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

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 patie...

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Autores: 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p19491
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=19491
Access Level:acceso abierto
Palabra clave:acute cardiac rejection
heart transplantation
biomarkers
NTproBNP
donor-derived cell-free DNA
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spelling Donor-derived cell-free DNA as a new biomarker for cardiac allograft rejection: A prospective study (FreeDNA-CAR)Jiménez-Blanco, MCrespo-Leiro, MGCarmena, MDGCBueno, MGLópez-Vilella, ROrtiz-Bautista, CFarrero-Torres, MZegrí-Reiriz, IDíaz-Molina, BGarcía-Romero, ERangel-Sousa, DSalterain, NBravo, IGSegovia-Cubero, Jacute cardiac rejectionheart transplantationbiomarkersNTproBNPdonor-derived cell-free DNABACKGROUND: 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/).ELSEVIER SCIENCE INC2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=19491JOURNAL OF HEART AND LUNG TRANSPLANTATIONISSN: 10532498ISSNe: 15573117reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p194912026-06-14T12:41:47Z
dc.title.none.fl_str_mv Donor-derived cell-free DNA as a new biomarker for cardiac allograft rejection: A prospective study (FreeDNA-CAR)
title Donor-derived cell-free DNA as a new biomarker for cardiac allograft rejection: A prospective study (FreeDNA-CAR)
spellingShingle Donor-derived cell-free DNA as a new biomarker for cardiac allograft rejection: A prospective study (FreeDNA-CAR)
Jiménez-Blanco, M
acute cardiac rejection
heart transplantation
biomarkers
NTproBNP
donor-derived cell-free DNA
title_short Donor-derived cell-free DNA as a new biomarker for cardiac allograft rejection: A prospective study (FreeDNA-CAR)
title_full Donor-derived cell-free DNA as a new biomarker for cardiac allograft rejection: A prospective study (FreeDNA-CAR)
title_fullStr Donor-derived cell-free DNA as a new biomarker for cardiac allograft rejection: A prospective study (FreeDNA-CAR)
title_full_unstemmed Donor-derived cell-free DNA as a new biomarker for cardiac allograft rejection: A prospective study (FreeDNA-CAR)
title_sort Donor-derived cell-free DNA as a new biomarker for cardiac allograft rejection: A prospective study (FreeDNA-CAR)
dc.creator.none.fl_str_mv 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
author Jiménez-Blanco, M
author_facet 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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv acute cardiac rejection
heart transplantation
biomarkers
NTproBNP
donor-derived cell-free DNA
topic acute cardiac rejection
heart transplantation
biomarkers
NTproBNP
donor-derived cell-free DNA
description 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/).
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=19491
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=19491
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv ELSEVIER SCIENCE INC
publisher.none.fl_str_mv ELSEVIER SCIENCE INC
dc.source.none.fl_str_mv JOURNAL OF HEART AND LUNG TRANSPLANTATION
ISSN: 10532498
ISSNe: 15573117
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
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