The Trifecta Study: Comparing Plasma Levels of Donor-derived Cell-Free DNA with the Molecular Phenotype of Kidney Transplant Biopsies,Journal of the American Society of Nephrology

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The Trifecta Study: Comparing Plasma Levels of Donor-derived Cell-Free DNA with the Molecular Phenotype of Kidney Transplant Biopsies
Journal of the American Society of Nephrology ( IF 13.6 ) Pub Date : 2022-02-01 , DOI: 10.1681/asn.2021091191
Philip F Halloran _{1,

2,

3} , Jeff Reeve ₁ , Katelynn S Madill-Thomsen _{1,

3} , Zachary Demko ₄ , Adam Prewett ₄ , Paul Billings ₄ ,

Affiliation

Background

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.

Methods

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.

Results

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-–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.

Conclusions

The dd-cfDNA(%) at time of indication biopsy strongly correlates with active molecular rejection and has the potential to reduce unnecessary biopsies.

Clinical Trial registration number:

NCT04239703

中文翻译：

Trifecta 研究：将供体来源的无细胞 DNA 的血浆水平与肾移植活检的分子表型进行比较

背景

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。

方法

在这项前瞻性、多中心的 Trifecta 研究中，我们从 289 名肾移植受者的 300 份活检样本中收集了组织，以比较活检样本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(%)。使用基于微阵列的分子显微镜诊断系统使用自动分配的排斥原型和分子报告注销以及遵循班夫指南的组织学评估来评估排斥。

结果

移植后活检的中位时间为 455 天（5 天至 32 年），病例组合与之前的研究相似：180 例 (60%) 无排斥反应，89 例 (30%) 抗体介导的排斥反应 (ABMR) , 和 31 (10%) T 细胞介导的排斥反应 (TCMR) 和混合。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 和所有类型的排斥反应相关，无论是自然杀伤 (NK) 细胞表达的（例如，GNLY、CCL4、TRDC和S1PR5）或 IFN-诱导型（例如PLA1A 、IDO1、CXCL11和WARS). 在基因集和分类器分数中，dd-cfDNA (%) 与 ABMR 和所有类型的排斥反应非常强相关，与活动 TCMR 相当强，与非活动 TCMR、肾损伤和萎缩纤维化弱相关。活性 ABMR、混合和活性 TCMR 的 dd-cfDNA(%) 最高，而 dd-cfDNA(%) 在晚期 ABMR 和活性较低的 TCMR 中较低。通过多元随机森林和逻辑回归，分子排斥变量比组织学变量更能预测 dd-cfDNA(%)。