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Absolute Quantification of Donor-Derived Cell-Free DNA Following Pediatric and Adult Heart Transplantation

Böhmer, Jens ; Wåhlander, Håkan ; Tran-Lundmark, Karin LU ; Odermarsky, Michal LU orcid ; Alpman, Maria Sjöborg ; Asp, Julia ; Nilsson, Staffan ; Karason, Kristjan ; Jan, Sunnegårdh and Ricksten, Anne , et al. (2025) In The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
Abstract

OBJECTIVE: Traditional rejection surveillance after heart transplantation (HTx) is based on endomyocardial biopsies (EMB), which are invasive, expensive and associated with complications. Monitoring using cell-free DNA (cfDNA) is promising, but most studies report only on the donor fraction (DF) as the percentage of donor derived-cfDNA (dd-cfDNA) relative to total-cfDNA. We evaluated the performance of absolute as well as relative levels of dd-cfDNA to detect rejection.

METHODS: HTx patients were prospectively enrolled in a multicenter study, and blood samples collected concurrently with EMB. Dd-cfDNA was quantified using droplet digital PCR (ddPCR). Rejection was defined by EMB-results and compared to non-rejection EMB. Patients... (More)

OBJECTIVE: Traditional rejection surveillance after heart transplantation (HTx) is based on endomyocardial biopsies (EMB), which are invasive, expensive and associated with complications. Monitoring using cell-free DNA (cfDNA) is promising, but most studies report only on the donor fraction (DF) as the percentage of donor derived-cfDNA (dd-cfDNA) relative to total-cfDNA. We evaluated the performance of absolute as well as relative levels of dd-cfDNA to detect rejection.

METHODS: HTx patients were prospectively enrolled in a multicenter study, and blood samples collected concurrently with EMB. Dd-cfDNA was quantified using droplet digital PCR (ddPCR). Rejection was defined by EMB-results and compared to non-rejection EMB. Patients with symptomatic rejection were studied as a subgroup and test performance was determined using ROC-analysis.

RESULTS: We included 94 patients (70 adults and 24 children) undergoing rejection surveillance during the first year after HTx, which resulted in 1007 EMB and blood samples. In 19 patients, there were 32 rejection episodes > 14 days past HTx, with 15 of them being symptomatic. In ROC analysis, dd-cfDNA and DF could discriminate quiescence from rejection with an AUC of 0.68 and 0.65, respectively. Dd-cDNA at a threshold of 25 copies/ml showed an AUC of 0.87 to detect symptomatic rejection, significantly better than DF (AUC of 0.75).

CONCLUSIONS: dd-cfDNA found good discrimination between cardiac recipients with and without rejection. Absolute quantification of dd-cfDNA with ddPCR is a fast and effective method to monitor graft health. Analyzing absolute dd-cfDNA levels helps identify other factors, besides rejection, that may influence cfDNA levels, potentially reducing the need for EMB.

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publishing date
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Contribution to journal
publication status
epub
subject
in
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
publisher
Elsevier
external identifiers
  • pmid:40345563
ISSN
1557-3117
DOI
10.1016/j.healun.2025.04.024
language
English
LU publication?
yes
additional info
Copyright © 2025. Published by Elsevier Inc.
id
0802acd7-8589-4a27-858e-b3b900a0d658
date added to LUP
2025-05-10 10:51:07
date last changed
2025-05-12 08:28:36
@article{0802acd7-8589-4a27-858e-b3b900a0d658,
  abstract     = {{<p>OBJECTIVE: Traditional rejection surveillance after heart transplantation (HTx) is based on endomyocardial biopsies (EMB), which are invasive, expensive and associated with complications. Monitoring using cell-free DNA (cfDNA) is promising, but most studies report only on the donor fraction (DF) as the percentage of donor derived-cfDNA (dd-cfDNA) relative to total-cfDNA. We evaluated the performance of absolute as well as relative levels of dd-cfDNA to detect rejection.</p><p>METHODS: HTx patients were prospectively enrolled in a multicenter study, and blood samples collected concurrently with EMB. Dd-cfDNA was quantified using droplet digital PCR (ddPCR). Rejection was defined by EMB-results and compared to non-rejection EMB. Patients with symptomatic rejection were studied as a subgroup and test performance was determined using ROC-analysis.</p><p>RESULTS: We included 94 patients (70 adults and 24 children) undergoing rejection surveillance during the first year after HTx, which resulted in 1007 EMB and blood samples. In 19 patients, there were 32 rejection episodes &gt; 14 days past HTx, with 15 of them being symptomatic. In ROC analysis, dd-cfDNA and DF could discriminate quiescence from rejection with an AUC of 0.68 and 0.65, respectively. Dd-cDNA at a threshold of 25 copies/ml showed an AUC of 0.87 to detect symptomatic rejection, significantly better than DF (AUC of 0.75).</p><p>CONCLUSIONS: dd-cfDNA found good discrimination between cardiac recipients with and without rejection. Absolute quantification of dd-cfDNA with ddPCR is a fast and effective method to monitor graft health. Analyzing absolute dd-cfDNA levels helps identify other factors, besides rejection, that may influence cfDNA levels, potentially reducing the need for EMB.</p>}},
  author       = {{Böhmer, Jens and Wåhlander, Håkan and Tran-Lundmark, Karin and Odermarsky, Michal and Alpman, Maria Sjöborg and Asp, Julia and Nilsson, Staffan and Karason, Kristjan and Jan, Sunnegårdh and Ricksten, Anne and Dellgren, Göran}},
  issn         = {{1557-3117}},
  language     = {{eng}},
  month        = {{05}},
  publisher    = {{Elsevier}},
  series       = {{The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation}},
  title        = {{Absolute Quantification of Donor-Derived Cell-Free DNA Following Pediatric and Adult Heart Transplantation}},
  url          = {{http://dx.doi.org/10.1016/j.healun.2025.04.024}},
  doi          = {{10.1016/j.healun.2025.04.024}},
  year         = {{2025}},
}