肾损伤分子-1在急性肾损伤早期诊断中的意义
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摘要
研究背景
急性肾损伤(acute kidney injury,AKI)是内科常见的急症,重症监护病房中约50%的患者可合并此症。伴随人口老龄化进程,医疗实践中抗生素、免疫抑制剂等药物使用以及各种造影检查、化疗、介入等日益普及,急性肾损伤的发病率和死亡率明显上升。急性肾损伤多为可逆性,及时发现和治疗可防止其发展成肾实质性肾衰竭。减少急性肾损伤患者病死率的关键是早期诊断、早期防治。传统的血肌酐、尿素氮等指标难以发现早期肾脏损害,无法满足临床早期诊断的需要。近年来研究者们运用基因和蛋白组学技术,发现了一系列急性肾损伤的标志物,其中肾损伤分子-1(kidney injury molecule-1,Kim-1)是一种新的Ⅰ型跨膜糖蛋白,它在正常的肾组织中几乎不表达。国内外相关研究证实,Kim-1在缺血、肾毒性等所致的急性肾损伤的肾小管上皮细胞呈高表达,其细胞外域在金属基质蛋白酶(matrixmetalloproteinases,MMP)的作用下可裂解为可溶性片段释放到细胞外,并排入尿中,尿Kim-1的升高早于血肌酐、尿素氮、尿蛋白等指标。由于Kim-1是近年新发现的一种糖蛋白,有关方面的研究多限于体外实验和动物模型,而在临床应用方面的研究报道甚少。Kim-1在临床各种病因所导致急性肾损伤患者尿液中的变化,及其在急性肾损伤早期诊断中的作用尚有待进一步研究。
目的
观察Kim-1在AKI患者体内的变化,探讨其在AKI早期诊断中的作用及意义。
方法
搜集2008年1月-2008年10月湘雅医院不同病因、不同程度的AKI患者,5.12汶川地震伤员,终末期肾病(end-stage renal disease,ESRD)患者及健康对照者的血清、尿液以及临床表现等资料;按照RIFLE标准,分为轻度AKI组10例、中重度AKI组15例、地震外伤组15例、ESRD组10例和健康对照组20例;采用ELISA方法检测尿Kim-1,比色法检测尿N-乙酰-β-D-氨基葡萄糖苷酶(N-acetyl-beta-D-glucosaminidase,NAG酶),黄嘌呤氧化酶法检测血清超氧化物歧化酶(superoxide dismutase,SOD),硫代巴比妥酸比色法检测血清丙二醛(malonaldehyde,MDA);对尿Kim-1与尿NAG酶、血清SOD以及MDA的相关性进行统计学分析,并以血肌酐(Scr)升高＞50%基础值作为AKI的诊断界限时绘制受试者工作特征曲线(receiver operator characteristic curve,ROC)曲线,评价尿Kim-1在AKI早期诊断中的敏感性及特异性。
结果
1.与健康对照组及ESRD组比较,轻度AKI组和中重度AKI组尿Kim-1均有明显升高(P＜0.05);其中中重度AKI组较轻度AKI组升高更明显(P＜0.05);尿Kim-1与尿NAG酶、血清SOD及MDA呈正相关关系;同时尿Kim-1的曲线下面积为0.914(P＜0.01)。
2.ESRD组尿Kim-1与健康对照组比较差异无统计学意义(P＞0.05)。
3.地震外伤组尿Kim-1较健康对照组升高(P＜0.05),部分尿NAG酶正常的患者已出现尿Kim-1的升高。
结论
1.尿Kim-1是AKI发生时出现较早的指标,其敏感性高于尿NAG酶,尿Kim-1的升高可能与AKI时的氧化应激有关,尿Kim-1是检测早期肾小管损伤新的内源性标志物。
2.ESRD患者尿Kim-1无明显升高,其可能原因与完全萎缩的肾小管无Kim-1的表达有关。
Background
Acute kidney injury is a common medical emergency, which is complicated with about 50% of patients in the Intensive Care Unit. With the population aging and the Large-scale useage of antibiotics and immunosuppressive agent in the clinical practices, as well as the increasing popularity of angiography and chemotherapy, the morbidity and mortality of acute kidney injury ascend significantly. Acute renal injury is not irreversible in most cases, detection and treatment in the early stage can prevent its progression into renal failure. The key to reduce mortality of acute renal injury is to diagnose earlier, prevent and treat earlier. Traditional serum creatinine and blood urea nitrogen are either not applicable for the early identification nor earlier diagnosis of kidney injury. In recent years, researchers have found a series of acute renal injury markers applied in genomics and proteomics, such as kidney injury molecule-1 , Neutrophil gelatinase-associated lipocalin , interleukin-18, cystatinC and et al. Kidney injury molecule-1 is a new type I transmembrane glycoprotein, which is not detectable in normal kidney tissue, but expressed at a very high level on dedifferentiated renal proximal tubule epithelial cells undergoing regeneration after toxic or ischemic injury. Related research has shown that , in both ischemia-reperfusion and cisplatin-induced nephrotoxicity models in the rat, urinary Kim-1 is a sensitive and specific indicator of proximal tubular kidney injury and is increased earlier than any of the conventional biomarkers, e.g. serum creatinine, blood urea nitrogen, glycosuria, proteinuria, and urinary NAG. Kim-1 protein is shed from cells into the urine in rodents and in humans. The research of Kim-1 is limited to in vitro experiments and animal models, and clinical applications have rarely been reported. It is worth further research how the Kim-1 changes in the patients with acute kidney injury, and its role in the earlier diagnosis of Acute renal injury.
Objectives
To investigate the change of Kim-1 in urine of the patients with acute kidney injury, and study the contribution and significance of it.
Methods
To collect cases in Xiangya hospital during January to October in 2008 according to the RIFLE criterion, including 10 cases of slight acute kidney injury, 15 cases of medium-severe acute kidney injury, 15 cases of the wounded in the 5.12 Wenchuan earthquake, 10 cases of end-stage renal disease and 20 healthy. ELISA method to detect urine Kim-1, colorimetric method to detect urine N-acetyl-beta-D-glucosaminidase, xanthine Oxidase method to detect serum superoxide dismutase, thibabituric acid method to detect serum malonaldehyde. To analyze the correlation between urine Kim-1 and urine NAG, and evaluate the sensitivity and specificity of urine Kim-1 using the receiver operator characteristic curve. To observe the variation of urine Kim-1 and evaluate the sensitivity and specificity of urine Kim-1 in early diagnosis of AKI.
Results
1. Compared with the healthy control group and ESRD group, the urine Kim-1 increases obviously in the slight acute kidney injury group and medium- Severe acute kidney injury group (P<0.05) ; In addition, the urine Kim-1 in the medium-severe acute kidney injury group increase more significantly. Urine Kim-1 is positively correlated with urine NAG, and the Kim-1 had an AUC-ROC of 0.914 (P<0.01) .
2. There is no statistical significance of urinary Kim-1 between ESRD group and the healthy control group (P>0.05) .
3. The urinary Kim-1 in the wounded in the 5.12 Wenchuan earthquake is also higher than the healthy control group (P<0.05) .
Conclusion
1. Urinary Kim-1 emerges earlier than any of the conventional biomarkers when AKI occurs; The serum SOD and MDA raise up accompanied by the urinary Kim-1, prompting that the increasing urinary Kim-1 may relate to the oxidative stress.
2. Urinary Kim-1 had no significant increase in ESRD group, it attribute to the totally atrophic tubular which may loss the expression of Kim-1.
急性肾损伤(acute kidney injury,AKI)是内科常见的急症,重症监护病房中约50%的患者可合并此症。伴随人口老龄化进程,医疗实践中抗生素、免疫抑制剂等药物使用以及各种造影检查、化疗、介入等日益普及,急性肾损伤的发病率和死亡率明显上升。急性肾损伤多为可逆性,及时发现和治疗可防止其发展成肾实质性肾衰竭。减少急性肾损伤患者病死率的关键是早期诊断、早期防治。传统的血肌酐、尿素氮等指标难以发现早期肾脏损害,无法满足临床早期诊断的需要。近年来研究者们运用基因和蛋白组学技术,发现了一系列急性肾损伤的标志物,其中肾损伤分子-1(kidney injury molecule-1,Kim-1)是一种新的Ⅰ型跨膜糖蛋白,它在正常的肾组织中几乎不表达。国内外相关研究证实,Kim-1在缺血、肾毒性等所致的急性肾损伤的肾小管上皮细胞呈高表达,其细胞外域在金属基质蛋白酶(matrixmetalloproteinases,MMP)的作用下可裂解为可溶性片段释放到细胞外,并排入尿中,尿Kim-1的升高早于血肌酐、尿素氮、尿蛋白等指标。由于Kim-1是近年新发现的一种糖蛋白,有关方面的研究多限于体外实验和动物模型,而在临床应用方面的研究报道甚少。Kim-1在临床各种病因所导致急性肾损伤患者尿液中的变化,及其在急性肾损伤早期诊断中的作用尚有待进一步研究。
目的
观察Kim-1在AKI患者体内的变化,探讨其在AKI早期诊断中的作用及意义。
方法
搜集2008年1月-2008年10月湘雅医院不同病因、不同程度的AKI患者,5.12汶川地震伤员,终末期肾病(end-stage renal disease,ESRD)患者及健康对照者的血清、尿液以及临床表现等资料;按照RIFLE标准,分为轻度AKI组10例、中重度AKI组15例、地震外伤组15例、ESRD组10例和健康对照组20例;采用ELISA方法检测尿Kim-1,比色法检测尿N-乙酰-β-D-氨基葡萄糖苷酶(N-acetyl-beta-D-glucosaminidase,NAG酶),黄嘌呤氧化酶法检测血清超氧化物歧化酶(superoxide dismutase,SOD),硫代巴比妥酸比色法检测血清丙二醛(malonaldehyde,MDA);对尿Kim-1与尿NAG酶、血清SOD以及MDA的相关性进行统计学分析,并以血肌酐(Scr)升高＞50%基础值作为AKI的诊断界限时绘制受试者工作特征曲线(receiver operator characteristic curve,ROC)曲线,评价尿Kim-1在AKI早期诊断中的敏感性及特异性。
结果
1.与健康对照组及ESRD组比较,轻度AKI组和中重度AKI组尿Kim-1均有明显升高(P＜0.05);其中中重度AKI组较轻度AKI组升高更明显(P＜0.05);尿Kim-1与尿NAG酶、血清SOD及MDA呈正相关关系;同时尿Kim-1的曲线下面积为0.914(P＜0.01)。
2.ESRD组尿Kim-1与健康对照组比较差异无统计学意义(P＞0.05)。
3.地震外伤组尿Kim-1较健康对照组升高(P＜0.05),部分尿NAG酶正常的患者已出现尿Kim-1的升高。
结论
1.尿Kim-1是AKI发生时出现较早的指标,其敏感性高于尿NAG酶,尿Kim-1的升高可能与AKI时的氧化应激有关,尿Kim-1是检测早期肾小管损伤新的内源性标志物。
2.ESRD患者尿Kim-1无明显升高,其可能原因与完全萎缩的肾小管无Kim-1的表达有关。
Background
Acute kidney injury is a common medical emergency, which is complicated with about 50% of patients in the Intensive Care Unit. With the population aging and the Large-scale useage of antibiotics and immunosuppressive agent in the clinical practices, as well as the increasing popularity of angiography and chemotherapy, the morbidity and mortality of acute kidney injury ascend significantly. Acute renal injury is not irreversible in most cases, detection and treatment in the early stage can prevent its progression into renal failure. The key to reduce mortality of acute renal injury is to diagnose earlier, prevent and treat earlier. Traditional serum creatinine and blood urea nitrogen are either not applicable for the early identification nor earlier diagnosis of kidney injury. In recent years, researchers have found a series of acute renal injury markers applied in genomics and proteomics, such as kidney injury molecule-1 , Neutrophil gelatinase-associated lipocalin , interleukin-18, cystatinC and et al. Kidney injury molecule-1 is a new type I transmembrane glycoprotein, which is not detectable in normal kidney tissue, but expressed at a very high level on dedifferentiated renal proximal tubule epithelial cells undergoing regeneration after toxic or ischemic injury. Related research has shown that , in both ischemia-reperfusion and cisplatin-induced nephrotoxicity models in the rat, urinary Kim-1 is a sensitive and specific indicator of proximal tubular kidney injury and is increased earlier than any of the conventional biomarkers, e.g. serum creatinine, blood urea nitrogen, glycosuria, proteinuria, and urinary NAG. Kim-1 protein is shed from cells into the urine in rodents and in humans. The research of Kim-1 is limited to in vitro experiments and animal models, and clinical applications have rarely been reported. It is worth further research how the Kim-1 changes in the patients with acute kidney injury, and its role in the earlier diagnosis of Acute renal injury.
Objectives
To investigate the change of Kim-1 in urine of the patients with acute kidney injury, and study the contribution and significance of it.
Methods
To collect cases in Xiangya hospital during January to October in 2008 according to the RIFLE criterion, including 10 cases of slight acute kidney injury, 15 cases of medium-severe acute kidney injury, 15 cases of the wounded in the 5.12 Wenchuan earthquake, 10 cases of end-stage renal disease and 20 healthy. ELISA method to detect urine Kim-1, colorimetric method to detect urine N-acetyl-beta-D-glucosaminidase, xanthine Oxidase method to detect serum superoxide dismutase, thibabituric acid method to detect serum malonaldehyde. To analyze the correlation between urine Kim-1 and urine NAG, and evaluate the sensitivity and specificity of urine Kim-1 using the receiver operator characteristic curve. To observe the variation of urine Kim-1 and evaluate the sensitivity and specificity of urine Kim-1 in early diagnosis of AKI.
Results
1. Compared with the healthy control group and ESRD group, the urine Kim-1 increases obviously in the slight acute kidney injury group and medium- Severe acute kidney injury group (P<0.05) ; In addition, the urine Kim-1 in the medium-severe acute kidney injury group increase more significantly. Urine Kim-1 is positively correlated with urine NAG, and the Kim-1 had an AUC-ROC of 0.914 (P<0.01) .
2. There is no statistical significance of urinary Kim-1 between ESRD group and the healthy control group (P>0.05) .
3. The urinary Kim-1 in the wounded in the 5.12 Wenchuan earthquake is also higher than the healthy control group (P<0.05) .
Conclusion
1. Urinary Kim-1 emerges earlier than any of the conventional biomarkers when AKI occurs; The serum SOD and MDA raise up accompanied by the urinary Kim-1, prompting that the increasing urinary Kim-1 may relate to the oxidative stress.
2. Urinary Kim-1 had no significant increase in ESRD group, it attribute to the totally atrophic tubular which may loss the expression of Kim-1.
引文
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[1] Ichimura T, Bonventre JV, Bailly V, et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem. 1998 ,273 (7):4135-4142.
[2] Toback FG. Regeneration after acute tubular necrosis. Kidney Int. 1992 ,41(11): 226-246.
[3] Humes HD, Liu S. Cellular and molecular basis of renal repair in acute renal failure. J Lab Clin Med. 1994,124(6): 749-754.
[4] Ichimura T, Hung CC, Yang SA ,et al. Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol. 2003 ,286(3): 552 - 563.
[5] Van Timmeren MM, Bakker SJ, Vaidya VS, et al. Tubular kidney injury molecule-1 in protein-overload nephropathy. Am J Physiol Renal Physiol.2006, 291(2): F456-F464.
[6] Bailly V, Zhang Z, Meier W, et al. Shedding of kidney injury molecule -1 , a putative adhesion protein involved in renal regeneration. J Biol Chem. 2002,277(42) : 39739-39748.
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[1] Ichimura T, Bonventre JV, Bailly V, et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem. 1998 ,273 (7):4135-4142.
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[5] Van Timmeren MM, Bakker SJ, Vaidya VS, et al. Tubular kidney injury molecule-1 in protein-overload nephropathy. Am J Physiol Renal Physiol.2006, 291(2): F456-F464.
[6] Bailly V, Zhang Z, Meier W, et al. Shedding of kidney injury molecule -1 , a putative adhesion protein involved in renal regeneration. J Biol Chem. 2002,277(42) : 39739-39748.
[7] Sheridan AM, Bonvent re JV. Cell biology and molecular mechanisms of injury in ischemic acute renal failure. Curr Opin NephrolHypertens. 2000, 9 (4):427-434.
[8] Kuehn EW, Park KM, Somlo S, et al. Kidney injury molecule-1 expression in murine polycystic kidney disease. Am J Physiol Renal Physiol. 2002 ,283(6):F1326-F1336.
[9] De Borst MH,Van Timmeren MM,Vaidya VS ,et al. Induction of kidney injury molecule-1 in homozygous Ren2 rats is attenuated by blockade of the renin-angiotensin system or p38 MAP kinase. Am J Physiol Renal Physiol. 2007,292(1): F313-F320.
[10] Li YG, Yang JW, DaiJ CS ,et al. Role for integrin - linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis.J Clin Invest. 2003, 112(4): 503-516.
[11] van MM , van MC, Bailly V, et al. Tubular kidney injury molecule-1 ( KIM-1) in human renal disease. J Pathol. 2007, 212(2): 209-217.
[12] Chakravorty SJ, Cockwell P, Girdlestone J, et al. Fractalkine expression on human renal tubular epithelial cells: potential role in mononuclear cell adhesion. ClinExp Immunol. 2002,129(1) : 150-159.
[13] Rodriguez-Iturbe B, Johnson RJ, Herrera - Acosta J. Tubulointerstitial damage and progression of renal failure. Kidney Int Suppl. 2005 (99): S82-S86.
[14] Meyers J H, Chakravarti S, Schlesinger D, et al. TIM-4 is the ligand for TIM-1,and the TIM-1-TIM-4 interaction regulates T cell proliferation. Nat Immunol.2005,6(5): 455-464.
[15] Mclntire JJ, Umet su SE, Akbari O, et al. Identification of Tapr (an airway hyperreactivity regulatory locus ) and the linked Tim gene family. Nat Immunol. 2001,2 (12): 1109-1116.
[16] Kuchroo V K, Umet su DT, DeKruyff RH, et al. The TIM gene family: emerging roles in immunity and disease. Nat Rev Immunol. 2003, 3 (6):454-462.
[17] Vaidya VS, Ramirez V, Ichimura T, et al. Urinary kidney injury molecule - 1:a sensitive quantitative biomarker for early detection of kidney tubular injury.Am J Physiol Renal Physiol. 2006 ,290 (2): F517-F529.
[18] Han WK, Bailly V, Abichandani R, et al. Kidney injury molecule-1 (KIM -1): a novel biomarker for human renal proximal tubule injury. Kidney Int.2002,62(1): 237-244.
[19] Liangos O, Perianayagam MC,Vaidya VS ,et al. Urinary N -acetyl - beta - (D) -glucosaminidase activity and kidney injury molecule - 1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol. 2007,18(3):904-912.
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[22]Han WK,Alinani A,Wu CL,et al.Human kidney injury molecule-1 is a tissue and urinary tumor marker of renal cell carcinoma.J Am Soc Nephrol.2005,16(4):1126-1134.
[23]急性肾损伤专家共识小组.急性肾损伤诊断与分类专家共识.中华肾脏病杂志.2006,22(11):661-663.
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[25]Chertow GM,Burdick E,Honour M,et al.Acute Kidney Injury,Mortality,Length of Stay,and Costs in Hospitalized Patients.J Am Soc Nephrol.2005,16(7):3365-3370.
[26]吉程程,梅长林.急性肾损伤定义、诊断及防治进展.中国血液净化.2008,7(1):46-48.
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