Donor-derived cell-free DNA first validated for noninvasive monitoring of acute rejection in an asian heart transplant population
S Zheng, Z Zhu, S LiuAbstract
Background
Endomyocardial biopsy (EMB) remains the gold standard for diagnosing acute rejection (AR) after heart transplantation but is invasive and carries procedural risks. Donor-derived cell-free DNA (dd-cfDNA) has emerged as a promising noninvasive biomarker for rejection surveillance; however, validated thresholds for Asian—particularly Chinese—heart transplant recipients are lacking.
Methods
This prospective single-center study enrolled 79 heart transplant recipients and analyzed 299 plasma dd-cfDNA samples using a newly developed Chinese next-generation sequencing assay targeting 48 Indel sites. A reference cohort (n = 42) was used to characterize post-transplant dd-cfDNA kinetics. A biopsy cohort (n = 41), consisting of acute cellular rejection (ACR, n = 18), antibody-mediated rejection (AMR, n = 9), and no rejection (NR, n = 14), was paired with EMB findings to evaluate diagnostic performance.
Results
In the reference cohort, dd-cfDNA peaked at 0.28% during week 1 and stabilized at 0.22% by week 4 after transplantation. In the biopsy cohort, patients with AR exhibited significantly higher dd-cfDNA levels (0.87%) compared with NR patients (0.23%, P < 0.001). The optimal threshold for detecting composite AR was 0.33%, yielding an AUC of 0.874, sensitivity 81.0%, and specificity 85.7%. Subgroup thresholds were 0.33% for ACR (AUC 0.832) and 0.69% for AMR (AUC 0.875). dd-cfDNA levels decreased significantly after anti-rejection therapy (P = 0.011) and showed an inverse correlation with left ventricular ejection fraction (r = −0.24, P < 0.001).
Conclusions
This study establishes 0.33% as the first Chinese-specific dd-cfDNA threshold for detecting acute rejection after heart transplantation. The findings support dd-cfDNA as a reliable noninvasive biomarker for rejection monitoring and highlight its potential value in optimizing post-transplant surveillance strategies in Asian recipients.For image description, please refer to the figure legend and surrounding text.