Maximize RAS Blockade in Diabetic Nephropathy

描述（由申请方提供）：通过抑制血管紧张素转换酶（ACE）阻断肾素-血管紧张素系统（RAS）可减少糖尿病肾病患者的蛋白尿并减缓肾功能丧失。但是，ACE抑制剂用于限制肾损伤的最佳方式却很少研究。特别是，需要进一步的研究，以确定治疗应结合ACE抑制，以最大限度地发挥RAS阻断的好处。拟议的研究将评估两种治疗方法的价值。 第一个目的是确定血管紧张素受体阻滞剂是否增加糖尿病肾病患者ACE抑制剂的抗蛋白尿作用。血管紧张素受体阻滞剂与ACE抑制剂合用的假定有益作用已被广泛宣传，但尚未得到充分验证。 迄今为止进行的研究仅表明，在维持相对低剂量的ACE抑制剂的患者中，添加血管紧张素受体阻滞剂（ARB）可减少蛋白尿。 拟议的研究将评估在高剂量ACE抑制剂中添加ARB的效果。 这些研究将揭示是否ARB添加有任何效果，不能获得更简单，更便宜的ACE抑制剂单独。 第二个目的是确定利尿剂的使用是否增加了糖尿病肾病患者ACE抑制剂的抗蛋白尿作用。先前的研究表明，在非糖尿病肾病患者中，加用利尿剂可降低蛋白尿，这些患者仍在使用ACE抑制剂。这一发现表明，当ECF量低时，ACE抑制剂最有效地减少蛋白尿。拟议的研究将确定在ACE抑制剂中添加利尿剂对糖尿病肾病患者具有相同的有益效果。 最终，改进的RAS阻断方案减缓糖尿病肾病进展的能力只能通过大型长期试验来确定。 但是可以进行的这种试验的数量是有限的。短期试验，如本提案中所述，迫切需要帮助确定值得进一步长期研究的治疗方案。

DESCRIPTION (provided by applicant): Blockade of the renin-angiotensin system (RAS) by inhibition of angiotensin converting enzyme (ACE) reduces proteinuria and slows loss of renal function in patients with diabetic nephropathy. But the optimal manner in which ACE inhibitors should be used to limit renal injury has been remarkably little studied. In particular, further studies are needed to identify treatments which should be combined with ACE inhibition to maximize the benefit of RAS blockade. The proposed studies will assess the value of two such treatments. The first aim will be to determine whether angiotensin receptor blockade increases the antiproteinuric effect of ACE inhibition is patients with diabetic nephropathy. The putative beneficial effect of adding angiotensin receptor blockade to ACE inhibition has been widely advertised but not adequately tested. Studies conducted to date have shown only that adding an angiotensin receptor blocker (ARB) reduces proteinuria in patients maintained on relatively low doses of an ACE inhibitor. The proposed study will assess the effect of adding an ARB to higher doses of an ACE inhibitor. These studies will reveal whether ARB addition has any effect that cannot be obtained more simply and more cheaply by ACE inhibition alone. The second aim will be to determine whether diuretic use increases the antiproteinuric effect of ACE inhibition in patients with diabetic nephropathy. Previous studies have shown that addition of a diuretic lowers proteinuria in patients with non-diabetic renal disease who are maintained on ACE inhibitors. This finding suggests that ACE inhibition reduces proteinuria most effectively when ECF volume is low. The proposed studies will establish where addition of a diuretic to an ACE inhibitor has the same beneficial effect in patients with diabetic nephropathy. Ultimately, the ability of improved RAS blocking regimens to slow the progression of diabetic nephropathy can only be established by large, long term trials. But the number of such trials which can be performed is limited. Short term trials, such as those described in this proposal, are urgently required to help identify treatment regimens which merit further, longer term study.