The Cardiovascular and Renal Toxicity of Aldosterone

描述（由申请人提供）：最近的研究表明，通过使用矿皮质激素受体拮抗剂（MRA）和上皮钠通道（ENaC）阻断，可以对慢性肾脏疾病（CKD）进行新的干预。据推测，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的发病机制中作为激素介质。我的建议将利用正在进行的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标志物，与单独接受ACEi的患者相比，来阐明毒性机制。研究结束时将招募少量患者，通过测量上述标记物来评估附加ENaC阻断剂（阿米洛利）+ ACEi的益处。没有关于MRA在CKD中的获益机制的数据，也没有关于阿米洛利在CKD中的使用的数据。该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导致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.