Oxalate and the Progression and Complications of CKD

草酸盐与 CKD 的进展和并发症

• 批准号: 9132782
• 负责人: Sushrut S. Waikar
• 金额: $ 39.49万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132782
• 关键词: Accounting; Adult; Affect; Aliquot; Ancillary Study; Animal Model; Apical; Biological; Biological Markers; Blood Vessels; Calcium Oxalate; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic Kidney Failure; Chronic Kidney Insufficiency; Cohort Analysis; Cohort Studies; Complication; Congestive Heart Failure; Crystal Formation; Data; Development; Diet; Dietary intake; Disease; Disease Outcome; Disease Progression; Enteral; Epidemiologic Studies; Epidemiology; Epithelial Cells; Evaluation; Event; Excretory function; Exposure to; Freezing; Future; Generations; Genetic; Glomerular Filtration Rate; Health; Heart; Hyperoxaluria; In Vitro; Individual; Inflammation; Inflammatory; Ingestion; Injury; Interleukin-1 beta; Intervention Trial; Investigation; Iothalamate; Kidney; Kidney Calculi; Kidney Diseases; Kidney Failure; Laboratories; Lead; Link; Liquid substance; Longitudinal Studies; Measurement; Measures; Mediator of activation protein; Metabolism; Mitochondria; Myocardial Infarction; Myocardium; Obstruction; Outcome; Oxalates; Oxidative Stress; Pathogenesis; Patients; Peripheral Vascular Diseases; Plasma; Population; Primary Hyperoxaluria; Progressive Disease; Renal Replacement Therapy; Renal function; Risk; Risk Factors; Route; Sampling; Signal Transduction; Statistical Models; Stratification; Stroke; Surface; Testing; Tissues; Translating; Tubular formation; United States National Institutes of Health; Urine; Vascular Endothelial Cell; absorption; adjudicate; cardiovascular disorder risk; cohort; cost; cytokine; disorder risk; endothelial dysfunction; ethylene glycol; falls; follow-up; high risk; improved outcome; in vivo; mortality; new therapeutic target; novel therapeutics; oxalosis; prospective; repository; urinary

 DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) affects 11% of the US population, costs tens of billions of dollars annually, and can lead to progressive kidney failure, cardiovascular disease (CVD), and early mortality. Although we understand much about the epidemiology of CKD and its associations with CVD, the underlying mechanisms of CKD pathogenesis, progression, and complications remain less well understood. In this proposal, we seek to test the hypothesis that oxalate-a toxic terminal metabolite that accumulates in all forms of CKD-contributes to the progression and complications of CKD. Kidney failure from oxalate nephropathy is a devastating complication of genetic and acquired diseases in which excessive oxalate is generated (primary hyperoxaluria) or absorbed (enteric hyperoxaluria). Oxalate has been shown to cause endothelial dysfunction, mitochondrial damage, oxidative stress, and inflammation in vitro and in animal models of oxalate nephropathy. As kidney function declines in all forms of CKD, oxalate levels increase in the plasma and glomerular ultrafiltrate, leading to increased systemic and intra-renal exposure to oxalate and consequent tissue injury. To test this hypothesis, we propose an ancillary study to the Chronic Renal Insufficiency Cohort (CRIC), an NIH-sponsored longitudinal study of 3,939 individuals with CKD that has stored biospecimens and adjudicated kidney and cardiovascular outcomes over an average of 6 years of follow-up. We will measure oxalate levels in baseline plasma and 24h urine samples to determine their associations with subsequent adverse CKD outcomes. Confirmation of our hypothesis may lead to a paradigm shift in CKD evaluation and risk stratification, and identify oxalate as a novel therapeutic target for interventional trials aimed t reducing oxalate absorption or generation.

 描述（由申请人提供）：慢性肾病 (CKD) 影响 11% 的美国人口，每年造成数百亿美元的损失，并可能导致进行性肾衰竭， 尽管我们对 CKD 的流行病学及其与 CVD 的关系了解很多，但 CKD 发病机制、进展和并发症的潜在机制仍不太清楚。假设草酸（一种在所有形式的 CKD 中积累的有毒终末代谢物）会导致草酸盐肾病导致的肾衰竭的进展和并发症，这是一种破坏性的并发症。草酸生成过多（原发性高草酸尿症）或吸收过多（肠道高草酸尿症）的获得性遗传病已被证明会在体外和草酸肾病动物模型中引起内皮功能障碍、线粒体损伤、氧化应激和炎症。在所有形式的 CKD 中，功能均下降，血浆和肾小球超滤液中的草酸水平增加，导致全身和肾内草酸盐水平增加为了检验这一假设，我们对慢性肾功能不全队列 (CRIC) 提出了一项辅助研究，这是一项由 NIH 赞助的纵向研究，对 3,939 名 CKD 患者进行了储存生物样本并判定了肾脏和心血管结局。我们将测量基线血浆和 24 小时尿液样本中的草酸盐水平，以确定它们与后续的关联。不良 CKD 结果的证实可能会导致 CKD 评估和风险分层的范式转变，并将草酸盐确定为旨在减少草酸盐吸收或生成的介入试验的新治疗靶点。