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，其中 预计到 2020 年，患者人数将增加到超过 500,000 人。估计有 45,500 名退伍军人正在接受治疗 血液透析，其中 2013 财年有 3,000 多名注册退伍军人在 VA 设施接受透析。 过去十年，尚无任何疗法被证明可以显着降低死亡率和发病风险 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，其特征是体内蛋白质分解增加 骨骼肌室。我们的小组已经表明，两个公认的且相互关联的代谢 异常、胰岛素抵抗和持续性炎症可能在 蛋白质能量消耗和相关营养和代谢异常的发病机制。我们的初步 数据显示，维持性血液透析 (MHD) 患者 1) 对蛋白质的反应不足 胰岛素的合成代谢作用； 2) 持续的全身炎症与以下因素密切且独立相关： 骨骼肌净蛋白质平衡； 3) 全身炎症和胰岛素的药理学调节 抵抗部分但不完全逆转净蛋白质分解代谢。研究表明，非渗透性钠 (Na) 储存在皮肤和肌肉中，但没有相应的保水性，这会导致局部免疫细胞 激活和加速促炎状态。我们的初步数据表明，皮肤和肌肉 Na+ MHD 患者中通过 23Na 磁共振成像 (MRI) 得出的含量显着更高 与匹配的健康对照相比。我们还表明，皮肤和肌肉的钠离子浓度增加 与炎症反应增加和外周胰岛素敏感性降低显着相关， 接受 MHD 的患者。这些数据表明组织钠含量、免疫途径和胰岛素抵抗 密切相关，并可能导致 MHD 患者蛋白质能量浪费的风险增加。据悉， 标准 4 小时传统血液透析可显着去除肌肉和皮肤中的钠，表明 通过调整血液透析处方可以调节组织Na和水的含量。总体目标 该应用的目的是阐明组织钠积累、持续免疫的机制 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钠积累的关键机制。 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。具体目标 1：检验骨骼肌中过量的 Na 积累和 皮肤导致局部和全身炎症，导致 MHD 患者对胰岛素的代谢作用产生抵抗 患者。我们将通过检查组织钠含量和净蛋白质平衡（主要结果）来实现这一目标， 炎症标志物和常量营养素（葡萄糖和氨基酸）处理率以及 60 名 MHD 患者 以及 30 个频率匹配的年龄、性别、种族和体重指数且无肾脏疾病的对照。具体的 目标 2：检验以下假设：通过调节血液​​透析处方来去除组织钠会 改善 MHD 患者的代谢环境和蛋白质能量浪费。我们将通过以下方式实现这一目标 交叉随机临床试验，其中透析液钠浓度将被调节（138 mEq/L 与 132 mEq/L，各 4 周），以去除 10% 的基线骨骼肌 Na 含量 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、炎症和 大量营养素的处置率。如果成功，我们提出的研究将具有影响临床的巨大潜力 因为所提出的干预方案很容易获得并且可以在 MHD 患者中进行实践 最终改善住院率和死亡率，对退伍军人的健康产生重大影响 关心退伍军人管理部的研究任务并做出重要贡献。