Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, 1830 East Monument Street, Baltimore, MD, United States; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, MD 20982, United States.
University of Maryland Medical Center, Baltimore, MD, United States.
EBioMedicine. 2019 Feb;40:541-553. doi: 10.1016/j.ebiom.2018.12.029. Epub 2019 Jan 26.
Allograft failure is common in lung-transplant recipients and leads to poor outcomes including early death. No reliable clinical tools exist to identify patients at high risk for allograft failure. This study tested the use of donor-derived cell-free DNA (%ddcfDNA) as a sensitive marker of early graft injury to predict impending allograft failure.
This multicenter, prospective cohort study enrolled 106 subjects who underwent lung transplantation and monitored them after transplantation for the development of allograft failure (defined as severe chronic lung allograft dysfunction [CLAD], retransplantation, and/or death from respiratory failure). Plasma samples were collected serially in the first three months following transplantation and assayed for %ddcfDNA by shotgun sequencing. We computed the average levels of ddcfDNA over three months for each patient (avddDNA) and determined its relationship to allograft failure using Cox-regression analysis.
avddDNA was highly variable among subjects: median values were 3·6%, 1·6% and 0·7% for the upper, middle, and low tertiles, respectively (range 0·1%-9·9%). Compared to subjects in the low and middle tertiles, those with avddDNA in the upper tertile had a 6·6-fold higher risk of developing allograft failure (95% confidence interval 1·6-19·9, p = 0·007), lower peak FEV1 values, and more frequent %ddcfDNA elevations that were not clinically detectable.
Lung transplant patients with early unresolving allograft injury measured via %ddcfDNA are at risk of subsequent allograft injury, which is often clinically silent, and progresses to allograft failure. FUND: National Institutes of Health.
肺移植受者的移植物失败很常见，导致预后不良，包括早期死亡。目前尚无可靠的临床工具来识别发生移植物失败的高风险患者。本研究检测了供体来源的无细胞游离 DNA（%ddcfDNA）作为早期移植物损伤的敏感标志物，以预测即将发生的移植物失败。
这项多中心前瞻性队列研究纳入了 106 名接受肺移植的患者，并在移植后对其进行监测，以观察移植物失败（定义为严重慢性肺移植物功能障碍[CLAD]、再次移植和/或呼吸衰竭导致的死亡）的发生。在移植后的头三个月内，连续采集血浆样本，并通过鸟枪法测序检测%ddcfDNA。我们计算了每位患者三个月内的平均 ddcfDNA 水平（avddDNA），并使用 Cox 回归分析来确定其与移植物失败的关系。
受试者之间的 avddDNA 差异很大：上、中、低三分位值分别为 3.6%、1.6%和 0.7%（范围 0.1%-9.9%）。与低和中三分位值的患者相比，avddDNA 处于上三分位值的患者发生移植物失败的风险增加了 6.6 倍（95%置信区间 1.6-19.9，p=0.007），其峰值 FEV1 值较低，且更频繁地出现临床上无法检测到的%ddcfDNA 升高。
通过%ddcfDNA 测量的肺移植患者早期未解决的移植物损伤与随后的移植物损伤相关，这种损伤通常是临床上无症状的，且进展为移植物失败。
美国国立卫生研究院。
