Oxalate and the Progression and Complications of CKD

 描述(申请人提供)：慢性肾脏病(CKD)影响美国11%的人口，每年造成数百亿美元的损失，并可导致进行性肾功能衰竭。 心血管疾病(CVD)和早期死亡率。虽然我们对CKD的流行病学及其与CVD的关系了解很多，但CKD的发病、进展和并发症的潜在机制仍然不太清楚。在这项提议中，我们试图检验草酸--一种在所有形式的CKD中积累的有毒终末代谢物--有助于CKD的进展和并发症的假设。草酸盐肾病引起的肾功能衰竭是遗传性和获得性疾病的一种破坏性并发症，在这些疾病中会产生过量的草酸(原发性高草酸尿)或吸收(肠源性高草酸尿)。在体外和草酸盐肾病的动物模型中，草酸盐已被证明会导致内皮功能障碍、线粒体损伤、氧化应激和炎症。随着所有形式的CKD的肾功能下降，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暴露增加，从而导致组织损伤。为了验证这一假设，我们建议对慢性肾功能不全队列(CRIC)进行一项辅助研究，这是一项由美国国立卫生研究院赞助的针对3939名CKD患者的纵向研究，该研究存储了生物样品，并在平均6年的随访中判断了肾脏和心血管结果。我们将测量基线血浆和24小时尿样中的草酸水平，以确定它们与后续不良CKD结局的相关性。证实我们的假设可能会导致慢性肾脏病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。

 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.