Valledor Andrea Fernandez, Moeller Cathrine M, Oren Daniel, Baranowska Julia, Rahman Salwa, Hertz Adi, Rahman Afsana, Hennecken Carolyn, Rubinstein Gal, Elad Boaz, Richter Ilan, Lotan Dor, Regan Matthew, LaBarre Brian, Yunis Adil, Fried Justin, DeFilippis Ersilia M, Colombo Paolo C, Yuzefpolskaya Melana, Raihkelkar Jayant, Latif Farhana, Clerkin Kevin D, Majure David T, Sayer Gabriel T, Uriel Nir
Division of Cardiology, Columbia University Irving Medical Center, New York, New York; Division of Cardiology, Weill Cornell Medical Center, New York, New York; University of Barcelona (UB), Barcelona, Spain.
Division of Cardiology, Columbia University Irving Medical Center, New York, New York.
J Heart Lung Transplant. 2025 Sep;44(9):1384-1393. doi: 10.1016/j.healun.2025.04.019. Epub 2025 May 13.
The introduction of donor-derived cell-free DNA (dd-cfDNA) and the Molecular Microscope Diagnostic System (MMDx) is changing how we diagnose rejection following heart transplantation (HT). This study aims to assess the accuracy of dd-cfDNA in detecting rejection as identified by MMDx and histology, with a focus on determining an optimal dd-cfDNA threshold to improve diagnostic performance.
Single-center prospective study of HT recipients undergoing for-cause biopsies with paired MMDx results and dd-cfDNA levels. We employed a receiver operator curve to evaluate the performance of dd-cfDNA levels to detect rejection assessed by both histology and MMDx. We also assessed the correlation between dd-cfDNA levels and MMDx rejection scores. A mixed-effects model was applied to account for repeated samples when appropriate.
247 for-cause biopsies were identified with a median of 21 months from HT and a median of 11 days between dd-cfDNA and biopsy. 56.7% of the samples had dd-cfDNA levels ≥0.20%. MMDx identified rejection in 27.1% of biopsies, compared to 7.7% identified by histology. Elevated dd-cfDNA levels were associated with a 4-fold increase in rejection rates by MMDx, mainly driven by a 5-fold increase in antibody-mediated rejection detection when compared to histology. Dd-cfDNA demonstrated superior performance in predicting rejection by MMDx (area under the curve [AUC] of 0.77; optimal cutoff dd-cfDNA value 0.30%). When incorporating a mixed-effects model, the predictive performance improved further (AUC of 0.89; optimal cutoff value 0.26%). In contrast, prediction based on histology resulted in a lower AUC of 0.64.
In a for-cause biopsy population, elevated dd-cfDNA levels were more predictive of rejection on MMDx than on histology, suggesting that molecular techniques may detect rejection at earlier stages than traditional histological methods. A dd-cfDNA cutoff of 0.26% provided the highest predictive accuracy for rejection by MMDx when applied within a mixed-effects model for repeated measures.
供体来源的游离DNA（dd-cfDNA）和分子显微镜诊断系统（MMDx）的引入正在改变我们诊断心脏移植（HT）后排斥反应的方式。本研究旨在评估dd-cfDNA在检测MMDx和组织学所确定的排斥反应方面的准确性，重点是确定最佳的dd-cfDNA阈值以提高诊断性能。
对接受因病因进行活检的HT受者进行单中心前瞻性研究，同时获取配对的MMDx结果和dd-cfDNA水平。我们采用受试者工作特征曲线来评估dd-cfDNA水平检测经组织学和MMDx评估的排斥反应的性能。我们还评估了dd-cfDNA水平与MMDx排斥反应评分之间的相关性。在适当情况下应用混合效应模型来处理重复样本。
共识别出247例因病因进行的活检，自HT后中位时间为21个月，dd-cfDNA检测与活检之间的中位间隔时间为11天。56.7%的样本dd-cfDNA水平≥0.20%。MMDx在27.1%的活检中识别出排斥反应，而组织学识别出的比例为7.7%。dd-cfDNA水平升高与MMDx检测的排斥反应率增加4倍相关，与组织学相比，主要是由抗体介导的排斥反应检测增加5倍所驱动。Dd-cfDNA在预测MMDx的排斥反应方面表现更优（曲线下面积[AUC]为0.77；最佳dd-cfDNA截断值为0.30%）。纳入混合效应模型后，预测性能进一步提高（AUC为0.89；最佳截断值为0.26%）。相比之下，基于组织学的预测AUC较低，为0.64。
在因病因进行活检的人群中，dd-cfDNA水平升高对MMDx排斥反应的预测性高于对组织学的预测性，这表明分子技术可能比传统组织学方法更早地检测到排斥反应。当在重复测量的混合效应模型中应用时，dd-cfDNA截断值为0.26%对MMDx排斥反应的预测准确性最高。
