Environmental Oxidant Stressors in Pediatric Chronic Kidney Disease - Resubmissio

描述(由申请人提供)：针对PA-12-265，“正在进行的重大临床研究的辅助研究，以推进NIDDK使命中的科学兴趣领域”，纽约大学医学院和纽约州卫生部建议评估暴露于环境氧化剂应激源双酚A(BPA)和邻苯二甲酸盐对慢性肾脏疾病(CKD)儿童患者的影响。CKD可由先天性泌尿生殖道异常或获得性肾小球疾病引起。不管潜在的病因，目前对慢性肾脏病的治疗进展到终末期肾脏疾病。重要的是令人失望的结局和许多受影响的儿童，找出影响CKD临床病程的可改变因素，设计干预措施，可以作为受影响儿童药物治疗的辅助手段。双酚A用于制造覆盖食品和饮料容器的聚碳酸酯树脂，邻苯二甲酸酯代谢物通常存在于加工食品中。这两种分子都会导致氧化应激，与儿童肥胖和高血压有关，并与成年人心血管疾病风险增加有关。初步数据表明，在健康儿童中，暴露于双酚A和邻苯二甲酸盐与低度蛋白尿的增加有关。然而，对于由于慢性肾脏病等疾病而更容易受到影响的儿童，这些暴露的影响还没有被研究。我们建议检验这一假设，即暴露于双酚A和邻苯二甲酸盐将对慢性肾脏病儿童产生不良影响，并与肾脏预后恶化的风险增加相关。这项辅助研究将利用在以下四项由NIDDK资助的临床研究--CKiD、NEPTUNE、FSGS临床试验和FONT试验期间获得的存储生物样本。它将比较两组患有CKD的儿童-一组患有局灶性节段性肾小球硬化(FSGS)，另一组患有非肾小球疾病。该项目将把重点放在儿童身上，因为他们对环境化学物质的独特脆弱性，并减少了成年人普遍存在的其他共病的混淆。我们将通过评估肾小球滤过率(EGFR)、蛋白尿、血压(BP)以及与双酚A和邻苯二甲酸盐暴露相关的肾小管损伤生物标志物(Kim-1和NGAL)的排泄来评估CKD儿童肾功能的纵向变化。最后，我们将评估环境化学物质是否会增加CKD儿童的氧化应激。这是第一项评估慢性肾脏病儿童对可通过饮食改变的环境暴露的独特脆弱性的研究，并可能为这类患者采取新的治疗方法提供理论依据。它将一位公认的儿科肾病学家(H.Trachtman)和一位儿童环境健康专家(L.Trasande)联合起来，并建立在多个PIs之间富有成效的合作记录之上。

DESCRIPTION (provided by applicant): In response to PA-12-265, "Ancillary Studies to Major Ongoing Clinical Research Studies to Advance Areas of Scientific Interest within the Mission of the NIDDK," NYU School of Medicine and the New York State Department of Health propose to assess the effect of exposure to environmental oxidant stressors, bisphenol A (BPA) and phthalates, in pediatric patients with chronic kidney disease (CKD). CKD can be caused by congenital abnormalities of the genitourinary tract or acquired glomerular disorders. Regardless of the underlying etiology, current treatment for CKD yields progress to end stage kidney disease. It is important disappointing outcomes and many affected children to identify modifiable factors that impact on the clinical course of CKD to design interventions can be adjuncts to medical therapy for affected children. BPA is used to manufacture polycarbonate resin that coat food and beverage containers, and phthalate metabolites are commonly found in processed foods. Both molecules cause oxidant stress, are associated with obesity and hypertension in children, and have been linked to increased risk of cardiovascular disease in adults. Preliminary data suggest that exposure to BPA and phthalates is associated with an increase in low-grade albuminuria in healthy children. However, the implications for these exposures in children who are more vulnerable because of medical conditions such as CKD has not been studied. We propose to test the hypothesis that exposure to BPA and phthalates will have an adverse effect in children with CKD and be associated with an increased risk of worse renal outcomes. This Ancillary Study will utilize stored biosamples that have been obtained during the performance of the following four NIDDK-funded clinical studies - CKiD, NEPTUNE, FSGS Clinical Trial and FONT trial. It will compare two groups of children with CKD - one with focal segmental glomerulosclerosis (FSGS) and a second with non-glomerular disease. The project will focus on children because of their unique vulnerability to environmental chemicals and reduced confounding by other co-morbidities that are prevalent in adults. We will assess longitudinal changes in kidney function assessed by estimated glomerular filtration rate (eGFR), proteinuria, blood pressure (BP), and excretion of biomarkers of tubular injury (KIM-1 and NGAL) associated with BPA and phthalate exposures in children with CKD. Finally, we will evaluate whether the environmental chemicals increase oxidant stress in children with CKD. This is the first study to assess the unique vulnerability of children with CKD to environmental exposures that are modifiable through diet and may provide rationale for newer therapeutic approaches to this group of patients. It unites a recognized pediatric nephrologist (H. Trachtman) with an expert in children's environmental health (L. Trasande), and builds upon a productive track record of collaboration between the multiple PIs.