Nutrition, Inflammation and Insulin Resistance in End-Stage Renal Disease

终末期肾病的营养、炎症和胰岛素抵抗

• 批准号: 10578660
• 负责人: TALAT Alp IKIZLER
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10578660
• 关键词: Acceleration; Age; Amino Acids; Body mass index; Catabolism; Chronic; Clinical; Data; Death Rate; Development; Diabetes Mellitus; Dialysis patients; Dialysis procedure; Diet; End stage renal failure; Enrollment; Equilibrium; Excision; Frequencies; Future; Gender; Glucose; Goals; Healthcare; Hemodialysis; Hour; Immune; Immune system; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Intake; Intervention; Kidney Diseases; Lead; Link; Macronutrients Nutrition; Magnetic Resonance Imaging; Maintenance; Metabolic; Mission; Morbidity - disease rate; Muscle; Nutritional; Obesity; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral; Persons; Pilot Projects; Play; Population; Progress Reports; Proteins; Protocols documentation; Race; Reporting; Research; Resistance; Risk; Role; Skeletal Muscle; Skin; Skin Tissue; Sodium; Testing; Tissues; Transplantation; United States; United States Department of Veterans Affairs; Veterans; Water; clinical practice; cohort; hospitalization rates; immune activation; improved; inflammatory marker; innovation; insulin sensitivity; mortality; nutrition; patient population; pharmacologic; prevent; primary outcome; protein metabolism; randomized, clinical trials; response; systemic inflammatory response; wasting

There are more than 420,000 patients receiving maintenance hemodialysis therapy in the United States, which is estimated to rise to over 500,000 patients by 2020. There are an estimated 45,500 veterans receiving hemodialysis, of which over 3,000 enrolled veterans were receiving dialysis at VA facilities in FY 2013. Over the last decade, there have been no therapies proven to significantly lower the mortality and morbidity risk for these patients. One of the most important determinants of this poor clinical outcome is protein energy wasting, a highly prevalent nutritional and metabolic abnormality characterized by increased protein breakdown in the skeletal muscle compartment. Our group has shown that two well-recognized and interrelated metabolic abnormalities, insulin resistance and persistent inflammation, are likely to play a critical role in the pathogenesis of protein energy wasting and related nutritional and metabolic abnormalities. Our preliminary data show that in maintenance hemodialysis (MHD) patients 1) There is an inadequate response to protein anabolic actions of insulin; 2) Persistent systemic inflammation is strongly and independently associated with skeletal muscle net protein balance; and 3) Pharmacological modulation of systemic inflammation and insulin resistance partially, but not fully, reverse net protein catabolism. It was demonstrated that non-osmotic sodium (Na) is stored in skin and muscle without commensurate water retention, which leads to local immune-cell activation and accelerated pro-inflammatory status. Our preliminary data show that the skin and muscle Na+ contents, derived by 23Na magnetic resonance imaging (MRI) are substantially higher in MHD patients compared to matched healthy controls. We also showed that increased skin and muscle Na concentrations are significantly associated with increased inflammatory response and decreased peripheral insulin sensitivity, in patients on MHD. These data suggest that tissue Na content, immune pathways and insulin resistance are closely linked and could lead to increased risk for protein energy wasting in MHD patients. It was reported that standard 4-hour conventional hemodialysis provides significant Na removal from muscle and skin suggesting that tissue Na and water content could be modulated by modulating hemodialysis prescription. The overall goal of this application is to elucidate the mechanisms by which tissue sodium accumulation, persistent immune system activation and insulin resistance influence the development of protein energy wasting in MHD patients. We hypothesize that the skin and muscle tissue sodium accumulation is a critical mechanism by which chronic inflammatory response and insulin resistance, alone or in combination, lead to protein energy wasting in MHD patients. Specific Aim 1: To test the hypothesis that excessive Na accumulation in the skeletal muscle and skin leads to local and systemic inflammation that result in resistance to metabolic effects of insulin in MHD patients. We will achieve this aim by examining tissue Na content and net protein balance (primary outcome), markers of inflammation and macronutrient (glucose and amino acid) disposal rates and in 60 MHD patients and 30 frequency matched age, gender, race and body mass index controls without kidney disease. Specific Aim 2: To test the hypothesis that removal of tissue sodium by modulating hemodialysis prescription would improve metabolic milieu and protein energy wasting in MHD patients. We will achieve this goal through a cross-over randomized clinical trial whereby dialysate sodium concentrations will be modulated (138 mEq/L versus 132 mEq/L, 4 weeks each) to remove 10% of baseline skeletal muscle Na content in the setting of stable sodium intake by diet. Our primary outcomes will be markers of net protein balance, inflammation, and macronutrient disposal rates. If successful, our proposed studies will have great potential to influence clinical practices in MHD patients because the proposed intervention protocol would be easily accessible and could ultimately lead to improvements in the hospitalization and death rates with great impact on Veterans' Health Care and make important contributions to the research mission of the Department of Veterans Administration.

美国有超过42万名患者接受维持性血液透析治疗， 预计到2020年将增加到50多万患者。估计有45，500名退伍军人接受 血液透析，其中3,000多名登记的退伍军人在2013财年在VA设施接受透析。超过 在过去的十年中，没有任何治疗方法被证明可以显著降低死亡率和发病率风险。 这些病人。这种不良临床结果的最重要决定因素之一是蛋白质能量浪费， 一种非常普遍的营养和代谢异常，其特征是 骨骼肌隔室我们的研究小组已经表明，两个公认的和相互关联的代谢 异常，胰岛素抵抗和持续性炎症，可能在这些疾病中发挥关键作用。 蛋白质能量消耗和相关的营养和代谢异常的发病机制。我们的初步 数据显示，在维持性血液透析（MHD）患者中，1）对蛋白质的反应不足， 胰岛素的合成代谢作用; 2）持续性全身性炎症与胰岛素的合成代谢作用强烈且独立相关。 骨骼肌净蛋白平衡;和3）全身炎症和胰岛素的药理学调节 抗性部分但不完全逆转净蛋白催化剂。结果表明，非渗透性钠 (Na)储存在皮肤和肌肉中，没有相应的水分保留，这导致局部免疫细胞 激活和加速的促炎状态。我们的初步数据显示，皮肤和肌肉Na+ 23 Na磁共振成像（MRI）显示，MHD患者的23 Na含量明显高于对照组 与健康对照组进行比较。我们还发现，皮肤和肌肉中钠浓度的增加 与增加的炎症反应和降低的外周胰岛素敏感性显著相关， 在MHD患者中。这些数据表明，组织钠含量，免疫途径和胰岛素抵抗是 密切相关，并可能导致MHD患者蛋白质能量浪费的风险增加。有消息称 标准的4小时常规血液透析提供了从肌肉和皮肤中显著的Na去除， 通过调整血液透析处方可以调节组织Na和水含量。总目标 本申请的主要目的是阐明组织钠积累、持续免疫抑制和免疫抑制的机制。 系统激活和胰岛素抵抗影响MHD患者蛋白质能量消耗的发展。 我们假设皮肤和肌肉组织钠积累是慢性炎症的关键机制， 炎症反应和胰岛素抵抗单独或联合导致MHD中蛋白质能量浪费 患者具体目的1：检验骨骼肌中过量Na蓄积的假设， 皮肤导致局部和全身炎症，导致MHD患者对胰岛素代谢作用的抵抗 患者我们将通过检查组织Na含量和净蛋白平衡（主要结局）来实现这一目标， 炎症标志物和大量营养素（葡萄糖和氨基酸）的处置率和60例MHD患者 和30个频率匹配的年龄、性别、种族和体重指数对照组，无肾脏疾病。具体 目的2：验证通过调整血液透析处方清除组织钠的假设， 改善MHD患者代谢环境和蛋白质能量消耗。我们将通过一个 交叉随机临床试验，其中将调节透析液钠浓度（138 mEq/L 与132 mEq/L，各4周），以去除基线骨骼肌Na含量的10%， 通过饮食稳定钠摄入量。我们的主要结果将是净蛋白质平衡，炎症， 常量营养素处置率。如果成功，我们提出的研究将有很大的潜力影响临床 在MHD患者中的实践，因为拟议的干预方案将很容易获得， 最终导致住院率和死亡率的改善，对退伍军人的健康产生重大影响 关心并为退伍军人管理部的研究使命做出重要贡献。