Donor-derived cell-free DNA as a new biomarker for cardiac allograft rejection: A prospective study (FreeDNA-CAR)
Por:
Jiménez-Blanco, M, Crespo-Leiro, MG, Carmena, MDGC, Bueno, MG, López-Vilella, R, Ortiz-Bautista, C, Farrero-Torres, M, Zegrí-Reiriz, I, Díaz-Molina, B, García-Romero, E, Rangel-Sousa, D, Salterain, N, Bravo, IG, Segovia-Cubero, J
Publicada:
1 abr 2025
Ahead of Print:
1 mar 2025
Resumen:
BACKGROUND: There is a long-standing need for a noninvasive biomarker that allows monitoring of cardiac allograft rejection, avoiding the need for periodic endomyocardial biopsies (EMB). METHODS: Multicenter, observational, prospective study, performed between 2019 and 2023 (NCT 04973943). 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 (Allonext assay, Eurofins Genome). The primary end-point was the association between dd-cfDNA levels and the presence of acute cellular rejection (ACR) in EMB. RESULTS: The study included 206 patients from 12 centers, with 1,090 pairs of EMB/dd-cfDNA determinations available for analysis. EMB with ACR (n = 49) were associated with dd-cfDNA levels significantly higher than those without, median 0.189% (interquartilic range 0.05-0.70) vs 0.095% (0.04-0.23), p = 0.013. A dd-cfDNA threshold of 0.10% showed a negative predictive value for ACR of 97%. A statistically significant association between N-terminal prohormone of brain (NTProBNP) and dd-cfDNA was also found, with an increase of 0.007% dd-cfDNA (95% confidence interval 0.003-0.011) for every 500 units of NTproBNP, p 0.001. The combination of both biomarkers for diagnosis of ACR showed an area under the receiver operating characteristic (ROC) curve of 0.681, and this combined approach was significantly better than dd-cfDNA alone (area under the ROC curve 0.603), p = 0.016. Using a cut-off point of 0.10% for dd-cfDNA and 1,000 UI/ml for NTproBNP, negative predictive value increased to 98.1%. 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, NCT 04973943. J Heart Lung Transplant 2025;44:560-569 (c) 2024 The Authors. Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Filiaciones:
Jiménez-Blanco, M:
Hosp Univ Puerta Hierro Majadahonda, Madrid, Spain
Hosp Univ Ramon y Cajal, Madrid, Spain
Ctr Invest Cardiovasc Red CIBER CV, Madrid, Spain
Crespo-Leiro, MG:
Ctr Invest Cardiovasc Red CIBER CV, Madrid, Spain
Univ A Coruna UDC, Complexo Hosp Univ A Coruna CHUAC, Inst Invest Biomed A Coruna INIBIC, La Coruna, Spain
Carmena, MDGC:
Ctr Invest Cardiovasc Red CIBER CV, Madrid, Spain
Hosp Univ 12 Octubre, Inst Invest Sanitaria Hosp Octubre 12 imas12, Serv Cardiol, Madrid, Spain
Bueno, MG:
Hosp Univ Puerta Hierro Majadahonda, Madrid, Spain
López-Vilella, R:
Hosp Univ La Fe, Valencia, Spain
Ortiz-Bautista, C:
Hosp Univ Gregorio Maranon, Madrid, Spain
Farrero-Torres, M:
Hosp Clin Barcelona, Barcelona, Spain
Zegrí-Reiriz, I:
Hosp Santa Creu & Sant Pau, Unidad Insuficiencia Cardiaca & Trasplante, Barcelona, Spain
Díaz-Molina, B:
Hosp Univ Cent Asturias, Asturias, Spain
García-Romero, E:
Ctr Invest Cardiovasc Red CIBER CV, Madrid, Spain
Hosp Univ Bellvitge, Inst Invest Biomed Bellvitge IDIBELL, Cardiovasc Resp & Syst Dis & Cellular Aging Progra, Cardiol Dept,Bioheart Grp, Lhospitalet De Llobregat, Spain
Univ Barcelona UB, Sch Med, Dept Clin Sci, Lhospitalet De Llobregat, Spain
Rangel-Sousa, D:
Hosp Univ Virgen Rocio, Seville, Spain
Salterain, N:
Clin Univ Navarra, Navarra, Spain
Bravo, IG:
Hosp Virgen Arrixaca, Murcia, Spain
Segovia-Cubero, J:
Hosp Univ Puerta Hierro Majadahonda, Madrid, Spain
Ctr Invest Cardiovasc Red CIBER CV, Madrid, Spain
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