大鼠梗阻肾脏AQP2、钠通道调节机制研究和儿童肾积水临床特点的随访分析
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摘要
背景
先天性肾积水是常见的儿童泌尿系畸形。其最常见的原因是肾盂输尿管连接部梗阻(ureteropelvic junction obstruction, UP JO),发病率为1/1000～1/1500。随着胎儿超声检查普及,越来越多的患儿可在胎儿期确诊。输尿管梗阻后可显著影响肾血流(RBF)、肾小球滤过率(GFR)和肾小管功能,尿液浓缩功能受损,水、H+、Na+、K+重吸收和排泄异常。梗阻解除后会出现大量低渗尿液。
水通道蛋白2(aquaporin-2, AQP2)是一种跨膜蛋白,是肾脏中最重要的一种水通道蛋白。Na-K-2Cl共转运蛋白2(Na-K-2Cl Cotransporter2, NKCC2)在肾脏特异性表达,是肾小管重吸收盐调节水盐平衡的重要分子基础之一。研究发现输尿管梗阻后AQP2和NKCC2表达下降,在梗阻肾脏浓缩稀释功能下降过程中发挥重要作用。肾素-血管紧张素系统也参与输尿管梗阻后肾脏功能变化的病理生理学过程,但其对肾功能改变的具体调节途径还不完全清楚。为了进一步了解血管紧张素Ⅱ(Angiotensin II, ANG II)对AQP2、NKCC2变化和肾脏功能的影响,本研究第一部分利用大鼠双侧输尿管梗阻(bilateral ureteral obstruction, BUO)动物模型检测ANG Ⅱ的AT1受体阻断剂对梗阻肾脏AQP2、NKCC2表达变化和肾小管功能改变的影响,为了解ANG Ⅱ调节肾脏AQP2、NKCC2表达的机制提供参考。考虑到梗阻形成早期24h内肾脏AQP2表达及肾功能变化趋势目前还不明确,本研究选择单侧输尿管梗阻(Unilateral Ureteral Obstruction, UUO)大鼠模型研究梗阻形成后早期肾脏AQP2表达及肾功能改变情况,为了解输尿管梗阻发病机制及早期诊断治疗提供依据。通过以上研究希望能够为深入理解肾积水患儿肾脏病理生理学改变的机制以及临床上对此类患儿肾脏功能改变的处理提供理论依据。
虽然肾积水患儿临床多见,但目前对先天性肾积水患儿是否需要手术和手术时机的选择还存在较多争议,肾积水的自然转归和发展规律仍不清楚。“三聚氰胺污染奶粉事件”爆发后临床出现大量三聚氰胺泌尿系结石及其引起的肾积水患儿。就诊的三聚氰胺泌尿系结石患儿中出现肾积水的比例显著高于正常儿童。虽然小儿先天性肾积水和小儿三聚氰胺奶粉引起的肾积水鉴别诊断并不难,但是个别患儿尤其是结石较小(X线阴性结石)的情况下,临床也常需要对先天性肾积水和后天三聚氰胺奶粉引起肾积水进行鉴别诊断。其治疗后临床转归和发展规律还不十分清楚。但是,三聚氰胺结石特点是体积小,超声检查对较小结石分辨率有限,常发生结石漏诊,尤其沙粒状结石是输尿管小结石漏诊率更高。此外,三聚氰胺结石为X线透过阴性结石,在X线平片不显影,这使常规X线检查对确诊三聚氰胺结石无用武之地。这样,当结石引起肾积水但是又不能发现结石时,就需要鉴别该肾积水是三聚氰胺结石引起还是小儿先天性肾积水。先天性肾积水也是小儿常见病,许多是体检时偶尔发现。位于输尿管引起积水,如果结石未发现容易与先天性肾积水混淆,而且这两种肾积水都也多发生在婴幼儿期,给临床鉴别诊断带来困难。所以,如何区分三聚氰胺结石肾积水和先天性肾积水是小儿泌尿外科临床医生关心的问题。因为两种肾积水的治疗措施不同。因此,,临床诊治过程中需将此两种肾积水进行鉴别诊断,对患儿制定更合理有效的治疗和随访方案非常重要。目前,两种肾积水进行对照研究未见文献报道。因此,本研究第二部分选择这两种肾积水患儿对其临床特点和发展转归随访结果进行随访并进行对比研究,为临床进一步了解小儿不同类型肾积水鉴别诊断特点和选择更合理治疗方案提供依据。目的
第一部分
1、通过观察ANGⅡ受体阻滞剂坎地沙坦对BUO大鼠肾脏AQP2表达的影响,探讨ANG Ⅱ对梗阻肾脏功能和AQP2的调控作用。2、观察ANG Ⅱ受体阻滞剂坎地沙坦干预BUO大鼠肾脏NKCC2表达变化,探讨ANG Ⅱ对梗阻肾脏功能和NKCC2的影响。3、探讨大鼠UUO24h内肾脏AQP2表达变化及其对肾脏功能的影响。
第二部分
1、比较婴幼儿三聚氰胺泌尿系结石引起肾积水与肾盂输尿管连接部梗阻性先天性肾积水(hydronephrosis due to congenital ureteropelvic junction obstruction, HNUPJO)的临床特点,为临床鉴别诊断提供依据。2、比较婴幼儿三聚氰胺泌尿系结石引起肾积水(hydronephrosis induced by melamine urinary stone, HNMUS)和HNUPJO所采用不同的治疗方法和疗效,为进一步制定合理治疗方案提供依据。3、比较婴幼儿HNMUS和HNUPJO随访结果及其预后转归,为这两类不同肾积水进行有效追踪随访和将来进一步保健措施提供依据。方法
第一部分
实验一：24只慕尼黑大鼠随机分为BUO组、坎地沙坦干预组(BUO+CAN)和对照组(Sham),每组n=8只。BUO组和BUO+CAN组均行双侧输尿管结扎并采用微型泵分别给以生理盐水和坎地沙坦,Sham组仅游离输尿管但不结扎,24h后解除梗阻并继续观察48h后收集血液和肾脏标本,采用免疫印记技术检测肾脏AQP2表达水平；实验二：30只慕尼黑大鼠随机分为假手术对照组(Sham)、BUO组和坎地沙坦干预组(BUO+CAN),每组n=10只。BUO组和BUO+CAN组均行双侧输尿管结扎,并采用微型泵分别给以生理盐水和坎地沙坦干预,24h后解除梗阻并继续观察48h后收集血液和肾脏标本,检测血浆电解质和渗透压,免疫印记检测肾脏NKCC2表达水平；实验三；28只慕尼黑大鼠行单侧输尿管结扎术,分别于术后2h(UUO-2组),6h(UUO-6组),12h(UUO-12组),24h(UUO-24组)收集血液和肾脏标本(各组n=7),检测血浆电解质和渗透压,免疫印记检测肾脏AQP2蛋白水平。各组均设等量(n=7)假手术对照组(Sham-2,-6,-12,-24)。
第二部分
选取2008年在我院治疗的有三聚氰胺污染奶粉喂养史并确诊为泌尿系结石婴幼儿165例,其中146例(年龄18.5±10.0月)合并肾积水(HNMUS组)。诊断标准包括有确定的三聚氰胺污染奶粉喂养史,临床症状包括不明原因哭闹拒食,出现少尿或无尿,血尿,急性梗阻性肾衰,且超声检查发现结石。诊断肾积水根据美国胎儿泌尿协会(Society for Fetal Urology, SFU)制定的超声检查标准。选取85例(年龄20.4+9.3月)无三聚氰胺污染奶粉喂养史的先天性肾积水患儿作为对照组(HNUPJO组)。通过电话、信件和预约门诊的方式对所有患儿进行出院后为期2年的随访。分别记录入院时和随访时的肾脏超声检查、肾脏功能、尿液分析等评估结果。对上述两组患儿的临床和随访特点进行比较,应用两随机样本t检验、x2检验和组间多重比较单因素方差分析的统计学方法分析相关参数。结果
第一部分
实验一：梗阻解除后BUO组与Sham组相比尿量显著增高,(92±7)μl·min-1·kg-1比(25+3)μl·min-1·kg-1、尿渗透压显著降低,(636±55) mosmol/kgH2O比(1853±163) mosmol/kgH2O、血浆渗透压和血浆醛固酮均显著增高,分别为(336±10)mosmol/kgH2O比(303±7) msmol/kgH2O和(4.1±0.2) nmol/L比(1.4±0.1) nmol/L;肾脏AQP2表达下调到Sham组17%(各组比较差异有统计学意义,P<0.05)。BUO+CAN组与BUO组相比尿量显著减少,(55±5)μ1?min-1·kg-1比(92±7)μl·min-1·kg-1,尿渗透压显著增高(783±47)μl·min-1·kg1比(636±55) msmol/kgH2O,血浆醛固酮含量显著降低(2.8±0.5) nmol/L比(4.1±0.2) nmol/L,肾脏AQP2表达增高(各组比较差异有统计学意义,P<0.05)。
实验二：梗阻解除后BUO组与Sham组相比尿量、尿Na显著增高(99±6vs.28±4μl·min-1·kg-1)和(7.0±0.7vs.4.0±0.4μmol·min-1·kg-1),尿渗透压显著降低(647±57vs.1879±157mosmol/kgH2O);血浆渗透压和醛固酮含量均显著升高(340±8vs.305±9mosmol/kgH2O)和(4.5±0.2vs.1.4±0.1nmol·L-1)。BUO+CAN组与BUO组相比尿量、尿Na显著降低(60±7vs.99±6μl·min·kg-1)和(4.9±0.4vs.7.0±0.7nmol·min-1·kg-1),尿渗透压显著增高(806±61vs.647±57mosmol/kgH2O);血浆渗透压和血浆醛固酮含量均显著降低(325±7vs.340±8mosmol/kgH2O)和(2.9±0.4vs.4.5±0.2nmol·L-1)。肾脏NKCC2表达BUO组显著下降到Sham组24%,BUO+CAN组显著高于BUO组(58+6%vs.24±7%)。各组比较差异均有统计学意义,P<0.05。
实验三：与Sham组相比,UUO-24h血浆渗透压升高(347.6±1.7vs.304.3±1.3mosmol/kgH2O), UUO-2h血浆肌酐(39.6±5.8vs.10.5μmol/L)、尿素(9.2±0.4vs.6.9±0.3mmol/L)和血钾(5.3±0.2vs.4.3±0.1mmol/L)升高,UUO-2,-6,-12,24h血浆肌酐呈上升趋势。UUO-6,-12,-24h血钠水平显著低于Sham组(135.6±1.3vs.137.4±0.8,126.3±1.3vs.136.5±1.2,135.2±1.0vs.139.7±1.5mmol/L)。免疫印记显示UUO-12h和UUO-24h分别导致AQP2在肾脏内髓表达下降到Sham组的69%和22%。各组比较P<0.05,差异有统计学意义。
第二部分
入院时,HNMUS组和HNUPJO组患儿男女比例无差异(2.8：1vs.4.0：1),但是均表现男性患儿占有明显优势。HNMUS组单侧肾积水35例(76%),双侧肾积水11例(24%)。HNUPJO组单侧肾积水77例(91%),双侧肾积水8例(9%)。HNMUS组双侧肾积水发生率显著高于HNUPJO组(24%,11/46vs.9%,8/85,P<0.05)。HNMUS组有症状患儿多与HNUPJO组(67%Vs.41%,p<0.05),主要表现为腹部包块、肾绞痛、血尿和少尿无尿等。5例HNMUS患儿出现急性肾功能衰竭,而HNUPJO组未见急性肾功能衰竭病例。分别有4例HNMUS和11例HNUPJO患儿出现2种以上临床症状。根据SFU制定的肾积水诊断标准,HNMUS组患儿轻度肾积水27例,中度肾积水19例,无重度肾积水；HNUPJO组患儿轻度肾积水30例,中度肾积水44例,重度肾积水11例。HNMUS组患儿积水程度低于HNUPJO组。实验室检查BUN和Scr两组间比较差异无统计学意义。HNMUS组尿pH值显著低于HNUPJO组,SUA显著高于HNUPJO组,差异均有统计学意义,P<0.05。所有HNMUS组患儿确诊后入院采取标准保守治疗。5例急性肾功能衰竭HNMUS患儿行透析治疗1-4次后逐渐恢复。1例HNMUS患儿行体外震波碎石法排出结石。HNUPJO组中55例有手术指征的患儿行离断性肾盂成形术,剩余30例未手术患儿进入本研究随访程序。在随访过程中有5例HNUPJO患儿由于积水加重或肾功能减退等情况恶化进行手术治疗。在24个月随访时无死亡病例发生,98%(45/46)的HNMUS患儿和83%(25/30)HNUPJO无任何临床症状。泌尿系超声随访显示HNMUS组肾积水患儿肾脏积水情况在6个月内恢复迅速。在24个月随访时,HNMUS组患儿中43例(93%)积水自行消失,2例(4%)仍存在积水,HNUPJO组患儿中无积水自行消失病例,仍有24例(80%)存在积水。HNMUS组肾积水消失率显著高于HNUPJO组。所有患儿肾脏功能和尿量均正常。结论
第一部分
1、ANG Ⅱ受体拮抗剂可通过阻止AQP2下调纠正水代谢紊乱,保护肾功能,提示ANG Ⅱ通过调节肾脏AQP2表达参与输尿管梗阻后肾脏水代谢变化。2、ANG Ⅱ受体拮抗剂可阻止BUO后NKCC2下调,纠正水代谢紊乱,保护肾功能,提示ANG Ⅱ通过调节肾脏NKCC2表达参与输尿管梗阻后肾脏盐代谢变化。3、单侧输尿管梗阻后12h开始出现肾脏AQP2蛋白表达显著下降,肾脏功能改变早于AQP2蛋白变化。
第二部分
三聚氰胺结石容易引起肾积水,发生率为28%,双侧积水率高于先天性肾积水。三聚氰胺结石肾积水与先天性肾积水男女比例近似,男性患儿易发病。与先天性肾积水比较,三聚氰胺结石肾积水患儿临床症状更明显,也更容易出现急性肾功能衰竭,但积水程度较轻,腹部包块不明显。超声是筛查和鉴别诊断两种肾积水的首选方法,尤其适合于发现三聚氰胺结石的存在。三聚氰胺结石肾积水多以内科保守治疗为主,出现肾衰竭患儿需透析治疗。碱化尿液和密切随访对多数三聚氰胺结石肾积水患儿安全有效。随着结石溶解排出肾积水也逐渐消失,而先天性肾积水随访过程中肾积水不会自动减轻,常需要采取外科手术治疗。24个月随访,多数三聚氰胺结石肾积水肾脏未见泌尿系结构和功能改变,未见泌尿系肿瘤发生。先天性肾积水部分病例明显积水增多,肾脏形态发生了变化。
Background
Pediatric hydronephrosis is a common disorder encountered by physicians in their daily practice. Nowadays, fetal hydronephrosis is more frequently detected due to popular used antenatal ultrasonography. It is well known that one of the most common causes of congenital hydronephrosis is ureteropelvic junction obstruction (UPJO) which has been previously characterized in the literature.Its incidence is around1/1000～1/1500. Ureteral obstruction significantly affect the renal blood flow(RBF), glomerular filtration rate(GFR) and renal tubular function. And those cause the reabsorption and excretion dysfunction of H+, Na+,K+. The release after obstruction results in hypotension urine.
As a transmembrane protein, Aquaporin-2(AQP2) is also the most important aquaporin in kidney. Na-K-2Cl Cotransporter2(NKCC2),which specifically express in kidney, is one of the most significant moleculars which regulate the reabsorption of water and salt. It has been shown that, the expression level of AQP2and Na-K-2CL decreased after ureteral obstruction. Renin-angiotensin system plays an important role in the pathophysiological processes of renal function change after ureteral obstruction. However, the regulation mechanism is unclear. To investigate the regulation of angiotensin Ⅱ on the expression of AQP2,NKCC2, and renal function,we administrated ANG II AT1receptor inhibitor on BUO rats, to see its effect on the expression of AQP2, NKCC2and renal function in part one.
In2008, the outbreaks of melamine related urinary stone (MRUS) occurred in China. Actually, hydornephrosis is one of the main complications in infants with MRUS, approximately reached1/3of cases. Clinically, hydronephrosis induced by urinary melamine stone (HNMUS) need to be distinguished with the hydronephrosis due to congenital ureteropelvic junction obstruction (HNUPJO) considering the different treatment and follow up strategy. However, the differential diagnosis is not always easy, especially in cases with mild degree of hydronephrosis and that induced by a small or occult MRUS. Although early diagnosis of patients with hydronephrosis is not difficult due to the advances in ultrasonography during the last two decades, disagreement exists over the different diagnostic tests to define obstruction accurately or predict which kidney will benefit from surgical intervention. Furthermore, the indications for and timing of surgery or initial non-operative approach for severe hydronephrosis are still debated. Therefore, we studied the different clinical features and outcome between HNMUS and HNUPJO in part two, to provide more evidence for the diagnosis and treatment of these two diseases.
Objective
Part1
(1)To investigate the regulation of angiotensin II on the expression of Aquaporin2(AQP2) and renal function after bilateral ureteral obstruction (BUO);(2)To investigate the regulation of angiotensin II on the dysregulation of Na-K-2C1Cotransporter2(NKCC2) and renal function in response to bilateral ureteral obstruction (BUO);(3) To investigate the early time course of dysregulation of AQP2and renal function after2-,6-,12-,24hours unilateral ureteral obstruction (UUO).
Part2
To study the difference of clinical features and follow-up reasults in HNMUS with that due to HNUPJO in infants at admission and the24-month follow up.
Materials and Methods
Part1
Protocal1:Tweenty-four Munich-Wistar rats were randomly divided into three groups (BUO, n=8; CAN n=8; Sham n=8). The BUO (and BUO+CAN) model was built by bilateral ureteral ligation, then the osmotic minipumps contained isotonic saline (n=8) or candesartan (n=8) were implanted subcutaneously. Age-and time-matched sham-operated controls (n=8) were prepared and observed in parallel. The rats were monitored for another48h after the24h BUO was released. The blood samples were collected and kidneys were harvested to examine the effects of angiotensin Ⅱ receptor antagonist candesartan on the dysregulation of AQP2by semi quantitative immunoblottling.
Protocal2:Thirty Munich-Wistar rats were randomly divided into three groups (BUO, n=10; CAN n=10; Sham n=10). The BUO (and BUO+CAN) model was built by bilateral ureteral ligation, then the osmotic minipumps contained isotonic saline (n=10) or candesartan (n=10) were implanted subcutaneously. Age-and time-matched sham-operated controls (n=10) were prepared and observed in parallel. The rats were monitored for another48h after the24h BUO was released. The blood samples were collected and kidneys were harvested to examine the effects of angiotensin Ⅱ receptor antagonist candesartan on the dysregulation of NKCC2by semi quantitative immunoblottling.
Protocal3:Twenty eight Munich-Wistar rats underwent UUO afterwards were followed2h (UUO-2, n=7),6h (UUO-6, n=7),12h (UUO-12, n=7),24h (UUO-24, n=7). Age-and time-matched sham-operated controls (n=7) were prepared and observed in parallel for each UUO group. The blood samples were collected and obstructed kidneys were harvested to examine the dysregulation of AQP2by semiquantitative immunoblottling.
Part2
Forty six infants (18.5±10.0months)(34boys and12girls) with HNMUS and85infants (20.4±9.3months)(68boys and17girls) with HNUPJO were included. Diagnostic criteria include the history of feeding melamine-contaminated infant formula; having one or more clinical manifestations such as unexplained crying and/or vomiting; macroscopic or microscopic hematuria (urinary red blood cell morphology shows normal morphology of red blood cells), acute obstructive renal failure:oliguria or anuria; parathyroid hormone test (normal); ultrasound B exam indicated urinary system stone imaging. The hydronephrosis diagnosis is mainly depending on the ultrasonography, which was graded according to the Society for Fetal Urology (SFU) guidelines. Radiographic, functional, and laboratory data of urinary system were recorded. All HNMUS and30HNUPJO infants with mild pelvic dilation similar to those of HNMUS were followed up for24months. Urinary ultrasonography, renal function and urinalysis were evaluated at admission and follow up. The clinical features of two groups were compared.
Results
Part1
Protocall: Release of BUO resulted in a marked polyuria(BUO vs. Sham:92±7vs.25±3μl·min-1·kg-1, n=8; P<0.05) and a reduced urine osmolality(BUO vs. Sham:636±55vs.1853±163mosmol/kgH2O, n=8; P<0.05), which persisted throughout the experimental period. Administration of candesartan partly prevented this increase in postobstructive urine production (55±5vs.92±7ul·min-1·kg-1, n=8; P<0.05) and decrease in urine osmolality (783±47vs.636±55mosmol/kgH2O, n=8; P<0.05). BUO induced a significantly increase in plasma osmolality (336±10vs.303±7mosmol/kgH2O, n=8; P<0.05) and plasma aldosterone concentration (4.1±0.2vs.1.4±0.1nmol·L-1, n=8; P<0.05) in BUO vs. in sham-operated control rats. Candesartan partly attenuated the increase of plasma aldosterone (2.8±0.5vs.4.1±0.2nmol·L-1, n=8; P<0.05). BUO resulted in a significantly decreased expression of AQP2compared with control, and candesartan prevented the reduction of AQP2(PO.05).
Protocal2: Release of BUO resulted in a marked polyuria (BUO vs. Sham:99±6vs.28±4ul·min-1·kg-1, n=10; P<0.05), increase of urine Na (BUO vs. Sham:7.0±0.7vs.4.0±0.4μmol·min-l·kg-l, n=10; PO.05) and a reduced urine osmolality (BUO vs. Sham:647±57vs.1879±157mosmol/kgH2O, n=10; PO.05), which persisted throughout the experimental period. BUO induced a significantly increase in plasma osmolality (BUO vs. Sham:340±8vs.305+9mosmol/kgH2O, n=10; PO.05) and plasma aldosterone concentration (BUO vs. Sham:4.5±0.2vs.1.4±0.1nmol·L-1, n=10; P<0.05) in BUO vs. in sham-operated control rats. Administration of candesartan partly prevented this increase in postobstructive urine production (BUO+CAN vs. BUO:60±7vs.99±6ul·min-1·kg-1, n=10; P<0.05), increase of urine Na (BUO+CAN vs. BUO:4.9±0.4vs.7.0±0.7μmol·min-1·kg-1, n=10; P<0.05) and decrease in urine osmolality (BUO+CAN vs. BUO:806±61vs.647±57mosmol/kgH2O, n=10; P<0.05). Candesartan attenuated partly the increase of plasma osmolality and aldosterone [(BUO+CAN vs. BUO:(325±7vs.340±8mosmol/kgH2O) and (2.9±0.4vs.4.5±0.2nmol·L-1), n=10; P<0.05]. BUO resulted in a significantly decreased expression of NKCC2compared with control, and candesartan prevented the reduction of NKCC2(P<0.05).
Protocal3:In rats subjected to UUO for varying durations between2and24h, osmolality and electrolyte concentrations in plasma were determined. Comparing with sham group, two-hour UUO resulted in a significant increase in the level of plasma creatinine.(39.6±5.8vs.10.5μmol/L), urea (9.2±0.4vs.6.9±0.3mmol/L) serum potassium (5.3±0.2vs.4.3±0.1mmol/L). Rats subjected to6,12, and24h of obstruction had decreased plasma sodium levels(135.6±1.3vs.137.4±0.8,126.3±1.3vs.136.5±1.2,135.2±1.0vs.139.7±1.5mmol/L, respectively) compared with sham group. Plasma osmolality was higher after24h UUO compared with sham group (347.6±1.7vs.304.3±1.3mosmol/kgH2O). Semiquantitative immunoblotting was performed to determine the time frame of the AQP2regulation in a UUO model. It showed that, AQP2protein abundance did not change in kidneys from2-and6-h UUO rats, but after12and24h UUO significant down regulation was observed (69%and22%, respectively), compared with sham group.
Part2
There was no significant difference in male-to-female ratio of HNMUS vs. HNUPJO (2.8:1vs.4.0:1); however, male preponderance in each group is obvious. Hydronephrosis was unilateral in35(76%) HNMUS and77(91%) HNUPJO patients. More bilateral hydronephrosis were found in HNMUS than in HNUPJO (24%,11/46vs.9%,8/85, P<0.05). HNMUS show more symptomatic (abdominal mass, dysuria, renal colic (unexplained crying, oliguria or anuria, macroscopic or microscopic haematuria and hypertension) than those of HNUPJO (67%vs.41%, p<0.05). Five cases of acute renal failure were observed in HNMUS and none in HNUPJO. More than2kinds of symptoms were found simultaneously in4of HNMUS and in11of HNUPJO. According to the SFU guidelines of hydronephrosis graduation, there were27HNMUS cases and30HNUPJO of a mild degree (SFU grade0,1),19HNMUS cases and44HNUPJO cases of a moderate degree (SFU grade2,3) and0HNMUS cases and11HNUPJO of a severe degree (SFU grade4). Mean degree of hydronephrosis of HNMUS was significantly lighter than HNUPJO (p<0.05). The PH value of urine was significantly lower in HNMUS children compared with HNUPJO (p<0.05), whereas the SUA was significantly higher in HNMUS children compared with HNUPJO (p<0.05). There was no significant difference of the BUN and Scr between HNMUS and HNUPJO (p>0.05).Conservative short-term treatments were used in all HNMUS patients immediately after diagnosis. Hemodialysis was performed in5HNMUS with severe renal failure, and all cases gradually recovered after1to4times of hemodialysis treatments. Extracorporeal shock wave lithotripsy was performed in1HNMUS cases. Primary pyeloplasty was performed in55cases with HNUPJO, whereas follow up was carried out in the remaining30cases HNUPJO, in which the degree of hydronephrosis is similar to those of HNMUS at discharging. During the follow up,5HNUPJO patients underwent pyeloplasty due to progressive hydronephrosis and/or reduction in renal function. At24-month of follow-up, no mortality was observed, and98%(45/46) HNMUS and83%(25/30) HNUPJO showed asymptomatic. Ultrasonogram follow-up showed that hydronephrosis of HNMUS decreased rapidly during the first6months and then more gradually with time. Hydronephrosis resolved spontaneously in43(93%) HNMUS and in none of HNUPJO, remained stable in2(4%) HNMUS and24(80%) HNUPJO. The dilation degree of hydronephrosis decreased significantly in HNMUS compared to those of HNUPJO (6.5%,3/46vs.97%,29/30, P<0.05). The renal function of all the patients were recovered to normal, and the urinary output of whom returned to normal levels.
Conclusions
Part1
(1)Angiotensin Ⅱ receptor antagonist prevents dysregulation of AQP2in response to BUO. Angiotensin Ⅱ is involved in the pathophusilogical changes in renal function after release of BUO;(2)Angiotensin Ⅱ receptor antagonist prevents dysregulation of NKCC2in response to BUO which is likely to contribute to the associated urinary concentrating defect. Angiotensin Ⅱ is involved in the pathophusilogical changes in renal function after release of BUO;(3)AQP2protein abundance did not change in obstructed kidneys from2-and6h UUO rats, but significant downregulate after12-and24h UUO. The damage of renal function observed is earlier than the downregulation of AQP2protein.
Part2
Significant difference of clinical feature existed between HNMUS and HNUPJO. The incidence of hydronephrosis in MRUS was28%. Comparing to HNUPJO group, the incidence of bilateral hydronephrosis in HNMUS was higher. The sex ratio of the two groups was similar. More male infants suffered from hydronephrosis. Comaring to HNUPJO group, the infants in HNMUS group had more severe clinical symptoms, and were more easily to suffer acute renal functional failure. However, the hydronephrosis degree in HNMUS was lower and the abdominal mass was not obvious. Ultrasound was the optimal method to differentiate the two kinds of hydronephrosis. It was especially useful for detcting the melamine stone in infants. The primary treatment for HNMUS was the conservative medical management. Alkalization of urine and the close follow-up were safe and effective for most of the HNMUS infants. The hydronephrosis in HNMUS infants would disappear with the excretion of the stone. However, the hydronephrosis in HNUPJO group wouldn't disappear automatically. In the24-month follow-up, the structure and function of the urinary system had no significant change, and no uninary system tumor occurred in HNMUS infants. Whereas, the hydroneprosis in HNUPJO group increased, and the morphology of kidney changed.
先天性肾积水是常见的儿童泌尿系畸形。其最常见的原因是肾盂输尿管连接部梗阻(ureteropelvic junction obstruction, UP JO),发病率为1/1000～1/1500。随着胎儿超声检查普及,越来越多的患儿可在胎儿期确诊。输尿管梗阻后可显著影响肾血流(RBF)、肾小球滤过率(GFR)和肾小管功能,尿液浓缩功能受损,水、H+、Na+、K+重吸收和排泄异常。梗阻解除后会出现大量低渗尿液。
水通道蛋白2(aquaporin-2, AQP2)是一种跨膜蛋白,是肾脏中最重要的一种水通道蛋白。Na-K-2Cl共转运蛋白2(Na-K-2Cl Cotransporter2, NKCC2)在肾脏特异性表达,是肾小管重吸收盐调节水盐平衡的重要分子基础之一。研究发现输尿管梗阻后AQP2和NKCC2表达下降,在梗阻肾脏浓缩稀释功能下降过程中发挥重要作用。肾素-血管紧张素系统也参与输尿管梗阻后肾脏功能变化的病理生理学过程,但其对肾功能改变的具体调节途径还不完全清楚。为了进一步了解血管紧张素Ⅱ(Angiotensin II, ANG II)对AQP2、NKCC2变化和肾脏功能的影响,本研究第一部分利用大鼠双侧输尿管梗阻(bilateral ureteral obstruction, BUO)动物模型检测ANG Ⅱ的AT1受体阻断剂对梗阻肾脏AQP2、NKCC2表达变化和肾小管功能改变的影响,为了解ANG Ⅱ调节肾脏AQP2、NKCC2表达的机制提供参考。考虑到梗阻形成早期24h内肾脏AQP2表达及肾功能变化趋势目前还不明确,本研究选择单侧输尿管梗阻(Unilateral Ureteral Obstruction, UUO)大鼠模型研究梗阻形成后早期肾脏AQP2表达及肾功能改变情况,为了解输尿管梗阻发病机制及早期诊断治疗提供依据。通过以上研究希望能够为深入理解肾积水患儿肾脏病理生理学改变的机制以及临床上对此类患儿肾脏功能改变的处理提供理论依据。
虽然肾积水患儿临床多见,但目前对先天性肾积水患儿是否需要手术和手术时机的选择还存在较多争议,肾积水的自然转归和发展规律仍不清楚。“三聚氰胺污染奶粉事件”爆发后临床出现大量三聚氰胺泌尿系结石及其引起的肾积水患儿。就诊的三聚氰胺泌尿系结石患儿中出现肾积水的比例显著高于正常儿童。虽然小儿先天性肾积水和小儿三聚氰胺奶粉引起的肾积水鉴别诊断并不难,但是个别患儿尤其是结石较小(X线阴性结石)的情况下,临床也常需要对先天性肾积水和后天三聚氰胺奶粉引起肾积水进行鉴别诊断。其治疗后临床转归和发展规律还不十分清楚。但是,三聚氰胺结石特点是体积小,超声检查对较小结石分辨率有限,常发生结石漏诊,尤其沙粒状结石是输尿管小结石漏诊率更高。此外,三聚氰胺结石为X线透过阴性结石,在X线平片不显影,这使常规X线检查对确诊三聚氰胺结石无用武之地。这样,当结石引起肾积水但是又不能发现结石时,就需要鉴别该肾积水是三聚氰胺结石引起还是小儿先天性肾积水。先天性肾积水也是小儿常见病,许多是体检时偶尔发现。位于输尿管引起积水,如果结石未发现容易与先天性肾积水混淆,而且这两种肾积水都也多发生在婴幼儿期,给临床鉴别诊断带来困难。所以,如何区分三聚氰胺结石肾积水和先天性肾积水是小儿泌尿外科临床医生关心的问题。因为两种肾积水的治疗措施不同。因此,,临床诊治过程中需将此两种肾积水进行鉴别诊断,对患儿制定更合理有效的治疗和随访方案非常重要。目前,两种肾积水进行对照研究未见文献报道。因此,本研究第二部分选择这两种肾积水患儿对其临床特点和发展转归随访结果进行随访并进行对比研究,为临床进一步了解小儿不同类型肾积水鉴别诊断特点和选择更合理治疗方案提供依据。目的
第一部分
1、通过观察ANGⅡ受体阻滞剂坎地沙坦对BUO大鼠肾脏AQP2表达的影响,探讨ANG Ⅱ对梗阻肾脏功能和AQP2的调控作用。2、观察ANG Ⅱ受体阻滞剂坎地沙坦干预BUO大鼠肾脏NKCC2表达变化,探讨ANG Ⅱ对梗阻肾脏功能和NKCC2的影响。3、探讨大鼠UUO24h内肾脏AQP2表达变化及其对肾脏功能的影响。
第二部分
1、比较婴幼儿三聚氰胺泌尿系结石引起肾积水与肾盂输尿管连接部梗阻性先天性肾积水(hydronephrosis due to congenital ureteropelvic junction obstruction, HNUPJO)的临床特点,为临床鉴别诊断提供依据。2、比较婴幼儿三聚氰胺泌尿系结石引起肾积水(hydronephrosis induced by melamine urinary stone, HNMUS)和HNUPJO所采用不同的治疗方法和疗效,为进一步制定合理治疗方案提供依据。3、比较婴幼儿HNMUS和HNUPJO随访结果及其预后转归,为这两类不同肾积水进行有效追踪随访和将来进一步保健措施提供依据。方法
第一部分
实验一：24只慕尼黑大鼠随机分为BUO组、坎地沙坦干预组(BUO+CAN)和对照组(Sham),每组n=8只。BUO组和BUO+CAN组均行双侧输尿管结扎并采用微型泵分别给以生理盐水和坎地沙坦,Sham组仅游离输尿管但不结扎,24h后解除梗阻并继续观察48h后收集血液和肾脏标本,采用免疫印记技术检测肾脏AQP2表达水平；实验二：30只慕尼黑大鼠随机分为假手术对照组(Sham)、BUO组和坎地沙坦干预组(BUO+CAN),每组n=10只。BUO组和BUO+CAN组均行双侧输尿管结扎,并采用微型泵分别给以生理盐水和坎地沙坦干预,24h后解除梗阻并继续观察48h后收集血液和肾脏标本,检测血浆电解质和渗透压,免疫印记检测肾脏NKCC2表达水平；实验三；28只慕尼黑大鼠行单侧输尿管结扎术,分别于术后2h(UUO-2组),6h(UUO-6组),12h(UUO-12组),24h(UUO-24组)收集血液和肾脏标本(各组n=7),检测血浆电解质和渗透压,免疫印记检测肾脏AQP2蛋白水平。各组均设等量(n=7)假手术对照组(Sham-2,-6,-12,-24)。
第二部分
选取2008年在我院治疗的有三聚氰胺污染奶粉喂养史并确诊为泌尿系结石婴幼儿165例,其中146例(年龄18.5±10.0月)合并肾积水(HNMUS组)。诊断标准包括有确定的三聚氰胺污染奶粉喂养史,临床症状包括不明原因哭闹拒食,出现少尿或无尿,血尿,急性梗阻性肾衰,且超声检查发现结石。诊断肾积水根据美国胎儿泌尿协会(Society for Fetal Urology, SFU)制定的超声检查标准。选取85例(年龄20.4+9.3月)无三聚氰胺污染奶粉喂养史的先天性肾积水患儿作为对照组(HNUPJO组)。通过电话、信件和预约门诊的方式对所有患儿进行出院后为期2年的随访。分别记录入院时和随访时的肾脏超声检查、肾脏功能、尿液分析等评估结果。对上述两组患儿的临床和随访特点进行比较,应用两随机样本t检验、x2检验和组间多重比较单因素方差分析的统计学方法分析相关参数。结果
第一部分
实验一：梗阻解除后BUO组与Sham组相比尿量显著增高,(92±7)μl·min-1·kg-1比(25+3)μl·min-1·kg-1、尿渗透压显著降低,(636±55) mosmol/kgH2O比(1853±163) mosmol/kgH2O、血浆渗透压和血浆醛固酮均显著增高,分别为(336±10)mosmol/kgH2O比(303±7) msmol/kgH2O和(4.1±0.2) nmol/L比(1.4±0.1) nmol/L;肾脏AQP2表达下调到Sham组17%(各组比较差异有统计学意义,P<0.05)。BUO+CAN组与BUO组相比尿量显著减少,(55±5)μ1?min-1·kg-1比(92±7)μl·min-1·kg-1,尿渗透压显著增高(783±47)μl·min-1·kg1比(636±55) msmol/kgH2O,血浆醛固酮含量显著降低(2.8±0.5) nmol/L比(4.1±0.2) nmol/L,肾脏AQP2表达增高(各组比较差异有统计学意义,P<0.05)。
实验二：梗阻解除后BUO组与Sham组相比尿量、尿Na显著增高(99±6vs.28±4μl·min-1·kg-1)和(7.0±0.7vs.4.0±0.4μmol·min-1·kg-1),尿渗透压显著降低(647±57vs.1879±157mosmol/kgH2O);血浆渗透压和醛固酮含量均显著升高(340±8vs.305±9mosmol/kgH2O)和(4.5±0.2vs.1.4±0.1nmol·L-1)。BUO+CAN组与BUO组相比尿量、尿Na显著降低(60±7vs.99±6μl·min·kg-1)和(4.9±0.4vs.7.0±0.7nmol·min-1·kg-1),尿渗透压显著增高(806±61vs.647±57mosmol/kgH2O);血浆渗透压和血浆醛固酮含量均显著降低(325±7vs.340±8mosmol/kgH2O)和(2.9±0.4vs.4.5±0.2nmol·L-1)。肾脏NKCC2表达BUO组显著下降到Sham组24%,BUO+CAN组显著高于BUO组(58+6%vs.24±7%)。各组比较差异均有统计学意义,P<0.05。
实验三：与Sham组相比,UUO-24h血浆渗透压升高(347.6±1.7vs.304.3±1.3mosmol/kgH2O), UUO-2h血浆肌酐(39.6±5.8vs.10.5μmol/L)、尿素(9.2±0.4vs.6.9±0.3mmol/L)和血钾(5.3±0.2vs.4.3±0.1mmol/L)升高,UUO-2,-6,-12,24h血浆肌酐呈上升趋势。UUO-6,-12,-24h血钠水平显著低于Sham组(135.6±1.3vs.137.4±0.8,126.3±1.3vs.136.5±1.2,135.2±1.0vs.139.7±1.5mmol/L)。免疫印记显示UUO-12h和UUO-24h分别导致AQP2在肾脏内髓表达下降到Sham组的69%和22%。各组比较P<0.05,差异有统计学意义。
第二部分
入院时,HNMUS组和HNUPJO组患儿男女比例无差异(2.8：1vs.4.0：1),但是均表现男性患儿占有明显优势。HNMUS组单侧肾积水35例(76%),双侧肾积水11例(24%)。HNUPJO组单侧肾积水77例(91%),双侧肾积水8例(9%)。HNMUS组双侧肾积水发生率显著高于HNUPJO组(24%,11/46vs.9%,8/85,P<0.05)。HNMUS组有症状患儿多与HNUPJO组(67%Vs.41%,p<0.05),主要表现为腹部包块、肾绞痛、血尿和少尿无尿等。5例HNMUS患儿出现急性肾功能衰竭,而HNUPJO组未见急性肾功能衰竭病例。分别有4例HNMUS和11例HNUPJO患儿出现2种以上临床症状。根据SFU制定的肾积水诊断标准,HNMUS组患儿轻度肾积水27例,中度肾积水19例,无重度肾积水；HNUPJO组患儿轻度肾积水30例,中度肾积水44例,重度肾积水11例。HNMUS组患儿积水程度低于HNUPJO组。实验室检查BUN和Scr两组间比较差异无统计学意义。HNMUS组尿pH值显著低于HNUPJO组,SUA显著高于HNUPJO组,差异均有统计学意义,P<0.05。所有HNMUS组患儿确诊后入院采取标准保守治疗。5例急性肾功能衰竭HNMUS患儿行透析治疗1-4次后逐渐恢复。1例HNMUS患儿行体外震波碎石法排出结石。HNUPJO组中55例有手术指征的患儿行离断性肾盂成形术,剩余30例未手术患儿进入本研究随访程序。在随访过程中有5例HNUPJO患儿由于积水加重或肾功能减退等情况恶化进行手术治疗。在24个月随访时无死亡病例发生,98%(45/46)的HNMUS患儿和83%(25/30)HNUPJO无任何临床症状。泌尿系超声随访显示HNMUS组肾积水患儿肾脏积水情况在6个月内恢复迅速。在24个月随访时,HNMUS组患儿中43例(93%)积水自行消失,2例(4%)仍存在积水,HNUPJO组患儿中无积水自行消失病例,仍有24例(80%)存在积水。HNMUS组肾积水消失率显著高于HNUPJO组。所有患儿肾脏功能和尿量均正常。结论
第一部分
1、ANG Ⅱ受体拮抗剂可通过阻止AQP2下调纠正水代谢紊乱,保护肾功能,提示ANG Ⅱ通过调节肾脏AQP2表达参与输尿管梗阻后肾脏水代谢变化。2、ANG Ⅱ受体拮抗剂可阻止BUO后NKCC2下调,纠正水代谢紊乱,保护肾功能,提示ANG Ⅱ通过调节肾脏NKCC2表达参与输尿管梗阻后肾脏盐代谢变化。3、单侧输尿管梗阻后12h开始出现肾脏AQP2蛋白表达显著下降,肾脏功能改变早于AQP2蛋白变化。
第二部分
三聚氰胺结石容易引起肾积水,发生率为28%,双侧积水率高于先天性肾积水。三聚氰胺结石肾积水与先天性肾积水男女比例近似,男性患儿易发病。与先天性肾积水比较,三聚氰胺结石肾积水患儿临床症状更明显,也更容易出现急性肾功能衰竭,但积水程度较轻,腹部包块不明显。超声是筛查和鉴别诊断两种肾积水的首选方法,尤其适合于发现三聚氰胺结石的存在。三聚氰胺结石肾积水多以内科保守治疗为主,出现肾衰竭患儿需透析治疗。碱化尿液和密切随访对多数三聚氰胺结石肾积水患儿安全有效。随着结石溶解排出肾积水也逐渐消失,而先天性肾积水随访过程中肾积水不会自动减轻,常需要采取外科手术治疗。24个月随访,多数三聚氰胺结石肾积水肾脏未见泌尿系结构和功能改变,未见泌尿系肿瘤发生。先天性肾积水部分病例明显积水增多,肾脏形态发生了变化。
Background
Pediatric hydronephrosis is a common disorder encountered by physicians in their daily practice. Nowadays, fetal hydronephrosis is more frequently detected due to popular used antenatal ultrasonography. It is well known that one of the most common causes of congenital hydronephrosis is ureteropelvic junction obstruction (UPJO) which has been previously characterized in the literature.Its incidence is around1/1000～1/1500. Ureteral obstruction significantly affect the renal blood flow(RBF), glomerular filtration rate(GFR) and renal tubular function. And those cause the reabsorption and excretion dysfunction of H+, Na+,K+. The release after obstruction results in hypotension urine.
As a transmembrane protein, Aquaporin-2(AQP2) is also the most important aquaporin in kidney. Na-K-2Cl Cotransporter2(NKCC2),which specifically express in kidney, is one of the most significant moleculars which regulate the reabsorption of water and salt. It has been shown that, the expression level of AQP2and Na-K-2CL decreased after ureteral obstruction. Renin-angiotensin system plays an important role in the pathophysiological processes of renal function change after ureteral obstruction. However, the regulation mechanism is unclear. To investigate the regulation of angiotensin Ⅱ on the expression of AQP2,NKCC2, and renal function,we administrated ANG II AT1receptor inhibitor on BUO rats, to see its effect on the expression of AQP2, NKCC2and renal function in part one.
In2008, the outbreaks of melamine related urinary stone (MRUS) occurred in China. Actually, hydornephrosis is one of the main complications in infants with MRUS, approximately reached1/3of cases. Clinically, hydronephrosis induced by urinary melamine stone (HNMUS) need to be distinguished with the hydronephrosis due to congenital ureteropelvic junction obstruction (HNUPJO) considering the different treatment and follow up strategy. However, the differential diagnosis is not always easy, especially in cases with mild degree of hydronephrosis and that induced by a small or occult MRUS. Although early diagnosis of patients with hydronephrosis is not difficult due to the advances in ultrasonography during the last two decades, disagreement exists over the different diagnostic tests to define obstruction accurately or predict which kidney will benefit from surgical intervention. Furthermore, the indications for and timing of surgery or initial non-operative approach for severe hydronephrosis are still debated. Therefore, we studied the different clinical features and outcome between HNMUS and HNUPJO in part two, to provide more evidence for the diagnosis and treatment of these two diseases.
Objective
Part1
(1)To investigate the regulation of angiotensin II on the expression of Aquaporin2(AQP2) and renal function after bilateral ureteral obstruction (BUO);(2)To investigate the regulation of angiotensin II on the dysregulation of Na-K-2C1Cotransporter2(NKCC2) and renal function in response to bilateral ureteral obstruction (BUO);(3) To investigate the early time course of dysregulation of AQP2and renal function after2-,6-,12-,24hours unilateral ureteral obstruction (UUO).
Part2
To study the difference of clinical features and follow-up reasults in HNMUS with that due to HNUPJO in infants at admission and the24-month follow up.
Materials and Methods
Part1
Protocal1:Tweenty-four Munich-Wistar rats were randomly divided into three groups (BUO, n=8; CAN n=8; Sham n=8). The BUO (and BUO+CAN) model was built by bilateral ureteral ligation, then the osmotic minipumps contained isotonic saline (n=8) or candesartan (n=8) were implanted subcutaneously. Age-and time-matched sham-operated controls (n=8) were prepared and observed in parallel. The rats were monitored for another48h after the24h BUO was released. The blood samples were collected and kidneys were harvested to examine the effects of angiotensin Ⅱ receptor antagonist candesartan on the dysregulation of AQP2by semi quantitative immunoblottling.
Protocal2:Thirty Munich-Wistar rats were randomly divided into three groups (BUO, n=10; CAN n=10; Sham n=10). The BUO (and BUO+CAN) model was built by bilateral ureteral ligation, then the osmotic minipumps contained isotonic saline (n=10) or candesartan (n=10) were implanted subcutaneously. Age-and time-matched sham-operated controls (n=10) were prepared and observed in parallel. The rats were monitored for another48h after the24h BUO was released. The blood samples were collected and kidneys were harvested to examine the effects of angiotensin Ⅱ receptor antagonist candesartan on the dysregulation of NKCC2by semi quantitative immunoblottling.
Protocal3:Twenty eight Munich-Wistar rats underwent UUO afterwards were followed2h (UUO-2, n=7),6h (UUO-6, n=7),12h (UUO-12, n=7),24h (UUO-24, n=7). Age-and time-matched sham-operated controls (n=7) were prepared and observed in parallel for each UUO group. The blood samples were collected and obstructed kidneys were harvested to examine the dysregulation of AQP2by semiquantitative immunoblottling.
Part2
Forty six infants (18.5±10.0months)(34boys and12girls) with HNMUS and85infants (20.4±9.3months)(68boys and17girls) with HNUPJO were included. Diagnostic criteria include the history of feeding melamine-contaminated infant formula; having one or more clinical manifestations such as unexplained crying and/or vomiting; macroscopic or microscopic hematuria (urinary red blood cell morphology shows normal morphology of red blood cells), acute obstructive renal failure:oliguria or anuria; parathyroid hormone test (normal); ultrasound B exam indicated urinary system stone imaging. The hydronephrosis diagnosis is mainly depending on the ultrasonography, which was graded according to the Society for Fetal Urology (SFU) guidelines. Radiographic, functional, and laboratory data of urinary system were recorded. All HNMUS and30HNUPJO infants with mild pelvic dilation similar to those of HNMUS were followed up for24months. Urinary ultrasonography, renal function and urinalysis were evaluated at admission and follow up. The clinical features of two groups were compared.
Results
Part1
Protocall: Release of BUO resulted in a marked polyuria(BUO vs. Sham:92±7vs.25±3μl·min-1·kg-1, n=8; P<0.05) and a reduced urine osmolality(BUO vs. Sham:636±55vs.1853±163mosmol/kgH2O, n=8; P<0.05), which persisted throughout the experimental period. Administration of candesartan partly prevented this increase in postobstructive urine production (55±5vs.92±7ul·min-1·kg-1, n=8; P<0.05) and decrease in urine osmolality (783±47vs.636±55mosmol/kgH2O, n=8; P<0.05). BUO induced a significantly increase in plasma osmolality (336±10vs.303±7mosmol/kgH2O, n=8; P<0.05) and plasma aldosterone concentration (4.1±0.2vs.1.4±0.1nmol·L-1, n=8; P<0.05) in BUO vs. in sham-operated control rats. Candesartan partly attenuated the increase of plasma aldosterone (2.8±0.5vs.4.1±0.2nmol·L-1, n=8; P<0.05). BUO resulted in a significantly decreased expression of AQP2compared with control, and candesartan prevented the reduction of AQP2(PO.05).
Protocal2: Release of BUO resulted in a marked polyuria (BUO vs. Sham:99±6vs.28±4ul·min-1·kg-1, n=10; P<0.05), increase of urine Na (BUO vs. Sham:7.0±0.7vs.4.0±0.4μmol·min-l·kg-l, n=10; PO.05) and a reduced urine osmolality (BUO vs. Sham:647±57vs.1879±157mosmol/kgH2O, n=10; PO.05), which persisted throughout the experimental period. BUO induced a significantly increase in plasma osmolality (BUO vs. Sham:340±8vs.305+9mosmol/kgH2O, n=10; PO.05) and plasma aldosterone concentration (BUO vs. Sham:4.5±0.2vs.1.4±0.1nmol·L-1, n=10; P<0.05) in BUO vs. in sham-operated control rats. Administration of candesartan partly prevented this increase in postobstructive urine production (BUO+CAN vs. BUO:60±7vs.99±6ul·min-1·kg-1, n=10; P<0.05), increase of urine Na (BUO+CAN vs. BUO:4.9±0.4vs.7.0±0.7μmol·min-1·kg-1, n=10; P<0.05) and decrease in urine osmolality (BUO+CAN vs. BUO:806±61vs.647±57mosmol/kgH2O, n=10; P<0.05). Candesartan attenuated partly the increase of plasma osmolality and aldosterone [(BUO+CAN vs. BUO:(325±7vs.340±8mosmol/kgH2O) and (2.9±0.4vs.4.5±0.2nmol·L-1), n=10; P<0.05]. BUO resulted in a significantly decreased expression of NKCC2compared with control, and candesartan prevented the reduction of NKCC2(P<0.05).
Protocal3:In rats subjected to UUO for varying durations between2and24h, osmolality and electrolyte concentrations in plasma were determined. Comparing with sham group, two-hour UUO resulted in a significant increase in the level of plasma creatinine.(39.6±5.8vs.10.5μmol/L), urea (9.2±0.4vs.6.9±0.3mmol/L) serum potassium (5.3±0.2vs.4.3±0.1mmol/L). Rats subjected to6,12, and24h of obstruction had decreased plasma sodium levels(135.6±1.3vs.137.4±0.8,126.3±1.3vs.136.5±1.2,135.2±1.0vs.139.7±1.5mmol/L, respectively) compared with sham group. Plasma osmolality was higher after24h UUO compared with sham group (347.6±1.7vs.304.3±1.3mosmol/kgH2O). Semiquantitative immunoblotting was performed to determine the time frame of the AQP2regulation in a UUO model. It showed that, AQP2protein abundance did not change in kidneys from2-and6-h UUO rats, but after12and24h UUO significant down regulation was observed (69%and22%, respectively), compared with sham group.
Part2
There was no significant difference in male-to-female ratio of HNMUS vs. HNUPJO (2.8:1vs.4.0:1); however, male preponderance in each group is obvious. Hydronephrosis was unilateral in35(76%) HNMUS and77(91%) HNUPJO patients. More bilateral hydronephrosis were found in HNMUS than in HNUPJO (24%,11/46vs.9%,8/85, P<0.05). HNMUS show more symptomatic (abdominal mass, dysuria, renal colic (unexplained crying, oliguria or anuria, macroscopic or microscopic haematuria and hypertension) than those of HNUPJO (67%vs.41%, p<0.05). Five cases of acute renal failure were observed in HNMUS and none in HNUPJO. More than2kinds of symptoms were found simultaneously in4of HNMUS and in11of HNUPJO. According to the SFU guidelines of hydronephrosis graduation, there were27HNMUS cases and30HNUPJO of a mild degree (SFU grade0,1),19HNMUS cases and44HNUPJO cases of a moderate degree (SFU grade2,3) and0HNMUS cases and11HNUPJO of a severe degree (SFU grade4). Mean degree of hydronephrosis of HNMUS was significantly lighter than HNUPJO (p<0.05). The PH value of urine was significantly lower in HNMUS children compared with HNUPJO (p<0.05), whereas the SUA was significantly higher in HNMUS children compared with HNUPJO (p<0.05). There was no significant difference of the BUN and Scr between HNMUS and HNUPJO (p>0.05).Conservative short-term treatments were used in all HNMUS patients immediately after diagnosis. Hemodialysis was performed in5HNMUS with severe renal failure, and all cases gradually recovered after1to4times of hemodialysis treatments. Extracorporeal shock wave lithotripsy was performed in1HNMUS cases. Primary pyeloplasty was performed in55cases with HNUPJO, whereas follow up was carried out in the remaining30cases HNUPJO, in which the degree of hydronephrosis is similar to those of HNMUS at discharging. During the follow up,5HNUPJO patients underwent pyeloplasty due to progressive hydronephrosis and/or reduction in renal function. At24-month of follow-up, no mortality was observed, and98%(45/46) HNMUS and83%(25/30) HNUPJO showed asymptomatic. Ultrasonogram follow-up showed that hydronephrosis of HNMUS decreased rapidly during the first6months and then more gradually with time. Hydronephrosis resolved spontaneously in43(93%) HNMUS and in none of HNUPJO, remained stable in2(4%) HNMUS and24(80%) HNUPJO. The dilation degree of hydronephrosis decreased significantly in HNMUS compared to those of HNUPJO (6.5%,3/46vs.97%,29/30, P<0.05). The renal function of all the patients were recovered to normal, and the urinary output of whom returned to normal levels.
Conclusions
Part1
(1)Angiotensin Ⅱ receptor antagonist prevents dysregulation of AQP2in response to BUO. Angiotensin Ⅱ is involved in the pathophusilogical changes in renal function after release of BUO;(2)Angiotensin Ⅱ receptor antagonist prevents dysregulation of NKCC2in response to BUO which is likely to contribute to the associated urinary concentrating defect. Angiotensin Ⅱ is involved in the pathophusilogical changes in renal function after release of BUO;(3)AQP2protein abundance did not change in obstructed kidneys from2-and6h UUO rats, but significant downregulate after12-and24h UUO. The damage of renal function observed is earlier than the downregulation of AQP2protein.
Part2
Significant difference of clinical feature existed between HNMUS and HNUPJO. The incidence of hydronephrosis in MRUS was28%. Comparing to HNUPJO group, the incidence of bilateral hydronephrosis in HNMUS was higher. The sex ratio of the two groups was similar. More male infants suffered from hydronephrosis. Comaring to HNUPJO group, the infants in HNMUS group had more severe clinical symptoms, and were more easily to suffer acute renal functional failure. However, the hydronephrosis degree in HNMUS was lower and the abdominal mass was not obvious. Ultrasound was the optimal method to differentiate the two kinds of hydronephrosis. It was especially useful for detcting the melamine stone in infants. The primary treatment for HNMUS was the conservative medical management. Alkalization of urine and the close follow-up were safe and effective for most of the HNMUS infants. The hydronephrosis in HNMUS infants would disappear with the excretion of the stone. However, the hydronephrosis in HNUPJO group wouldn't disappear automatically. In the24-month follow-up, the structure and function of the urinary system had no significant change, and no uninary system tumor occurred in HNMUS infants. Whereas, the hydroneprosis in HNUPJO group increased, and the morphology of kidney changed.
引文
[1]Josephson S. Suspected pyelo-ureteral junction obstruction in the fetus:when to do what? I. A clinical update. Eur Urol,1990,18(4):267-275.
[2]Li C, Wang W, Knepper MA, et al.Downregulation of renal aquaporins in response to unilateral ureteral obstruction.Am J Physiol Renal Physiol,2003,284(5):F1066-1079.
[3]Wamsley-Davis A,Padda R,Truong LD,et al. AT1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy:preservation of kidney tissue mass using candesartan.Am J Physiol Renal Physiol,2004,287(3):F474-480.
[4]Huang WY, Peters CA, Zurakowski D, et al. Renal biopsy in congenital ureteropelvic junction obstruction:evidence for parenchymal maldevelopment.Kidney Int,2006, 69(1):137-143.
[5]Fr(?)kiaer J, Marples D, Knepper MA, et al. Bilateral ureteral obstruction downregulates expression of vasopressin-sensitive AQP-2 water channel in rat kidney. Am J Physiol, 1996,270(4 Pt 2):F657-668.
[6]Li C, Wang W, Kwon TH, et al. Downregulation of AQP1,-2, and-3 after ureteral obstruction is associated with a long-term urine-concentrating defect. Am J Physiol Renal Physiol,2001,281(1):F163-171.
[7]rregaard R,Jensen BL,Topcu SO,et al.COX-2 activity transiently contributes to increased water and NaCl excretion in the polyuric phase after release of ureteral obstruction.Am J Physiol Renal Physiol,2007,292(5):F1322-1333.
[8]Kwon TH, Nielsen J, M(?)ller HB, et al. Aquaporins in the kidney. Handb Exp Pharmacol. 2009,(190):95-132.
[9]Norregaard R, Jensen BL, Topcu SO, et al. Urinary tract obstruction induces transient accumulation of COX-2-derived prostanoids in kidney tissue. Am J Physiol Regul Integr Comp Physiol.2010,298(4):R1017-1025.
[10]文建国,王焱,李真珍,等.先天性肾积水肾脏及其尿液中水通道蛋白2表达的相关性研究.中华小儿外科杂志,2009,30(2)：86-90.
[11]Reams G,Villarreal D,Wu Z, et al. Renal tissue angiotensin Ⅱ:response to infusions of angiotensin I and an angiotensin-converting enzyme inhibitor. Am J Kidney Dis, 1993,22(6):851-857.
[12]Fr(?)kiaer J, Knudsen L, Nielsen AS, et al.Enhanced intrarenal angiotensin Ⅱ generation in response to obstruction of the pig ureter. Am J Physiol,1992,263(3 Pt 2):F527-533.
[13]Fr(?)kiaer J, Djurhuus JC, Nielsen M, et al-Renal hemodynamic response to ureteral obstruction during converting enzyme inhibition.Urol Res,1996,24(4):217-227.
[14]Harris RC. Cyclooxygenase-2 in the kidney. J Am Soc Nephrol.2000, 11(12):2387-2394.
[15]Kwon TH, Nielsen J, Kim YH, et al. Regulation of sodium transporters in the thick ascending limb of rat kidney:response to angiotensin II. Am J Physiol Renal Physiol,2003, 285(1):F152-165.
[16]Dal Canton A, Corradi A, Stanziale R, et al. Glomerular hemodynamics before and after release of 24-hour bilateral ureteral obstruction. Kidney Int,1980,17(4):491-496.
[17]Fr(?)kiaer J, Christensen BM, Marples D, et al. Downregulation of aquaporin-2 parallels changes in renal water excretion in unilateral ureteral obstruction. Am J Physiol,1997, 273(2):F213-223.
[18]Li C, Wang W, Kwon TH, et al. Altered expression of major renal Na transporters in rats with bilateral ureteral obstruction and release of obstruction. Am J Physiol Renal Physiol, 2003,285(5):F889-901.
[19]Oliverio MI, Madsen K, Best CF, et al. Renal growth and development in mice lacking ATI A receptors for angiotensin II. Am J Physiol,1998,274(1 Pt 2):F43-50.
[20]Burns KD, Homma T, Harris RC. The intrarenal renin-angiotensin system. Semin Nephrol, 1993,13(1):13-30.
[21]Saccomani G, Mitchell KD, Navar LG. Angiotensin Ⅱ stimulation of Na-H exchange in proximal tubule cells. Am J Physiol,1990,258(5 Pt 2):F1188-1195.
[22]Moriyama T, Kawada N, Akagi Y, et al. TCV-116 inhibits interstitial fibrosis and HSP47 mRNA in rat obstructive nephropathy. Kidney Int Suppl,1997,63:S232-235.
[23]Yosypiv IV. Renin-angiotensin system in ureteric bud branching morphogenesis:Insights into the mechanisms. Pediatr Nephrol,2011,26:1499-1512
[24]Stipsanelli A, Daskalakis G, Koutra P, et al. Renin-angiotensin system dysregulation in fetuses with hydronephrosis. Eur J Obstet Gynecol Reprod Biol,2010,150:39-41
[25]Hayasaka K, Ogino D, Matsunaga A. [molecular basis of hydronephrosis]. Nihon Rinsho, 2006,64 Suppl 2:545-549
[26]Yosypiv IV, Schroeder M, El-Dahr SS. Angiotensin ii type 1 receptor-egf receptor cross-talk regulates ureteric bud branching morphogenesis. J Am Soc Nephrol,2006, 17:1005-1014
[27]Wang G, Yuan W, Kwon TH, et al. Age-related changes in expression in renal aqps in response to congenital, partial, unilateral ureteral obstruction in rats. Pediatr Nephrol,2012, 27:83-94
[28]Knoers N. Nephrogenic diabetes insipidus.1993,
[29]Ampawong S, Klincomhum A, Likitsuntonwong W, et al. Expression of aquaporin-1,-2 and-4 in mice with a spontaneous mutation leading to hydronephrosis. J Comp Pathol, 2012,146:332-337
[30]Nishimura N, Matsumura F, Vogel CF, et al. Critical role of cyclooxygenase-2 activation in pathogenesis of hydronephrosis caused by lactational exposure of mice to dioxin. Toxicol Appl Pharmacol,2008,231:374-383
[31]Takahashi N, Chernavvsky DR, Gomez RA, et al. Uncompensated polyuria in a mouse model of bartter's syndrome. Proc Natl Acad Sci U S A,2000,97:5434-5439
[32]Ares GR, Caceres PS, Ortiz PA. Molecular regulation of nkcc2 in the thick ascending limb. Am J Physiol Renal Physiol,2011,301:F1143-1159
[33]Olesen ET, de Seigneux S, Wang G, et al. Rapid and segmental specific dysregulation of aqp2, s256-paqp2 and renal sodium transporters in rats with lps-induced endotoxaemia. Nephrol Dial Transplant,2009,24:2338-2349
[34]Stechman MJ, Loh NY, Thakker RV. Genetic causes of hypercalciuric nephrolithiasis. Pediatr Nephrol,2009,24:2321-2332
[35]Benziane B, Demaretz S, Defontaine N, et al. Nkcc2 surface expression in mammalian cells:Down-regulation by novel interaction with aldolase b. J Biol Chem,2007, 282:33817-33830
[36]Huang CL, Yang SS, Lin SH. Mechanism of regulation of renal ion transport by wnk kinases. Curr Opin Nephrol Hypertens,2008,17:519-525
[37]Welker P, Bohlick A, Mutig K, et al. Renal na+-k+-cl-cotransporter activity and vasopressin-induced trafficking are lipid raft-dependent. Am J Physiol Renal Physiol,2008, 295:F789-802
[38]Capasso G, Rizzo M, Garavaglia ML, et al. Upregulation of apical sodium-chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt-sensitive hypertension. Am J Physiol Renal Physiol,2008,295:F556-567
[39]Stodkilde L, Norregaard R, Fenton RA, et al. Bilateral ureteral obstruction induces early downregulation and redistribution of aqp2 and phosphorylated aqp2. Am J Physiol Renal Physiol,2011,301:F226-235
[40]Li W, Zhang Y, Bouley R, et al. Simvastatin enhances aquaporin-2 surface expression and urinary concentration in vasopressin-deficient brattleboro rats through modulation of rho gtpase. Am J Physiol Renal Physiol,2011,301:F309-318
[41]Kim HY, Choi HJ, Lim JS, et al. Emerging role of akt substrate protein as160 in the regulation of aqp2 translocation. Am J Physiol Renal Physiol,2011,301:F151-161
[42]Jung HJ, Kwon TH. Membrane trafficking of collecting duct water channel protein aqp2 regulated by akt/as160. Electrolyte Blood Press,2010,8:59-65
[43]Velasco Cano MV, Runkle de la Vega I. [current considerations in syndrome of inappropriate secretion of antidiuretic hormone/syndrome of inappropriate antidiuresis]. Endocrinol Nutr,2010,57 Suppl 2:22-29
[44]Mollajew R, Zocher F, Homer A, et al. Routes of epithelial water flow:Aquaporins versus cotransporters. Biophys J,2010,99:3647-3656
[45]Lutken SC, Kim SW, Jonassen T, et al. Changes of renal aqp2, enac, and nhe3 in experimentally induced heart failure:Response to angiotensin ii atl receptor blockade. Am J Physiol Renal Physiol,2009,297:F1678-1688
[46]Li JH, Chou CL, Li B, et al. A selective ep4 pge2 receptor agonist alleviates disease in a new mouse model of x-linked nephrogenic diabetes insipidus. J Clin Invest,2009, 119:3115-3126
[47]Li XC, Shao Y, Zhuo JL. Atla receptor knockout in mice impairs urine concentration by reducing basal vasopressin levels and its receptor signaling proteins in the inner medulla. Kidney Int,2009,76:169-177
[48]Yasuhara A, Wada J, Malakauskas SM, et al. Collectrin is involved in the development of salt-sensitive hypertension by facilitating the membrane trafficking of apical membrane proteins via interaction with soluble n-ethylmaleiamide-sensitive factor attachment protein receptor complex. Circulation,2008,118:2146-2155
[49]Zhang Y, Sands JM, Kohan DE, et al. Potential role of purinergic signaling in urinary concentration in inner medulla:Insights from p2y2 receptor gene knockout mice. Am J Physiol Renal Physiol,2008,295:F1715-1724
[50]Yano Y, Cesar KR, Araujo M, et al. Aquaporin 2 expression increased by glucagon in normal rat inner medullary collecting ducts. Am J Physiol Renal Physiol,2009,296:F54-59
[51]Nicchia GP, Cogotzi L, Rossi A, et al. Expression of multiple aqp4 pools in the plasma membrane and their association with the dystrophin complex. J Neurochem,2008, 105:2156-2165
[52]Albertoni Borghese MF, Majowicz MP, Ortiz MC, et al. Renal sodium-glucose cotransporter activity and aquaporin-2 expression in rat kidney during chronic nitric oxide synthase inhibition. Nephron Physiol,2007,107:p77-86
[53]Nishimura H, Yang Y, Lau K, et al. Aquaporin-2 water channel in developing quail kidney: Possible role in programming adult fluid homeostasis. Am J Physiol Regul Integr Comp Physiol,2007,293:R2147-2158
[54]Goel M, Sinkins WG, Zuo CD, et al. Vasopressin-induced membrane trafficking of trpc3 and aqp2 channels in cells of the rat renal collecting duct. Am J Physiol Renal Physiol, 2007,293:F1476-1488
[55]Abreu N, Tardin JC, Boim MA, et al. Hemodynamic parameters during normal and hypertensive pregnancy in rats:Evaluation of renal salt and water transporters. Hypertens Pregnancy,2008,27:49-63
[56]Vossenkamper A, Nedvetsky PI, Wiesner B, et al. Microtubules are needed for the perinuclear positioning of aquaporin-2 after its endocytic retrieval in renal principal cells. Am J Physiol Cell Physiol,2007,293:C1129-1138
[57]Takata K. Aquaporin-2 (aqp2):Its intracellular compartment and trafficking. Cell Mol Biol (Noisy-le-grand),2006,52:34-39
[58]Zimmerman SL, Frisbie J, Goldstein DL, et al. Excretion and conservation of glycerol, and expression of aquaporins and glyceroporins, during cold acclimation in cope's gray tree frog hyla chrysoscelis. Am J Physiol Regul Integr Comp Physiol,2007,292:R544-555
[59]Han KH, Croker BP, Clapp WL, et al. Expression of the ammonia transporter, rh c glycoprotein, in normal and neoplastic human kidney. J Am Soc Nephrol,2006, 17:2670-2679
[60]Iacobelli S, Addabbo F, Bonsante F, et al. Aquaporin-2 excretion and renal function during the 1st week of life in preterm newborn infants. Nephron Physiol,2006,104:121-125
[61]Kazama I, Arata T, Michimata M, et al. Lithium effectively complements vasopressin v2 receptor antagonist in the treatment of hyponatraemia of siadh rats. Nephrol Dial Transplant,2007,22:68-76
[62]Yip KP. Epac-mediated ca(2+) mobilization and exocytosis in inner medullary collecting duct. Am J Physiol Renal Physiol,2006,291:F882-890
[63]Bustamante M, Hosler U, Kotova O, et al. Insulin potentiates avp-induced aqp2 expression in cultured renal collecting duct principal cells. Am J Physiol Renal Physiol,2005, 288:F334-344
[64]Lam AK, Ko BC, Tam S, et al. Osmotic response element-binding protein (orebp) is an essential regulator of the urine concentrating mechanism. J Biol Chem,2004, 279:48048-48054
[65]Gong H, Wang W, Kwon TH, et al. Epo and alpha-msh prevent ischemia/reperfusion-induced down-regulation of aqps and sodium transporters in rat kidney. Kidney Int,2004,66:683-695
[66]Horster M. Embryonic epithelial membrane transporters. Am J Physiol Renal Physiol,2000, 279:F982-996
[67]Yang B, Gillespie A, Carlson EJ, et al. Neonatal mortality in an aquaporin-2 knock-in mouse model of recessive nephrogenic diabetes insipidus. J Biol Chem,2001, 276:2775-2779
[68]El-Dahr SS, Harrison-Bernard LM, Dipp S, et al. Bradykinin b2 null mice are prone to renal dysplasia:Gene-environment interactions in kidney development. Physiol Genomics, 2000,3:121-131
[69]Deen PM, van Balkom BW, Kamsteeg EJ. Routing of the aquaporin-2 water channel in health and disease. Eur J Cell Biol,2000,79:523-530
[70]Chou CL, Yip KP, Michea L, et al. Regulation of aquaporin-2 trafficking by vasopressin in the renal collecting duct. Roles of ryanodine-sensitive ca2+stores and calmodulin. J Biol Chem,2000,275:36839-36846
[71]Saito T, Ishikawa SE, Ando F, et al. Vasopressin-dependent upregulation of aquaporin-2 gene expression in glucocorticoid-deficient rats. Am J Physiol Renal Physiol,2000, 279:F502-508
[72]Promeneur D, Kwon TH, Frokiaer J, et al. Vasopressin v(2)-receptor-dependent regulation of aqp2 expression in brattleboro rats. Am J Physiol Renal Physiol,2000,279:F370-382
[73]Klussmann E, Marie K, Rosenthal W. The mechanisms of aquaporin control in the renal collecting duct. Rev Physiol Biochem Pharmacol,2000,141:33-95
[74]Li C, Wang W, Rivard CJ, et al. Molecular mechanisms of angiotensin ii stimulation on aquaporin-2 expression and trafficking. Am J Physiol Renal Physiol,2011, 300:F1255-1261
[75]Nowik M, Kampik NB, Mihailova M, et al. Induction of metabolic acidosis with ammonium chloride (nh4cl) in mice and rats--species differences and technical considerations. Cell Physiol Biochem,2010,26:1059-1072
[76]Albertoni Borghese MF, Bettini LM, Nitta CH, et al. Aquaporin-2 promoter is synergistically regulated by nitric oxide and nuclear factor of activated t cells. Nephron Extra,2011,1:124-138
[77]Li Y, Zelenina M, Plat-Willson G, et al. Urinary aquaporin-2 excretion during ibuprofen or indomethacin treatment in preterm infants with patent ductus arteriosus. Acta Paediatr, 2011,100:59-66
[78]Baggaley E, Nielsen S, Marples D. Dehydration-induced increase in aquaporin-2 protein abundance is blocked by nonsteroidal anti-inflammatory drugs. Am J Physiol Renal Physiol, 2010,298:F1051-1058
[79]Noda Y, Sohara E, Ohta E, et al. Aquaporins in kidney pathophysiology. Nat Rev Nephrol, 2010,6:168-178
[80]Kim YH, Choi YJ, Bae HR, et al. P2 receptor-mediated inhibition of vasopressin-stimulated fluid transport and camp responses in aqp2-transfected mdck cells. Korean J Physiol Pharmacol,2009,13:9-14
[81]Boone M, Kortenoeven M, Robben JH, et al. Effect of the cgmp pathway on aqp2 expression and translocation:Potential implications for nephrogenic diabetes insipidus. Nephrol Dial Transplant,2010,25:48-54
[82]Chung SH, Jun DW, Kim KT, et al. Aquaporin-2 urinary excretion in cirrhosis: Relationship to vasopressin and nitric oxide. Dig Dis Sci,2010,55:1135-1141
[83]Li G, Wang ZX, Fu WJ, et al. Introduction to biodegradable polylactic acid ureteral stent application for treatment of ureteral war injury. BJU Int,2011,108:901-906
[84]Yao Y, Zhang J, Tan DQ, et al. Interferon-gamma improves renal interstitial fibrosis and decreases intrarenal vascular resistance of hydronephrosis in an animal model. Urology, 2011,77:761 e768-713
[85]Baynes J, Murray DB. Cardiac and renal function are progressively impaired with aging in zucker diabetic fatty type ii diabetic rats. Oxid Med Cell Longev,2009,2:328-334
[86]Chew BH, Lange D, Paterson RF, et al. Next generation biodegradable ureteral stent in a yucatan pig model. J Urol,2010,183:765-771
[87]Helin I, Persson PH.Prenatal diagnosis of urinary tract abnormalities by ultrasound. Pediatrics.1986,78(5):879-83
[88]Shi Y, Pedersen M, Li C, Wen JG, Thomsen K, St(?)dkilde-J(?)rgensen H, J(?)rgensen TM, Knepper MA, Nielsen S, Djurhuus JC, Fr(?)kiaer J.. Early release of neonatal ureteral obstruction preserves renal function. Am J Physiol Renal Physiol.2004,286(6):F1087-99.
[89]Lam HS, Ng PC, Chu WC, et al. Renal screening in children after exposure to low dose melamine in Hong Kong:cross sectional study. BMJ,2008,337:2991.
[90]Melamine and food safety in China. The Lancet,2009,373(9661):353.
[91]Choong S, Whitfield H, Duffy P, et al. The management of paediatric urolithiasis. BJU Int, 2000,86(7):857-60.
[92]Dogan HS, Tekgul S. Management of pediatric stone disease. Curr Urol Rep.2007,8(2): 163-73.
[93]Hamann MF, Melchior D,Juenemann KP, et al. Stone management in children. Aktuelle Urol,2007,38(5):398-402
[94]W.L.Lipschitz, E.Stokey. The mode of action of three new diuretics:melamine, adenine and formoguanamine.Journal of Pharmacology And Experimental herapeutics,1945,83(4): 235-49.
[95]Mast RW, Jeffcoat AR, Sadler BM, et al. Metabolism, disposition and excretion of [14C]: Melamine in male Fischer 344 rats. Food Chem Toxicol,1983,21 (6):807-810.
[96]http://www.who.int/foodsafety/fs_management/infosan_events/en/index3.html.
[97]Ghani AA, Al Helal B, Hussain N. Acute renal failure in pediatric patients:Etiology and predictors of outcome. Saudi J Kidney Dis Transpl,2009,20(1):69-76.
[98]Dudley JA, Haworth J M, McGraw M E, et al. Clinical relevance and implications of antenatal hydronephrosis. Achieves of Disease in Childhood,1997,76(1):31-34.
[99]de Onis M, Garza C, Onyango AW, Rolland-Cachera MF. WHO growth standards for infants and young children. Arch Pediatr,2009,16(1):47-53.
[100]Lattupalli R, Kolluru A, Yee J. Nephrotoxicity of mala fide Melamine:modern era milk. ScientificWorldJournal,2008,8:949-950.
[101]Hau AK, Kwan TH, Li PK. Melamine toxicity and the kidney. J Am Soc Nephrol,2009, 20(2):245-50.
[102]孟群,沈颖,孙宁,等.儿童尿路结石及其致急性肾功能衰竭临床分析.中国小儿急救医学,2008,15：122～124.
[103]木拉提·马合木提,阿里木·太来提,安尼瓦尔·牙生,等.小儿上尿路结石286例临床分析.临床泌尿外科杂志,2007,4：280～282.
[104]小儿尿石症.见：张金哲,潘少川,黄澄如,主编.实用小儿外科学.下册.杭州：浙江 科学技术出版社,2003,1017-1025.
[105]Neerman MF, Zhang W, Parrish AR, et al. In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery. Int J Pharm,2004,281:129-132.
[106]米华,邓耀良.中国尿石症的流行病学特征.中华泌尿外科杂志,2003,10：715-716.
[107]Coward RJ, Peters CJ, Duffy PG, et al. Epidemiology of paediatric renal stone disease in the UK. Arch Dis Child,2003,88:962-965.
[108]Menon M. Urinary lithiasis:etiology, diagnosis, and medical management. Campbell's urology. Vol 4.8th ed. Philadelphia:Saunders,2002,3231.
[109]Melnick RL, Boorman GA, Haseman JK, et al. Urolithiasis and bladder carcinogenicity of melamine in rodents. Toxicol Appl Pharmacol,1984,72:292-303.
[110]Kamoun A, Daudon M, Abdelmoula J, et al. Urolithiasis in Tunisian children:a study of 120 cases based on stone composition. Pediatr Nephrol,1999,13:920-925.
[111]孟繁英,刘玉荣,孟群,等.婴幼儿泌尿系结石29例.实用儿科临床杂志,2003,1：66-68.
[112]Spencer BA, Wood BJ, Dretler SP, et al. Helical CT and ureteral colic. Urol Clin North Am, 2000,27:231-241.
[113]Jia LQ, Shen Y, Wang XM,et al. Ultrasonographic diagnosis of urinary calculus caused by melamine in children. Chin Med J (Engl),2009,122(3):252-256.
[114]Mandel NS, Mandel GS. Urinary tract stone disease in the United States veteran population Ⅱ. Geographical analysis of variations in composition. J Urol,1989,142:1516-1521.
[115]沈绍基,袁之敏.尿石症概论.见：吴阶平,主编.吴阶平泌尿外科学.上卷.济南：山东科学技术出版社,2004,713-742.
[116]Maalouf NM, Cameron MA, Moe OW, et al. Novel insights into the pathogenesis of uric acid nephrolithiasis. Curr Opin Nephrl Hypertens,2004,13:181-189.
[117]黄东平,李伟东,黄树声,等.泌尿系尿酸结石的现代观.医学临床研究,2006,23(3)：393-396.
[118]Preminger GM. Pharmacologic treatment of uric acid calculi. Urol Clin North Am,1987, 14(2):335-338.
[119]Albrecht H. Urinary stones:diagnoses, treatment, and prevention of recurrence. New York: Basel Karger,2000:86.
[120]陈志强,曾令启,叶章群,等.氮基于三醇E液局部灌注治疗输尿管尿酸结石.中华泌尿外科杂志,2004,6：401～403.
[121]Alken CE. Steinauflsung und Steinprophylaxe. In:Alken CE, May P, BraunJ. Eds. Harnsteinleiden.2 Auflage. Stuttgart:Geory Thieme Verlag,1982,130-144.
[122]孙西钊,叶章群,孙则禹.儿童上尿路结石的处理方法.临床泌尿外科杂志,2000,15：99～101.
[123]Al-Busaidy SS, Prem AR, Medhat M. Pediatrics taghom calculi:Pediatric staghorn calculi: the role of extracorporeal shock wave lithotripsy monotherapy with special reference to ureteral stenting. J Urol,2003,169(2):629-633.
[124]Claro Jde A, Denardi F, Ferreira U, et al. Effects of extracorporeal shockwave lithotripsy on renal growth and function:an animal model. J Endourol,1994,8(3):191-194.
[125]Rodrigues Netto N Jr, Longo JA, Ikonomidis J A, et al. Extracorporeal shock wave lithotripsy in children, J Urol,2002,167(5):2164-2166.
[126]Shen Y, Liu XR, Zhang GJ, et al. Blood purification therapy in treatment of acute renal failure in infants with melamine-induced stones. Chin Med J (Engl).2009,122 (3):257-61.
[127]孙宁,沈颖,贾立群.三聚氰胺所致的婴幼儿泌尿系统结石诊治,中华小儿外科杂志,2009,30(1)：54～55.
[128]贾建业,叶敏,陈方,等.低能级体外震波碎石治疗儿童上尿路结石.中华小儿外科杂志,2005,26：239-241.
[129]范应中,张震,张谦,等.三聚氰胺致婴幼儿泌尿系结石合并肾积水与先天性肾积水的对比观察.郑州大学学报(医学版),2009,44(5)：1011-1013.
[130]Moe O W. Kidney stones:pathophysiology and medical management, lancet,2006,367: 333-44.
[131]Matlaga B R, Coe F L, Evan A P, Lingeman J E. The role of Randall's plaques in the pathogenesis of calcium stones. J Urol,2007,177:31-38.
[132]Matkovic V, Ilich JZ, Andon MB, et al. Urinary calcium, sodium, and bone mass of young females. Am J Clin Nutr,1995,62(2):417-425.
[133]Bonjour JP, Carrie AL, Ferrari S, et al. Calcium-enriched foods and bone mass growth in prepubertal girls:a randomized, double-blind, placebo-controlled trial. J Clin Invest,1997, 99(6):1287-1294.
[134]Heck HD, Tyl RW. The induction of bladder stones by terephthalic acid, dimethyl terephthalate, and melamine (2,4,6-triamino-s-triazine) and its relevance to risk assessment. Regul Toxicol Pharmacol.1985,5(3):294-313.
[135]Guan N, Fan Q, Ding J, Zhao Y, et al. Melamine-contaminated powdered formula and urolithiasis in young children. N Engl J Med,2009,360(11):1067-74.
[1]Benfield M.R., McDonald R.A., Bartosh S., Ho P.L., Harmon W. Changing trends in pediatric transplantation:2001 Annual Report of the North American Pediatric Renal Transplant Coop-erative Study. Pediatr. Transplant.2003,7,321-335
[2]Chang C.P., McDill B.W., Neilson J.R. et al. Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery. J. Clin. Invest. 2004,113,1051-1058.
[3]Mendelsohn C. Functional obstruction:the renal pelvis rules. J. Clin. Invest.2004,113, 957-959.
[4]Yiee J.H., Johnson-Welch S., Baker L.A., Wilcox D.T. Histo-logic Differences Between Extrinsic and Intrinsic Ureteropelvic Junction Obstruction. Urology.2010,76,181-184.
[5]Roth K.S., Koo H.P., Spottswood S.E., Chan J.C. Obstruc-tive uropathy:an important cause of chronic renal failure in chil-dren.Clin. Pediatr. (Phila).2002,41,309-314.
[6]Broadbelt N.V., Stahl P.J., Chen J. et al. Early upregulation of iNOS mRNA expression and increase in NO metabolites in pressurized renal epithelial cells. Am. J. Physiol. Renal Physiol.2007,293, F1877-F1888
[7]Coleman C.M., Minor J.J., Burt L.E., Thornhill B.A., Forbes M.S., Chevalier R.L. Angiotensin AT1-receptor inhibition exac-erbates renal injury resulting from partial unilateral ureteral obstruction in the neonatal rat. Am. J. Physiol. Renal Physiol.2007,293, F262-F268.
[8]Yoo K.H., Norwood V.F., el-Dahr S.S., Yosipiv I., Chevalier R.L. Regulation of angiotensin Ⅱ AT1 and AT2 receptors in neonatal ureteral obstruction. Am. J. Physiol.1997,273, R503-R509.
[9]Wen J.G, Frokiaer J., Zhao J.B., Ringgaard S., Jorgensen T.M., Djurhuus J.C. Severe partial ureteric obstruction in new-born rats can produce renal dysplasia. BJU Int.2002,89, 740-745.
[10]Grandaliano G., Gesualdo L., Bartoli F.et al. MCP-1 and EGF renal expression and urine excretion in human congenital obstructive nephropathy. Kidney Int.2000,58,182-192
[11]Chen C.O., Park M.H., Forbes M.S.et al. Angiotensin-con-verting enzyme inhibition aggravates renal interstitial injury resulting from partial unilateral ureteral obstruction in the neona-tal rat. Am. J. Physiol. Renal Physiol.2007,292, F946-F955
[12]Le Normand L., Buzelin J.M., Bouchot O., Rigaud J., Karam G. Upper urinary tract: physiology, pathophysiology of obstructions and function assessment. Ann. Urol.2005, 39,30-48
[13]Taha M.A., Shokeir A.A., Osman H.G., Abd el-Aziz Ael A., Farahat S.E. Diagnosis of ureteropelvic junction obstruction in children:role of endothelin-1 in voided urine. Urology,2007,69,560-564.
[14]Padovano V, Massari S., Mazzucchelli S., Pietrini G. PKC induces internalization and retention of the EAAC1 glutamate transporter in recycling endosomes of MDCK cells. Am. J. Phys-iol. Cell Physiol.2009,297, C835-C844.
[15]Rosen S., Peters C.A., Chevalier R.L., Huang W.Y. The kid-ney in congenital ureteropelvic junction obstruction:a spectrum from normal to nephrectomy. J. Urol.2008,179, 1257-1263.
[16]Wolak T., Kim H., Ren Y., Kim J., Vaziri N.D., Nicholas S.B. Osteopontin modulates angiotensin II-induced inflamma-tion, oxidative stress, and fibrosis of the kidney. Kidney Int.2009,76,32-43
[17]Zhang P.L., Peters C.A., Rosen S. Ureteropelvic junction obstruction:morphological and clinical studies. Pediatr. Nephrol.2000,14,820-826.
[18]Durvasula R.V., Petermann A.T., Hiromura K. et al. Activa-tion of a local tissue angiotensin system in podocytes by mechani-cal strain. Kidney Int.2004,65,30-39.
[19]Chevalier R.L. Chronic partial ureteral obstruction and the developing kidney.Pediatr. Radiol.38(Suppl.1),2008,S35-S40.
[20]Lange-Sperandio B., Trautmann A., Eickelberg O. et al. Leu-kocytes induce epithelial to mesenchymal transition after unilat-eral ureteral obstruction in neonatal mice. Am. J. Pathol.2007,171,861-871.
[21]Garvin J.L.& Hong N.J. Cellular stretch increases superox-ide production in the thick ascending limb. Hypertension.2008,51,488-493.
[22]Sipos A., Vargas S.L., Toma I., Hanner F., Willecke K., Peti-Peterdi J. Connexin 30 deficiency impairs renal tubular ATP release and pressure natriuresis. J. Am. Soc. Nephrol. 2009,20,1724-1732.
[23]Taha M.A., Shokeir A.A., Osman H.G., Abd El-Aziz Ael A., Fara-hat S.E. Pelvi-ureteric junction obstruction in children:the role of urinary transforming growth factor-beta and epidermal growth factor. BJU Int.2007,99,899-903
[24]Kolb R.J., Woost P.G., Hopfer U. Membrane trafficking of angiotensin receptor type-1 and mechanochemical signal transduc-tion in proximal tubule cells. Hypertension.2004,44, 352-359.
[25]Guerin F., Azoulay R., Berrebi D. et al. (2008) Partial unilateral ure-teral obstruction in newborn mice:magnetic resonance imaging and pathology studies. J. Urol.2008,179, 1553-1563.
[26]Qin X.S., Tsukaguchi H., Shono A.. Yamamoto A., Kurihara H., Doi T. Phosphorylation of nephrin triggers its internalization by raft-mediated endocytosis. J. Am. Soc. Nephrol. 2009,20,2534-2545.
[27]Guerin F., Azoulay R., Berrebi D. et al. Partial unilateral ure-teral obstruction in newborn mice:magnetic resonance imaging and pathology studies. J. Urol.2008,179,1553-1563.
[28]Coleman C.M., Minor J.J., Burt L.E., Thornhill B.A., Forbes M.S., Chevalier R.L. Angiotensin AT1-receptor inhibition exac-erbates renal injury resulting from partial unilateral ureteral obstruction in the neonatal rat. Am. J. Physiol. Renal Physiol.2007,293, F262-F268.
[29]Chang C.P., McDill B.W., Neilson J.R. et al. Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery. J. Clin. Invest.2004,113,1051-1058.
[30]Thornhill B.A., Forbes M.S., Marcinko E.S., Chevalier R.L. Glomerulotubular disconnection in neonatal mice after relief of partial ureteral obstruction. Kidney Int. 2007,72,1103-1112.
[31]杨贺军.三聚氰胺所致婴幼儿泌尿系结石临床诊治和随访分析.《郑州大学硕士论文》2010.05.01
[32]Ulman I, Venkata R, Jayanthi, Koff SA The long-term followup of newborns with severe unilateral HN initially treated nonoperatively. J Urol.2000,164:1101-1105
[33]Lam HS, Ng PC, Chu WC, et al. Renal screening in children after exposure to low dose melamine in Hong Kong:cross sectional study. BMJ 2008;337:a2991
[34]Wang IJ, Chen PC, Hwang KC. Melami ne and nephr olithiasis in children in Taiwan. N Engl J Med 2009;360:1157-8.
[35]Liu CC, Huang CH, Wu WJ, et al. Associ ation of vitamin D receptor (Fok-I) polymorphism with the clinical presentation of calcium urolithiasis. BJU Int 2007;99:1534-8
[36]Langman CB. Melamine, powdered milk, and nephr olithiasis in Chinese infants. N Engl J Med 2009;360:1139-41
[37]Lam CW, Lan L, Che X, et al. Diagnosis and spectrum of melamine-related renal disease: plausible mechanism of stone formation in humans. Clin Chim Acta 2009;402:150-5
[38]Chung FM, Yang YH, Shieh TY, Shin SJ, Tsai JC, Lee YJ. Effect of alcohol consumption on estimated glo merularfiltration rate and creatinine clearance rate. Nephrol Dial Transplant 2005;20:1610-6
[39]Shekarriz B, Stoller ML. Uric acid nephrolithiasis:current concepts and controversies. J U ro 12002; 20:294-301
[40]Lee YH, Huang WC, Tsai JY, et al. Epidemiologic al studies on the prevalence of upper urinary calculi in Taiwan. Urol Int 2002;68:172-7
[41]Kuehn BM. Melamine scandals highlight hazards of increasingly globalized food chain. JAMA 2009;301:473-5
[42]Khan SR. Renal tubular damage/dysfunction:key to the formation of kidney stones. Urol Res 2006;34:86-91
[43]Siener R, Glatz S, Nicola y C, Hesse A. The role of overweight and obesity in calcium oxalate stone formation. Obes Res 2004; 12:106-13
[44]Brown CA, Jeong KS, Poppenga RH, Puschner B, Miller DM, Ellis AE, et al. Outbreaks of renal failure associated with melamine and cyanuric acid in dogs and cats in 2004 and 2007. J Vet Diagn Invest 2007; 19:525-531
[45]高健刚,复溟.上尿路结石治疗方法的选择及进展.中华泌尿外科杂志,2006,6：429-431
[46]Puschner B, Poppenga RH, Lowenstine LJ, Filigenzi MS, Pesavento PA. Assessment of melamine and cyanuric acid toxicity in cats. J Vet Diagn Invest 2007;19:616-624
[47]木拉提·马合木提,阿里木等.小儿上尿路结石286例临床分析.临床泌尿外科杂志,2007.4：280～282.
[48]Ministry of health of the People's of Republic of China. [http://www.moh.gov.cn/ publicfiles/business/htmlfiles/mohbgt/s3582/200809/37769.htm]
[49]Xin H, Stone R. Tainted milk scandal. Chinese probe unmasks high-tech adulteration with melamine. Science 2008; 322:1310-1311
[50]Jiang GP, Zhao ZY, He J. The characteristics of melamine-related renal stones by ultrasound. In Press 2009. World J Pediatr
[51]Hu YM, Jiang ZF. Development. In:Hu YM, Jiang ZF, eds.Zhu Futang Textbook of Pediatrics. Beijing:Chinese Pepole's Health Publisher,2002:11-66
[52]Wen JG, Li ZZ, Zhang H, Wang Y, Zhang RF, Yang L, Chen Y, Wang JX, Zhang SJ. Melamine related bilateral renal calculi in 50 children:single center experience in clinical diagnosis and treatment. J Urol.2010,183(4):1533-7
[53]米华,邓耀良.中国尿石症的流行病学特征.中华泌尿外科杂志,2003,10：715～716.
[54]Wen JG, Chang QL, Lou AF, Li ZZ, Lu S, Wang Y, Wang YL, Hu JH, Mao SP, Zhang Y, Xue R, Ren C, Xing L, Zhang GX, Zhang S, Djurhuus JC, Fr(?)kiaer J. Melamine-related urinary stones in 195 infants and young children:clinical features within 2 years of follow-up. Urol Int.2011;87(4):429-33
[55]Xin H, Stone R. Tainted milk scandal. Chinese probe unmasks high-tech adulteration with melamine. Science 2008; 322:1310-1311
[56]Ingelfi nger JR. Melamine and the global implications of food contamination. N Engl J Med 2008;359:2745-2748
[57]Cianciolo RE, Bischoff K, Ebel JG, Van Winkle TJ, Goldstein RE, Ser fi lippi LM. Clinicopathologic, histologic, and toxicologic fi ndings in 70 cats inadvertently exposed to pet food contaminated with melamine and cyanuric acid. J Am Vet Med Assoc 2008;233:729-737
[58]廖承琳,潘家骅,吕勇,等.问题奶粉导致小儿泌尿系统结石的诊疗策略.安徽医学,2008,29(6)：676-677.
[59]Cremonezzi DC, Diaz MP, Valentich MA, Eynard AR. Neoplastic and preneoplastic lesions induced by melamine in rat urothelium are modulated by dietary polyunsaturated fatty acids. Food Chem Toxicol 2004;42:1999-2007
[60]Jiang GP, Zhao ZY, He J. The characteristics of melamine-related renal stones by ultrasound. In Press 2009. World J Pediatr
[61]Shen Y, Sun N, Jiang YP. Diagnosis, explanation of a proposal of treatment of kidney disease from powdered infant formula-based melamine exposure in Chinese infants. Chin J Pediatr (Chin) 2008; 46:816-819
[62]Wang ZG. Blood purification. Beijing:Beijing Science and Technology Press; 2003: 367-375
[63]Melnick RL, Boorman GA, Haseman JK, Montali RJ, Huff J. Urolithiasis and bladder carcinogenicity of melamine in rodents. Toxicol Appl Pharmacol 1984;72:292-303
[64]Ho SSY, Chu WCW, Wong KT, et al. Ultrasonographic evalu-4. Ation of melamine-exposed children in Hong Kong. N Engl J Med 2009;360
[65]Wang I-J, Chen P-C, Hwang K-C. Melamine and nephrolithiasis in children in Taiwan. N Engl J Med 2009;360
[66]Gillen DL, Worcester EM, Coe FL. Decreased renal function among adults with a history of nephrolithiasis:a study of NHANES Ⅲ. Kidney Int 2005;67:685-90
[67]Jia LQ et al. Ultrasonographic diagnosis of urinary calculuscaused by melamine in children. Chin Med J (Engl).2009,122(3):252-256
[68]Ogasawara H, Imaida K, lshiwata H, et al. Urinary bladder carcinogenesis induced by melamine in F344 male rats, eorrelation between carcinogenieity and urolith formation. Carcinogenesis,1995,16:2773-2777.
[69]Tiselius HG.Epidemiology and medical management of stone disease. BJU Int 2003,91 (8):758-767
[70]王养民,王楠,高晓东等.婴幼儿三聚氰胺致泌尿系结石诊疗分析.中华腔镜泌尿外科杂志,2009,3(4)：295～298.
[71]Ren FY, Wang Y, Hou XB, Zhang CR, Ma L.Clinical and imaging features in 16 infants exposed to food contaminated with melamine and cyanuric acid. AJR Am J Roentgenol.2009,192:707-710
[72]Liu JM, Ren A, Yang L, Gao J, Pei L, Ye R, Qu Q, Zheng X.Urinary tract abnormalities in Chinese rural children who consumed melamine-contaminated dairy products:a population-based screening and follow-up study. CMAJ.2010,182:439-443
[73]Th om ps on M E, Le wi n-Smith MR, Kalasinsky V F, et al. Characterization o fmelamine-containing and calcium oxalate crystals in three dogs with suspectedpet food-induced nephrotoxicosis. Vet Pathol 2008;45:417-26
[74]张宁.三聚氰胺尿路结石患儿128例内科诊疗效果分析.《郑州大学硕士论文》
[75]龙福芝.三聚氰胺对婴幼儿肝肾功能损害的随访研究《广西医科大学硕士论文》
[76]Bhalla V, Grimm PC, Chertow GM, Pao AC. Melamine nephrotoxicity:an emerging epidemic in an era of glo balization. Kidney Int 2009;75:774-9.
[77]Sugita T, Ishiwata H, Yoshihira K. Release of formaldehyde and melamine from tableware made of melamine-formaldehyde resin. Food Addit Contam 1990;7:21-7
[78]王伟.奶制品中三聚氰胺、三聚氰酸检测影响因素的研究《重庆大学硕士论文》
[79]Liu CC, Huang CH, Wu WJ, et al. Associ ation of vitamin D receptor (Fok-I) polymorphism with the clinical presentation of calcium urolithiasis. BJU Int 2007;99:1534-8
[80]Cremonezzi DC, Silva RA, del Pilar Diaz M, Valentich MA, Eynard AR. Dietary polyunsatured fatty acids (PUFA) differentially modulate melamine-induced preneoplastic urothelial proliferation and apoptosis in mice. Prostaglandins Leukot Essent Fatty Acids 2001;64:151-159.
[81]Reimschues sel R, Gieseker CM, Miller RA, et al. Evaluation of the renal effects ofexperimental feeding of melamine and cyanuric acid to fish and pigs. Am J Vet Res 20 08;69:1217-28
[82]Mast RW, Jeffcoat AR, Sadler BM, Kraska RC, Friedman MA. Metabolism, disposition and excretion of melamine in male Fischer 344 rats. Food Chem Toxicol 1983;21:807-810
[83]Lattupalli R, Yee J, Kolluru A. Nephrotoxicity of mala fidemelamine:modern era milk scandal. ScientificWorldJournal.2008;8:949-850
[84]Yang VL, Batlle D. Acute renal failure from adulteration of milkwith melamine. Scientific World Journal.2008;8:974-975
[85]Kaya M, Boleken ME, Soran M, Kanmaz T, Yucesan S. Acute renal failure due to bilateral uric acid lithiasis in infants. Urol Res 2007;35:119-22
[86]Dobson RL, Motlagh S, Quijano M, et al. Identification and characterization of toxicity of contaminants in pet food leading to an outbreak of renal toxicity in cats and dogs. Toxicol Sci 2008; 106:251-62
[87]Woo PC, Lau SK, Yuen KY. Infectious diseases emerging from Chinese wet-markets: zoonotic origins of severe respiratory viral infections. Curr Opin Infect Dis 2006;5:401-7
[88]Fong BM, Siu TS, Lee JS, Tam S. Determination of mercury in whole blood and urine by inductively coupled pla sma mass spectrometry. J Anal Toxicol 2007;31:281-7
[89]Cianciolo RE, Bischoff K, Ebel JG, et al. Clinic opathologic, histologic, and toxicologic findings in 70 cats inadvertently exposed to pet food contaminated with melam ine and cyanuric acid. J Am Vet Med Assoc 2008;233:729-37
[90]Chan E Y, Griffiths SM, Chan CW. Public-health r isks of melamine in milk products. Lancet 2008; 372:1444-5
[91]Kupeli B, Biri H, Isen K, et al. Treatment of ureteral stones Comparison of ESWL and endourologic alternative. Eur Urol,1998,34 (4):474-479.
[92]P arry J. C hin a's t ainted milk sc andal spr eads ar ound w orld.BMJ2008;337:a1890
[93]Robbiani JH, S i mo netti GD, C rosazzo L, Ferrarini A, P ronzini F, Bian che tti M G. Fals epositivedip stick forurinary blood in child hood. J Nephrol2006; 19:605-6
[94]Parks JH, Goldfisher E, Asplin JR, Coe FL. A single 24-hour urine collection is inad-equate for the medical evaluation of nephro-lithiasis. J Urol 2002; 167:1607-12
[2]Li C, Wang W, Knepper MA, et al.Downregulation of renal aquaporins in response to unilateral ureteral obstruction.Am J Physiol Renal Physiol,2003,284(5):F1066-1079.
[3]Wamsley-Davis A,Padda R,Truong LD,et al. AT1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy:preservation of kidney tissue mass using candesartan.Am J Physiol Renal Physiol,2004,287(3):F474-480.
[4]Huang WY, Peters CA, Zurakowski D, et al. Renal biopsy in congenital ureteropelvic junction obstruction:evidence for parenchymal maldevelopment.Kidney Int,2006, 69(1):137-143.
[5]Fr(?)kiaer J, Marples D, Knepper MA, et al. Bilateral ureteral obstruction downregulates expression of vasopressin-sensitive AQP-2 water channel in rat kidney. Am J Physiol, 1996,270(4 Pt 2):F657-668.
[6]Li C, Wang W, Kwon TH, et al. Downregulation of AQP1,-2, and-3 after ureteral obstruction is associated with a long-term urine-concentrating defect. Am J Physiol Renal Physiol,2001,281(1):F163-171.
[7]rregaard R,Jensen BL,Topcu SO,et al.COX-2 activity transiently contributes to increased water and NaCl excretion in the polyuric phase after release of ureteral obstruction.Am J Physiol Renal Physiol,2007,292(5):F1322-1333.
[8]Kwon TH, Nielsen J, M(?)ller HB, et al. Aquaporins in the kidney. Handb Exp Pharmacol. 2009,(190):95-132.
[9]Norregaard R, Jensen BL, Topcu SO, et al. Urinary tract obstruction induces transient accumulation of COX-2-derived prostanoids in kidney tissue. Am J Physiol Regul Integr Comp Physiol.2010,298(4):R1017-1025.
[10]文建国,王焱,李真珍,等.先天性肾积水肾脏及其尿液中水通道蛋白2表达的相关性研究.中华小儿外科杂志,2009,30(2)：86-90.
[11]Reams G,Villarreal D,Wu Z, et al. Renal tissue angiotensin Ⅱ:response to infusions of angiotensin I and an angiotensin-converting enzyme inhibitor. Am J Kidney Dis, 1993,22(6):851-857.
[12]Fr(?)kiaer J, Knudsen L, Nielsen AS, et al.Enhanced intrarenal angiotensin Ⅱ generation in response to obstruction of the pig ureter. Am J Physiol,1992,263(3 Pt 2):F527-533.
[13]Fr(?)kiaer J, Djurhuus JC, Nielsen M, et al-Renal hemodynamic response to ureteral obstruction during converting enzyme inhibition.Urol Res,1996,24(4):217-227.
[14]Harris RC. Cyclooxygenase-2 in the kidney. J Am Soc Nephrol.2000, 11(12):2387-2394.
[15]Kwon TH, Nielsen J, Kim YH, et al. Regulation of sodium transporters in the thick ascending limb of rat kidney:response to angiotensin II. Am J Physiol Renal Physiol,2003, 285(1):F152-165.
[16]Dal Canton A, Corradi A, Stanziale R, et al. Glomerular hemodynamics before and after release of 24-hour bilateral ureteral obstruction. Kidney Int,1980,17(4):491-496.
[17]Fr(?)kiaer J, Christensen BM, Marples D, et al. Downregulation of aquaporin-2 parallels changes in renal water excretion in unilateral ureteral obstruction. Am J Physiol,1997, 273(2):F213-223.
[18]Li C, Wang W, Kwon TH, et al. Altered expression of major renal Na transporters in rats with bilateral ureteral obstruction and release of obstruction. Am J Physiol Renal Physiol, 2003,285(5):F889-901.
[19]Oliverio MI, Madsen K, Best CF, et al. Renal growth and development in mice lacking ATI A receptors for angiotensin II. Am J Physiol,1998,274(1 Pt 2):F43-50.
[20]Burns KD, Homma T, Harris RC. The intrarenal renin-angiotensin system. Semin Nephrol, 1993,13(1):13-30.
[21]Saccomani G, Mitchell KD, Navar LG. Angiotensin Ⅱ stimulation of Na-H exchange in proximal tubule cells. Am J Physiol,1990,258(5 Pt 2):F1188-1195.
[22]Moriyama T, Kawada N, Akagi Y, et al. TCV-116 inhibits interstitial fibrosis and HSP47 mRNA in rat obstructive nephropathy. Kidney Int Suppl,1997,63:S232-235.
[23]Yosypiv IV. Renin-angiotensin system in ureteric bud branching morphogenesis:Insights into the mechanisms. Pediatr Nephrol,2011,26:1499-1512
[24]Stipsanelli A, Daskalakis G, Koutra P, et al. Renin-angiotensin system dysregulation in fetuses with hydronephrosis. Eur J Obstet Gynecol Reprod Biol,2010,150:39-41
[25]Hayasaka K, Ogino D, Matsunaga A. [molecular basis of hydronephrosis]. Nihon Rinsho, 2006,64 Suppl 2:545-549
[26]Yosypiv IV, Schroeder M, El-Dahr SS. Angiotensin ii type 1 receptor-egf receptor cross-talk regulates ureteric bud branching morphogenesis. J Am Soc Nephrol,2006, 17:1005-1014
[27]Wang G, Yuan W, Kwon TH, et al. Age-related changes in expression in renal aqps in response to congenital, partial, unilateral ureteral obstruction in rats. Pediatr Nephrol,2012, 27:83-94
[28]Knoers N. Nephrogenic diabetes insipidus.1993,
[29]Ampawong S, Klincomhum A, Likitsuntonwong W, et al. Expression of aquaporin-1,-2 and-4 in mice with a spontaneous mutation leading to hydronephrosis. J Comp Pathol, 2012,146:332-337
[30]Nishimura N, Matsumura F, Vogel CF, et al. Critical role of cyclooxygenase-2 activation in pathogenesis of hydronephrosis caused by lactational exposure of mice to dioxin. Toxicol Appl Pharmacol,2008,231:374-383
[31]Takahashi N, Chernavvsky DR, Gomez RA, et al. Uncompensated polyuria in a mouse model of bartter's syndrome. Proc Natl Acad Sci U S A,2000,97:5434-5439
[32]Ares GR, Caceres PS, Ortiz PA. Molecular regulation of nkcc2 in the thick ascending limb. Am J Physiol Renal Physiol,2011,301:F1143-1159
[33]Olesen ET, de Seigneux S, Wang G, et al. Rapid and segmental specific dysregulation of aqp2, s256-paqp2 and renal sodium transporters in rats with lps-induced endotoxaemia. Nephrol Dial Transplant,2009,24:2338-2349
[34]Stechman MJ, Loh NY, Thakker RV. Genetic causes of hypercalciuric nephrolithiasis. Pediatr Nephrol,2009,24:2321-2332
[35]Benziane B, Demaretz S, Defontaine N, et al. Nkcc2 surface expression in mammalian cells:Down-regulation by novel interaction with aldolase b. J Biol Chem,2007, 282:33817-33830
[36]Huang CL, Yang SS, Lin SH. Mechanism of regulation of renal ion transport by wnk kinases. Curr Opin Nephrol Hypertens,2008,17:519-525
[37]Welker P, Bohlick A, Mutig K, et al. Renal na+-k+-cl-cotransporter activity and vasopressin-induced trafficking are lipid raft-dependent. Am J Physiol Renal Physiol,2008, 295:F789-802
[38]Capasso G, Rizzo M, Garavaglia ML, et al. Upregulation of apical sodium-chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt-sensitive hypertension. Am J Physiol Renal Physiol,2008,295:F556-567
[39]Stodkilde L, Norregaard R, Fenton RA, et al. Bilateral ureteral obstruction induces early downregulation and redistribution of aqp2 and phosphorylated aqp2. Am J Physiol Renal Physiol,2011,301:F226-235
[40]Li W, Zhang Y, Bouley R, et al. Simvastatin enhances aquaporin-2 surface expression and urinary concentration in vasopressin-deficient brattleboro rats through modulation of rho gtpase. Am J Physiol Renal Physiol,2011,301:F309-318
[41]Kim HY, Choi HJ, Lim JS, et al. Emerging role of akt substrate protein as160 in the regulation of aqp2 translocation. Am J Physiol Renal Physiol,2011,301:F151-161
[42]Jung HJ, Kwon TH. Membrane trafficking of collecting duct water channel protein aqp2 regulated by akt/as160. Electrolyte Blood Press,2010,8:59-65
[43]Velasco Cano MV, Runkle de la Vega I. [current considerations in syndrome of inappropriate secretion of antidiuretic hormone/syndrome of inappropriate antidiuresis]. Endocrinol Nutr,2010,57 Suppl 2:22-29
[44]Mollajew R, Zocher F, Homer A, et al. Routes of epithelial water flow:Aquaporins versus cotransporters. Biophys J,2010,99:3647-3656
[45]Lutken SC, Kim SW, Jonassen T, et al. Changes of renal aqp2, enac, and nhe3 in experimentally induced heart failure:Response to angiotensin ii atl receptor blockade. Am J Physiol Renal Physiol,2009,297:F1678-1688
[46]Li JH, Chou CL, Li B, et al. A selective ep4 pge2 receptor agonist alleviates disease in a new mouse model of x-linked nephrogenic diabetes insipidus. J Clin Invest,2009, 119:3115-3126
[47]Li XC, Shao Y, Zhuo JL. Atla receptor knockout in mice impairs urine concentration by reducing basal vasopressin levels and its receptor signaling proteins in the inner medulla. Kidney Int,2009,76:169-177
[48]Yasuhara A, Wada J, Malakauskas SM, et al. Collectrin is involved in the development of salt-sensitive hypertension by facilitating the membrane trafficking of apical membrane proteins via interaction with soluble n-ethylmaleiamide-sensitive factor attachment protein receptor complex. Circulation,2008,118:2146-2155
[49]Zhang Y, Sands JM, Kohan DE, et al. Potential role of purinergic signaling in urinary concentration in inner medulla:Insights from p2y2 receptor gene knockout mice. Am J Physiol Renal Physiol,2008,295:F1715-1724
[50]Yano Y, Cesar KR, Araujo M, et al. Aquaporin 2 expression increased by glucagon in normal rat inner medullary collecting ducts. Am J Physiol Renal Physiol,2009,296:F54-59
[51]Nicchia GP, Cogotzi L, Rossi A, et al. Expression of multiple aqp4 pools in the plasma membrane and their association with the dystrophin complex. J Neurochem,2008, 105:2156-2165
[52]Albertoni Borghese MF, Majowicz MP, Ortiz MC, et al. Renal sodium-glucose cotransporter activity and aquaporin-2 expression in rat kidney during chronic nitric oxide synthase inhibition. Nephron Physiol,2007,107:p77-86
[53]Nishimura H, Yang Y, Lau K, et al. Aquaporin-2 water channel in developing quail kidney: Possible role in programming adult fluid homeostasis. Am J Physiol Regul Integr Comp Physiol,2007,293:R2147-2158
[54]Goel M, Sinkins WG, Zuo CD, et al. Vasopressin-induced membrane trafficking of trpc3 and aqp2 channels in cells of the rat renal collecting duct. Am J Physiol Renal Physiol, 2007,293:F1476-1488
[55]Abreu N, Tardin JC, Boim MA, et al. Hemodynamic parameters during normal and hypertensive pregnancy in rats:Evaluation of renal salt and water transporters. Hypertens Pregnancy,2008,27:49-63
[56]Vossenkamper A, Nedvetsky PI, Wiesner B, et al. Microtubules are needed for the perinuclear positioning of aquaporin-2 after its endocytic retrieval in renal principal cells. Am J Physiol Cell Physiol,2007,293:C1129-1138
[57]Takata K. Aquaporin-2 (aqp2):Its intracellular compartment and trafficking. Cell Mol Biol (Noisy-le-grand),2006,52:34-39
[58]Zimmerman SL, Frisbie J, Goldstein DL, et al. Excretion and conservation of glycerol, and expression of aquaporins and glyceroporins, during cold acclimation in cope's gray tree frog hyla chrysoscelis. Am J Physiol Regul Integr Comp Physiol,2007,292:R544-555
[59]Han KH, Croker BP, Clapp WL, et al. Expression of the ammonia transporter, rh c glycoprotein, in normal and neoplastic human kidney. J Am Soc Nephrol,2006, 17:2670-2679
[60]Iacobelli S, Addabbo F, Bonsante F, et al. Aquaporin-2 excretion and renal function during the 1st week of life in preterm newborn infants. Nephron Physiol,2006,104:121-125
[61]Kazama I, Arata T, Michimata M, et al. Lithium effectively complements vasopressin v2 receptor antagonist in the treatment of hyponatraemia of siadh rats. Nephrol Dial Transplant,2007,22:68-76
[62]Yip KP. Epac-mediated ca(2+) mobilization and exocytosis in inner medullary collecting duct. Am J Physiol Renal Physiol,2006,291:F882-890
[63]Bustamante M, Hosler U, Kotova O, et al. Insulin potentiates avp-induced aqp2 expression in cultured renal collecting duct principal cells. Am J Physiol Renal Physiol,2005, 288:F334-344
[64]Lam AK, Ko BC, Tam S, et al. Osmotic response element-binding protein (orebp) is an essential regulator of the urine concentrating mechanism. J Biol Chem,2004, 279:48048-48054
[65]Gong H, Wang W, Kwon TH, et al. Epo and alpha-msh prevent ischemia/reperfusion-induced down-regulation of aqps and sodium transporters in rat kidney. Kidney Int,2004,66:683-695
[66]Horster M. Embryonic epithelial membrane transporters. Am J Physiol Renal Physiol,2000, 279:F982-996
[67]Yang B, Gillespie A, Carlson EJ, et al. Neonatal mortality in an aquaporin-2 knock-in mouse model of recessive nephrogenic diabetes insipidus. J Biol Chem,2001, 276:2775-2779
[68]El-Dahr SS, Harrison-Bernard LM, Dipp S, et al. Bradykinin b2 null mice are prone to renal dysplasia:Gene-environment interactions in kidney development. Physiol Genomics, 2000,3:121-131
[69]Deen PM, van Balkom BW, Kamsteeg EJ. Routing of the aquaporin-2 water channel in health and disease. Eur J Cell Biol,2000,79:523-530
[70]Chou CL, Yip KP, Michea L, et al. Regulation of aquaporin-2 trafficking by vasopressin in the renal collecting duct. Roles of ryanodine-sensitive ca2+stores and calmodulin. J Biol Chem,2000,275:36839-36846
[71]Saito T, Ishikawa SE, Ando F, et al. Vasopressin-dependent upregulation of aquaporin-2 gene expression in glucocorticoid-deficient rats. Am J Physiol Renal Physiol,2000, 279:F502-508
[72]Promeneur D, Kwon TH, Frokiaer J, et al. Vasopressin v(2)-receptor-dependent regulation of aqp2 expression in brattleboro rats. Am J Physiol Renal Physiol,2000,279:F370-382
[73]Klussmann E, Marie K, Rosenthal W. The mechanisms of aquaporin control in the renal collecting duct. Rev Physiol Biochem Pharmacol,2000,141:33-95
[74]Li C, Wang W, Rivard CJ, et al. Molecular mechanisms of angiotensin ii stimulation on aquaporin-2 expression and trafficking. Am J Physiol Renal Physiol,2011, 300:F1255-1261
[75]Nowik M, Kampik NB, Mihailova M, et al. Induction of metabolic acidosis with ammonium chloride (nh4cl) in mice and rats--species differences and technical considerations. Cell Physiol Biochem,2010,26:1059-1072
[76]Albertoni Borghese MF, Bettini LM, Nitta CH, et al. Aquaporin-2 promoter is synergistically regulated by nitric oxide and nuclear factor of activated t cells. Nephron Extra,2011,1:124-138
[77]Li Y, Zelenina M, Plat-Willson G, et al. Urinary aquaporin-2 excretion during ibuprofen or indomethacin treatment in preterm infants with patent ductus arteriosus. Acta Paediatr, 2011,100:59-66
[78]Baggaley E, Nielsen S, Marples D. Dehydration-induced increase in aquaporin-2 protein abundance is blocked by nonsteroidal anti-inflammatory drugs. Am J Physiol Renal Physiol, 2010,298:F1051-1058
[79]Noda Y, Sohara E, Ohta E, et al. Aquaporins in kidney pathophysiology. Nat Rev Nephrol, 2010,6:168-178
[80]Kim YH, Choi YJ, Bae HR, et al. P2 receptor-mediated inhibition of vasopressin-stimulated fluid transport and camp responses in aqp2-transfected mdck cells. Korean J Physiol Pharmacol,2009,13:9-14
[81]Boone M, Kortenoeven M, Robben JH, et al. Effect of the cgmp pathway on aqp2 expression and translocation:Potential implications for nephrogenic diabetes insipidus. Nephrol Dial Transplant,2010,25:48-54
[82]Chung SH, Jun DW, Kim KT, et al. Aquaporin-2 urinary excretion in cirrhosis: Relationship to vasopressin and nitric oxide. Dig Dis Sci,2010,55:1135-1141
[83]Li G, Wang ZX, Fu WJ, et al. Introduction to biodegradable polylactic acid ureteral stent application for treatment of ureteral war injury. BJU Int,2011,108:901-906
[84]Yao Y, Zhang J, Tan DQ, et al. Interferon-gamma improves renal interstitial fibrosis and decreases intrarenal vascular resistance of hydronephrosis in an animal model. Urology, 2011,77:761 e768-713
[85]Baynes J, Murray DB. Cardiac and renal function are progressively impaired with aging in zucker diabetic fatty type ii diabetic rats. Oxid Med Cell Longev,2009,2:328-334
[86]Chew BH, Lange D, Paterson RF, et al. Next generation biodegradable ureteral stent in a yucatan pig model. J Urol,2010,183:765-771
[87]Helin I, Persson PH.Prenatal diagnosis of urinary tract abnormalities by ultrasound. Pediatrics.1986,78(5):879-83
[88]Shi Y, Pedersen M, Li C, Wen JG, Thomsen K, St(?)dkilde-J(?)rgensen H, J(?)rgensen TM, Knepper MA, Nielsen S, Djurhuus JC, Fr(?)kiaer J.. Early release of neonatal ureteral obstruction preserves renal function. Am J Physiol Renal Physiol.2004,286(6):F1087-99.
[89]Lam HS, Ng PC, Chu WC, et al. Renal screening in children after exposure to low dose melamine in Hong Kong:cross sectional study. BMJ,2008,337:2991.
[90]Melamine and food safety in China. The Lancet,2009,373(9661):353.
[91]Choong S, Whitfield H, Duffy P, et al. The management of paediatric urolithiasis. BJU Int, 2000,86(7):857-60.
[92]Dogan HS, Tekgul S. Management of pediatric stone disease. Curr Urol Rep.2007,8(2): 163-73.
[93]Hamann MF, Melchior D,Juenemann KP, et al. Stone management in children. Aktuelle Urol,2007,38(5):398-402
[94]W.L.Lipschitz, E.Stokey. The mode of action of three new diuretics:melamine, adenine and formoguanamine.Journal of Pharmacology And Experimental herapeutics,1945,83(4): 235-49.
[95]Mast RW, Jeffcoat AR, Sadler BM, et al. Metabolism, disposition and excretion of [14C]: Melamine in male Fischer 344 rats. Food Chem Toxicol,1983,21 (6):807-810.
[96]http://www.who.int/foodsafety/fs_management/infosan_events/en/index3.html.
[97]Ghani AA, Al Helal B, Hussain N. Acute renal failure in pediatric patients:Etiology and predictors of outcome. Saudi J Kidney Dis Transpl,2009,20(1):69-76.
[98]Dudley JA, Haworth J M, McGraw M E, et al. Clinical relevance and implications of antenatal hydronephrosis. Achieves of Disease in Childhood,1997,76(1):31-34.
[99]de Onis M, Garza C, Onyango AW, Rolland-Cachera MF. WHO growth standards for infants and young children. Arch Pediatr,2009,16(1):47-53.
[100]Lattupalli R, Kolluru A, Yee J. Nephrotoxicity of mala fide Melamine:modern era milk. ScientificWorldJournal,2008,8:949-950.
[101]Hau AK, Kwan TH, Li PK. Melamine toxicity and the kidney. J Am Soc Nephrol,2009, 20(2):245-50.
[102]孟群,沈颖,孙宁,等.儿童尿路结石及其致急性肾功能衰竭临床分析.中国小儿急救医学,2008,15：122～124.
[103]木拉提·马合木提,阿里木·太来提,安尼瓦尔·牙生,等.小儿上尿路结石286例临床分析.临床泌尿外科杂志,2007,4：280～282.
[104]小儿尿石症.见：张金哲,潘少川,黄澄如,主编.实用小儿外科学.下册.杭州：浙江 科学技术出版社,2003,1017-1025.
[105]Neerman MF, Zhang W, Parrish AR, et al. In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery. Int J Pharm,2004,281:129-132.
[106]米华,邓耀良.中国尿石症的流行病学特征.中华泌尿外科杂志,2003,10：715-716.
[107]Coward RJ, Peters CJ, Duffy PG, et al. Epidemiology of paediatric renal stone disease in the UK. Arch Dis Child,2003,88:962-965.
[108]Menon M. Urinary lithiasis:etiology, diagnosis, and medical management. Campbell's urology. Vol 4.8th ed. Philadelphia:Saunders,2002,3231.
[109]Melnick RL, Boorman GA, Haseman JK, et al. Urolithiasis and bladder carcinogenicity of melamine in rodents. Toxicol Appl Pharmacol,1984,72:292-303.
[110]Kamoun A, Daudon M, Abdelmoula J, et al. Urolithiasis in Tunisian children:a study of 120 cases based on stone composition. Pediatr Nephrol,1999,13:920-925.
[111]孟繁英,刘玉荣,孟群,等.婴幼儿泌尿系结石29例.实用儿科临床杂志,2003,1：66-68.
[112]Spencer BA, Wood BJ, Dretler SP, et al. Helical CT and ureteral colic. Urol Clin North Am, 2000,27:231-241.
[113]Jia LQ, Shen Y, Wang XM,et al. Ultrasonographic diagnosis of urinary calculus caused by melamine in children. Chin Med J (Engl),2009,122(3):252-256.
[114]Mandel NS, Mandel GS. Urinary tract stone disease in the United States veteran population Ⅱ. Geographical analysis of variations in composition. J Urol,1989,142:1516-1521.
[115]沈绍基,袁之敏.尿石症概论.见：吴阶平,主编.吴阶平泌尿外科学.上卷.济南：山东科学技术出版社,2004,713-742.
[116]Maalouf NM, Cameron MA, Moe OW, et al. Novel insights into the pathogenesis of uric acid nephrolithiasis. Curr Opin Nephrl Hypertens,2004,13:181-189.
[117]黄东平,李伟东,黄树声,等.泌尿系尿酸结石的现代观.医学临床研究,2006,23(3)：393-396.
[118]Preminger GM. Pharmacologic treatment of uric acid calculi. Urol Clin North Am,1987, 14(2):335-338.
[119]Albrecht H. Urinary stones:diagnoses, treatment, and prevention of recurrence. New York: Basel Karger,2000:86.
[120]陈志强,曾令启,叶章群,等.氮基于三醇E液局部灌注治疗输尿管尿酸结石.中华泌尿外科杂志,2004,6：401～403.
[121]Alken CE. Steinauflsung und Steinprophylaxe. In:Alken CE, May P, BraunJ. Eds. Harnsteinleiden.2 Auflage. Stuttgart:Geory Thieme Verlag,1982,130-144.
[122]孙西钊,叶章群,孙则禹.儿童上尿路结石的处理方法.临床泌尿外科杂志,2000,15：99～101.
[123]Al-Busaidy SS, Prem AR, Medhat M. Pediatrics taghom calculi:Pediatric staghorn calculi: the role of extracorporeal shock wave lithotripsy monotherapy with special reference to ureteral stenting. J Urol,2003,169(2):629-633.
[124]Claro Jde A, Denardi F, Ferreira U, et al. Effects of extracorporeal shockwave lithotripsy on renal growth and function:an animal model. J Endourol,1994,8(3):191-194.
[125]Rodrigues Netto N Jr, Longo JA, Ikonomidis J A, et al. Extracorporeal shock wave lithotripsy in children, J Urol,2002,167(5):2164-2166.
[126]Shen Y, Liu XR, Zhang GJ, et al. Blood purification therapy in treatment of acute renal failure in infants with melamine-induced stones. Chin Med J (Engl).2009,122 (3):257-61.
[127]孙宁,沈颖,贾立群.三聚氰胺所致的婴幼儿泌尿系统结石诊治,中华小儿外科杂志,2009,30(1)：54～55.
[128]贾建业,叶敏,陈方,等.低能级体外震波碎石治疗儿童上尿路结石.中华小儿外科杂志,2005,26：239-241.
[129]范应中,张震,张谦,等.三聚氰胺致婴幼儿泌尿系结石合并肾积水与先天性肾积水的对比观察.郑州大学学报(医学版),2009,44(5)：1011-1013.
[130]Moe O W. Kidney stones:pathophysiology and medical management, lancet,2006,367: 333-44.
[131]Matlaga B R, Coe F L, Evan A P, Lingeman J E. The role of Randall's plaques in the pathogenesis of calcium stones. J Urol,2007,177:31-38.
[132]Matkovic V, Ilich JZ, Andon MB, et al. Urinary calcium, sodium, and bone mass of young females. Am J Clin Nutr,1995,62(2):417-425.
[133]Bonjour JP, Carrie AL, Ferrari S, et al. Calcium-enriched foods and bone mass growth in prepubertal girls:a randomized, double-blind, placebo-controlled trial. J Clin Invest,1997, 99(6):1287-1294.
[134]Heck HD, Tyl RW. The induction of bladder stones by terephthalic acid, dimethyl terephthalate, and melamine (2,4,6-triamino-s-triazine) and its relevance to risk assessment. Regul Toxicol Pharmacol.1985,5(3):294-313.
[135]Guan N, Fan Q, Ding J, Zhao Y, et al. Melamine-contaminated powdered formula and urolithiasis in young children. N Engl J Med,2009,360(11):1067-74.
[1]Benfield M.R., McDonald R.A., Bartosh S., Ho P.L., Harmon W. Changing trends in pediatric transplantation:2001 Annual Report of the North American Pediatric Renal Transplant Coop-erative Study. Pediatr. Transplant.2003,7,321-335
[2]Chang C.P., McDill B.W., Neilson J.R. et al. Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery. J. Clin. Invest. 2004,113,1051-1058.
[3]Mendelsohn C. Functional obstruction:the renal pelvis rules. J. Clin. Invest.2004,113, 957-959.
[4]Yiee J.H., Johnson-Welch S., Baker L.A., Wilcox D.T. Histo-logic Differences Between Extrinsic and Intrinsic Ureteropelvic Junction Obstruction. Urology.2010,76,181-184.
[5]Roth K.S., Koo H.P., Spottswood S.E., Chan J.C. Obstruc-tive uropathy:an important cause of chronic renal failure in chil-dren.Clin. Pediatr. (Phila).2002,41,309-314.
[6]Broadbelt N.V., Stahl P.J., Chen J. et al. Early upregulation of iNOS mRNA expression and increase in NO metabolites in pressurized renal epithelial cells. Am. J. Physiol. Renal Physiol.2007,293, F1877-F1888
[7]Coleman C.M., Minor J.J., Burt L.E., Thornhill B.A., Forbes M.S., Chevalier R.L. Angiotensin AT1-receptor inhibition exac-erbates renal injury resulting from partial unilateral ureteral obstruction in the neonatal rat. Am. J. Physiol. Renal Physiol.2007,293, F262-F268.
[8]Yoo K.H., Norwood V.F., el-Dahr S.S., Yosipiv I., Chevalier R.L. Regulation of angiotensin Ⅱ AT1 and AT2 receptors in neonatal ureteral obstruction. Am. J. Physiol.1997,273, R503-R509.
[9]Wen J.G, Frokiaer J., Zhao J.B., Ringgaard S., Jorgensen T.M., Djurhuus J.C. Severe partial ureteric obstruction in new-born rats can produce renal dysplasia. BJU Int.2002,89, 740-745.
[10]Grandaliano G., Gesualdo L., Bartoli F.et al. MCP-1 and EGF renal expression and urine excretion in human congenital obstructive nephropathy. Kidney Int.2000,58,182-192
[11]Chen C.O., Park M.H., Forbes M.S.et al. Angiotensin-con-verting enzyme inhibition aggravates renal interstitial injury resulting from partial unilateral ureteral obstruction in the neona-tal rat. Am. J. Physiol. Renal Physiol.2007,292, F946-F955
[12]Le Normand L., Buzelin J.M., Bouchot O., Rigaud J., Karam G. Upper urinary tract: physiology, pathophysiology of obstructions and function assessment. Ann. Urol.2005, 39,30-48
[13]Taha M.A., Shokeir A.A., Osman H.G., Abd el-Aziz Ael A., Farahat S.E. Diagnosis of ureteropelvic junction obstruction in children:role of endothelin-1 in voided urine. Urology,2007,69,560-564.
[14]Padovano V, Massari S., Mazzucchelli S., Pietrini G. PKC induces internalization and retention of the EAAC1 glutamate transporter in recycling endosomes of MDCK cells. Am. J. Phys-iol. Cell Physiol.2009,297, C835-C844.
[15]Rosen S., Peters C.A., Chevalier R.L., Huang W.Y. The kid-ney in congenital ureteropelvic junction obstruction:a spectrum from normal to nephrectomy. J. Urol.2008,179, 1257-1263.
[16]Wolak T., Kim H., Ren Y., Kim J., Vaziri N.D., Nicholas S.B. Osteopontin modulates angiotensin II-induced inflamma-tion, oxidative stress, and fibrosis of the kidney. Kidney Int.2009,76,32-43
[17]Zhang P.L., Peters C.A., Rosen S. Ureteropelvic junction obstruction:morphological and clinical studies. Pediatr. Nephrol.2000,14,820-826.
[18]Durvasula R.V., Petermann A.T., Hiromura K. et al. Activa-tion of a local tissue angiotensin system in podocytes by mechani-cal strain. Kidney Int.2004,65,30-39.
[19]Chevalier R.L. Chronic partial ureteral obstruction and the developing kidney.Pediatr. Radiol.38(Suppl.1),2008,S35-S40.
[20]Lange-Sperandio B., Trautmann A., Eickelberg O. et al. Leu-kocytes induce epithelial to mesenchymal transition after unilat-eral ureteral obstruction in neonatal mice. Am. J. Pathol.2007,171,861-871.
[21]Garvin J.L.& Hong N.J. Cellular stretch increases superox-ide production in the thick ascending limb. Hypertension.2008,51,488-493.
[22]Sipos A., Vargas S.L., Toma I., Hanner F., Willecke K., Peti-Peterdi J. Connexin 30 deficiency impairs renal tubular ATP release and pressure natriuresis. J. Am. Soc. Nephrol. 2009,20,1724-1732.
[23]Taha M.A., Shokeir A.A., Osman H.G., Abd El-Aziz Ael A., Fara-hat S.E. Pelvi-ureteric junction obstruction in children:the role of urinary transforming growth factor-beta and epidermal growth factor. BJU Int.2007,99,899-903
[24]Kolb R.J., Woost P.G., Hopfer U. Membrane trafficking of angiotensin receptor type-1 and mechanochemical signal transduc-tion in proximal tubule cells. Hypertension.2004,44, 352-359.
[25]Guerin F., Azoulay R., Berrebi D. et al. (2008) Partial unilateral ure-teral obstruction in newborn mice:magnetic resonance imaging and pathology studies. J. Urol.2008,179, 1553-1563.
[26]Qin X.S., Tsukaguchi H., Shono A.. Yamamoto A., Kurihara H., Doi T. Phosphorylation of nephrin triggers its internalization by raft-mediated endocytosis. J. Am. Soc. Nephrol. 2009,20,2534-2545.
[27]Guerin F., Azoulay R., Berrebi D. et al. Partial unilateral ure-teral obstruction in newborn mice:magnetic resonance imaging and pathology studies. J. Urol.2008,179,1553-1563.
[28]Coleman C.M., Minor J.J., Burt L.E., Thornhill B.A., Forbes M.S., Chevalier R.L. Angiotensin AT1-receptor inhibition exac-erbates renal injury resulting from partial unilateral ureteral obstruction in the neonatal rat. Am. J. Physiol. Renal Physiol.2007,293, F262-F268.
[29]Chang C.P., McDill B.W., Neilson J.R. et al. Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery. J. Clin. Invest.2004,113,1051-1058.
[30]Thornhill B.A., Forbes M.S., Marcinko E.S., Chevalier R.L. Glomerulotubular disconnection in neonatal mice after relief of partial ureteral obstruction. Kidney Int. 2007,72,1103-1112.
[31]杨贺军.三聚氰胺所致婴幼儿泌尿系结石临床诊治和随访分析.《郑州大学硕士论文》2010.05.01
[32]Ulman I, Venkata R, Jayanthi, Koff SA The long-term followup of newborns with severe unilateral HN initially treated nonoperatively. J Urol.2000,164:1101-1105
[33]Lam HS, Ng PC, Chu WC, et al. Renal screening in children after exposure to low dose melamine in Hong Kong:cross sectional study. BMJ 2008;337:a2991
[34]Wang IJ, Chen PC, Hwang KC. Melami ne and nephr olithiasis in children in Taiwan. N Engl J Med 2009;360:1157-8.
[35]Liu CC, Huang CH, Wu WJ, et al. Associ ation of vitamin D receptor (Fok-I) polymorphism with the clinical presentation of calcium urolithiasis. BJU Int 2007;99:1534-8
[36]Langman CB. Melamine, powdered milk, and nephr olithiasis in Chinese infants. N Engl J Med 2009;360:1139-41
[37]Lam CW, Lan L, Che X, et al. Diagnosis and spectrum of melamine-related renal disease: plausible mechanism of stone formation in humans. Clin Chim Acta 2009;402:150-5
[38]Chung FM, Yang YH, Shieh TY, Shin SJ, Tsai JC, Lee YJ. Effect of alcohol consumption on estimated glo merularfiltration rate and creatinine clearance rate. Nephrol Dial Transplant 2005;20:1610-6
[39]Shekarriz B, Stoller ML. Uric acid nephrolithiasis:current concepts and controversies. J U ro 12002; 20:294-301
[40]Lee YH, Huang WC, Tsai JY, et al. Epidemiologic al studies on the prevalence of upper urinary calculi in Taiwan. Urol Int 2002;68:172-7
[41]Kuehn BM. Melamine scandals highlight hazards of increasingly globalized food chain. JAMA 2009;301:473-5
[42]Khan SR. Renal tubular damage/dysfunction:key to the formation of kidney stones. Urol Res 2006;34:86-91
[43]Siener R, Glatz S, Nicola y C, Hesse A. The role of overweight and obesity in calcium oxalate stone formation. Obes Res 2004; 12:106-13
[44]Brown CA, Jeong KS, Poppenga RH, Puschner B, Miller DM, Ellis AE, et al. Outbreaks of renal failure associated with melamine and cyanuric acid in dogs and cats in 2004 and 2007. J Vet Diagn Invest 2007; 19:525-531
[45]高健刚,复溟.上尿路结石治疗方法的选择及进展.中华泌尿外科杂志,2006,6：429-431
[46]Puschner B, Poppenga RH, Lowenstine LJ, Filigenzi MS, Pesavento PA. Assessment of melamine and cyanuric acid toxicity in cats. J Vet Diagn Invest 2007;19:616-624
[47]木拉提·马合木提,阿里木等.小儿上尿路结石286例临床分析.临床泌尿外科杂志,2007.4：280～282.
[48]Ministry of health of the People's of Republic of China. [http://www.moh.gov.cn/ publicfiles/business/htmlfiles/mohbgt/s3582/200809/37769.htm]
[49]Xin H, Stone R. Tainted milk scandal. Chinese probe unmasks high-tech adulteration with melamine. Science 2008; 322:1310-1311
[50]Jiang GP, Zhao ZY, He J. The characteristics of melamine-related renal stones by ultrasound. In Press 2009. World J Pediatr
[51]Hu YM, Jiang ZF. Development. In:Hu YM, Jiang ZF, eds.Zhu Futang Textbook of Pediatrics. Beijing:Chinese Pepole's Health Publisher,2002:11-66
[52]Wen JG, Li ZZ, Zhang H, Wang Y, Zhang RF, Yang L, Chen Y, Wang JX, Zhang SJ. Melamine related bilateral renal calculi in 50 children:single center experience in clinical diagnosis and treatment. J Urol.2010,183(4):1533-7
[53]米华,邓耀良.中国尿石症的流行病学特征.中华泌尿外科杂志,2003,10：715～716.
[54]Wen JG, Chang QL, Lou AF, Li ZZ, Lu S, Wang Y, Wang YL, Hu JH, Mao SP, Zhang Y, Xue R, Ren C, Xing L, Zhang GX, Zhang S, Djurhuus JC, Fr(?)kiaer J. Melamine-related urinary stones in 195 infants and young children:clinical features within 2 years of follow-up. Urol Int.2011;87(4):429-33
[55]Xin H, Stone R. Tainted milk scandal. Chinese probe unmasks high-tech adulteration with melamine. Science 2008; 322:1310-1311
[56]Ingelfi nger JR. Melamine and the global implications of food contamination. N Engl J Med 2008;359:2745-2748
[57]Cianciolo RE, Bischoff K, Ebel JG, Van Winkle TJ, Goldstein RE, Ser fi lippi LM. Clinicopathologic, histologic, and toxicologic fi ndings in 70 cats inadvertently exposed to pet food contaminated with melamine and cyanuric acid. J Am Vet Med Assoc 2008;233:729-737
[58]廖承琳,潘家骅,吕勇,等.问题奶粉导致小儿泌尿系统结石的诊疗策略.安徽医学,2008,29(6)：676-677.
[59]Cremonezzi DC, Diaz MP, Valentich MA, Eynard AR. Neoplastic and preneoplastic lesions induced by melamine in rat urothelium are modulated by dietary polyunsaturated fatty acids. Food Chem Toxicol 2004;42:1999-2007
[60]Jiang GP, Zhao ZY, He J. The characteristics of melamine-related renal stones by ultrasound. In Press 2009. World J Pediatr
[61]Shen Y, Sun N, Jiang YP. Diagnosis, explanation of a proposal of treatment of kidney disease from powdered infant formula-based melamine exposure in Chinese infants. Chin J Pediatr (Chin) 2008; 46:816-819
[62]Wang ZG. Blood purification. Beijing:Beijing Science and Technology Press; 2003: 367-375
[63]Melnick RL, Boorman GA, Haseman JK, Montali RJ, Huff J. Urolithiasis and bladder carcinogenicity of melamine in rodents. Toxicol Appl Pharmacol 1984;72:292-303
[64]Ho SSY, Chu WCW, Wong KT, et al. Ultrasonographic evalu-4. Ation of melamine-exposed children in Hong Kong. N Engl J Med 2009;360
[65]Wang I-J, Chen P-C, Hwang K-C. Melamine and nephrolithiasis in children in Taiwan. N Engl J Med 2009;360
[66]Gillen DL, Worcester EM, Coe FL. Decreased renal function among adults with a history of nephrolithiasis:a study of NHANES Ⅲ. Kidney Int 2005;67:685-90
[67]Jia LQ et al. Ultrasonographic diagnosis of urinary calculuscaused by melamine in children. Chin Med J (Engl).2009,122(3):252-256
[68]Ogasawara H, Imaida K, lshiwata H, et al. Urinary bladder carcinogenesis induced by melamine in F344 male rats, eorrelation between carcinogenieity and urolith formation. Carcinogenesis,1995,16:2773-2777.
[69]Tiselius HG.Epidemiology and medical management of stone disease. BJU Int 2003,91 (8):758-767
[70]王养民,王楠,高晓东等.婴幼儿三聚氰胺致泌尿系结石诊疗分析.中华腔镜泌尿外科杂志,2009,3(4)：295～298.
[71]Ren FY, Wang Y, Hou XB, Zhang CR, Ma L.Clinical and imaging features in 16 infants exposed to food contaminated with melamine and cyanuric acid. AJR Am J Roentgenol.2009,192:707-710
[72]Liu JM, Ren A, Yang L, Gao J, Pei L, Ye R, Qu Q, Zheng X.Urinary tract abnormalities in Chinese rural children who consumed melamine-contaminated dairy products:a population-based screening and follow-up study. CMAJ.2010,182:439-443
[73]Th om ps on M E, Le wi n-Smith MR, Kalasinsky V F, et al. Characterization o fmelamine-containing and calcium oxalate crystals in three dogs with suspectedpet food-induced nephrotoxicosis. Vet Pathol 2008;45:417-26
[74]张宁.三聚氰胺尿路结石患儿128例内科诊疗效果分析.《郑州大学硕士论文》
[75]龙福芝.三聚氰胺对婴幼儿肝肾功能损害的随访研究《广西医科大学硕士论文》
[76]Bhalla V, Grimm PC, Chertow GM, Pao AC. Melamine nephrotoxicity:an emerging epidemic in an era of glo balization. Kidney Int 2009;75:774-9.
[77]Sugita T, Ishiwata H, Yoshihira K. Release of formaldehyde and melamine from tableware made of melamine-formaldehyde resin. Food Addit Contam 1990;7:21-7
[78]王伟.奶制品中三聚氰胺、三聚氰酸检测影响因素的研究《重庆大学硕士论文》
[79]Liu CC, Huang CH, Wu WJ, et al. Associ ation of vitamin D receptor (Fok-I) polymorphism with the clinical presentation of calcium urolithiasis. BJU Int 2007;99:1534-8
[80]Cremonezzi DC, Silva RA, del Pilar Diaz M, Valentich MA, Eynard AR. Dietary polyunsatured fatty acids (PUFA) differentially modulate melamine-induced preneoplastic urothelial proliferation and apoptosis in mice. Prostaglandins Leukot Essent Fatty Acids 2001;64:151-159.
[81]Reimschues sel R, Gieseker CM, Miller RA, et al. Evaluation of the renal effects ofexperimental feeding of melamine and cyanuric acid to fish and pigs. Am J Vet Res 20 08;69:1217-28
[82]Mast RW, Jeffcoat AR, Sadler BM, Kraska RC, Friedman MA. Metabolism, disposition and excretion of melamine in male Fischer 344 rats. Food Chem Toxicol 1983;21:807-810
[83]Lattupalli R, Yee J, Kolluru A. Nephrotoxicity of mala fidemelamine:modern era milk scandal. ScientificWorldJournal.2008;8:949-850
[84]Yang VL, Batlle D. Acute renal failure from adulteration of milkwith melamine. Scientific World Journal.2008;8:974-975
[85]Kaya M, Boleken ME, Soran M, Kanmaz T, Yucesan S. Acute renal failure due to bilateral uric acid lithiasis in infants. Urol Res 2007;35:119-22
[86]Dobson RL, Motlagh S, Quijano M, et al. Identification and characterization of toxicity of contaminants in pet food leading to an outbreak of renal toxicity in cats and dogs. Toxicol Sci 2008; 106:251-62
[87]Woo PC, Lau SK, Yuen KY. Infectious diseases emerging from Chinese wet-markets: zoonotic origins of severe respiratory viral infections. Curr Opin Infect Dis 2006;5:401-7
[88]Fong BM, Siu TS, Lee JS, Tam S. Determination of mercury in whole blood and urine by inductively coupled pla sma mass spectrometry. J Anal Toxicol 2007;31:281-7
[89]Cianciolo RE, Bischoff K, Ebel JG, et al. Clinic opathologic, histologic, and toxicologic findings in 70 cats inadvertently exposed to pet food contaminated with melam ine and cyanuric acid. J Am Vet Med Assoc 2008;233:729-37
[90]Chan E Y, Griffiths SM, Chan CW. Public-health r isks of melamine in milk products. Lancet 2008; 372:1444-5
[91]Kupeli B, Biri H, Isen K, et al. Treatment of ureteral stones Comparison of ESWL and endourologic alternative. Eur Urol,1998,34 (4):474-479.
[92]P arry J. C hin a's t ainted milk sc andal spr eads ar ound w orld.BMJ2008;337:a1890
[93]Robbiani JH, S i mo netti GD, C rosazzo L, Ferrarini A, P ronzini F, Bian che tti M G. Fals epositivedip stick forurinary blood in child hood. J Nephrol2006; 19:605-6
[94]Parks JH, Goldfisher E, Asplin JR, Coe FL. A single 24-hour urine collection is inad-equate for the medical evaluation of nephro-lithiasis. J Urol 2002; 167:1607-12