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

IF 6 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Journal of Heart and Lung Transplantation Pub Date : 2025-04-01 Epub Date: 2024-11-20 DOI:10.1016/j.healun.2024.11.009

Marta Jiménez-Blanco MD , Maria Generosa Crespo-Leiro MD, PhD , Maria Dolores García-Cosío Carmena MD, PhD , Manuel Gómez Bueno MD , Raquel López-Vilella MD , Carlos Ortiz-Bautista MD , Marta Farrero-Torres MD PhD , Isabel Zegrí-Reiriz MD, PhD , Beatriz Díaz-Molina MD PhD , Elena García-Romero MD , Diego Rangel-Sousa MD , Nahikari Salterain MD , Iris Garrido Bravo MD PhD , Javier Segovia-Cubero MD, PhD

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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.

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作为心脏异体移植排斥反应新生物标志物的供体源性细胞游离 DNA：一项前瞻性研究（FreeDNA-CAR）。

背景：长期以来，人们一直需要一种无创生物标记物来监测心脏异体移植排斥反应，从而避免定期进行心内膜活检（EMB）：长期以来，人们一直需要一种无创生物标志物来监测心脏异体移植排斥反应，从而避免定期进行心内膜活检（EMB）：多中心、观察性、前瞻性研究，在 2019 年至 2023 年期间进行（NCT04973943）。所有患者在HT术后第一年内均接受了7次按方案进行的监测性EMB检查。在每次 EMB 之前，使用新一代测序技术（Allonext™ 分析法，Eurofins Genome）测定捐献者来源的无细胞 DNA（dd-cfDNA）水平。主要终点是 dd-cfDNA 水平与 EMB 中出现急性细胞排斥反应（ACR）之间的关联：该研究包括来自12个中心的206名患者，共有1090对EMB/dd-cfDNA测定结果可供分析。有ACR的EMB（49例）的dd-cfDNA水平明显高于无ACR的EMB，中位数为0.189% (IQR 0.05-0.70) vs 0.095% (0.04-0.23)，P=0.013。dd-cfDNA阈值为0.10%时，ACR的阴性预测值为97%。NTproBNP 与 dd-cfDNA 之间也存在统计学意义上的显著关联，NTproBNP 每增加 500 单位，dd-cfDNA 就会增加 0.007%（95%CI 0.003-0.011），p 结论：Dd-cfDNA 可能是一种有用的生物标志物，可用于排除低风险人群中的重大 ACR。然而，高于正常阈值的 dd-cfDNA 值与疾病的存在并不密切相关。与 NTproBNP（一种现成的生物标记物）结合使用可提高 dd-cfDNA 单独使用时的鉴别力。

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来源期刊

Journal of Heart and Lung Transplantation 医学-呼吸系统

CiteScore

10.10

自引率

6.70%

发文量

1667

审稿时长

69 days

期刊介绍： The Journal of Heart and Lung Transplantation, the official publication of the International Society for Heart and Lung Transplantation, brings readers essential scholarly and timely information in the field of cardio-pulmonary transplantation, mechanical and biological support of the failing heart, advanced lung disease (including pulmonary vascular disease) and cell replacement therapy. Importantly, the journal also serves as a medium of communication of pre-clinical sciences in all these rapidly expanding areas.