中性粒细胞明胶酶相关运载蛋白在过敏性紫癜患儿肾小管上皮细胞转分化过程中的变化和意义
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摘要
研究背景与研究目的：
过敏性紫癜(Henoch-Schonlein purpura, HSP)是一种以变态反应性炎症为主要病理改变的系统性小血管炎,肾脏受累与否是决定其预后的关健因素,由紫癜性肾炎(Henoch-Schonlein purpura nephropathy, HSPN)导致的急慢性肾功能衰竭是HSP患儿死亡的主要原因。但是,HSPN的确切发病机制至今仍不清楚,关于其治疗也尚无统一有效的药物。已知细胞外基质(Extracellular matrix, ECM)的产生过多而降解减少导致ECM过度沉积是肾小球硬化、肾脏纤维化的主要原因。而HSPN的主要病理特点为系膜细胞增生,大量基质堆积,系膜区变宽、基底膜增厚,随着病情进展逐步发展为肾小球硬化,最终导致整个肾脏功能的丧失。近年研究发现肾小管上皮细胞转分化(epithelial-mesenchymal transition, EMT)是肾间质纤维化的关键。α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA),作为肌成纤维细胞的标志蛋白,现被普遍用于检测肾小管上皮细胞向肌成纤维细胞的表型转化。已有研究证明中性粒细胞明胶酶相关运载蛋白(neutrophil gelatinase-associated lipocalin, NGAL)可以通过多种途径影响到肾脏纤维化,促进肾小管细胞的增生和修复。本实验将通过观察HSP及HSPN患儿肾组织α-SMA、NGAL的表达及变化以及NGAL在这些患儿血清和尿中的变化,探讨其在HSPN发生、发展中的作用,为HSPN的早期诊断和估计病情提供新的思路。
研究方法：
选择临床诊断为HSP的患儿81例,根据HSP患儿急性期尿微量白蛋白排泄率(urinary albumin excretion rate, UAER)的不同将其分为：正常白蛋白尿组(A组,38例)：UAER<20μg／min；微量白蛋白尿组(B组,26例)：UAER 20-200μg／min；大量白蛋白尿组(C组,17例)：UAER>200μg／min或总蛋白>50mg／kg·d。以年龄、性别相匹配的正常健康体检儿童35例(男20例,女15例,平均年龄7.6岁)作为健康对照组(D组)。81例HSP患儿中共有22例于急性期行经皮肾穿刺活检,其中,A组5例,B组9例；C组8例,以2例无肾脏病史因外伤而行肾切除患者的肾组织作为对照。
2.血清和尿NGAL的检测：采用酶联免疫吸附法(ELISA)
3.肾组织病理形态学的观察
各组肾组织石蜡切片分别进行苏木精-伊红(HE)和过碘酸-希夫氏(PAS)染色,光镜下观察,对肾脏病理损害程度进行分级。
4.肾组织α-SMA、NGAL和Ⅳ型胶原表达的检测
采用免疫组织化学SABC法检测肾组织α-SMA、NGAL和Ⅳ型胶原的表达,应用Image-Pro plus图像分析软件测定α-SMA、NGAL和Ⅳ型胶原的累积光密度值(IOD)。
5.统计学处理
统计学处理采用SPSS 16.0软件进行统计学处理,所有实验数据数据均用x±s表示,各组间比较采用最小显著差(LSD)t检验。部分指标进行直线相关分析,P<0.05为差异有统计学意义。研究结果：
1.HSP急性期各组患儿血清和尿液NGAL的变化：与正常对照组比较,A、B组患儿血清NGAL浓度变化无统计学意义,C组明显增高(P<0.05)；与正常对照组比较,A、B、C组患儿尿NGAL水平均明显升高(A组P<0.05,B组P<0.01,C组P<0.01),且随尿白蛋白排泄率的增加而呈递增趋势
(P<0.05)：
2.HSP患儿肾组织α-SMA的表达：在正常的肾组织中仅有少量或无α-SMA的表达,HSP患儿肾组织α-SMA的表达较之有明显的增加,且在A、B、C组呈递增趋势(P<0.05)。
3.HSP患儿肾组织Ⅳ型胶原的表达：在正常的肾组织中仅有少量或无Ⅳ型胶原的表达,HSP患儿肾组织Ⅳ型胶原的表达较之有明显的增加,且在A、B、C组呈递增趋势(P<0.05)。
4.HSP患儿肾组织NGAL的表达：在正常的肾组织中仅有少量或无NGAL的表达,HSP患儿肾组织NGAL的表达较之有明显的增加,且在A、B、C组呈递增趋势(P<0.05)。
5.相关分析结果显示肾组织NGAL与Ⅳ型胶原表达呈正相关, (r=0.823,P<0.01)；HSP患儿肾组织NGAL的表达与尿NGAL水平呈正相关(r=0.604,P=0.03)；HSP患儿肾组织NGAL表达与α-SMA表达也呈正相关,(r=0.792,P<0.01)。
研究结论：
1.随着尿白蛋白的升高和肾组织病理损害的加重,HSP患儿尿NGAL水平和肾组织NGAL也呈递增趋势,提示NGAL与HSPN的发生和发展有关。
2.HSP患儿肾组织存在α-SMA的异常表达,表明在HSPN的发生和发展中存在肾小管上皮细胞转分化,并且α-SMA在正常白蛋白尿组就已表达,表明这种转化在正常白蛋白尿组就已发生。
3.肾组织NGAL与α-SMA呈正相关,提示NGAL可能对EMT起调节作用。
4.HSP患儿的尿NGAL水平与肾组织NGAL的表达呈正相关,提示尿NGAL的水平可以反映肾组织中NGAL的表达水平。
5.HSP患儿在正常白蛋白尿组尿NGAL水平已升高,提示其可作为早于尿白蛋白的早期诊断HSPN的敏感指标。
Background and objective:
It is well known that Henoch-Schonlein purpura (HSP) is a systemic abnormal reactive vasculitis, and renal function failure induced by progressive Henoch-Schonlein purpura nephropathy (HSPN) is the primary cause of the mortality. However, the exact pathogenesis of HSPN remains unknown, and no unified and effective medicine have been found to heal HSPN. The pathological hallmarks of HSPN are mesangial cell proliferation and extracellular matrix(ECM) accumulation, which lead to increased thickness of the glomerular and tubular basement membrane(GBM) and mesangial expansion, and finally result in glomerulosclerosis and loss of the renal function. These mainly result from an imbalance between the synthesis and degradation of ECM. Recent study show that epithelial-mesenchymal transition is the key point of renal fibrosis.α-Smooth Muscle Actin, as the marker of myofibroblast, is generally used to detect the phenotype transformation from renal tubular epithelial cell to myofibroblast. Most study have indicate that neutrophil gelatinase associated lipocalin can decrease the degree of renal fibrosis by many ways and promote a certain proliferative effect on renal tubular cell. In this study, we examined the expression of a-SMA and NGAL in renal tissue of HSP children and HSPN children, also detected serum and urinary changes of NGAL in these cases, discussed their function in the development and progression of HSPN. Our results suggest novel approaches for the early diagnosis and accurate evaluation of HSPN progression.
Methods:
1. Subjects:
Our study included 81 patients who had been diagnosed with HSP and 35 healthy children as the control. Based on the urinary albumin excretion rate (UAER) in the acute phase, the HSP children were divided into three groups. Group A (the normoalbuminuria group, N= 38), group B (the microalbuminuria group, N=26), and group C (the macroalbuminuria group, N=17). Among the above 81 patients, 22 received renal biopsy in the acute phase, including five children from group A, nine children from group B, and eight children from group C. The control kidney samples were taken from the normal portions of nephrectomy specimens of patients who underwent surgery due to trauma.
2.Blood serum and urinary NGAL excretion was determined by ELISA.
3. Renal pathology observation:The nephridial tissues were stained by HE and PAS seperately, then observed by a light microscope.
4.α-SMA/ NGAL andⅣ-collagen expression in renal tissues: Immunoenzymic-SABC method was applied, then film reading was viewed by LEICA Qwin V3 image processing system and Image-Pro plus software was used to determine the integral optical density (IOD) ofα-SMA/NGAL andⅣ-collagen exression.
5. Statistical methods:
Software used:SPSS 16.0
Data representation:x±SD
Comparison among control group and HSP groups:the least significant difference, LSD (P＜0.05)
Association between the urinary NGAL level and the renal NGAL expression and the renal NGAL expression with a-SMA expression:linear correlation analysis
Results:
1.The blood serum and urinary NGAL level in acute phase
Compared with the control group, the serum NGAL level in group A and B were not found statistical difference(P＞0.05), howerve, the serum NGAL level in group C was increased obviously(P＜0.05). The urinary NGAL level was increased in group A (P＜0.05)、group B (P＜0.01) and group C(P＜0.01).
2. The a-SMA expression in kidney
None or little a-SMA was expressed in the renal tissues of the controls while much more a-SMA was apparently expressed in the HSP patients. The IOD ofα-SMA staining was increased with the aggravate of renal damage(P＜0.05).
3. TheⅣ-collagen expression in kidney
None or littleⅣ-collagen was expressed in the renal tissues of the controls while much moreⅣ-collagen was apparently expressed in the HSP patients. The IOD ofⅣ-collagen staining was increased with the aggravate of renal damage(P＜0.05).
4. The NGAL expression in kidney
None or little NGAL was expressed in the renal tissues of the controls while much more NGAL was apparently expressed in the HSP patients. The IOD of NGAL staining was increased with the aggravate of renal damage(P＜0.05).
5. The correlation
The linear correlation analysis revealed a tight correlation between NGAL expression andⅣ-collagen expression (r=0.823, P＜0.01)
The linear correlation analysis revealed a tight correlation between urinry NGAL level and renal NGAL expression (r=0.604, P=0.03).
The linear correlation analysis revealed a tight correlation between NGAL expression and a-SMA expression (r=0.792, P＜0.01)
Conclusion:
1. NGAL is related to the development and progression of HSPN, expression of NGAL will increase along with the aggravation of pathological damages in HSPN cases.
2. Children with HSP has a-SMA expression, which show there exists EMT of renal tubular epithelial cells in Children with HSPN, and a-SMA has expressed in normal albuminuria group, which can indicate this change has appeared in normal albuminuria group.
3. The linear correlation between NGAL expression andα-SMA expression is positive, which prompt that NGAL can accommodate the process of EMT.
4. In children with HSP, NGAL levels in urine is significantly positively related to expression of NGAL, this result reveals NGAL level in urine can reflect levels of NGAL expression in renal tissue.
5. The urinary NGAL is appeared in normal albuminuria group which indicate NGAL could be an early marker for predicting HSPN.
过敏性紫癜(Henoch-Schonlein purpura, HSP)是一种以变态反应性炎症为主要病理改变的系统性小血管炎,肾脏受累与否是决定其预后的关健因素,由紫癜性肾炎(Henoch-Schonlein purpura nephropathy, HSPN)导致的急慢性肾功能衰竭是HSP患儿死亡的主要原因。但是,HSPN的确切发病机制至今仍不清楚,关于其治疗也尚无统一有效的药物。已知细胞外基质(Extracellular matrix, ECM)的产生过多而降解减少导致ECM过度沉积是肾小球硬化、肾脏纤维化的主要原因。而HSPN的主要病理特点为系膜细胞增生,大量基质堆积,系膜区变宽、基底膜增厚,随着病情进展逐步发展为肾小球硬化,最终导致整个肾脏功能的丧失。近年研究发现肾小管上皮细胞转分化(epithelial-mesenchymal transition, EMT)是肾间质纤维化的关键。α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA),作为肌成纤维细胞的标志蛋白,现被普遍用于检测肾小管上皮细胞向肌成纤维细胞的表型转化。已有研究证明中性粒细胞明胶酶相关运载蛋白(neutrophil gelatinase-associated lipocalin, NGAL)可以通过多种途径影响到肾脏纤维化,促进肾小管细胞的增生和修复。本实验将通过观察HSP及HSPN患儿肾组织α-SMA、NGAL的表达及变化以及NGAL在这些患儿血清和尿中的变化,探讨其在HSPN发生、发展中的作用,为HSPN的早期诊断和估计病情提供新的思路。
研究方法：
选择临床诊断为HSP的患儿81例,根据HSP患儿急性期尿微量白蛋白排泄率(urinary albumin excretion rate, UAER)的不同将其分为：正常白蛋白尿组(A组,38例)：UAER<20μg／min；微量白蛋白尿组(B组,26例)：UAER 20-200μg／min；大量白蛋白尿组(C组,17例)：UAER>200μg／min或总蛋白>50mg／kg·d。以年龄、性别相匹配的正常健康体检儿童35例(男20例,女15例,平均年龄7.6岁)作为健康对照组(D组)。81例HSP患儿中共有22例于急性期行经皮肾穿刺活检,其中,A组5例,B组9例；C组8例,以2例无肾脏病史因外伤而行肾切除患者的肾组织作为对照。
2.血清和尿NGAL的检测：采用酶联免疫吸附法(ELISA)
3.肾组织病理形态学的观察
各组肾组织石蜡切片分别进行苏木精-伊红(HE)和过碘酸-希夫氏(PAS)染色,光镜下观察,对肾脏病理损害程度进行分级。
4.肾组织α-SMA、NGAL和Ⅳ型胶原表达的检测
采用免疫组织化学SABC法检测肾组织α-SMA、NGAL和Ⅳ型胶原的表达,应用Image-Pro plus图像分析软件测定α-SMA、NGAL和Ⅳ型胶原的累积光密度值(IOD)。
5.统计学处理
统计学处理采用SPSS 16.0软件进行统计学处理,所有实验数据数据均用x±s表示,各组间比较采用最小显著差(LSD)t检验。部分指标进行直线相关分析,P<0.05为差异有统计学意义。研究结果：
1.HSP急性期各组患儿血清和尿液NGAL的变化：与正常对照组比较,A、B组患儿血清NGAL浓度变化无统计学意义,C组明显增高(P<0.05)；与正常对照组比较,A、B、C组患儿尿NGAL水平均明显升高(A组P<0.05,B组P<0.01,C组P<0.01),且随尿白蛋白排泄率的增加而呈递增趋势
(P<0.05)：
2.HSP患儿肾组织α-SMA的表达：在正常的肾组织中仅有少量或无α-SMA的表达,HSP患儿肾组织α-SMA的表达较之有明显的增加,且在A、B、C组呈递增趋势(P<0.05)。
3.HSP患儿肾组织Ⅳ型胶原的表达：在正常的肾组织中仅有少量或无Ⅳ型胶原的表达,HSP患儿肾组织Ⅳ型胶原的表达较之有明显的增加,且在A、B、C组呈递增趋势(P<0.05)。
4.HSP患儿肾组织NGAL的表达：在正常的肾组织中仅有少量或无NGAL的表达,HSP患儿肾组织NGAL的表达较之有明显的增加,且在A、B、C组呈递增趋势(P<0.05)。
5.相关分析结果显示肾组织NGAL与Ⅳ型胶原表达呈正相关, (r=0.823,P<0.01)；HSP患儿肾组织NGAL的表达与尿NGAL水平呈正相关(r=0.604,P=0.03)；HSP患儿肾组织NGAL表达与α-SMA表达也呈正相关,(r=0.792,P<0.01)。
研究结论：
1.随着尿白蛋白的升高和肾组织病理损害的加重,HSP患儿尿NGAL水平和肾组织NGAL也呈递增趋势,提示NGAL与HSPN的发生和发展有关。
2.HSP患儿肾组织存在α-SMA的异常表达,表明在HSPN的发生和发展中存在肾小管上皮细胞转分化,并且α-SMA在正常白蛋白尿组就已表达,表明这种转化在正常白蛋白尿组就已发生。
3.肾组织NGAL与α-SMA呈正相关,提示NGAL可能对EMT起调节作用。
4.HSP患儿的尿NGAL水平与肾组织NGAL的表达呈正相关,提示尿NGAL的水平可以反映肾组织中NGAL的表达水平。
5.HSP患儿在正常白蛋白尿组尿NGAL水平已升高,提示其可作为早于尿白蛋白的早期诊断HSPN的敏感指标。
Background and objective:
It is well known that Henoch-Schonlein purpura (HSP) is a systemic abnormal reactive vasculitis, and renal function failure induced by progressive Henoch-Schonlein purpura nephropathy (HSPN) is the primary cause of the mortality. However, the exact pathogenesis of HSPN remains unknown, and no unified and effective medicine have been found to heal HSPN. The pathological hallmarks of HSPN are mesangial cell proliferation and extracellular matrix(ECM) accumulation, which lead to increased thickness of the glomerular and tubular basement membrane(GBM) and mesangial expansion, and finally result in glomerulosclerosis and loss of the renal function. These mainly result from an imbalance between the synthesis and degradation of ECM. Recent study show that epithelial-mesenchymal transition is the key point of renal fibrosis.α-Smooth Muscle Actin, as the marker of myofibroblast, is generally used to detect the phenotype transformation from renal tubular epithelial cell to myofibroblast. Most study have indicate that neutrophil gelatinase associated lipocalin can decrease the degree of renal fibrosis by many ways and promote a certain proliferative effect on renal tubular cell. In this study, we examined the expression of a-SMA and NGAL in renal tissue of HSP children and HSPN children, also detected serum and urinary changes of NGAL in these cases, discussed their function in the development and progression of HSPN. Our results suggest novel approaches for the early diagnosis and accurate evaluation of HSPN progression.
Methods:
1. Subjects:
Our study included 81 patients who had been diagnosed with HSP and 35 healthy children as the control. Based on the urinary albumin excretion rate (UAER) in the acute phase, the HSP children were divided into three groups. Group A (the normoalbuminuria group, N= 38), group B (the microalbuminuria group, N=26), and group C (the macroalbuminuria group, N=17). Among the above 81 patients, 22 received renal biopsy in the acute phase, including five children from group A, nine children from group B, and eight children from group C. The control kidney samples were taken from the normal portions of nephrectomy specimens of patients who underwent surgery due to trauma.
2.Blood serum and urinary NGAL excretion was determined by ELISA.
3. Renal pathology observation:The nephridial tissues were stained by HE and PAS seperately, then observed by a light microscope.
4.α-SMA/ NGAL andⅣ-collagen expression in renal tissues: Immunoenzymic-SABC method was applied, then film reading was viewed by LEICA Qwin V3 image processing system and Image-Pro plus software was used to determine the integral optical density (IOD) ofα-SMA/NGAL andⅣ-collagen exression.
5. Statistical methods:
Software used:SPSS 16.0
Data representation:x±SD
Comparison among control group and HSP groups:the least significant difference, LSD (P＜0.05)
Association between the urinary NGAL level and the renal NGAL expression and the renal NGAL expression with a-SMA expression:linear correlation analysis
Results:
1.The blood serum and urinary NGAL level in acute phase
Compared with the control group, the serum NGAL level in group A and B were not found statistical difference(P＞0.05), howerve, the serum NGAL level in group C was increased obviously(P＜0.05). The urinary NGAL level was increased in group A (P＜0.05)、group B (P＜0.01) and group C(P＜0.01).
2. The a-SMA expression in kidney
None or little a-SMA was expressed in the renal tissues of the controls while much more a-SMA was apparently expressed in the HSP patients. The IOD ofα-SMA staining was increased with the aggravate of renal damage(P＜0.05).
3. TheⅣ-collagen expression in kidney
None or littleⅣ-collagen was expressed in the renal tissues of the controls while much moreⅣ-collagen was apparently expressed in the HSP patients. The IOD ofⅣ-collagen staining was increased with the aggravate of renal damage(P＜0.05).
4. The NGAL expression in kidney
None or little NGAL was expressed in the renal tissues of the controls while much more NGAL was apparently expressed in the HSP patients. The IOD of NGAL staining was increased with the aggravate of renal damage(P＜0.05).
5. The correlation
The linear correlation analysis revealed a tight correlation between NGAL expression andⅣ-collagen expression (r=0.823, P＜0.01)
The linear correlation analysis revealed a tight correlation between urinry NGAL level and renal NGAL expression (r=0.604, P=0.03).
The linear correlation analysis revealed a tight correlation between NGAL expression and a-SMA expression (r=0.792, P＜0.01)
Conclusion:
1. NGAL is related to the development and progression of HSPN, expression of NGAL will increase along with the aggravation of pathological damages in HSPN cases.
2. Children with HSP has a-SMA expression, which show there exists EMT of renal tubular epithelial cells in Children with HSPN, and a-SMA has expressed in normal albuminuria group, which can indicate this change has appeared in normal albuminuria group.
3. The linear correlation between NGAL expression andα-SMA expression is positive, which prompt that NGAL can accommodate the process of EMT.
4. In children with HSP, NGAL levels in urine is significantly positively related to expression of NGAL, this result reveals NGAL level in urine can reflect levels of NGAL expression in renal tissue.
5. The urinary NGAL is appeared in normal albuminuria group which indicate NGAL could be an early marker for predicting HSPN.
引文
[1]赵丹,王君,李惠芳,等.儿童过敏性紫癜性肾炎药物治疗的Mete分析.中国循证儿科杂志2007,2(2)：88-100.
[2]张宇,卢立肖 儿童紫癜性肾炎的临床和病理研究 中国中西医结合肾病杂志2008,11：9(11)：981-983.
[3]Pillebout E, Nochy D, Thervet E. Henoch-Shonlein purpura. Nephrol Ther. 2009,5 (7):663-675.
[4]中华医学会儿科学分会肾脏病学组.91所医院1990-2002年小儿慢性肾衰竭1268例调查报告.中华儿科杂志,2004,42(10)：724-730.
[5]Junwei Yang, Youhua Liu. Dissection of key events in tubular epithelial to myofibroblast transition and its implication in renal interstitialfibrosis. Amerian Journal of Path,2001; 159 (4):1465-1476.
[6]Rhyu DY,Yang Y,Ha H,et al.Role of reactive oxygen species in TGF-betal-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells[J].J Am Soc Nephrol,2005, 16(3):667.
[7]樊力NGAL和肾脏纤维化.国际泌尿系统杂志2007,27(6)：848-851.
[8]Haycock GB The nephritis of Henoch-Schonlein purpura. In:Cameron JS (ed) Oxford textbook of nephrology,2nd edn. Oxford University Press, Oxford,1998,2: 585-612
[9]Coppo R, Mazzucco G, Cagnoli L, Lupo A, Schena P, Italian Group of Renal Immunopathology Collaborative Study on Henoch-Schonlein Purpura Long-term prognosis of Henoch-Schonlein nephritis in adults and children. Nephrol Dial Transplant,1997,12 (11):2277-2283
[10]Liu Y. Epithelial to Mesenchymal Transition in Renal Fibrogenesis:Pathologic Significance, Molecular Mechanism, and Therapeutic Intervention. J Am Soc Nephrol. 2004 Jan;15(1):1-12.
[11]王强,刘献华.尿微量蛋白对过敏性紫癜患儿肾损害的早期诊断价值.实用儿科临床杂志.2003,9(18)：693-694.
[12]Okonogi H,Nishimura M,Utsunomiya Y,et al.Urinary type IV collagen excretion reflects renal morphological alterations and type IV collagen expression in patients with type 2 diabetes mellitus[J].Clin Nephrol,2001,55(5):357-364.
[13]Yang J, Dai C, Liu Y. A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchy maltransition [J]. JAm SocNephro,l 2005,16(1): 68-78.
[14]JindeK,Nikolic-Paterson DJ,HuangXR,etal.Tubularphenotypic change in progressive tubulointerstitial fibrosis in human glomerulo-nephritis. [J].Am JKidneyDis,2001,38(4):761-769.
[15]Fan JM, NgYY, HillPA, eta.l Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiationin vitro[J].Kidney Int,1999,56 (4):1455-1467.
[16]BrunskillNJ. Albumin signals the coming of age of proteinuric nephropathy [J]. J Am Soc Nephro,l 2004,15(2):504-505.
[17]Yang JW, Dai CS, Liu YH. Hepatocyte growth factor gene therapy and angiotensin Ⅱ blockade synergistically attenuate renal interstitial fibrosis inmice [J]. JAm Soc Nephro,l 2002,13(10):2464-2477.
[18]Coles M, Diercks T, Muehlenweg Bet al.The solution structure and dynamics of human neutrophil gelatinase-associated lipocalin. J Mol Biol,1999,289(1):139
[19]Fried A,Stoesz S P,Buckley P,et al.Neutrophil gelatinase-associated in mormal and neoplastic human tissues.Cell type specific pattern of expression[J]. Histochem J,1999,31(7):433-441.
[20]Cecilia A, Fernandez, Li Yan, et al. The matrix metalloproteinase-9/ neutrophil gelatinase- associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancerpatients. Clin Cancer Res,2005, 11(15):5390-5395.
[21]Yang J. An iorn delivery pathway mediated reperfusion injury. J Mol Cell,2002, 10:1045-1056.
[22]Mori K, Lee HT, Rapoport D et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemiareperfusion injury. J Clin Invest 2005; 115:610-621
[23]Kalluril R, Neilson EG. Epithelial -mesenchymal transition and its implications for fibrosis. J Clin Invest,2003,112(12):1776-1784.
[24]Jun-ichi H, Tadanori, Pankaj S, et al. Lipccalin2 diminishes invasiveness and metastasis of ras-transformed cells. J Biol Chem,2005, 208(4):13641-13647.
[25]Yang J, Morik, Li JY, et al. Iron, Lipocalin and kidney epithelial. AmJ Physiol Renal Ph ysiol,2003,285(3):F9-F18.
[26]Nagase H, Woessner J F, et al. Matrixmetalloproteinase. J Biol Chem,1999, 274(31):21491-21494.
[27]Jiang Yang, Li Yan, Marsha A, Moses. Over expression of neutrophil gelatinase-associated lipocalin(NGAL)induce epithelial-myofibroblast transition in MCF-7 breast cancer cells AACR meeting ab stracts,2005:1138
[28]刘欣颖,罗海,王宓,等.肝细胞生长因子对IL-lot刺激肾小管上皮细胞肌纤维母细胞转分化的作用.四川大学学报(医学版),2005,36(1)：9—12.
[29]Ferris CD, Jaffrey SR, Sawa Aetal. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol,1999,1(3):152
[30]Junwei Yang, Youhua Liu. Dissection of key events in tubular epithelial to myofibroblast transition and its implication in renal interstitialfibrosis. Amerian Journal of Path,2001; 159 (4):1465-1476.
[31]丁文捷,孙书珍,等.过敏性紫癜患儿尿中肝细胞生长因子的检测及临床意义.中国实用儿科杂志,2009；24(5)：251-253.
[32]Schmidt-Ott KM, Mori K, Li JY, et al:Dual action of neutrophil gelatinase-Associated lipocalin. J Am Soc Nephrol 18:407-413,2007
[33]Mori K, Lee HT, Rapoport D et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemiareperfusion injury. J Clin Invest 2005; 115:610-621
[34]Hailing SF, Soderberg MP, Berg UB. Henoch Schonlein nephritis:clinical findings related to renal function and morphology. Pediatr Nephrol.2005 Jan;20(1):46-51.
[1]Kjeldsen L,Johnsen A H,Sengelov H,et al.Isolation and primary structure of NGAL,a novel protein associated with human neutrophil gelatinase[J].J Biol Chem,1993,268(14):10425-10432.
[2]许丽艳,李恩民,熊华琪.NGAL的结构与功能研究进展[J].生命科学,2002,14(1)：27-29.
[3]Fried A,Stoesz S P,Buckley P,et al.Neutrophil gelatinase-associated in mormal and neoplastic human tissues.Cell type specific pattern of expression[J]. Histochem J,1999,31(7):433-441.
[4]Devireddy LR, Gazin C, Zhu X, Green MR:A cellsurface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 2005,123:1293-1305.
[5]Hvidberg V, Jacobsen C, Strong RK, Cowland JB, Moestrup SK, Borregaard N: The endocytic receptor megalin binds the iron transporting neutrophil-gelatinase-associated lipocalin with high affinity and mediates its cellular uptake. FEBS Lett 2005,579:773-777.
[6]Yan L, Borregaard N, Kjeldsen L, Moses MA:The high molecular weight urinary matrix metalloproteinase(MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin(NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem 2001,276:37258-37265.
[7]Yang J, Goetz D, Li JY, et al:An iron delivery pathway mediated by a lipocalin. Mol Cell 2002,10:1045-1056.
[8]Flo TH, Smith KD, Sato S, et al:Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 2004,432:917-921.
[9]Gwira JA, Wei F, Ishibe S, Uelang JM, Barasch J, Cantley LG:Expression of neutrophil gelatinase-associated lipocalin regulates epithelial morphogenesis in vitro. J Biol Chem 2005,280:7875-7882.
[10]Berger T, Togawa A, Duncan GS, et al:Lipocalin2-deficient mice exhibit increased semsitivity to Escherichia coli infection but not to ischemia-reperfusion injury. Proc Natl Acad Sci USA 2006,103:1834-1839.
[11]Fjaertoft G, Foucard T, Xu S, Venge P:Human neutrophil lipocalin(HNL) as a diagnostic tool in children with acute infections:A study of the kinetics. Acta Paediatr 2005,94:661-666.
[12]Playford RJ, Belo A, Poulsom R,et al:Effects of mouse and human lipocalin homologues 24p3/1cn2 and neutrophil gelatinase-associated lipocalin on gastrointestinal mucosal integrity and repair. Gastroenterology 2006,131:809-817.
[13]Cowland JB, Sorensen OE, Sehested M, Borregaard N:Neutrophil gelatinase-Associated lipocalin is up-regulated in human epithelial cells by IL-1 beta, but not by TNF-alpha. J Immunol 2003,171:6630-6639.
[14]Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P:Neutrophil gelatinase-Associated lipocalin:A Novel early urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol 2004,24:307-315.
[15]Mishra J, Ma Q, Prada A,et al:Identification of neutrophil gelatinase-associated Lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003,14:2534-2543.
[16]Mishra J, Mori K, Ma Q, et al:Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin.J Am Soc Nephrol 2004,15:3073-3082.
[17]Mishra J, Dent C, Tarabishi R, et al:Neutrophilgelatinase-associated lipocalin(NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005,365:1231-1238.
[18]Hirsch R, Dent C, Pfriem H,et al:NGAL is an early predictive biomarker of contrast-induced nephropathy in children.Pedoatr Nephrol.2007,22:2089-2095.
[19]Wagener G,Jan M,Kim M,et al:Association between increases in urinary neutrophil Neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery.Anesthesiology.2006,105:485-491.
[20]Bachorzewska-Gajewska H,Malyszko J,Sitniewska E,MalyszkoJS,Dobrzycki S:Neutr-ophil-gelatinase-associated lipocalin and renal function after percutaneous cornonary inteventions,Am J Nephrol.2006,26:287-292.
[21]Bachorzewska-Gajewska E, Malyszko J, Sitniewska E, Malyszko JS, Dobrzycki S:Neutrophil gelatinase-associated lipocalin(NGAL) correlations with cystatin C,Serum creatinine and eGFR in patients with normal serum creatinine undergoing coronary angiography. Nephrol Dial Transplant.2007,22:295-296.
[22]Boldt J, Brosch C, Ducke M et al. Influence of volume therapy with a modern hydroxyethylstarch preparation on kidney function in cardiac surgery patients with compromised renal function:a comparison with human albumin. Crit Care Med.2007; 35:2740-2746.
[23]Boldt J, Brosch CH, Rohm K et al. Comparison of the effects of gelatin and a modern hydroxyethylstarch solution on renal function and inflammatory response in elderly cardiac surgery patients. Br JAnaesth 2008; 100:457-464.
[24]Haase M, Fielitz-Haase A, Bellomo R et al. Sodium bicarbonate toprevent acute kidney injury after cardiac surgery:a pilot doubleblind, randomised controlled trial. Nephrol Dial Transplant.2008;1(Suppl.2):212-215.
[25]Wagener G, Gubitosa G, Wang S et al. Increased incidence of acute kidney injury with aprotinin use during cardiac surgery detected with urinary NGAL. Am J Nephrol.2008; 28:576-582.
[26]Trachtman H, Christen E, Cnaan A et al. Urinary neutrophil gelatinase-associated lipocalcin in D+HUS:a novel marker of renal injury. Pediatr Nephrol. 2006; 21:989-994.
[27]Mishra J, Ma Q, Kelly C et al. Kidney NGAL is a novel early marker of acute injury following transplantation. Pediatr Nephrol.2006; 21:856-863.
[28]Parikh CR, Jani A, Mishra J et al. Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation. Am J Transplant.2006; 6:1639-1645.
[29]Kusaka M, Kuroyanagi Y, Mori T et al. Serum neutrophil gelatinaseassociated lipocalin as a predictor of organ recovery from delayed graft function after kidney transplantation from donors after cardiac death. Cell Transplant.2008; 17:129-34.
[30]Schmidt-Ott KM, Mori K, Li JY, et al:Dual action of neutrophil gelatinase-Associated lipocalin. J Am Soc Nephrol.2007,18:407-413.
[31]Mori K, Lee HT, Rapoport D et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemiareperfusion injury. J Clin Invest.2005; 115:610-621.
[32]Ma Q, Devarajan P. Induction of proapoptotic Daxx following ischemic acute kidney injury. Kidney Int.2008; 74:310-318.
[33]Arany I. When less is more:apoptosis during acute kidney injury.Kidney Int. 2008; 74:261-262.
[34]Srichai MB, Hao C, Davis L et al. Apoptosis of the thick ascending limb results in acute kidney injury. J Am Soc Nephrol.2008; 19:1538-1546.
[35]Castaneda MP, Swiatecka-Urban A, Mitsnefes MM et al. Activation of mitochondrial apoptotic pathways in human renal allografts after ischemia-reperfusion injury. Transplantation.2003; 76:50-54.
[36]Grigoryev DN, Liu M, Hassoun HT et al. The local and systemic inflammatory transcriptome after acute kidney injury. J Am Soc Nephrol.2008; 19:547-558.
[37]Liu Q, Nilsen-Hamilton M. Identification of a newacute phase protein. J Biol Chem.1995; 270:22565-22570.
[38]Brunner HI, Mueller M, Rutherford C, et al:Urinary neutrophil gelatinase-associated lipocalin as a biomarker of nephritis in childhood-onset systemic lupus erythematosus. Arthritis Rheum.2006,54: 2577-2584.
[39]Mitsnefes MM, Kathman TS, Mishra J, et al:Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in children with chronic kidney disease. Pediatr Nephrol.2007,22:101-108.
[40]Ding H, He Y, Li K, Yang J, Li X, Lu R, et al. Urinary neutrophil gelatinase-associated lipocalin(NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy. Clin Immunol.2007; 123:227-234.
[41]Bolignano D, Coppolino G, Campo S,et al:Urinary neutrophil gelatinase-associated lipocalin (NGAL) is associated with severity of renal disease in proteinuric patients. Nephrol Dial Transplant.2008,23:414-416.
[42]Mori K, Nakao k:Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage. Kidney Int.2007,71:967-970.
[43]Abbate M, Zoja C, Remuzzi G:How does proteinuria cause progressive renal damage? J Am Soc Nephrol.2006,17:2974-2984.
[44]Morita Y, Ikeguchi H, Nakamura J, Hotta N, Yuzawa Y, Matsuo S:Complement activation Products in the urine from proteinuric patients. J Am Soc Nephrol.2000, 11:700-707
[45]樊力NGAL和肾脏纤维化.国际泌尿系统杂志2007,27(6)：848-851.
[2]张宇,卢立肖 儿童紫癜性肾炎的临床和病理研究 中国中西医结合肾病杂志2008,11：9(11)：981-983.
[3]Pillebout E, Nochy D, Thervet E. Henoch-Shonlein purpura. Nephrol Ther. 2009,5 (7):663-675.
[4]中华医学会儿科学分会肾脏病学组.91所医院1990-2002年小儿慢性肾衰竭1268例调查报告.中华儿科杂志,2004,42(10)：724-730.
[5]Junwei Yang, Youhua Liu. Dissection of key events in tubular epithelial to myofibroblast transition and its implication in renal interstitialfibrosis. Amerian Journal of Path,2001; 159 (4):1465-1476.
[6]Rhyu DY,Yang Y,Ha H,et al.Role of reactive oxygen species in TGF-betal-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells[J].J Am Soc Nephrol,2005, 16(3):667.
[7]樊力NGAL和肾脏纤维化.国际泌尿系统杂志2007,27(6)：848-851.
[8]Haycock GB The nephritis of Henoch-Schonlein purpura. In:Cameron JS (ed) Oxford textbook of nephrology,2nd edn. Oxford University Press, Oxford,1998,2: 585-612
[9]Coppo R, Mazzucco G, Cagnoli L, Lupo A, Schena P, Italian Group of Renal Immunopathology Collaborative Study on Henoch-Schonlein Purpura Long-term prognosis of Henoch-Schonlein nephritis in adults and children. Nephrol Dial Transplant,1997,12 (11):2277-2283
[10]Liu Y. Epithelial to Mesenchymal Transition in Renal Fibrogenesis:Pathologic Significance, Molecular Mechanism, and Therapeutic Intervention. J Am Soc Nephrol. 2004 Jan;15(1):1-12.
[11]王强,刘献华.尿微量蛋白对过敏性紫癜患儿肾损害的早期诊断价值.实用儿科临床杂志.2003,9(18)：693-694.
[12]Okonogi H,Nishimura M,Utsunomiya Y,et al.Urinary type IV collagen excretion reflects renal morphological alterations and type IV collagen expression in patients with type 2 diabetes mellitus[J].Clin Nephrol,2001,55(5):357-364.
[13]Yang J, Dai C, Liu Y. A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchy maltransition [J]. JAm SocNephro,l 2005,16(1): 68-78.
[14]JindeK,Nikolic-Paterson DJ,HuangXR,etal.Tubularphenotypic change in progressive tubulointerstitial fibrosis in human glomerulo-nephritis. [J].Am JKidneyDis,2001,38(4):761-769.
[15]Fan JM, NgYY, HillPA, eta.l Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiationin vitro[J].Kidney Int,1999,56 (4):1455-1467.
[16]BrunskillNJ. Albumin signals the coming of age of proteinuric nephropathy [J]. J Am Soc Nephro,l 2004,15(2):504-505.
[17]Yang JW, Dai CS, Liu YH. Hepatocyte growth factor gene therapy and angiotensin Ⅱ blockade synergistically attenuate renal interstitial fibrosis inmice [J]. JAm Soc Nephro,l 2002,13(10):2464-2477.
[18]Coles M, Diercks T, Muehlenweg Bet al.The solution structure and dynamics of human neutrophil gelatinase-associated lipocalin. J Mol Biol,1999,289(1):139
[19]Fried A,Stoesz S P,Buckley P,et al.Neutrophil gelatinase-associated in mormal and neoplastic human tissues.Cell type specific pattern of expression[J]. Histochem J,1999,31(7):433-441.
[20]Cecilia A, Fernandez, Li Yan, et al. The matrix metalloproteinase-9/ neutrophil gelatinase- associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancerpatients. Clin Cancer Res,2005, 11(15):5390-5395.
[21]Yang J. An iorn delivery pathway mediated reperfusion injury. J Mol Cell,2002, 10:1045-1056.
[22]Mori K, Lee HT, Rapoport D et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemiareperfusion injury. J Clin Invest 2005; 115:610-621
[23]Kalluril R, Neilson EG. Epithelial -mesenchymal transition and its implications for fibrosis. J Clin Invest,2003,112(12):1776-1784.
[24]Jun-ichi H, Tadanori, Pankaj S, et al. Lipccalin2 diminishes invasiveness and metastasis of ras-transformed cells. J Biol Chem,2005, 208(4):13641-13647.
[25]Yang J, Morik, Li JY, et al. Iron, Lipocalin and kidney epithelial. AmJ Physiol Renal Ph ysiol,2003,285(3):F9-F18.
[26]Nagase H, Woessner J F, et al. Matrixmetalloproteinase. J Biol Chem,1999, 274(31):21491-21494.
[27]Jiang Yang, Li Yan, Marsha A, Moses. Over expression of neutrophil gelatinase-associated lipocalin(NGAL)induce epithelial-myofibroblast transition in MCF-7 breast cancer cells AACR meeting ab stracts,2005:1138
[28]刘欣颖,罗海,王宓,等.肝细胞生长因子对IL-lot刺激肾小管上皮细胞肌纤维母细胞转分化的作用.四川大学学报(医学版),2005,36(1)：9—12.
[29]Ferris CD, Jaffrey SR, Sawa Aetal. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol,1999,1(3):152
[30]Junwei Yang, Youhua Liu. Dissection of key events in tubular epithelial to myofibroblast transition and its implication in renal interstitialfibrosis. Amerian Journal of Path,2001; 159 (4):1465-1476.
[31]丁文捷,孙书珍,等.过敏性紫癜患儿尿中肝细胞生长因子的检测及临床意义.中国实用儿科杂志,2009；24(5)：251-253.
[32]Schmidt-Ott KM, Mori K, Li JY, et al:Dual action of neutrophil gelatinase-Associated lipocalin. J Am Soc Nephrol 18:407-413,2007
[33]Mori K, Lee HT, Rapoport D et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemiareperfusion injury. J Clin Invest 2005; 115:610-621
[34]Hailing SF, Soderberg MP, Berg UB. Henoch Schonlein nephritis:clinical findings related to renal function and morphology. Pediatr Nephrol.2005 Jan;20(1):46-51.
[1]Kjeldsen L,Johnsen A H,Sengelov H,et al.Isolation and primary structure of NGAL,a novel protein associated with human neutrophil gelatinase[J].J Biol Chem,1993,268(14):10425-10432.
[2]许丽艳,李恩民,熊华琪.NGAL的结构与功能研究进展[J].生命科学,2002,14(1)：27-29.
[3]Fried A,Stoesz S P,Buckley P,et al.Neutrophil gelatinase-associated in mormal and neoplastic human tissues.Cell type specific pattern of expression[J]. Histochem J,1999,31(7):433-441.
[4]Devireddy LR, Gazin C, Zhu X, Green MR:A cellsurface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 2005,123:1293-1305.
[5]Hvidberg V, Jacobsen C, Strong RK, Cowland JB, Moestrup SK, Borregaard N: The endocytic receptor megalin binds the iron transporting neutrophil-gelatinase-associated lipocalin with high affinity and mediates its cellular uptake. FEBS Lett 2005,579:773-777.
[6]Yan L, Borregaard N, Kjeldsen L, Moses MA:The high molecular weight urinary matrix metalloproteinase(MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin(NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem 2001,276:37258-37265.
[7]Yang J, Goetz D, Li JY, et al:An iron delivery pathway mediated by a lipocalin. Mol Cell 2002,10:1045-1056.
[8]Flo TH, Smith KD, Sato S, et al:Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 2004,432:917-921.
[9]Gwira JA, Wei F, Ishibe S, Uelang JM, Barasch J, Cantley LG:Expression of neutrophil gelatinase-associated lipocalin regulates epithelial morphogenesis in vitro. J Biol Chem 2005,280:7875-7882.
[10]Berger T, Togawa A, Duncan GS, et al:Lipocalin2-deficient mice exhibit increased semsitivity to Escherichia coli infection but not to ischemia-reperfusion injury. Proc Natl Acad Sci USA 2006,103:1834-1839.
[11]Fjaertoft G, Foucard T, Xu S, Venge P:Human neutrophil lipocalin(HNL) as a diagnostic tool in children with acute infections:A study of the kinetics. Acta Paediatr 2005,94:661-666.
[12]Playford RJ, Belo A, Poulsom R,et al:Effects of mouse and human lipocalin homologues 24p3/1cn2 and neutrophil gelatinase-associated lipocalin on gastrointestinal mucosal integrity and repair. Gastroenterology 2006,131:809-817.
[13]Cowland JB, Sorensen OE, Sehested M, Borregaard N:Neutrophil gelatinase-Associated lipocalin is up-regulated in human epithelial cells by IL-1 beta, but not by TNF-alpha. J Immunol 2003,171:6630-6639.
[14]Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P:Neutrophil gelatinase-Associated lipocalin:A Novel early urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol 2004,24:307-315.
[15]Mishra J, Ma Q, Prada A,et al:Identification of neutrophil gelatinase-associated Lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003,14:2534-2543.
[16]Mishra J, Mori K, Ma Q, et al:Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin.J Am Soc Nephrol 2004,15:3073-3082.
[17]Mishra J, Dent C, Tarabishi R, et al:Neutrophilgelatinase-associated lipocalin(NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005,365:1231-1238.
[18]Hirsch R, Dent C, Pfriem H,et al:NGAL is an early predictive biomarker of contrast-induced nephropathy in children.Pedoatr Nephrol.2007,22:2089-2095.
[19]Wagener G,Jan M,Kim M,et al:Association between increases in urinary neutrophil Neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery.Anesthesiology.2006,105:485-491.
[20]Bachorzewska-Gajewska H,Malyszko J,Sitniewska E,MalyszkoJS,Dobrzycki S:Neutr-ophil-gelatinase-associated lipocalin and renal function after percutaneous cornonary inteventions,Am J Nephrol.2006,26:287-292.
[21]Bachorzewska-Gajewska E, Malyszko J, Sitniewska E, Malyszko JS, Dobrzycki S:Neutrophil gelatinase-associated lipocalin(NGAL) correlations with cystatin C,Serum creatinine and eGFR in patients with normal serum creatinine undergoing coronary angiography. Nephrol Dial Transplant.2007,22:295-296.
[22]Boldt J, Brosch C, Ducke M et al. Influence of volume therapy with a modern hydroxyethylstarch preparation on kidney function in cardiac surgery patients with compromised renal function:a comparison with human albumin. Crit Care Med.2007; 35:2740-2746.
[23]Boldt J, Brosch CH, Rohm K et al. Comparison of the effects of gelatin and a modern hydroxyethylstarch solution on renal function and inflammatory response in elderly cardiac surgery patients. Br JAnaesth 2008; 100:457-464.
[24]Haase M, Fielitz-Haase A, Bellomo R et al. Sodium bicarbonate toprevent acute kidney injury after cardiac surgery:a pilot doubleblind, randomised controlled trial. Nephrol Dial Transplant.2008;1(Suppl.2):212-215.
[25]Wagener G, Gubitosa G, Wang S et al. Increased incidence of acute kidney injury with aprotinin use during cardiac surgery detected with urinary NGAL. Am J Nephrol.2008; 28:576-582.
[26]Trachtman H, Christen E, Cnaan A et al. Urinary neutrophil gelatinase-associated lipocalcin in D+HUS:a novel marker of renal injury. Pediatr Nephrol. 2006; 21:989-994.
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