Improving Outcomes in Diabetic Nephropathy

改善糖尿病肾病的治疗效果

• 批准号: 6561616
• 负责人: ROBERT Daniel TOTO
• 金额: $ 56.52万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6561616
• 关键词: ACE inhibitors; aldosterone; angiotensin II; antihypertensive agents; blood lipid; blood pressure; clinical research; clinical trials; combination chemotherapy; creatinine; diabetes mellitus; diabetes mellitus therapy; diabetic nephropathy; diuretics; human subject; human therapy evaluation; kidney disorder chemotherapy; longitudinal human study; losartan; monitoring device; outcomes research; pathologic process; patient oriented research; potassium; proteinuria; renin; renin angiotensin system; transforming growth factors; young adult human (21-34)

DESCRIPTION (provided by applicant): The long-range objective of this project is to prevent progression of diabetic nephropathy, the leading cause of end-stage renal disease (ESRD). In most patients diabetic nephropathy progresses inexorably to ESRD despite inhibition of the renin-angiotensin-aldosterone system with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs). The specific aims of this proposal are to: 1) recruit a multi ethnic cohort of 72 young adults (ages 20-40) with type 1 (n=36) or type 2 (n=36) diabetes and overt nephropathy (defined as a urine albumin/creatinine ratio > 300 mg albumin/g creatinine) and randomize in a double blind fashion to a control group consisting of ACEI-based therapy alone (ramipril 40 mg once daily) or one of two experimental groups: a) ACEI + ARB (ramipril 40 mg once daily plus Iosartan100 mg once daily) or b) ACEI + mineralocorticoid receptor antagonist (MRA) (ramipril40 mg once daily plus spironolactone 25 mg once daily); 2) conduct a 12-month prospective study to determine if proteinuria is reduced to a greater extent when either the ARB or MRA is added to ACEi-based therapy. This study is powered to detect a 40% greater reduction in 24-hour urine albumin/creatinine ratio in either experimental group versus control (alpha= 0.05, beta=0.20, repeated measures analysis of variance). Secondary endpoints to be examined include:(a) serum potassium and creatinine to assess safety, (b) TGF-beta, as a surrogate marker for ongoing renal injury, (c) plasma renin activity, angiotensin II and aldosterone levels and (d) plasma lipids and lipoprotein composition; and 3) perform repeated ambulatory blood pressure monitoring (ABPM) to examine the renoprotective effect of the 3 different regimens at comparable 24-hour BP of < 125/75 mmHg. The deliverables include: 1) documentation of the safety of maximal dose combination therapy; 2) the feasibility of utilizing 24-hr ABPM to establish BP independent renoprotective effects of specific antihypertensive therapies; and 3) provide preliminary data for future large-scale studies to test efficacy and safety of combining ACEi with MIRA therapy on renal outcomes.

描述（由申请人提供）：该项目的长期目标是预防糖尿病肾病的进展，糖尿病肾病是终末期肾病（ESRD）的主要原因。在大多数患者中，尽管使用血管紧张素转换酶抑制剂 (ACEI) 或血管紧张素 II 1 型受体阻滞剂 (ARB) 抑制肾素-血管紧张素-醛固酮系统，但糖尿病肾病仍不可避免地进展为 ESRD。 该提案的具体目标是：1) 招募 72 名患有 1 型 (n=36) 或 2 型 (n=36) 糖尿病和明显肾病（定义为尿白蛋白/肌酐比值 > 300 mg 白蛋白/g 肌酐），并以双盲方式随机分配至仅接受基于 ACEI 的治疗的对照组（雷米普利 40 mg，一次每日）或两个实验组之一：a）ACEI + ARB（雷米普利 40 mg 每日一次加碘沙坦 100 mg 每日一次）或 b）ACEI + 盐皮质激素受体拮抗剂（MRA）（雷米普利 40 mg 每日一次加螺内酯 25 mg 每日一次）； 2) 进行一项为期 12 个月的前瞻性研究，以确定当 ARB 或 MRA 添加到基于 ACEi 的治疗中时，蛋白尿是否会得到更大程度的降低。本研究检测到，与对照组相比，任一实验组的 24 小时尿白蛋白/肌酐比值降低了 40%（α= 0.05，β=0.20，重复测量方差分析）。要检查的次要终点包括：(a) 血清钾和肌酐，以评估安全性；(b) TGF-β，作为持续肾损伤的替代标志物；(c) 血浆肾素活性、血管紧张素 II 和醛固酮水平；(d)血浆脂质和脂蛋白成分； 3) 进行重复动态血压监测 (ABPM)，以检查 3 种不同方案在 24 小时血压 < 125/75 mmHg 的可比情况下的肾脏保护作用。可交付成果包括： 1) 最大剂量联合治疗的安全性文件； 2) 利用 24 小时 ABPM 建立特定抗高血压疗法的独立于血压的肾脏保护作用的可行性； 3) 为未来大规模研究提供初步数据，以测试 ACEi 与 MIRA 联合治疗对肾脏结局的疗效和安全性。