Abstract：
The relationship between the donor-derived cell-free DNA fraction (dd-cfDNA[%]) in plasma in kidney transplant recipients at time of indication biopsy and gene expression in the biopsied allograft has not been defined.
In the prospective, multicenter Trifecta study, we collected tissue from 300 biopsies from 289 kidney transplant recipients to compare genome-wide gene expression in biopsies with dd-cfDNA(%) in corresponding plasma samples drawn just before biopsy. Rejection was assessed with the microarray-based Molecular Microscope Diagnostic System using automatically assigned rejection archetypes and molecular report sign-outs, and histology assessments that followed Banff guidelines.
The median time of biopsy post-transplantation was 455 days (5 days to 32 years), with a case mix similar to that of previous studies: 180 (60%) no rejection, 89 (30%) antibody-mediated rejection (ABMR), and 31 (10%) T cell-mediated rejection (TCMR) and mixed. In genome-wide mRNA measurements, all 20 top probe sets correlating with dd-cfDNA(%) were previously annotated for association with ABMR and all types of rejection, either natural killer (NK) cell-expressed (e.g., GNLY, CCL4, TRDC, and S1PR5) or IFN-γ-inducible (e.g., PLA1A, IDO1, CXCL11, and WARS). Among gene set and classifier scores, dd-cfDNA(%) correlated very strongly with ABMR and all types of rejection, reasonably strongly with active TCMR, and weakly with inactive TCMR, kidney injury, and atrophy fibrosis. Active ABMR, mixed, and active TCMR had the highest dd-cfDNA(%), whereas dd-cfDNA(%) was lower in late-stage ABMR and less-active TCMR. By multivariate random forests and logistic regression, molecular rejection variables predicted dd-cfDNA(%) better than histologic variables.
The dd-cfDNA(%) at time of indication biopsy strongly correlates with active molecular rejection and has the potential to reduce unnecessary biopsies.
NCT04239703.
In the prospective, multicenter Trifecta study, we collected tissue from 300 biopsies from 289 kidney transplant recipients to compare genome-wide gene expression in biopsies with dd-cfDNA(%) in corresponding plasma samples drawn just before biopsy. Rejection was assessed with the microarray-based Molecular Microscope Diagnostic System using automatically assigned rejection archetypes and molecular report sign-outs, and histology assessments that followed Banff guidelines.
The median time of biopsy post-transplantation was 455 days (5 days to 32 years), with a case mix similar to that of previous studies: 180 (60%) no rejection, 89 (30%) antibody-mediated rejection (ABMR), and 31 (10%) T cell-mediated rejection (TCMR) and mixed. In genome-wide mRNA measurements, all 20 top probe sets correlating with dd-cfDNA(%) were previously annotated for association with ABMR and all types of rejection, either natural killer (NK) cell-expressed (e.g., GNLY, CCL4, TRDC, and S1PR5) or IFN-γ-inducible (e.g., PLA1A, IDO1, CXCL11, and WARS). Among gene set and classifier scores, dd-cfDNA(%) correlated very strongly with ABMR and all types of rejection, reasonably strongly with active TCMR, and weakly with inactive TCMR, kidney injury, and atrophy fibrosis. Active ABMR, mixed, and active TCMR had the highest dd-cfDNA(%), whereas dd-cfDNA(%) was lower in late-stage ABMR and less-active TCMR. By multivariate random forests and logistic regression, molecular rejection variables predicted dd-cfDNA(%) better than histologic variables.
The dd-cfDNA(%) at time of indication biopsy strongly correlates with active molecular rejection and has the potential to reduce unnecessary biopsies.
NCT04239703.
摘要：
在适应症活检时，肾移植受者血浆中供体来源的无细胞DNA分数（dd-cfDNA[％]）与活检同种异体移植物中基因表达之间的关系尚未确定。
在未来，多中心Trifecta研究，我们从289例肾移植受者的300例活检组织中收集组织,以比较活检组织中的全基因组基因表达与活检前抽取的相应血浆样本中的dd-cfDNA(%).使用自动分配的排斥原型和分子报告签出，使用基于微阵列的分子显微镜诊断系统评估排斥反应。以及遵循班夫指南的组织学评估。
移植后活检的中位时间为455天（5天至32年），与以前的研究相似的病例组合：180(60%)没有拒绝，89（30%）抗体介导的排斥反应（ABMR），和31（10％）T细胞介导的排斥（TCMR）并混合。在全基因组mRNA测量中，与dd-cfDNA（％）相关的所有20个顶级探针组先前都被注释为与ABMR和所有类型的排斥相关，自然杀伤（NK）细胞表达（例如，GNLY,CCL4,TRDC,和S1PR5)或IFN-γ诱导型(例如，PLA1A,IDO1、CXCL11和WARS)。在基因集和分类器评分中，dd-cfDNA（％）与ABMR和所有类型的排斥反应密切相关，与主动TCMR相当强烈，而不活跃的TCMR较弱，肾损伤,和萎缩纤维化。活动ABMR,混合,活性TCMR具有最高的dd-cfDNA(%)，而dd-cfDNA(%)在晚期ABMR和低活性TCMR中更低。通过多元随机森林和逻辑回归，分子排斥变量预测dd-cfDNA(%)优于组织学变量。
指示活检时的dd-cfDNA（％）与活性分子排斥密切相关，并有可能减少不必要的活检。
NCT04239703。
在未来，
移植后活检的中位时间为455天（5天至32年），
指示活检时的dd-cfDNA（％）与活性分子排斥密切相关，并有可能减少不必要的活检。
NCT04239703。
