Mühlbacher Jakob, Doberer Konstantin, Kozakowski Nicolas, Regele Heinz, Camovic Sümeyra, Haindl Susanne, Bond Gregor, Haslacher Helmuth, Eskandary Farsad, Reeve Jeff, Böhmig Georg A, Wahrmann Markus
Division of General Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.
Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Front Med (Lausanne). 2020 Apr 9;7:114. doi: 10.3389/fmed.2020.00114. eCollection 2020.
Screening for donor-specific antibodies (DSA) has limited diagnostic value in patients with late antibody-mediated rejection (ABMR). Here, we evaluated whether biomarkers reflecting microcirculation inflammation or tissue injury-as an adjunct to DSA detection-are able to improve non-invasive ABMR monitoring. Upon prospective cross-sectional antibody screening of 741 long-term kidney transplant recipients with a silent clinical course, 86 DSA-positive patients were identified and biopsied. Serum and urine levels of E-selectin/CD62E, vascular cell adhesion molecule 1 (VCAM-1), granzyme B, hepatocyte growth factor (HGF), C-C motif chemokine ligand (CCL)3, CCL4, C-X-C motif chemokine ligand (CXCL)9, CXCL10, and CXCL11 in DSA-positive recipients were investigated applying multiplexed bead-based immunoassays. Diagnosis of ABMR (50 patients) was associated with significantly higher levels of CXCL9 and CXCL10 in blood and urine and of HGF in blood. Overall, urinary CXCL9 had the highest diagnostic accuracy for ABMR (area under the receiver operating characteristic curve: 0.77; accuracy: 80%) and its combined evaluation with the mean fluorescence intensity of the immunodominant DSA (DSAmax MFI) revealed a net reclassification improvement of 73% compared to DSAmax MFI alone. Our results suggest urinary CXCL9 testing, combined with DSA analysis, as a valuable non-invasive tool to uncover clinically silent ABMR late after transplantation.
对供体特异性抗体（DSA）进行筛查在晚期抗体介导的排斥反应（ABMR）患者中的诊断价值有限。在此，我们评估了反映微循环炎症或组织损伤的生物标志物作为DSA检测的辅助手段，是否能够改善对ABMR的无创监测。在对741例临床过程无异常的长期肾移植受者进行前瞻性横断面抗体筛查时，确定了86例DSA阳性患者并进行活检。应用基于微珠的多重免疫分析法，对DSA阳性受者血清和尿液中的E-选择素/CD62E、血管细胞黏附分子1（VCAM-1）、颗粒酶B、肝细胞生长因子（HGF）、C-C基序趋化因子配体（CCL）3、CCL4、C-X-C基序趋化因子配体（CXCL）9、CXCL10和CXCL11水平进行了研究。ABMR诊断（50例患者）与血液和尿液中CXCL9和CXCL10以及血液中HGF水平显著升高相关。总体而言，尿CXCL9对ABMR的诊断准确性最高（受试者操作特征曲线下面积：0.77；准确率：80%），与免疫显性DSA的平均荧光强度（DSAmax MFI）联合评估显示，与单独使用DSAmax MFI相比，净重新分类改善率为73%。我们的结果表明，尿CXCL9检测联合DSA分析是一种有价值的无创工具，可用于发现移植后期临床上无症状的ABMR。
