Jiménez M, Crespo MG, Carmena MDG, Bueno MG, López R, Ortiz C, Farrero M, Zegrí I, Díaz B, García E, Rangel D, Salterain N, Bravo IG, Segovia J. Donor-derived cell-free DNA as a new biomarker for cardiac allograft rejection: A prospective study (FreeDNA-CAR)
J Heart Lung Transplant . 2025
"Donor-derived cell-free DNA is a useful biomarker to rule out acute cellular rejection in the first post-HT year. Its combination with NTproBNP, an easily available biomarker, could further improve the performance, allowing a reduction of more than 50% of endomyocardial biopsies currently performed in these patients." - Dr. Jiménez-Blanco
Summary:
Background: There is a long-standing need for a noninvasive biomarker that allows monitoring of cardiac allograft rejection in heart transplant (HT) recipients, avoiding the need for periodic endomyocardial biopsies (EMB).
Methods: Multicenter, observational, prospective study, performed between 2019 and 2023. All patients underwent 7 per-protocol surveillance EMB during the first postheart transplantation year. Donor-derived cell-free DNA (dd-cfDNA) levels were determined before each EMB, using Next Generation Sequencing Technology. The primary end-point was the association between dd-cfDNA levels and the presence of acute cellular rejection (ACR) in EMB.
Results: The study analyzed 206 patients and found that dd-cfDNA levels were higher in those with ACR. A dd-cfDNA threshold of 0.10% had a 97% negative predictive value for ACR. Combining dd-cfDNA with NTproBNP improved diagnostic accuracy, with a combined ROC curve area of 0.681 compared to 0.603 for dd-cfDNA alone. Using cut-off points of 0.10% for dd-cfDNA and 1,000 UI/ml for NTproBNP increased the negative predictive value to 98.1%. Combination of these biomarkers is more effective than dd-cfDNA alone for diagnosing ACR.
Conclusions: dd-cfDNA may be a useful biomarker to rule out significant ACR in a low-risk population. However, a dd-cfDNA value above normal threshold does not correlate robustly with the presence of disease. The combination with NTproBNP, a readily available biomarker, increased the discrimination power of dd-cfDNA alone.
Clinical trial notation: Donor-derived Cell-Free DNA as a New Biomarker in Cardiac Acute Rejection, NCT04973943.
Why do you highlight this publication?
It represents one of the largest studies conducted in this field to date, involving collaboration from 12 cardiac transplant centers across Spain. This collaborative effort has led to a robust, multi-center dataset, significantly enhancing the generalizability and clinical relevance of the findings.
The study's results have the potential to revolutionize post-heart transplant monitoring. By demonstrating that a combined non-invasive surveillance approach can achieve a high negative predictive value (NPV), the research supports a shift from the traditional "invasive" strategy using endomyocardial biopsies (EMB) to a more patient-friendly, "non-invasive", biomarker-based strategy. Importantly, this approach would allow for the elimination of more than 50% of the EMBs currently performed on heart transplant recipients during the critical first year after transplantation, reducing patient burden and healthcare costs while maintaining clinical efficacy.
Publication commented by:
Dr. Marta Jiménez-Blanco Bravo
Cardiovascular Diseases research group, IRYCIS
Cardiology department, HURYC
