Gupta Gaurav, Moinuddin Irfan, Kamal Layla, King Anne L, Winstead Ryan, Demehin Moses, Kang Le, Kimball Pamela, Levy Marlon, Bhati Chandra, Massey H Davis, Kumar Dhiren, Halloran Philip F
Division of Nephrology, Virginia Commonwealth University, Richmond, VA.
Division of Transplant Surgery, Virginia Commonwealth University, Richmond, VA.
Transplantation. 2022 May 1;106(5):1061-1070. doi: 10.1097/TP.0000000000003838. Epub 2021 May 28.
Circulating donor-derived cell-free DNA (cfDNA), a minimally invasive diagnostic tool for kidney transplant rejection, was validated using traditional histology. The molecular microscope diagnostic system (MMDx) tissue gene expression platform may provide increased precision to traditional histology.
In this single-center prospective study of 208 biopsies (median = 5.8 mo) posttransplant, we report on the calibration of cfDNA with simultaneous biopsy assessments using MMDx and histology by area under the curve (AUC) analyses for optimal criterion, as well as for, previously published cfDNA cutoffs ≤ 0.21% to "rule-out" rejection and ≥1% to "rule-in" rejection.
There were significant discrepancies between histology and MMDx, with MMDx identifying more antibody-mediated rejection (65; 31%) than histology (43; 21%); the opposite was true for T cell-mediated rejection [TCMR; histology: 27 (13%) versus MMDx: 13 (6%)]. Most of the TCMR discrepancies were seen for histologic borderline/1A TCMR. AUC for cfDNA and prediction of rejection were slightly better with MMDx (AUC = 0.80; 95% CI: 0.74-0.86) versus histology (AUC = 0.75; 95% CI: 0.69-0.81). A cfDNA ≤ 0.21% had similar sensitivity (~91%) to "rule-out" rejection by histology and MMDx. Specificity was slightly higher with MMDx (92%) compared with histology (85%) to "rule-in" rejection using cfDNA criterion ≥1%. Strong positive quantitative correlations were observed between cfDNA scores and molecular acute kidney injury for both "rejection" and "nonrejection" biopsies.
Molecular diagnostics using tissue gene expression and blood-based donor-derived cell-free DNA may add precision to some cases of traditional histology. The positive correlation of cfDNA with molecular acute kidney injury suggests a dose-dependent association with tissue injury irrespective of rejection characteristics.
循环供体来源的游离DNA（cfDNA）是一种用于肾移植排斥反应的微创诊断工具，已通过传统组织学方法进行了验证。分子显微镜诊断系统（MMDx）组织基因表达平台可能会提高传统组织学的准确性。
在这项对208例移植后活检（中位数=5.8个月）的单中心前瞻性研究中，我们报告了通过曲线下面积（AUC）分析对cfDNA进行校准，并同时使用MMDx和组织学进行活检评估，以确定最佳标准，以及针对先前公布的cfDNA临界值≤0.21%以“排除”排斥反应和≥1%以“纳入”排斥反应的情况。
组织学和MMDx之间存在显著差异，MMDx识别出的抗体介导排斥反应（65例；31%）比组织学（43例；21%）更多；T细胞介导排斥反应[TCMR]则相反[组织学：27例（13%）对MMDx：13例（6%）]。大多数TCMR差异见于组织学临界/1A类TCMR。与组织学（AUC=0.75；95%CI：0.69-0.81）相比，MMDx检测cfDNA和预测排斥反应的AUC略好（AUC=0.80；95%CI：0.74-0.86）。cfDNA≤0.21%时，通过组织学和MMDx“排除”排斥反应的敏感性相似（约91%）。使用cfDNA标准≥1%“纳入”排斥反应时，MMDx的特异性（92%）略高于组织学（85%）。对于“排斥”和“非排斥”活检，cfDNA评分与分子急性肾损伤之间均观察到强正定量相关性。
使用组织基因表达和基于血液的供体来源游离DNA进行分子诊断可能会提高某些传统组织学病例的准确性。cfDNA与分子急性肾损伤的正相关性表明，无论排斥反应特征如何，其与组织损伤存在剂量依赖性关联。
