Cell-Free DNA to Detect Heart Allograft Acute Rejection.
Cell-Free DNA to Detect Heart Allograft Acute Rejection.
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游离DNA检测心脏移植急性排斥反应
DOI：
10.1161/circulationaha.120.049098
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发表时间：
2021-03-23
期刊：
影响因子：
37.8
通讯作者：
GRAfT Investigators
中科院分区：
文献类型：
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作者：
Agbor-Enoh S;Shah P;Tunc I;Hsu S;Russell S;Feller E;Shah K;Rodrigo ME;Najjar SS;Kong H;Pirooznia M;Fideli U;Bikineyeva A;Marishta A;Bhatti K;Yang Y;Mutebi C;Yu K;Kyoo Jang M;Marboe C;Berry GJ;Valantine HA;GRAfT Investigators
心脏移植术后，肌内膜活检（EMBx）用于监测急性排斥反应（AR）。不幸的是，EMBx是侵入性的，其传统的组织学解释有局限性。这是一项验证研究，旨在评估敏感的血液生物标志物-供体来源的细胞游离DNA百分比（%ddcfDNA）-用于检测心脏移植受者中的AR的性能。这项多中心、前瞻性队列研究招募了心脏移植受试者，并与EMBx同时采集血浆样本，通过鸟枪测序法测定%ddcfDNA。收集组织学数据以定义AR、其两种表型（急性细胞排斥，ACR和抗体介导的排斥，AMR）和无排斥的对照。主要分析是将AR、AMR和ACR的%ddcfDNA水平（中位数和四分位距- IQR）与对照进行比较，并使用接受者-操作者特征分析确定%ddcfDNA检测特征。该研究包括171名受试者，移植后中位随访时间为17.7个月（IQR：12.1-23.6），有1，392个EMBx和1，834个ddcfDNA测量值可用于分析。术后28天，中位%ddcfDNA水平下降至0.13%（0.03-0.21）。与对照值相比，AR再次增加%ddcfDNA（0.38，IQR=0.31-0.83，对比0.03，IQR=0.01-0.14 p<0.001）。在ACR和AMR的组织病理学诊断前0.5和3.2个月检测到升高。AR的受试者操作者特征曲线下面积（AUROC）为0.92。0.25%ddcfDNA阈值具有99%的AR阴性预测值（NPV），并且将安全地消除81%的EMBx。与AMR相比，%ddcfDNA显示出独特的特征，包括高5倍的水平（pAMR ≥2 1.68，IQR=0.49-2.79 vs. ACR等级≥ 2 R 0.34，IQR=0.28-0.72）、更高的AUROC（0.95 vs. 0.85）、更高的鸟苷-胞嘧啶含量和更高的短ddcfDNA片段百分比。%ddcfDNA检测到AR，具有高AUROC和NPV。使用ddcfDNA进行监测，证明了ACR和AMR的优异性能特征，并导致比基于EMBx的监测更早的检测。这项研究支持使用%ddcfDNA监测心脏移植患者的AR，并为临床实用性研究铺平了道路。http://clinicaltrials.gov/ct2/show/NCT02423070 #02423070）
After heart transplantation, Endomyocardial biopsy (EMBx) is used to monitor for acute rejection (AR). Unfortunately, EMBx is invasive and its conventional histologic interpretation has limitations. This is a validation study to assesses the performance of a sensitive blood biomarker— percent donor-derived cell-free DNA (%ddcfDNA) — for detection of AR in cardiac transplant recipients. This multicenter, prospective cohort study recruited heart transplant subjects and collected plasma samples contemporaneously with EMBx for %ddcfDNA measurement by shotgun sequencing. Histopathology data was collected to define AR, its two phenotypes (acute cellular rejection, ACR, and antibody-mediated rejection, AMR) and controls without rejection. The primary analysis was to compare %ddcfDNA levels (median and interquartile range – IQR) for AR, AMR and ACR to controls and to determine %ddcfDNA test characteristics using receiver-operator characteristics analysis. The study included 171 subjects with median post-transplant follow-up of 17.7 months (IQR: 12.1-23.6), with 1,392 EMBx, and 1,834 ddcfDNA measures available for analysis. Median %ddcfDNA levels decayed after surgery to 0.13% (0.03-0.21) by 28 days. %ddcfDNA increased again with AR compared to controls values (0.38, IQR=0.31-0.83, vs. 0.03, IQR=0.01-0.14 p<0.001). The rise was detected 0.5 and 3.2 months before histopathological diagnosis of ACR and AMR. The area-under-the- receiver-operator characteristics curve (AUROC) for AR was 0.92. A 0.25 %ddcfDNA threshold had a negative predictive value (NPV) for AR of 99% and would have safely eliminated 81% of EMBx. %ddcfDNA showed distinctive characteristics comparing AMR to ACR, included 5-fold higher levels (pAMR ≥2 1.68, IQR=0.49-2.79 vs. ACR grade ≥2R 0.34, IQR=0.28-0.72), higher AUROC (0.95 vs. 0.85), higher guanosine-cytosine content, and higher percentage of short ddcfDNA fragments. %ddcfDNA detected AR with a high AUROC and NPV. Monitoring with ddcfDNA, demonstrated excellent performance characteristics for both ACR and AMR and led to earlier detection than the EMBx-based monitoring. This study supports the use of %ddcfDNA to monitor for AR in heart transplant patients and paves the way for a clinical utility study. http://clinicaltrials.gov/ct2/show/NCT02423070 (NCT#02423070)