肾移植活检中献血者来源的游离DNA水平与班夫评分和组织病理学病变的关联：一项观察性研究的结果
Association of Blood Donor-derived Cell-free DNA Levels With Banff Scores and Histopathological Lesions in Kidney Allograft Biopsies: Results From an Observational Study.
作者信息
Akifova Aylin, Budde Klemens, Choi Mira, Amann Kerstin, Buettner-Herold Maike, Oellerich Michael, Beck Julia, Bornemann-Kolatzki Kirsten, Schütz Ekkehard, Bachmann Friederike, Halleck Fabian, Schrezenmeier Eva V, Seelow Evelyn, Zukunft Bianca, Hammett Charlotte, Pohl Nathan A, Mordà Benedetta, Kowald Jan, Lachmann Nils, Stauch Diana, Osmanodja Bilgin
机构信息
Department of Nephrology and Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
出版信息
Transplant Direct. 2025 Apr 10;11(5):e1794. doi: 10.1097/TXD.0000000000001794. eCollection 2025 May.
BACKGROUND
Donor-derived cell-free DNA (dd-cfDNA) is an emerging biomarker of kidney allograft injury, mainly investigated in the context of rejection. However, the dd-cfDNA dynamics in other graft pathologies merit further investigation.
METHODS
In this single-center observational study, we prospectively collected dd-cfDNA at indication biopsies. To evaluate the association between dd-cfDNA and different histological patterns, we correlated absolute and relative dd-cfDNA (thresholds of 50 copies/mL and 0.5%, respectively) with the Banff 2022 lesion scores and the assigned diagnoses.
RESULTS
We examined 151 dd-cfDNA paired biopsies in 131 kidney transplant recipients and found significantly higher absolute dd-cfDNA levels in antibody-mediated rejection (n, median, IQR: 45, 63 copies/mL, 42-89), microvascular inflammation (MVI) without donor-specific antibodies or C4d-deposition (6, 102 copies/mL, 61-134), mixed rejection (8, 140 copies/mL, 77-171), and BK virus-associated nephropathy (6, 213 copies/mL, 83-298) compared with glomerulonephritis (20, 12 copies/mL, 8-18), calcineurin toxicity (19, 10 copies/mL, 7-16), interstitial fibrosis/tubular atrophy (12, 10 copies/mL, 9-16) and normal histology (6, 9 copies/mL, 7-16). In the multivariable analysis, absolute and relative dd-cfDNA correlated with the peritubular capillaritis (ptc), glomerulitis (g), and tubulitis (t) scores. In the receiver operating characteristic analysis, absolute dd-cfDNA showed best discrimination for MVI of any cause (area under the curve [AUC] 0.88, sensitivity 0.71, specificity 0.86, positive predictive value [PPV] 0.76, negative predictive value [NPV] 0.82), followed by antibody-mediated rejection including mixed rejection (AUC 0.85, sensitivity 0.72, specificity 0.83, PPV 0.69, NPV 0.84), and overall rejection (AUC 0.83, sensitivity 0.66, specificity 0.85, PPV 0.76, NPV 0.77). T cell-mediated rejection was only detectable by dd-cfDNA when associated with vascular lesions.
CONCLUSIONS
Altogether, we conclude that dd-cfDNA-release is not limited to rejection-related injury phenotypes and is mainly driven by MVI in kidney allografts.
背景
供体来源的游离DNA（dd-cfDNA）是肾移植损伤的一种新兴生物标志物，主要在排斥反应的背景下进行研究。然而，dd-cfDNA在其他移植病理中的动态变化值得进一步研究。
方法
在这项单中心观察性研究中，我们在指征性活检时前瞻性收集dd-cfDNA。为了评估dd-cfDNA与不同组织学模式之间的关联，我们将绝对和相对dd-cfDNA（阈值分别为50拷贝/毫升和0.5%）与2022年班夫病变评分及指定诊断进行关联分析。
结果
我们检查了131例肾移植受者的151对dd-cfDNA活检样本，发现抗体介导的排斥反应（n，中位数，四分位间距：45，63拷贝/毫升，42 - 89）、无微血管炎症（MVI）且无供体特异性抗体或C4d沉积（6，102拷贝/毫升，61 - 134）、混合性排斥反应（8，140拷贝/毫升，77 - 171）以及BK病毒相关性肾病（6，213拷贝/毫升，83 - 298）中的绝对dd-cfDNA水平显著高于肾小球肾炎（20，12拷贝/毫升，8 - 18）、钙调神经磷酸酶毒性（19，10拷贝/毫升，7 - 16）、间质纤维化/肾小管萎缩（12，10拷贝/毫升，9 - 16）和正常组织学（6，9拷贝/毫升，7 - 16）。在多变量分析中，绝对和相对dd-cfDNA与肾小管周围毛细血管炎（ptc）、肾小球炎（g）和肾小管炎（t）评分相关。在受试者工作特征分析中，绝对dd-cfDNA对任何原因引起的MVI显示出最佳的区分能力（曲线下面积[AUC] 0.88，敏感性0.71，特异性0.86，阳性预测值[PPV] 0.76，阴性预测值[NPV] 0.82），其次是包括混合性排斥反应在内的抗体介导的排斥反应（AUC 0.85，敏感性0.72，特异性0.83，PPV 0.69，NPV 0.84），以及总体排斥反应（AUC 0.83，敏感性0.66，特异性0.85，PPV 0.76，NPV 0.77）。仅当与血管病变相关时，T细胞介导的排斥反应才能通过dd-cfDNA检测到。
结论
总之，我们得出结论，dd-cfDNA释放不仅限于与排斥反应相关的损伤表型，并且在肾移植中主要由MVI驱动。
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