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; 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（由适用提供）：慢性肾脏疾病（CKD）影响美国人口的11％，每年成本数十亿美元，并可能导致渐进的肾脏衰竭， 心血管疾病（CVD）和早期死亡率。尽管我们对CKD的流行病学及其与CVD的关联有很多了解，但CKD发病机理，进展和并发症的潜在机制仍然不太了解。在此提案中，我们试图检验以下假设：草酸A毒性末端代谢产物在各种形式的CKD核对基团中积累到CKD的进展和并发症。草酸盐肾病的肾衰竭是遗传和获得性疾病的毁灭性并发症，其中产生过量的草酸盐（原发性高氧钙）或吸收（肠催眠尿症）。草酸盐已被证明会引起内皮功能障碍，线粒体损伤，氧化应激和体外和草酸动物模型的炎症。随着肾功能在各种形式的CKD中下降，草酸盐水平增加了血浆和肾小球超滤，从而导致全身性和肾内暴露于草酸盐以及随之而来的组织损伤。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，这是对NIH赞助的3,939名CKD患者的纵向研究，该研究储存了生物测量和调整后的肾脏和心血管疾病，在平均6年的随访中。我们将测量基线血浆和24小时尿液样品中的草酸盐水平，以确定它们与随后的不良CKD结局的关联。确认我们的假设可能导致CKD评估和风险分层的范式转移，并确定草酸盐是旨在减少草酸盐吸收或产生的介入试验的新型治疗靶标。