Chen Dajin, Peng Wenhan, Jiang Hong, Yang Hao, Wu Jianyong, Wang Huiping, Chen Jianghua
Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
Mol Med Rep. 2017 Jul;16(1):915-921. doi: 10.3892/mmr.2017.6670. Epub 2017 May 31.
The purpose of the present study was to assess whether urinary soluble T-cell immunoglobulin and mucin domain-containing protein 3 (sTim-3) could be adopted as a novel non‑invasive biomarker for acute rejection (AR) following renal transplantation. A total of 156 patients were enrolled between January 2006 and December 2009, comprising 49 patients with biopsy‑proven AR, 58 patients with stable grafts and no abnormal histological findings (NO‑AR), 10 patients with subclinical rejection (SCR) in protocol biopsies, 10 patients with acute tubular necrosis (ATN) and 29 patients with chronic allograft nephropathy (CAN). Additionally, urine samples from 40 healthy individuals were also collected as controls. The urinary concentration of sTim‑3 was determined by ELISA in the 156 renal allograft recipients and 40 healthy controls. Compared with NO‑AR and healthy controls, patients with AR excreted urinary sTim‑3 at a significantly higher level (4,356±440.4, 95% CI: 3,473‑5,242 ng/mmol creatinine). Likewise, patients with ATN exhibited a significantly lower level of urinary sTim‑3 (2,060±217, 95% CI: 1,679‑2,680 ng/mmol creatinine) than patients with AR. The discriminatory value was measured by the area under the receiver operating characteristic curve (ROC), which had a value of 0.88 (95% CI: 0.809‑0.951), demonstrating that sTim‑3 was a suitable marker for the diagnosis of AR. At a cut-off point of 1,836 ng/mmol creatinine, the sensitivity was 89.8% and the specificity was 82.8% (P<0.001). Amongst the patients with AR, patients with steroid‑resistant acute rejection (n=31) had significantly higher urinary sTim‑3 concentrations than patients with steroid‑sensitive acute rejection (n=18; 5,548±613.5, 95%CI: 4,287‑6,809 ng/mmol creatinine vs. 2,653±391.7, 95% CI: 1,830‑3,476 ng/mmol creatinine; P=0.0002). No significant difference in urinary sTim‑3 was found between patients with AR and CAN (3,920±543.5, 95% CI: 3,473‑5,242 ng/mmol creatinine), and a significantly higher level of Tim‑3 was excreted by patients with CAN compared with patients with NO‑AR and healthy controls (P<0.001). The present study, therefore, suggests that urinary sTim‑3 may be used as a valuable non‑invasive biomarker for the detection of AR. In addition, urinary sTim‑3 levels were demonstrated to be associated with the response to anti‑rejection therapy. The results of the present study may provide support future research into the screening of novel immune suppressants.
本研究的目的是评估尿可溶性T细胞免疫球蛋白和粘蛋白结构域蛋白3（sTim-3）是否可作为肾移植后急性排斥反应（AR）的一种新型非侵入性生物标志物。2006年1月至2009年12月共纳入156例患者，包括49例经活检证实的AR患者、58例移植肾功能稳定且组织学检查无异常（无AR）的患者、10例在方案活检中出现亚临床排斥反应（SCR）的患者、10例急性肾小管坏死（ATN）患者和29例慢性移植肾肾病（CAN）患者。此外，还收集了40名健康个体的尿液样本作为对照。通过酶联免疫吸附测定（ELISA）法测定了156例肾移植受者和40名健康对照者尿液中sTim-3的浓度。与无AR患者和健康对照相比，AR患者排出的尿sTim-3水平显著更高（4356±440.4，95%置信区间：3473-5242 ng/mmol肌酐）。同样，ATN患者的尿sTim-3水平（2060±217，95%置信区间：1679-2680 ng/mmol肌酐）显著低于AR患者。通过受试者工作特征曲线（ROC）下面积测量鉴别价值，其值为0.88（95%置信区间：0.809-0.951），表明sTim-3是诊断AR的合适标志物。在肌酐水平为1836 ng/mmol的截断点时，敏感性为89.8%，特异性为82.8%（P<0.001）。在AR患者中，激素抵抗性急性排斥反应患者（n=31）的尿sTim-3浓度显著高于激素敏感性急性排斥反应患者（n=18；5548±613.5，95%置信区间：4287-6809 ng/mmol肌酐 vs. 2653±391.7，95%置信区间：1830-3476 ng/mmol肌酐；P=0.0002）。AR患者与CAN患者的尿sTim-3无显著差异（3920±543.5，95%置信区间：3473-5242 ng/mmol肌酐），与无AR患者和健康对照相比，CAN患者排出的Tim-3水平显著更高（P<0.001）。因此，本研究表明尿sTim-3可作为检测AR的有价值的非侵入性生物标志物。此外，尿sTim-3水平被证明与抗排斥治疗反应相关。本研究结果可能为未来新型免疫抑制剂筛查研究提供支持。
