The Cardiovascular and Renal Toxicity of Aldosterone

描述(申请人提供)：最近的研究提出了一种通过使用盐皮质激素受体拮抗剂(MRA)和上皮钠通道(ENaC)阻断来干预慢性肾脏疾病(CKD)的新方法。有人假设，醛固酮通过激活ENaC在多种细胞系中发挥作用，通过增加内皮功能障碍和炎症，在CKD的发病机制中发挥激素介质的作用。我的提案将利用正在进行的NIH、RO-1支持的糖尿病肾病临床试验的现有基础设施。我建议通过测量接受ACEI+MRA的患者的尿液和血清炎症、氧化应激和内皮功能障碍的标记物来阐明毒性的机制，并与仅接受ACEI的患者进行比较。这项试验中的一小部分患者将在研究结束时被招募，通过测量上述标志物来评估附加ENaC阻滞剂(阿米洛利)+血管紧张素转换酶抑制剂的益处。目前还没有关于MRA在慢性肾脏病中的作用机制的数据，也没有关于阿米洛利在慢性肾脏病中的使用情况的数据。这项试验的结果将有助于确定MRA和ENaC阻断在CKD/ESRD中的未来作用，CKD/ESRD是一种已知炎症状态，心血管死亡率增加的疾病状态。

DESCRIPTION (provided by applicant): Recent research suggests a novel intervention in chronic kidney disease (CKD) by the use of mineralcorticoid receptor antagonism (MRA) and epithelial sodium channel (ENaC) blockade. It is hypothesized that aldosterone, via activation of the ENaC, has effects in multiple cellular lines acts as a hormonal mediator in the pathogenesis of CKD by increasing endothelial dysfunction and inflammation. My proposal will utilize the existing infrastructure of an ongoing NIH, RO-1 supported clinical trial in diabetic nephropathy. I propose to elucidate the mechanism of toxicity by measuring urinary and serum markers of inflammation, oxidative stress and endothelial dysfunction in patients receiving ACEi + MRA, compared to ACEi-based alone. A small number of patients within this trial will be recruited at study completion to assess benefit with add-on ENaC blockade (amiloride) + ACEi by measurement of the aforementioned markers. There is no data on mechanism of benefit of MRA in CKD and no data, at all, in the use of amiloride in CKD. The results of this trial will help to define the future roles of MRA and ENaC blockade in CKD/ESRD, disease states plagued with increased cardiovascular mortality from a known inflammatory state.