Dysmetabolism of Chronic Kidney Disease and Vascular Health

描述(由申请人提供)： 慢性肾脏疾病(CKD)是一个日益严重的公共卫生问题，目前影响着全球超过5亿人。鉴于肥胖、高血压和糖尿病(DM)等主要危险因素的增加，慢性肾脏病的患病率及其后果将继续扩大。除了进展为终末期肾病的风险外，慢性肾脏病患者还会因心血管疾病(CVD)而过早死亡。晚期慢性肾脏病的死亡率是医疗保险人群的6倍。过去十年的新数据表明，“非传统”危险因素在心血管疾病的发病机制中起着关键作用。这些危险因素包括肥胖和胰岛素抵抗(IR)--这两个因素目前不是标准疗法的目标。存在着一个重要的知识缺口，详细说明了这一人群中IR的主要决定因素，如何最佳地描述这种错乱，以及是否可以有效地修改它以改善这一人群的结果。慢性肾脏病胰岛素抵抗的病理生理学机制是独一无二的。除了肥胖率高(近50%)外，CKD患者还存在重要的代谢紊乱，如胰岛素和脂肪因子清除减少、代谢性酸中毒和慢性炎症，这些都改变了胰岛素抵抗的病理生理。脂肪组织是分泌“脂肪因子”的内分泌器官，其中包括但不限于脂联素和瘦素。脂联素是一种重要的胰岛素增敏激素，具有抗动脉粥样硬化作用。相比之下，瘦素是致动脉粥样硬化的，并促进胰岛素抵抗。瘦素/脂联素比值(LAR)被认为是糖尿病致动脉粥样硬化的指标，并被证明是代谢综合征的敏感标志。此外，LAR已被证明是终末期肾病患者IR的最佳相关性。鉴于肥胖和与CKD相关的代谢紊乱的高患病率，详细说明这两种情况之间的相互作用及其对心血管风险的影响是至关重要的。这项建议的主要目的是了解这些相互作用对脂肪因子失衡和胰岛素抵抗的产生的影响，以及这些影响对血管健康的组合。新的生物标志物，包括脂肪因子谱中的失衡，将接受测试，以确定它们对患者分层的风险。最后，针对脂肪因子失调和胰岛素抵抗的干预措施将测试其逆转中度CKD患者这一高风险特征的能力。S的具体目标如下：1)表征中度慢性肾脏病肥胖患者肥胖增加和胰岛素和脂肪因子清除减少交叉点引起的代谢紊乱，1a)比较有和没有慢性KD患者之间使用高胰岛素正糖钳研究的IR程度和肥胖改变的程度，1b)检查LAR是否比针对HEGC的传统胰岛素抵抗更合适地反映中度CKD背景下肥胖的代谢状态，1c)确定LAR是否是CKD肥胖背景下炎症、内皮功能、氧化应激和动脉粥样硬化的决定因素；2)研究AMP-K激活剂二甲双胍对与慢性肾脏病和肥胖相关的代谢紊乱，即胰岛素抵抗、全身炎症和氧化应激的影响，2a)测试与安慰剂相比，二甲双胍是否会改善肥胖CKD患者的LAR，2b)测试与安慰剂相比，二甲双胍是否会改善这一人群的全身炎症、氧化应激和内皮功能的标记物。2C)测试与安慰剂相比，二甲双胍是否会改善中度CKD肥胖患者的动脉粥样硬化标志物并减少临床心血管事件。我们建议的研究可能会通过提供新的监测工具和潜在的干预目标来降低CKD患者的心血管死亡率，从而潜在地影响临床实践。我们的研究结果可能会对退伍军人健康护理产生重大影响，并通过改善我们为CKD退伍军人患者提供的护理，为退伍军人健康管理部的研究使命做出贡献。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is a growing public health problem that currently affects more than 500 million people worldwide. Given the growth of major risk factors, including obesity, hypertension and diabetes mellitus (DM), the prevalence of CKD and its consequences will continue to expand. In addition to the risk of progressing to end stage renal disease, patients with CKD suffer from premature death due to cardiovascular disease (CVD). The mortality rates in advanced CKD are six times higher than the Medicare population. Emerging data over the past decade suggest a critical role of "non-traditional" risk factors in the pathogenesis of CVD. These risk factors include obesity and insulin resistance (IR)-two elements not currently targeted by standard therapies. A significant knowledge gap exists detailing the main determinants of IR in this population, how to optimally characterize this derangement, and whether it can be effectively modified to improve outcomes in this population. The pathophysiology of insulin resistance in CKD is unique. In addition to a high prevalence of obesity (nearly 50%), patients with CKD have important metabolic derangements, such as decreased clearance of insulin and adipokines, metabolic acidosis, and chronic inflammation, that modify the pathophysiology of insulin resistance. Adipose tissue is an endocrine organ that secretes "adipokines" which include, but are not limited to, adiponectin and leptin.6 These two adipokines have opposing actions. Adiponectin is a key insulin sensitizing hormone with anti-atherogenic effects. In contrast, leptin is atherogenic and promotes insulin resistance. Leptin to adiponectin ratio (LAR) has been proposed as an atherogenic index in diabetes and has been shown to be a sensitive marker of metabolic syndrome. Furthermore, LAR has been shown to be the best correlate of IR in end stage renal disease patients. Given the high prevalence of obesity and metabolic derangements associated with CKD, detailing the interaction between these two conditions and their effect on CV risk is critical. The overarching aim of this proposal is to understand the effect of these interactions on adipokine imbalances and the generation of insulin resistance, and the combination of these effects on vascular health. Novel biomarkers, including imbalances in adipokine profiles, will be tested for their ability to risk stratify patiets. Finally, interventions directed at adipokine dysregulation and insulin resistance will be tested fo its ability to reverse this high risk profile in patients with moderate CKD. Our specific aims are s follows: 1) To characterize the metabolic disturbances that arise from the intersection of increased adiposity and decreased clearance of insulin and adipokines in obese patients with moderate CKD, 1a) To compare the extent of IR using hyperinsulinemic euglycemic clamp (HEGC) studies between patients with and without CKD and the degree to which this is modified by obesity, 1b) To examine if LAR will more appropriately reflect the metabolic state of obesity in the setting of moderate CKD compared to conventional measures of insulin resistance validated against HEGC, 1c) To determine if LAR is a determinant of inflammation, endothelial function, oxidative stress and atherosclerosis in the setting of obesity in CKD; 2) To study the effects of metformin, an AMP-K activator, on the metabolic disturbances associated with CKD and obesity, i.e. insulin resistance, systemic inflammation and oxidative stress, 2a) To test if metformin will improve LAR in obese CKD patients compared to placebo, 2b) To test if metformin will improve markers of systemic inflammation, oxidative stress and endothelial function in this population compared to placebo. 2c) To test if metformin will improve atherosclerosis markers and reduce clinical CVD events in obese patients with moderate CKD compared to placebo. Our proposed studies could potentially impact clinical practice, by providing new monitoring tools and potential targets for intervention to reduce CV mortality in CKD patients. Our study results could have a great impact on VETERANS HEALTH CARE and contribute to the research mission of the Department of Veterans Health administration by improving the care we provide to veteran patients with CKD.