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Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation.
The Journal of Heart and Lung Transplantation ( IF 8.9 ) Pub Date : 2019-11-29 , DOI: 10.1016/j.healun.2019.11.015
Marc E Richmond 1 , Steven D Zangwill 2 , Steven J Kindel 3 , Shriprasad R Deshpande 4 , Jacob N Schroder 5 , David P Bichell 6 , Kenneth R Knecht 7 , William T Mahle 8 , Mark A Wigger 9 , Nunzio A Gaglianello 10 , Elfriede Pahl 11 , Pippa M Simpson 12 , Mahua Dasgupta 13 , Paula E North 14 , Mats Hidestrand 13 , Aoy Tomita-Mitchell 15 , Michael E Mitchell 15
Affiliation  

BACKGROUND Endomyocardial biopsy (EMB) is the current standard for rejection surveillance in heart transplant recipients. The quantification of donor-specific cell-free DNA (cfDNA) may be an appropriate biomarker for non-invasive rejection surveillance. A multicenter prospective blinded study (DNA-Based Transplant Rejection Test, DTRT) investigated the value of donor fraction (DF), defined as the ratio of cfDNA specific to the transplanted organ to the total amount of cfDNA present in a blood sample. METHODS A total of 241 heart transplant patients were recruited from 7 centers. Age at transplant ranged from 8 days to 73 years, with 146 subjects <18 years and 95 ≥18 years. All the patients were followed for at least 1 year, with blood samples drawn at routine and for-cause biopsies. A total of 624 biopsy-paired samples were included for analysis through a commercially available cfDNA assay (myTAIHEART, TAI Diagnostics Inc.). A blinded analysis of repeated measures compared the outcomes using receiver operating characteristic (ROC) curves. All primary clinical end-points were monitored at 100%. All analysis and conclusions were reviewed by both an independent external oversight committee and the National Institutes of Health-mandated DTRT steering committee. RESULTS DF in acute cellular rejection (ACR) 1R/2R (n = 15) was higher than ACR 0R (n = 42) (p = 0.02); DF in antibody-mediated rejection pAMR1 (n = 8) and pAMR2 (n = 12) (p = 0.05) were higher than pAMR0 (n = 466) (p = 0.04 and p = 0.05 respectively). An optimal DF threshold was determined by the use of an ROC analysis, which ruled out the presence of either ACR or antibody-mediated rejection. CONCLUSIONS The cell-free DNA DF holds promise as a non-invasive diagnostic test to rule out acute rejection in both adult and pediatric heart transplant populations.

中文翻译:

供体部分无细胞 DNA 和成人和儿童心脏移植中的排斥反应。

背景心内膜心肌活检(EMB)是心脏移植受者排斥反应监测的当前标准。供体特异性无细胞 DNA (cfDNA) 的量化可能是用于无创排斥监测的合适生物标志物。一项多中心前瞻性盲研究(基于 DNA 的移植排斥试验,DTRT)研究了供体分数 (DF) 的值,DF 定义为移植器官特异性 cfDNA 与血液样本中存在的 cfDNA 总量的比率。方法从7个中心共招募241名心脏移植患者。移植年龄从 8 天到 73 岁不等,146 名受试者 <18 岁,95 名 ≥18 岁。对所有患者进行至少 1 年的随访,在常规和有因活检中抽取血样。总共包括 624 个活检配对样本,用于通过市售 cfDNA 检测(myTAIHEART,TAI Diagnostics Inc.)进行分析。重复测量的盲法分析使用受试者工作特征 (ROC) 曲线比较了结果。所有主要临床终点均以 100% 进行监测。所有分析和结论均由独立的外部监督委员会和美国国立卫生研究院授权的 DTRT 指导委员会审查。结果 急性细胞排斥反应 (ACR) 1R/2R (n = 15) 中的 DF 高于 ACR 0R (n = 42) (p = 0.02);抗体介导的排斥 pAMR1 (n = 8) 和 pAMR2 (n = 12) (p = 0.05) 中的 DF 高于 pAMR0 (n = 466)(分别为 p = 0.04 和 p = 0.05)。通过使用 ROC 分析确定最佳 DF 阈值,这排除了 ACR 或抗体介导的排斥的存在。结论 无细胞 DNA DF 有望作为一种非侵入性诊断测试来排除成人和儿童心脏移植人群的急性排斥反应。
更新日期:2019-11-29
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