Dysmetabolism of Chronic Kidney Disease and Vascular Health

慢性肾脏病的代谢障碍与血管健康

• 批准号: 8970558
• 负责人: Adriana Hung
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970558
• 关键词: Adipose tissue; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Atherosclerosis; Blood Vessels; Cardiovascular Diseases; Caring; Cessation of life; Chronic; Chronic Kidney Failure; Clinical; Data; Development; Diabetes Mellitus; Elements; End stage renal failure; Endocrine Glands; Epidemic; Euglycemic Clamping; Event; Fatty acid glycerol esters; Functional disorder; General Population; Generations; Glucose Clamp; Gold; Growth; Health; Healthcare Systems; High Prevalence; Hormones; Hyperinsulinism; Hypertension; Inflammation; Insulin; Insulin Resistance; Intervention; Kidney; Knowledge; Lead; Leptin; Measures; Medicare; Metabolic; Metabolic Diseases; Metabolic Marker; Metabolic acidosis; Metabolic syndrome; Metformin; Mission; Monitor; Morbidity - disease rate; Names; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Output; Oxidative Stress; Pathogenesis; Patients; Pharmaceutical Preparations; Placebos; Play; Population; Prevalence; Production; Public Health; Renal function; Research; Risk; Risk Factors; Role; Testing; Time; Veterans; Work; adipokines; adiponectin; burden of illness; clinical practice; endothelial dysfunction; glucose disposal; health administration; high risk; improved; improved outcome; indexing; kidney vascular structure; moderate obesity; mortality; novel marker; premature; prevent; primary outcome; profiles in patients; public health relevance; tool

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.

描述（由申请人提供）： 慢性肾病 (CKD) 是一个日益严重的公共卫生问题，目前影响着全球 5 亿多人。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，CKD 患者还因心血管疾病 (CVD) 而过早死亡。晚期 CKD 患者的死亡率是医疗保险人群的六倍。过去十年的新数据表明，“非传统”危险因素在 CVD 发病机制中发挥着关键作用。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。在详细描述该人群中 IR 的主要决定因素、如何最佳地描述这种紊乱以及是否可以有效地修改它以改善该人群的结果方面，存在重大的知识差距。 CKD 中胰岛素抵抗的病理生理学是独特的。除了肥胖患病率高（近 50%）外，CKD 患者还存在重要的代谢紊乱，例如胰岛素和脂肪因子清除率降低、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学。脂肪组织是分泌“脂肪因子”的内分泌器官，“脂肪因子”包括但不限于脂联素和瘦素。6这两种脂肪因子具有相反的作用。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。相反，瘦素会导致动脉粥样硬化并促进胰岛素抵抗。瘦素与脂联素比率（LAR）已被提议作为糖尿病的动脉粥样硬化指数，并已被证明是代谢综合征的敏感标志物。此外，LAR 已被证明是终末期肾病患者 IR 的最佳相关性。鉴于与 CKD 相关的肥胖和代谢紊乱的患病率很高，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至关重要。该提案的总体目标是了解这些相互作用对脂肪因子失衡和胰岛素抵抗产生的影响，以及这些影响对血管健康的综合影响。新型生物标志物，包括脂肪因子分布的不平衡，将测试其对患者进行风险分层的能力。最后，将测试针对脂肪因子失调和胰岛素抵抗的干预措施是否能够逆转中度 CKD 患者的这种高风险状况。我们的具体目标如下：1) 表征中度 CKD 肥胖患者中肥胖增加与胰岛素和脂肪因子清除率降低交叉引起的代谢紊乱，1a) 比较患有和不患有 CKD 患者之间使用高胰岛素正常血糖钳夹 (HEGC) 研究的 IR 程度，以及肥胖改变这种情况的程度，1b) 检验 LAR 是否会更有效 与针对 HEGC 验证的传统胰岛素抵抗测量相比，适当地反映了中度 CKD 情况下的肥胖代谢状态，1c) 确定 LAR 是否是 CKD 肥胖情况下炎症、内皮功能、氧化应激和动脉粥样硬化的决定因素； 2) 研究二甲双胍（一种 AMP-K 激活剂）对与 CKD 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该人群的全身炎症、氧化应激和内皮功能标志物。 2c) 测试与安慰剂相比，二甲双胍是否会改善患有中度 CKD 的肥胖患者的动脉粥样硬化标志物并减少临床 CVD 事件。我们提出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，从而影响临床实践。我们的研究结果可能对退伍军人医疗保健产生重大影响，并通过改善我们为患有 CKD 的退伍军人患者提供的护理，为退伍军人健康管理部的研究任务做出贡献。