Nocturnal Hypertension and Prevention of Microalbuminuria in Type I Diabetics

描述（由申请人提供）：只有一小部分1型糖尿病患者，不到40%，会发展为肾病。在那些易患肾病的个体中，自然史的特征是相当可预测的事件模式。当尿白蛋白排泄在正常范围内时，基于诊室血压读数的高血压患病率与一般人群相似。然而，这些患者中的许多人在出现微量白蛋白尿之前就出现了夜间高血压。然而，目前仅建议在出现肾损害指征（如微量白蛋白尿所反映）后，才使用ACE抑制剂进行早期药物干预。目前不建议在微量白蛋白尿之前开始ACE治疗，因为这会导致大多数受试者过度治疗，这些受试者永远不会发生微量白蛋白尿或明显肾病。然而，当出现微量白蛋白尿时，糖尿病的肾脏病变往往已经出现，许多患者进展为明显的临床肾病。因此，如果能够识别出那些易发生微量白蛋白尿的患者，从而能够对那些高危个体进行早期治疗，这将是非常有益的。拟定的研究旨在证明，有可能通过对“血压正常”、白蛋白尿正常的1型糖尿病受试者（基于夜间高血压，即睡眠血压生理性下降减弱的受试者（“非杓型”））预先给予ACE抑制剂来预防进展为微量白蛋白尿。这种方法在糖尿病病程的非常早期阶段，即在发生微量白蛋白尿或高血压之前，具有很大的预防价值。因此，我们提出了一个新的试验，一级预防微量白蛋白尿的“血压正常”的1型糖尿病的基础上夜间高血压的目标。本研究的具体目的是：1）证明在夜间高血压（“非勺型”）受试者中，ACE抑制剂雷米普利的给药将降低微量白蛋白尿的发生率。2)证明接受安慰剂治疗的夜间高血压受试者（“非勺型”）中进展至微量白蛋白尿的比例高于也接受安慰剂治疗的“勺型”受试者。此外，这些研究将提供新的信息，以内皮功能障碍，评估肱动脉血流介导的血管舒张是否早于微量白蛋白尿的1型糖尿病受试者，特别是那些夜间高血压。此外，这些研究将揭示长期ACE抑制对血压正常的1型糖尿病患者夜间高血压和内皮功能障碍的影响。

DESCRIPTION (provided by applicant): Only a fraction of persons with Type 1 diabetes, less than 40%, go on to develop nephropathy. In those individuals susceptible to nephropathy, the natural history is characterized by a fairly predictable pattern of events. When urinary albumin excretion is within the normal range, the prevalence of hypertension based on office blood pressure readings is similar to that in the general population. Many of these patients, however, develop nocturnal hypertension before the development of microalbuminuria. Yet, early pharmacological intervention with ACE inhibitors is currently recommended only after there is an indication of kidney damage, as reflected by the presence of microalbuminuria. Prior to microalbuminuria initiation of ACE therapy is currently not recommended because it would result in over-treatment of a majority of subjects who will never develop microalbuminuria or overt nephropathy. By the time that microalbuminuria develops, however, the renal lesions of diabetes are often present and many patients progress to overt clinical nephropathy. It would therefore be greatly beneficial if one could identify those patients susceptible to develop microalbuminuria, so that therapy could be instituted early for those individuals at high risk. The proposed study is aimed at demonstrating that it is possible to prevent the progression to microalbuminuria by the preemptive administration of an ACE inhibitor to "normotensive", normoalbuminuric subjects with type 1 diabetes targeted on the basis of nocturnal hypertension, i.e. those in whom the physiologic fall in sleep blood pressure is blunted ("non-dippers"). This approach would be of great preventative value at a very early stage in the course of diabetes, i.e. prior to the development of either microalbuminuria or hypertension. Thus, we propose a novel trial of primary prevention of microalbuminuria in "normotensive" type 1 diabetes targeted on the basis of nocturnal hypertension. The specific aims of this study are: 1) to demonstrate that in subjects with nocturnal hypertension ("non- dippers"), the administration of the ACE inhibitor, ramipril, will decrease the rate of development microalbuminuria. 2) To demonstrate that progression to microalbuminuria in subjects with nocturnal hypertension, "non-dippers", treated with placebo is higher than in "dippers" also treated with placebo. In addition, these studies will provide novel information as to whether endothelial dysfunction, assessed by brachial artery flow mediated vasodilation antedates microalbuminuria in subjects with Type 1 diabetes, particularly in those with nocturnal hypertension. Moreover, these studies will reveal the impact of long-term ACE inhibition on nocturnal hypertension and endothelial dysfunction in normotensive type 1 diabetics.