Donor-derived cell-free DNA as a new biomarker for cardiac allograft rejection: A prospective study (FreeDNA-CAR)

Fecha de publicación: 01/01/2025

Autores de IIS La Fe

Raquel López Vilella

Autor

Participantes ajenos a IIS La Fe

Jiménez-Blanco M.
Crespo-Leiro M.G.
García-Cosío Carmena M.D.
Gómez Bueno M.
Ortiz-Bautista C.
Farrero-Torres M.
Zegrí-Reiriz I.
Díaz-Molina B.
García-Romero E.
Rangel-Sousa D.
Salterain N.
Garrido Bravo I.
Segovia-Cubero J.

Grupos

Grupo de Investigación Clínica y Traslacional en Cardiología

Abstract

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. © 2024 The Authors

Datos de la publicación

ISSN/ISSNe:: 1053-2498, 1557-3117
Tipo:: Article
Páginas:: 560-569
DOI:: 10.1016/j.healun.2024.11.009
PubMed:: 39577511
Enlace a otro recurso:: www.scopus.com
Factor de Impacto:: 2,472 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Filiaciones

Jiménez-Blanco M.:: Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

Hospital Universitario Ramón y Cajal, Madrid, Spain

Centro de Investigación Cardiovascular en Red CIBER-CV, Madrid, Spain
Crespo-Leiro M.G.:: Centro de Investigación Cardiovascular en Red CIBER-CV, Madrid, Spain

Complexo Hospitalario Universitario A Coruña (CHUAC), Instituto de Investigación Biomédica A Coruña (INIBIC), Universidad de A Coruña (UDC), A Coruña, Spain
García-Cosío Carmena M.D.:: Centro de Investigación Cardiovascular en Red CIBER-CV, Madrid, Spain

Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
Gómez Bueno M.:: Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
López-Vilella R.:: Hospital Universitario la Fe, Valencia, Spain
Ortiz-Bautista C.:: Hospital Universitario Gregorio Marañón, Madrid, Spain
Farrero-Torres M.:: Hospital Clinic de Barcelona, Barcelona, Spain
Zegrí-Reiriz I.:: Unidad de Insuficiencia cardiaca y Trasplante, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Díaz-Molina B.:: Hospital Universitario Central de Asturias, Asturias, Spain
García-Romero E.:: Centro de Investigación Cardiovascular en Red CIBER-CV, Madrid, Spain

Cardiology Department, Hospital Universitari de Bellvitge, Bioheart Group, Cardiovascular, Respiratory and Systemic Diseases and Cellular Aging Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain

Department of Clinical Sciences, School of Medicine, Universitat de Barcelona (UB), L'Hospitalet de Llobregat, Spain
Rangel-Sousa D.:: Hospital Universitario Virgen del Rocío, Sevilla, Spain
Salterain N.:: Clínica Universitaria de Navarra, Navarra, Spain
Garrido Bravo I.:: Hospital Virgen de la Arrixaca, Murcia, Spain
Segovia-Cubero J.:: Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

Centro de Investigación Cardiovascular en Red CIBER-CV, Madrid, Spain

Keywords

Adult; Allografts; Biomarkers; Biopsy; Cell-Free Nucleic Acids; Female; Graft Rejection; Heart Transplantation; Humans; Male; Middle Aged; Myocardium; Prospective Studies; Tissue Donors; biological marker; circulating free DNA; Donor-derived cell-free DNA; genomic DNA; hormone precursor; unclassified drug; cell free nucleic acid; acute graft rejection; adult; amino terminal sequence; antibody mediated rejection; Article; cardiac graft rejection; cardiologist; controlled study; coronavirus disease 2019; demographics; diagnostic test accuracy study; echocardiography; follow up; heart muscle biopsy; heart transplantation; high throughput sequencing; human; human tissue; hypertrophic cardiomyopathy; hypothesis; ischemic cardiomyopathy; kidney transplantation; major clinical study; male; middle aged; multicenter study; observational study; primary graft dysfunction; prospective study; receiver operating characteristic; sensitivity and specificity; single nucleotide polymorphism; allograft;

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