CHRONIC KIDNEY INJURY FROM ENDOTHELIAL DYSFUNCTION AFTER ACUTE KIDNEY INJURY

急性肾损伤后内皮功能障碍导致的慢性肾损伤

基本信息

批准号：
7603252
负责人：
DAVID J ASKENAZI
金额：
$ 0.47万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2008-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7603252
关键词：
Acute Renal Failure with Renal Papillary Necrosis Age Animal Model Biological Markers Bladder Blood Pressure Cardiac Cardiovascular system Child Chronic Chronic Kidney Failure Cimetidine Clinic Visits Collection Computer Retrieval of Information on Scientific Projects Database Creatinine Creatinine clearance measurement Endothelial Cells Endothelium Event Factor VIII-Related Antigen Functional disorder Funding Grant Health Hour Hypertension Injury Institution Kidney Lead Measures Meat Methods Microalbuminuria Morbidity - disease rate Outcome Patients Process Proteins Proteomics Renal Tissue Renal function Research Research Personnel Resources Series Serum Source Techniques Therapeutic Intervention Time Tubular formation Ultrasonography United States National Institutes of Health Urine VWF gene Vascular Endothelial Cell Visit day glomerular function kidney vascular structure mortality sex urinary von Willebrand Factor

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background. After an ischemic acute kidney injury (AKI) event, tubular and glomerular function usually return to baseline, but growing evidence in animal models shows that damage occurring to the innermost layer of the renal vasculature (endothelial cells) can propagate a series of events that cause progressive renal injury. Endothelial damage has been show to independently predict poor cardiovascular health in cardiac and renal patients. Not much is know about the mechanisms involved in this process that begins with AKI and culminates in chronic renal disease. Children who develop AKI are an ideal group to study because the timing of initiation of events is known and they are less likely to have co-morbid illness. Therapeutic interventions to halt this progression can greatly reduce the morbidity and mortality associated with AKI. Hvpothesis and Aims: After AKI, most chil dren regain the majority of their renal function but the damage to renal vascular endothelial cells occurs which initiates events that lead to CKD and poor cardiovascular health. AIM 1: One month after AKI, children have less renal function reserve (RFR) compared to controls. AIM 2: One year after event, children with AKI have worsening RFR compared to controls. AIM 3: After AKI children with decreased RFR have elevated endothelial biomarkers. Proteomic techniques will discover new urinary biomarkers that occur in this setting. Methods: 20 otherwise healthy children with AKI and 20 age and sex matched controls will have blood pressure, serum and urine analysis on 2 separate clinic visits 9 months apart. Because 20-25% of existing renal tissue needs to be damaged prior to seeing change in GFR, RFR will be our primary outcome as it is more specific for renal injury. Briefly, RFR is performed as follows: Children will be on cimetidine for 2 days to block tubular secretion of creatinine. First, a baseline GFR will be measured by a 2-hour creatinine clearance (this method has previously b en validated as an adequate measure of GFR). Next, a 1 g/kg of non-meat protein meal challenge will be given prior to a second 2-hour reatinine clearance. RFR is the difference between baseline GFR and protein challenged GFR. Bladder ultrasound will confirm complete emptying before and after collection. AIM I: Compare RFR between those with recent AKI and controls. AIM 2: Compare the 9 month difference in RFR between the two groups. AIM 3: At both visits known biomarkers of endothelium damage will be measured and compared between the groups. These include microalbuminuria, hypertension, and serum biomarkers (hs-CRP, vWF,). Urine proteomic techniques will be performed to investigate for potential urine biomarkers present in children after AKI.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目及研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。背景。缺血性急性肾损伤 (AKI) 事件后，肾小管和肾小球功能通常会恢复到基线，但动物模型中越来越多的证据表明，肾脉管系统最内层（内皮细胞）发生的损伤可以传播一系列事件，导致进行性肾损伤。内皮损伤已被证明可以独立预测心脏病和肾脏患者心血管健康状况不佳。对于这一从 AKI 开始并最终导致慢性肾病的过程所涉及的机制知之甚少。发生 AKI 的儿童是理想的研究群体，因为事件发生的时间是已知的，而且他们患有共病的可能性较小。阻止这种进展的治疗干预措施可以大大降低 AKI 相关的发病率和死亡率。假设和目标：AKI 后，大多数儿童恢复了大部分肾功能，但肾血管内皮细胞发生损伤，从而引发导致 CKD 和心血管健康状况不佳的事件。目标 1：AKI 后一个月，与对照组相比，儿童的肾功能储备 (RFR) 较低。目标 2：事件发生一年后，与对照组相比，AKI 儿童的 RFR 恶化。目标 3：AKI 后 RFR 降低的儿童内皮生物标志物升高。蛋白质组学技术将发现在这种情况下出现的新的尿液生物标志物。方法：20 名其他方面健康的 AKI 儿童和 20 名年龄和性别匹配的对照儿童将在相隔 9 个月的 2 次单独就诊中进行血压、血清和尿液分析。由于 20-25% 的现有肾组织需要先受损才能看到 GFR 的变化，因此 RFR 将是我们的主要结果，因为它对于肾损伤更具有特异性。简而言之，RFR 的实施方式如下：儿童将服用西咪替丁 2 天，以阻止肾小管分泌肌酐。首先，将通过 2 小时肌酐清除率来测量基线 GFR（该方法之前已被验证为适当的测量方法）肾小球滤过率）。接下来，在第二次 2 小时肌酐清除之前，将进行 1 g/kg 的非肉蛋白粉挑战。 RFR 是基线 GFR 与蛋白质攻击 GFR 之间的差异。膀胱超声将确认收集前后的完全排空。目标 I：比较近期 AKI 患者和对照患者之间的 RFR。目标 2：比较两组之间 9 个月的 RFR 差异。目标 3：在两次访视中，将测量并比较各组之间已知的内皮损伤生物标志物。这些包括微量白蛋白尿、高血压和血清生物标志物（hs-CRP、vWF）。将进行尿液蛋白质组学技术来研究 AKI 后儿童中存在的潜在尿液生物标志物。