Oxalate and the Progression and Complications of CKD

 描述（由申请人提供）：慢性肾脏疾病（CKD）影响11%的美国人口，每年花费数百亿美元，并可导致进行性肾衰竭， 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的关系有了很大的了解，但CKD发病机制、进展和并发症的潜在机制仍不太清楚。在这项研究中，我们试图验证以下假设：在所有形式的CKD中积累的毒性终末代谢物--草酸盐肾病引起的肾衰竭是遗传性和获得性疾病的一种毁灭性并发症，其中产生过量的草酸盐（原发性高尿酸）或吸收过量的草酸盐（肠性高尿酸）。在体外和草酸盐肾病动物模型中，草酸盐已被证明可导致内皮功能障碍、线粒体损伤、氧化应激和炎症。由于所有形式的CKD的肾功能下降，血浆和肾小球超滤液中的草酸盐水平增加，导致全身和肾内暴露于草酸盐的增加和随后的组织损伤。为了验证这一假设，我们提出了一项慢性肾功能不全队列（CRIC）的辅助研究，这是一项由NIH赞助的纵向研究，共有3，939名CKD患者，在平均6年的随访期间储存了生物标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，以确定其与随后的不良CKD结局的相关性。我们假设的证实可能导致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干预性试验的新治疗靶点。

 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.