a tacrolimus-based immunosuppressive regimen on postoperative day (POD) 1 and were followed for at least 1 month. GcfDNA levels were measured by droplet digital PCR.
Results: GcfDNA (%) declined significantly during the first month. Median percentages on POD 1, 7, 14, 21, and 28 were 41.40%, 12.93%, 6.86%, 5.95%, and 3.23%, respectively. The acute rejection group maintained higher GcfDNA levels, with significant differences observed at POD 14, 21, and 28 ( P < 0.001). GcfDNA (%) was strongly correlated with rejection activity index score (r = 0.854, P < 0.001). In this exploratory single-center analysis, receiver operating characteristic (ROC) curve analysis identified an optimal GcfDNA cutoff of 10.21% for predicting acute rejection, with an area under the curve (AUC) of 0.757 (95% CI: 0.691–0.823, P < 0.001). The optimal tacrolimus trough concentration (C ₀ ) threshold was 7.75 ng/mL (AUC = 0.732, 95% CI: 0.655–0.810, P < 0.001).
Conclusion: We suggest that GcfDNA may serve as a potential biomarker for acute rejection monitoring in pediatric liver transplantation, with an exploratory predictive cutoff value of 10.21% identified in this single-center cohort. Our findings also tentatively point to a minimal effective tacrolimus C ₀ of 7.75 ng/mL within the first month post-transplantation, alongside an upper safety limit of 10 ng/mL that is primarily grounded in published peer-reviewed literatures. These thresholds, however, were optimized against stable grafts rather than the full spectrum of graft injury and require multicenter validation before clinical adoption.
Related
- Late-onset Acute Cellular Rejection after Lung Transplantation Triggered by a Fluctuation in the Tacrolimus Trough Level Which Was Successfully Treated with Steroid Pulse Therapy
- High tacrolimus intrapatient variability is associated with graft loss after kidney transplantation: a systematic review and meta-analysis
- Post Heart Transplantation Immunosuppression and Rejection: What the General Cardiologist Needs to Know
- Phenotyping Antibody-mediated Rejection Without Detectable Donor-specific Antibodies 8 d After Heart Transplantation: A Case Study
- Athlete-AI: a multi-modal artificial intelligence framework for personalized athlete monitoring and injury risk forecasting
BibTeX
@article{yan2026dynamic,
title = {{Dynamic kinetics of graft-derived cell-free DNA and personalized tacrolimus target ranges for acute rejection monitoring in pediatric liver transplantation}},
author = {Meiling Yan and Jia Zhao and Wei Gao and Yinpeng Qin and Jun Lu and Yi Zhang},
journal = {Frontiers in pharmacology},
year = {2026},
month = sep,
doi = {10.3389/fphar.2026.1939581},
url = {https://europepmc.org/article/PMC/PMC13662168},
note = {CC BY},
}
RIS
TY - JOUR
TI - Dynamic kinetics of graft-derived cell-free DNA and personalized tacrolimus target ranges for acute rejection monitoring in pediatric liver transplantation
AU - Meiling Yan
AU - Jia Zhao
AU - Wei Gao
AU - Yinpeng Qin
AU - Jun Lu
AU - Yi Zhang
PY - 2026
DA - 2026/09/30
JO - Frontiers in pharmacology
DO - 10.3389/fphar.2026.1939581
UR - https://europepmc.org/article/PMC/PMC13662168
AB - Introduction: Acute rejection remains the most common complication during the early post-transplantation period for pediatric patients. Given the limitations of current diagnostic strategies, there is an urgent need to develop accurate and noninvasive biomarkers for allograft monitoring. Tacrolimus-based immunosuppression represents the cornerstone regimen following liver transplantation. However, for pediatric patients, current evidence remains insufficient to establish well-defined therapeutic target ranges for personalized tacrolimus therapy in pediatric patients. We investigated perioperative graft-derived cell-free DNA (GcfDNA) kinetics in pediatric recipients to establish the utility of GcfDNA for monitoring acute rejection and to explore the tacrolimus target concentration range in this population. Methods: Forty children (age ≤ 3 years) with biliary atresia who underwent liver transplantation were enrolled. All received a tacrolimus-based immunosuppressive regimen on postoperative day (POD) 1 and were followed for at least 1 month. GcfDNA levels were measured by droplet digital PCR. Results: GcfDNA (%) declined significantly during the first month. Median percentages on POD 1, 7, 14, 21, and 28 were 41.40%, 12.93%, 6.86%, 5.95%, and 3.23%, respectively. The acute rejection group maintained higher GcfDNA levels, with significant differences observed at POD 14, 21, and 28 ( P < 0.001). GcfDNA (%) was strongly correlated with rejection activity index score (r = 0.854, P < 0.001). In this exploratory single-center analysis, receiver operating characteristic (ROC) curve analysis identified an optimal GcfDNA cutoff of 10.21% for predicting acute rejection, with an area under the curve (AUC) of 0.757 (95% CI: 0.691–0.823, P < 0.001). The optimal tacrolimus trough concentration (C ₀ ) threshold was 7.75 ng/mL (AUC = 0.732, 95% CI: 0.655–0.810, P < 0.001). Conclusion: We suggest that GcfDNA may serve as a potential biomarker for acute rejection monitoring in pediatric liver transplantation, with an exploratory predictive cutoff value of 10.21% identified in this single-center cohort. Our findings also tentatively point to a minimal effective tacrolimus C ₀ of 7.75 ng/mL within the first month post-transplantation, alongside an upper safety limit of 10 ng/mL that is primarily grounded in published peer-reviewed literatures. These thresholds, however, were optimized against stable grafts rather than the full spectrum of graft injury and require multicenter validation before clinical adoption.
SN - 1663-9812
ER -