血清半胱氨酸蛋白酶抑制剂C对高血压患者早期肾损伤的诊断性能评价

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欧阳旭, 陈汉红, 云大壮, 吴璐思, 张敏. 血清半胱氨酸蛋白酶抑制剂C对高血压患者早期肾损伤的诊断性能评价. 2011, 26(5): 317-320
OUYANG Xu, CHEN Hanhong, YUN Dazhuang, WU Lusi, ZHANG Min. Evaluation of the diagnosis value of serum cystatin C for early renal impairment in patients with hypertension. Labratory Medicine, 2011, 26(5): 317-320 复制到剪切板

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《检验医学》编辑部

血清半胱氨酸蛋白酶抑制剂C对高血压患者早期肾损伤的诊断性能评价

欧阳旭¹, 陈汉红², 云大壮², 吴璐思², 张敏²

1.宁远县人民医院检验科,湖南宁远 425600

2.广东省医学科学院广东省人民医院病理医学部检验科,广东广州 510080

作者简介：欧阳旭,男,1975年生,学士,主管技师,主要从事生物化学检验项目的诊断性能研究。

摘要

目的

评价血清半胱氨酸蛋白酶抑制剂C(Cys C)对高血压患者早期肾损伤的诊断价值,为Cys C在临床的应用提供循证医学证据。

方法

对318例原发性高血压并怀疑合并早期肾损伤的患者同时进行血清Cys C和^99mTc-二乙三胺五醋酸(^99mTc-DTPA)清除率的检测。以^99mTc-DTPA清除率为诊断标准将318例患者分为肾损伤组(127例)和对照组(191例)。用受试者工作特征(ROC)曲线选取血清Cys C诊断原发性高血压患者早期肾损伤的最佳临界点,计算敏感性、特异性、Youden指数等指标,评价血清Cys C诊断原发性高血压患者早期肾损伤的真实性。同时做血清Cys C检测的重复性试验,评价血清Cys C检测方法的可靠性。

结果

根据ROC曲线,Cys C诊断原发性高血压患者早期肾损伤的最佳临界点为1.26 mg/L,其敏感性为84.3%、特异性为79.1%、阳性预测值为72.8%、阴性预测值为88.3%、阳性似然比为4.03、阴性似然比为0.20、漏诊率为15.7%、误诊率为20.9%、总符合率为81.1%、Youden指数为0.63、ROC曲线下面积[95%可信区间(CI)]为0.855(0.814~0.896)。当Cys C日平均均值分别为1.21 、1.67 mg/ L 时,该法的批内变异系数(CV)分别为2.9%、2.7%,批间CV分别为3.6%、3.3%,日间CV分别为4.1%、3.8%,总CV分别为7.0%、6.4%。

结论

血清Cys C对原发性高血压患者早期肾损伤有较好的诊断价值,尤其适合早期筛查。

关键词: 半胱氨酸蛋白酶抑制剂C; 高血压; 肾功能试验; 肾小球滤过率

中图分类号:R446.1 文献标志码:A 文章编号:1673-8640(2011)05-0317-04

Evaluation of the diagnosis value of serum cystatin C for early renal impairment in patients with hypertension

OUYANG Xu¹, CHEN Hanhong², YUN Dazhuang², WU Lusi², ZHANG Min²

1.Department of Clinical Laboratory, Ningyuan County People's Hospital, Hunan Ningyuan 425600, China

2. Department of Clinical Laboratory,Pathology Department, Guangdong Academy of Medical Sciences and Guangdong General Hospital, Guangdong Guangzhou 510080,China

Abstract

Objective

To evaluate the clinical significance of serum cystatin C (Cys C) in early renal impairment in patients with hypertension, and provide the reference for Cys C in the clinical application.

Methods

318 patients with primary hypertension and suspected early renal impairment were enrolled. Serum Cys C and the clearance of^99mTc-diethy lenetriaminepentaacetic acid (^99mTc-DTPA) were determined. 318 patients were classified into 2 groups according to the clearance of^99m Tc-DTPA (renal impairment group: 127 cases and control group: 191 cases). The receiver operating characteristic (ROC) curve was used to confirm the cut-off value, and the sensitivity, specificity and Youden index were calculated. The accuracy of diagnosing the early renal impairment by serum Cys C was evaluated. The repeatability was assessed simultaneously, and the reliability was analyzed.

Results

According to the ROC curve, the best cut-off value of diagnosing patients with primary hypertension and early renal impairment was 1.26 mg/L. The sensitivity and specificity were 84.3% and 79.1%. The positive and negative predictive values were 72.8% and 88.3% respectively. The positive and negative likelihood ratios were 4.03 and 0.20. The rate of missed diagnosis was 15.7%, and the misdiagnosis rate was 20.9%. The total coincidence and Youden index were 81.1% and 0.63. The area under ROC curve [95% confidence interval (CI)] was 0.855 (0.814-0.896). When the daily mean of Cys C was 1.21 and 1.67 mg/L, the within-run coefficient of varication (CV) were 2.9% and 2.7%, and the between-runCV were 3.6% and 3.3%. The daytimeCV were 4.1% and 3.8%, and the totalCV were 7.0% and 6.4%.

Conclusions

Serum Cys C has significant diagnosis value for early renal impairment in primary hypertension patients, and it is suitable for early screening.

Keyword: Cystatin C; Hypertension; Kidney function test; Glomerular filtration rate

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肾功能损伤是原发性高血压的严重并发症,起病隐匿,若能在早期发现高血压性肾损伤,对降低病死率和改善患者生存质量意义重大。长期以来用血清肌酐来判断肾功能损伤,但是敏感性较低。同位素标志物清除率结果虽然可靠,但价格昂贵,且需放射显影,故限制了在临床的广泛应用。半胱氨酸蛋白酶抑制剂C(Cys C)的发现,无疑给高血压早期肾损害的诊断带来了新的希望。国外的一些研究表明,血清Cys C是评价早期肾功能损害的指标^{[ 1]}。在肾功能仅轻度损伤时,血清Cys C的敏感性远优于血清肌酐^{[ 2, 3]}。为了阐明血清Cys C在诊断中国人群高血压患者早期肾损伤的价值,我们检测了318例高血压患者的Cys C水平,以期为血清Cys C的临床应用提供可靠的循证医学证据。

材料和方法

一、研究对象

2007年8月至2009年11月期间,从广东省人民医院心内科诊断为原发性高血压并怀疑合并早期肾损伤的439例患者中选取研究对象。排除妊娠或哺乳期的妇女、肾移植、1周内使用过肾毒性药物、1周内大剂量使用过糖皮质激素、甲状腺功能异常、男性血清肌酐>115 μmol/L、女性血清肌酐>97 μmol/L等情况,共排除93例;因各种原因失访28例。最终,成功收集到318例患者。

1. 肾损伤组 318例研究对象中,经^99mTc-二乙三胺五醋酸(^99mTc-DTPA)清除率诊断为肾损伤的127例患者作为肾损伤组。其中男76例,女51例,年龄23~96岁。

2. 对照组所有研究对象中,经^99mTc-DTPA清除率诊断肾功能未受到损伤的191例患者作为对照组,其中男109例,女82例,年龄21~97岁。

二、仪器和试剂

1. Cys C 仪器为Beckman-Coulter公司生产的SYNCHONLX20全自动生化分析仪。试剂由北京利得曼生化技术有限公司提供。试剂盒的线性范围为0.2~8.0 mg/L,可报告范围为0.02~64.00 mg/L。

2.^99mTc-DTPA清除率显像仪器为PHILIPS PRECEDENCE 6型SPECT/CT仪(低能准直器)。显像剂^99mTc-DTPA由广东希埃公司提供,标记率>96%。

三、方法

318例患者均在治疗以前同时、独立进行血清Cys C与^99mTc-DTPA清除率的检测。

1. 血清Cys C检测用干燥管抽取全血4.0 mL送检,经3 000 r/min(离心半径20.8 cm)离心10 min后用免疫比浊法检测血清Cys C水平。用2个不同浓度的样本每天测定2次(2次测定间隔>2 h),每次测定均作双份,共测定20 d,从而对血清Cys C测定的精密度作出评价。

2.^99mTc-DTPA清除率采用动态检测法进行测定。测试前20~30 min饮水300 mL,检查时患者取坐位,将探针贴至患者后腰处,静脉注射185 MBq的^99mTc-DTPA,视野包括双肾。用SPECT/CT仪测定^99mTc-DTPA的放射活性,并用体表面积进行校正。以^99mTc-DTPA清除率<68 mL/min判断为肾功能受损。

四、统计学方法

将研究对象的血清Cys C、^99mTc-DTPA清除率、性别、年龄等变量的结果录入SPSS 13.0统计软件数据库。核对资料后,对血清Cys C、^99mTc-DTPA清除率、性别、年龄等变量作统计描述,并对肾损伤组与对照组在性别、年龄等基线资料作均衡性检验,比较肾损伤组与对照组的基线资料是否具有可比性。然后,作受试者工作特征(ROC)曲线,计算ROC曲线下的面积。计算比较不同临界点时的敏感性、特异性等评价指标,并选取血清Cys C诊断原发性高血压患者早期肾损伤的最佳临界点。最后,依据最佳临界点制作诊断试验评价的四格表,分别计算敏感性、特异性等评价指标。进行离群值的检查后,计算血清Cys C批内变异系数( CV)、批间 CV、日间 CV、总 CV^{[ 4]}。

结果

一、对照组与肾损伤组基线资料的均衡性检验

1. 性别对照组与肾损伤组比较,差异无统计学意义( χ²=0.241, P=0.623)。

2. 年龄对照组与肾损伤组比较,差异无统计学意义( t=0.250, P=0.802)。

二、主要评价指标

根据血清Cys C与^99mTc-DTPA清除率的判定结果作ROC曲线,见图1。ROC曲线下的面积[95%可信区间( CI)]为0.855(0.814~0.896)。计算比较不同临界点时的敏感性、特异性等评价指标,见表1。用ROC曲线选取1.26 mg/L作为诊断原发性高血压患者早期肾损伤的最佳临界点,依据选取的最佳临界点绘制血清Cys C诊断原发性高血压患者早期肾损伤四格表,见表2。计算各项评价指标:敏感性=84.3%; 特异性=79.1%; 阳性预测值=72.8%; 阴性预测值=88.3%;阳性似然比=4.03;阴性似然比=0.20;漏诊率=15.7%; 误诊率=20.9%;总符合率=81.1%;

Youden指数=0.63。

	Figure Option View Download New Window
	图1 血清Cys C诊断高血压患者早期肾损伤的ROC曲线

三、Cys C检测方法的重复性评价指标

日平均均值=1.21 mg/ L时的精密度结果:批内 CV=2.9%;批间 CV=3.6%;日间 CV=4.1%;总 CV=7.0%。

日平均均值=1.67 mg/ L时的精密度结果:批内 CV=2.7%;批间 CV=3.3%;日间 CV=3.8%;总 CV=6.4%。

表1 不同临界点时血清Cys C对高血压患者早期肾损伤的诊断价值

表2 血清Cys C诊断原发性高血压患者早期肾损伤的四格表(例)

讨论

过去,临床工作中常以血清肌酐来判断肾功能,但对早期肾损害的诊断价值却存在一定的局限性。本研究显示血清Cys C对高血压患者早期肾损伤具有良好的诊断价值,敏感性与特异性分别达84.3%、79.1%。以往的一些研究与此结果相似,如李海霞等^{[ 5]}在评价Cys C对慢性肾脏病患者肾小球滤过功能的研究时显示,Cys C诊断肾小球滤过功能下降的敏感性与特异性分别为83.6%、85.6%。其原因可能是Cys C的相对分子质量低、带正电荷,能自由通过肾小球滤过膜,滤过后由近端小管完全重吸收和分解,肾小管不分泌Cys C^{[ 6]}。因此,血清Cys C浓度可较好地反映肾小球滤过率。

本研究中用ROC曲线选取1.26 mg/ L作为诊断原发性高血压患者早期肾损伤的临界点,可获得最佳的临床诊断价值。以往的研究对于临界点的选取争议较大,如李海霞等^{[ 7]}在评价Cys C对糖尿病患者肾小球滤过功能的研究显示,以1.02 mg/L为临界点,其敏感性、特异性分别为92.3%、68.4%,可获得最佳的临床诊断价值。最佳临界点的差异悬殊可能是由于不同的检测系统所造成的。当然,研究人群的不同也可能导致不同的最佳临界点。这就要求不同的实验室应对最佳临界点进行评定。

有关血清Cys C诊断高血压患者早期肾损伤的预测值与似然比报道甚少。本研究显示阳性预测值与阳性似然比分别为72.8%、4.03。若患者用血清Cys C诊断原发性高血压患者早期肾损伤为阳性,有必要联合别的检测项目进行确诊。不过,本研究提示血清Cys C诊断高血压患者早期肾损伤的阴性预测值和阴性似然比分别为88.3%、0.20,具有较好的临床应用价值。若血清Cys C<1.26 mg/L,基本可排除早期肾损伤。

本研究对Cys C与^99mTc-DTPA清除率进行了同步盲法的测定,资料收集时严格执行了纳入标准与排除标准,所得结果能较客观地反映血清Cys C对高血压患者早期肾损伤的诊断价值。但仍存在一些不足之处,如在招募研究对象时,由于条件所限未能进行随机抽样;一家医院招募研究对象,入院率不同所导致的选择偏倚未能进行有效的控制。未来有必要开展随机抽样的多中心调查,进一步明确血清Cys C对高血压患者早期肾损伤的诊断价值。值得注意的是,本研究排除了妊娠、哺乳期的妇女以及甲状腺功能异常的患者,所以本研究中的结果外推至这样一些人群时需慎重考虑是否合适。

总之,血清Cys C对原发性高血压患者早期肾损伤有良好的诊断价值,与^99mTc-DTPA清除率相比费用低廉,速度快捷,尤其适合原发性高血压患者早期肾损伤的筛查。

The authors have declared that no competing interests exist.

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2005

0.0

... 国外的一些研究表明,血清Cys C是评价早期肾功能损害的指标^[1] ...

2005

1.5

0.0

. 2005, 9(1):28-32

Intra-individual variation of cystatin C and creatinine in pediatric solid organ transplant recipients

Ludmila Podracka 1,2 ,Janusz Feber 1 ,Nathalie Lepage 3 andGuido Filler 1

1 Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ont., Canada 2 Department of Pediatrics, University P.J. Safarik, Kosice, Slovak Republic 3 Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ont., Canada * Guido Filler MD, PhD, FRCPC, Division of Nephrology, Department of Pediatrics, Children's Hospital of Eastern Ontario, 401 Smyth Rd, K1H 8L1 Ottawa, Canada Tel.: +1 (613) 737 7600 ext. 2441 Fax: +1 (613) 738 3254 E-mail: filler@cheo.on.ca

> Abstract: There is controversy about the feasibility of cystatin C (CysC) as a marker of glomerular filtration rate (GFR) post-transplant (Tx). We studied intra-patient variability of CysC in comparison with serum creatinine (SCr) in 20 children (11 males, mean age 11.5 ± 6.4 yr) with solid organ transplants (14 kidney, four liver, and two combined liver + kidney transplants). The mean age at Tx was 7.0 ± 5.6 yr. A total of 178 simultaneous SCr and CysC measurements (median 8 per patient) were analyzed. In addition, GFR was calculated using the Schwartz and a novel CysC-based formula. Intra-individual coefficient of variations (CV) was calculated as ratio of standard deviation over mean. The mean CV was significantly lower for SCr (7.71 ± 4.16%) when compared with CysC (10.27 ± 4.87, p = 0.04), but was no longer significantly different when excluding patients with a bladder augment. The CV of the GFR estimated by Schwartz formula (7.44 ± 3.77) was significantly lower than GFR calculated from CysC (12.52 ± 7.37), p = 0.001. The mean ratio between the Schwartz GFR and the GFR calculated from CysC was 102.6 ± 12.8%, not significantly different from 100% (p = 0.3796). The only potential confounding factors to explain increased CV after Tx were gender and bladder augmentation, whereas calcineurin inhibitors or steroids did not influence CV. With the limitation of a small number of subjects, our data suggest that the CysC and the CysC-calculated GFR is equivalent but not better than SCr and Schwartz formula. We therefore conclude that measurement of CysC can be used for longitudinal intra-individual follow-up of renal function post-Tx.

... 在肾功能仅轻度损伤时,血清Cys C的敏感性远优于血清肌酐^[2,3] ...

2005

0.0

... 在肾功能仅轻度损伤时,血清Cys C的敏感性远优于血清肌酐^[2,3] ...

2008

0.0

... 进行离群值的检查后,计算血清Cys C批内变异系数(CV)、批间CV、日间CV、总CV^[4] ...

2006

0.0

... 以往的一些研究与此结果相似,如李海霞等^[5]在评价Cys C对慢性肾脏病患者肾小球滤过功能的研究时显示,Cys C诊断肾小球滤过功能下降的敏感性与特异性分别为83 ...

1995

2.857

0.0

. 1995, 26(6):559-564

Transthyretin and cystatin C are catabolized in proximal tubular epithelial cells and the proteins are not useful as markers for renal cell carcinomas

B. JACOBSSON 1,* ,H. LIGNELID 1 andU.S.R. BERGERHEIM 2

1 Department of Clinical Chemistry and Pathology, Danderyd Hospital, Stockholm, Sweden 2 Department of Urology, Karolinska Hospital, Stockholm, Sweden * Address for correspondence: Dr Björn Jacobsson, Department of Clinical Chemistry and Pathology, Danderyd Hospital, 182 88 Danderyd, Sweden.

> Ten human kidney specimens and thirty-two renal cell carcinomas were investigated for the presence of transthyretin mRNA and cystatin C mRNA using Northern blot analysis. Five of ten kidney specimens and 15 of 32 renal carcinomas were also immunohistochemically investigated for the presence of the corresponding proteins. Transthyretin mRNA could not be detected in any of the normal or neoplastic tissue preparations, whereas low amounts of cystatin C mRNA were found in nine of ten normal kidneys and in 24 of 32 renal cell carcinomas. Immunoreactive transthyretin and cystatin C were present in proximal tubular epithelial cells of all kidney specimens, whereas neither of the proteins was detected in the tumour cells of the renal carcinomas. Immunoreactive cystatin C was, however, demonstrated in scattered monocyte/macrophage-like cells. We conclude that the presence of immunoreactive transthyretin and cystatin C in proximal tubular cells of the kidney is most likely due to reabsorption of the proteins from the primary urine. The small amounts of cystatin C mRNA in some of the normal and neoplastic renal preparations are probably due to cystatin C synthesis in macrophages. Transthyretin has been recommended as an immunohistochemical marker for renal cell carcinomas. Our results, however, clearly indicate that neither transthyretin nor cystatin C constitutes a useful marker for such neoplasms.

... 其原因可能是Cys C的相对分子质量低、带正电荷,能自由通过肾小球滤过膜,滤过后由近端小管完全重吸收和分解,肾小管不分泌Cys C^[6] ...

2005

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... 以往的研究对于临界点的选取争议较大,如李海霞等^[7]在评价Cys C对糖尿病患者肾小球滤过功能的研究显示,以1 ...