CN112630442A - 一种血浆可溶性尿激酶型纤溶酶原激活物受体及其应用 - Google Patents

一种血浆可溶性尿激酶型纤溶酶原激活物受体及其应用 Download PDF

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CN112630442A
CN112630442A CN202011213083.4A CN202011213083A CN112630442A CN 112630442 A CN112630442 A CN 112630442A CN 202011213083 A CN202011213083 A CN 202011213083A CN 112630442 A CN112630442 A CN 112630442A
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supar
plasminogen activator
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朱海红
王云云
吴凤天
陈超
陈智
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Abstract

本发明属临床医学领域，涉及可溶性尿激酶型纤溶酶原激活物受体(soluble urokinase plasminogen activator receptor，suPAR)可作为慢加急性肝衰竭患者临床转归的独立生物标志物。本发明提供一种血浆可溶性尿激酶型纤溶酶原激活物受体及其应用。用于可溶性尿激酶型纤溶酶原激活物受体的试剂用于制备肝癌早期诊断试剂盒中的应用。

Description

一种血浆可溶性尿激酶型纤溶酶原激活物受体及其应用
技术领域
本发明属临床医学领域，涉及可溶性尿激酶型纤溶酶原激活物受体(solubleurokinase plasminogen activator receptor，suPAR)可作为慢加急性肝衰竭患者临床转归的独立生物标志物。
背景技术
慢加急性肝功能衰竭(ACLF)是一种复杂的综合征，由已存在的慢性肝病患者的急性肝衰竭发作定义。它的特点是短期死亡率高，器官衰竭和全身性炎症过多。过度的全身性炎症被认为是ACLF发生的主要驱动力。传统的评分系统终末期肝病(MELD)，MELD-Na和Child-Turcotte-Pugh(CTP)评分模型无法准确预测ACLF的死亡率和多器官功能衰竭(MOF)。最近，CANONIC研究开发了CLIF联合体器官衰竭(CLIF-C)评分，事实证明，与常规评分系统相比，CLIF-C评分对预测ACLF的结果更为有用。但是，评分过程有点复杂，可能会妨碍及时了解患者状况。因此，需要发现具有良好预测价值的新生物标志物。
尿激酶型纤溶酶原激活物受体(uPAR)是纤溶酶原激活物(PA)系统的一部分。该系统涉及许多生理和病理学过程，包括血栓形成、炎症、组织重塑和肿瘤发生。suPAR是一种稳定的蛋白质，在炎症过程中从尿激酶纤溶酶原激活剂受体(uPAR，CD87)的裂解中释放出来。uPAR主要在循环免疫细胞(如单核细胞和嗜中性粒细胞)膜上表达，并与免疫功能(如细胞附着、运动、迁移、增殖和纤维蛋白溶解)密切相关。suPAR保留了uPAR的大部分功能。此外，suPAR可能与足细胞β3整合素结合而引起肾脏疾病，并增强脂多糖诱导的中性粒细胞活化。在各种感染(如HIV感染、疟疾、结核病和败血症)中，其水平均升高，表明其可能预测这些疾病转归。这种预测能力在ACLF中也可能有用，但是很少有研究关注ACLF患者的suPAR水平。应用商业化的ELISA试剂盒，suPAR的含量测定既简单又快速。因此，我们探讨了suPAR是否是预测ACLF患者转归的合适生物标志物。
发明内容
针对现有技术所存在的上述技术问题，本发明提供了一种慢加急性肝衰竭患者临床转归的独立生物标志物。
一种慢加急性肝衰竭患者临床转归的独立生物标志物，所述标志物为可溶性尿激酶型纤溶酶原激活物受体。
另外本发明提供了用于述独立生物标志物的试剂的新用途。
用于可溶性尿激酶型纤溶酶原激活物受体的试剂用于制备肝癌早期诊断试剂盒中的应用。
检测方法为：根据酶联免疫吸附法，血浆样品(25μL)用于通过酶联免疫吸附测定法(suiro)(丹麦ViroGates)测量suPAR。
本发明提供了一种慢加急性肝衰竭患者临床转归的独立生物标志物。
附图说明
图1不同疾病群血浆suPAR浓度的比较。
(a)在健康对照组(n＝14)、慢性乙型肝炎患者组(n＝14)和慢加急性肝衰竭患者组(n＝42)血浆suPAR浓度。
(b)有或没有临床并发症的慢加急性肝衰竭患者的suPAR水平进行比较。水平线表示中值。
ns,没有统计学差异；*P<0.05；**P<0.01,***P<0.001,****P<0.0001。图2有或无肝硬化的慢加急性肝衰竭患者以及有或无肝性脑病之间的K-M生存曲线进行比较。使用对数秩检验比较了组间累计90天的存活率。
具体实施方式
为了更为具体地描述本发明，下面结合附图及具体实施方式对本发明的技术方案进行详细说明。
1、病例、材料和方法
(1)病例入组
于2016年12月10日至2018年3月10日期间在浙江大学医学院附属第一医院、浙江省青春医院和宁波市鄞州第二医院入组疑似ACLF成年患者。ACLF诊断基于亚太研究协会(APASL)的标准：“急性肝损伤表现为黄疸(胆红素≥5mg/dl)和凝血病(INR>1.5)在先前已诊断或未诊断的慢性肝病患者中，在4周内并发腹水和/或脑病。”肝硬化由先前的肝活检、内窥镜检查、放射学证据或肝脏代偿失调的临床表现诊断出来。分别使用国际腹水协会(International Ascites Club)和美国肝病研究协会(American Association for theStudy of Liver Disease)制定的标准诊断肝肾综合征(HRS)、自发性细菌性腹膜炎(SBP)和腹水。然后，根据存在两个或多个肝外器官衰竭，其他为ACLF，将ACLF患者进一步分类为急性多发性肝功能衰竭(ACLF-MOF)，并将其分类为ACLF。排除标准为妊娠、被诊断为获得性免疫缺陷综合症(AIDS)、患有任何类型的恶性肿瘤或进行了肝移植。慢性乙型肝炎(CHB)定义为患有慢性乙型肝炎的患者，通过组织学、影像学、实验室或临床或肝硬化或肝纤维化或长期肝脏炎症以及血清HBsAg阳性超过六个月的证据进行诊断。健康对照(HC)没有既往或当前病史或临床证据，血清HBsAg阴性。CHB和HC与ACLF患者的性别和年龄相匹配。该研究符合赫尔辛基宣言的原则，并经浙江大学医学院附属第一医院伦理委员会批准。入组后随访研究队列90天，终点为死亡或肝移植。
(2)suPAR和细胞因子测量
采集自愿者全血样本，离心后获得血浆并立即储存在-80℃。根据酶联免疫吸附法，血浆样品(25μL)用于通过酶联免疫吸附测定法(suiro)(丹麦ViroGates)测量suPAR，血浆样品(20μL)用于多种细胞因子测定(Bio-Rad，Hercules，CA)。
2、结果
(1)患者特征：
共入组了282名符合纳入和排除标准的ACLF患者。表1显示了这些有或没有MOF的患者的基线特征的比较。suPAR和基线特征在所有参与者中进行了测量。有MOF的患者入院时血浆suPAR明显高于无MOF的患者(11.9(9.1-15.5)ng.mL和16.4(11.5-24.0)ng/mL；p<0.001，表1)。两组之间在某些临床事件(例如HRS和肝性脑病(HE))，实验室数据(例如白细胞计数(WBC)，国际标准化比率(INR)和总胆红素(Tbil))之间也存在显著差异，以及预后评分系统(例如CTP、MELD和SOFA评分)。在该点的末尾对所有患者进行随访。(2)基线血浆suPAR水平及其与ACLF疾病进展的关系：
HC、CHB和ACLF患者血浆suPAR测定，发现ACLF患者的suPAR水平显著高于HC和CHB患者。(图1a，12.16(7.61–17.57)vs.2.3(2.00-2.89)vs 2.7(2.16-4.00)ng/L；p<0.001)。但是，HC和CHB之间没有差异。然后，进一步比较了入院时或随访期间有无并发症的ACLF患者的血浆suPAR水平。入院时，HE、HRS、UGBI或感染患者的suPAR水平高于无这些并发症的患者。在HRS患者中，血浆suPAR水平的差异最为明显(30.15(13.57–36.35)ng/L与12.30(9.33–16.46)ng/L；p<0.001)。随访期间表现出循环衰竭的患者也显示出suPAR水平明显高于无循环衰竭的患者(图1b)。
除临床特征外，临床实验室数据还发现与血浆suPAR的显著相关性，并且预后评分与死亡率相关(表2)。所有三个预后评分均与suPAR水平相关。与MELD的相关性最强(r＝0.421，p<0.001)(表2)。在实验室数据中，各种与感染、免疫相关的数据显示与suPAR水平呈正相关，包括细菌或真菌感染、WBC和PCT的发生率。发现40例患者中的27种细胞因子中的两种趋化因子MIP1beta和IL-8与血浆suPAR水平之间存在很强的相关性(分别为r＝0.453，p＝0.007；r＝0.448，p＝0.003)(表2)。suPAR与肝脏相关数据，肾脏相关数据和甲状腺相关数据之间也存在显著相关性，但与心脏相关的数据之间无显著相关性(表2)。
(3)生存分析：
在为期30天的随访中，62名患者(22.0％)死亡，34名患者(12.1％)接受了肝移植。在90天的随访期间，82位患者(29.1％)死亡，41位患者(14.5％)接受了肝移植。在90天的随访期间，死亡或接受移植手术的患者(n＝123)的基线血浆suPAR高于未进行肝移植存活的患者(n＝159)(16.03(11.65–23.70)vs.11.14(8.41–14.14)ng/L，p<0.001；图1b)。
根据Youden指数计算，血浆suPAR预测90天死亡率的最佳临界点为14.7ng/mL。基于该最佳临界点，Kaplan-Meier曲线显著表明ACLF患者的30天和90天死亡率。有趣的是，在没有肝硬化或有HE的患者中，suPAR水平对死亡率的影响明显更大(图2)。高suPAR水平对ACLF和肝硬化患者30天死亡率的影响不及90天死亡率影响大(图2)。在90天的随访期间，高suPAR(suPAR≥14.7ng/mL)和HE的患者死亡率最高，而suPAR低而无HE的ACLF患者的死亡率最低(图2)。
使用Cox回归多元分析确定suPAR≥14.7ng/mL和WBC≥6.6×109，以及MELD≥23.1SOFA≥9.5，是90天和30天死亡率独立预测因子(表3)。
此外，对接受者工作特征曲线(ROC-AUC)下面积的分析表明，suPAR可能是ACLF患者30天和90天死亡率的有用预测指标(分别为0.751和0.742)(表4)。
表1.ACLF患者的基线特征
Figure BDA0002759440910000041
Figure BDA0002759440910000051
ACLF：慢加急性肝功能衰竭；ACLF-MOF：ACLF-多器官衰竭；CHB：慢性乙型肝炎；HC：健康对照组；UGIB：上消化道出血；HRS：肝肾综合症；HE：肝性脑病；SBP：自发性细菌性腹膜炎；WBC：白细胞计数；INR：国际标准化比率；CTP：Child-Turcotte-Pugh；MELD：终末期肝病模型；SOFA：序贯器官衰竭评估。
表2临床参数和含suPAR浓度预后评分系统的相关性
Figure BDA0002759440910000061
Figure BDA0002759440910000071
HBcAb：抗HBV核心抗体；PCT：降钙素原；CRP：c反应蛋白；MIP1beta：巨噬细胞炎性蛋白1beta；INR：国际标准化比率；MAP：平均动脉压；hsTnI：高度敏感肌钙蛋白I；GFR：肾小球滤过率；T3：总三碘甲状腺氨酸；FT3：游离三碘甲状腺氨酸；CTP：Child-Turcotte-Pugh；MELD：终末期肝病模型；SOFA：序贯器官衰竭评估；UGIB：上消化道出血；WBC：白细胞计数。*p<0.05,**p<0.01，***p<0.001
表3.慢加急性肝衰竭患者短期病死率的多变量Cox回归模型
Figure BDA0002759440910000072
Figure BDA0002759440910000081
表4.suPAR预测ACLF患者病死率的ROC面积
Figure BDA0002759440910000091

Claims (2)

1.一种慢加急性肝衰竭患者临床转归的独立生物标志物，所述标志物为可溶性尿激酶型纤溶酶原激活物受体。
2.用于检测权利要求1所述独立生物标志物的试剂在用于制备肝癌早期诊断试剂盒中的应用。
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