Polycystic Kidney Disease Clinical Trials Network

多囊肾临床试验网络

• 批准号: 6546953
• 负责人: ARLENE B CHAPMAN
• 金额: $ 25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6546953
• 关键词: ACE inhibitors; adolescence (12-20); angiotensin /renin /aldosterone hypertension; autosomal dominant trait; blood flow measurement; blood pressure; clinical research; combination chemotherapy; cooperative study; drug screening /evaluation; enalapril; human subject; human therapy evaluation; kidney disorder chemotherapy; kidney function; kidney pharmacology; longitudinal human study; losartan; magnetic resonance imaging; patient oriented research; pharmacokinetics; polycystic kidney; renin angiotensin system; spironolactone; ultrasonography

DESCRIPTION (provided by applicant): We seek to be a participating clinical center (PCC) in the RFA entitled "Polycystic Kidney Disease Clinical Trials Network." Hypertension is common, occurs early, and is associated with a faster progression to renal failure in ADPKD. We have shown activation of the systemic renin-angiotensin-aldosterone system (RAAS) in hypertension associated with ADPKD prior to loss of renal function, and that intrarenal activation of RAAS is present. We have demonstrated that angiotensin converting enzyme inhibition alone (ACEI) has beneficial effects by reducing proteinuria and regression of left ventricular hypertrophy as well as improving effective renal plasma flow, and this may relate to filtration fraction. In contrast to other kidney diseases, ACEI has not been as successful in preventing loss of renal function. This may relate to study design issues, sample size, inclusion of low risk individuals not progressing, and less than maximal blockade of RAAS. Therefore, we propose to assess the effect of combination therapy, i.e. ACEI, angiotensin receptor blockade (ARB), and aldosterone antagonism (spironolactone) in the setting of rigorous blood pressure control (<125/75 mm Hg) on the rate of loss of renal function in ADPKD while controlling for other potential contributors to loss of renal function. ADPKD children with hypertension demonstrate a greater increase in renal volume than other ADPKD children in the setting of normal renal function. Using MRI, we have shown decreased renal blood flow in ADPKD as compared to age and gender-matched children suggesting that activation of RAAS occurs early in ADPKD children. We propose to study a special population of ADPKD subjects (children) throughout adolescence to determine the safety and efficacy of ACE/ARB combination therapy in the acute and chronic setting on renal blood flow, and the rate of renal cyst and total renal growth. Taken together, these studies will determine if maximal inhibition of RAAS prevents loss of renal function in ADPKD adults and if combination ACEI/ARB therapy maintains renal blood flow while slowing renal and cyst growth in ADPKD children. Ultimately these studies should demonstrate slowing or halting progression of ADPKD.

描述（由申请人提供）： 我们寻求成为参与临床中心（PCC），标题为“多囊肾脏疾病临床试验网络”。高血压很常见，发生早期发生，并且与ADPKD中肾衰竭更快的进展有关。我们已经在肾功能丧失之前显示了与ADPKD相关的高血压的全身性肾素 - 血管紧张素 - 醛固酮系统（RAAS）的激活，并且存在RAAS的肾内激活。我们已经证明，仅通过减少蛋白尿和左心室肥大的消退以及改善有效的肾等血浆流量，血管紧张素转化酶抑制（ACEI）具有有益的作用，这可能与滤液分数有关。与其他肾脏疾病相比，ACEI在防止肾功能丧失方面并没有成功。这可能与研究设计问题，样本量，低风险个体不进步的范围以及少于RAAS的最大封锁有关。因此，我们建议评估组合疗法的影响，即ACEI，血管紧张素受体阻滞（ARB）和醛固酮拮抗作用（螺内酯）在严格的血压控制的情况下（<125/75 mm Hg）在控制肾功能丧失的其他潜在贡献者的同时，ADPKD中的肾功能。在正常的肾功能下，患有高血压的ADPKD儿童与其他ADPKD儿童相比表现出比其他ADPKD儿童更大的增加。使用MRI，与年龄和性别匹配的儿童相比，ADPKD的肾血流减少了，这表明RAAS在ADPKD儿童的早期发生。我们建议在整个青春期研究特殊的ADPKD受试者（儿童），以确定ACE/ARB联合疗法在肾血流中的急性和慢性环境中的安全性和功效，以及肾脏囊肿的速度和总肾脏生长速度。综上所述，这些研究将确定对RAAS的最大抑制是否可以防止ADPKD成年人的肾功能丧失，并且ACEI/ARB疗法是否会保持肾脏血流，同时减慢ADPKD儿童的肾脏和囊肿生长。最终，这些研究应证明ADPKD的放缓或停止进展。