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

在美国，有超过42万名患者正在接受维持性血液透析治疗，其中 预计到2020年将增加到50多万名患者。据估计，有45500名退伍军人获得了 血液透析，其中超过3,000名登记退伍军人在2013财年在退伍军人管理局接受透析。完毕 在过去的十年里，还没有任何治疗方法被证明可以显著降低糖尿病的死亡率和发病率风险。 这些病人。这种糟糕的临床结果最重要的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，其特征是蛋白质分解增加 骨骼肌间隔区。我们的团队已经证明了两种公认且相互关联的新陈代谢 胰岛素抵抗和持续性炎症的异常很可能在 蛋白质能量消耗及相关营养代谢异常的发病机制。我们的预赛 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)持续性全身炎症与 骨骼肌净蛋白平衡；3)全身炎症和胰岛素的药理调节 抗性部分地，但不完全地，逆转净蛋白分解代谢。已经证明，非渗透性钠 (NA)储存在皮肤和肌肉中，没有相应的水分保持，从而导致局部免疫细胞 激活和加速促炎状态。我们的初步数据显示，皮肤和肌肉中的Na+ MHD患者的~(23)Na磁共振成像(MRI)所得的含量显著高于对照组 与匹配的健康对照组进行比较。我们还表明，皮肤和肌肉中的钠浓度增加 与炎症反应增加和外周胰岛素敏感性降低显著相关， 在接受MHD治疗的患者中。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。据报道， 标准的4小时常规血液透析可显著清除肌肉和皮肤中的钠 通过调整血液透析处方，可调节组织钠和水分含量。总目标 这一应用的目的是阐明组织钠蓄积、持久免疫的机制 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的钠蓄积是慢性 炎症反应和胰岛素抵抗单独或联合导致MHD患者蛋白质能量浪费 病人。具体目标1：检验骨骼肌中过多的钠蓄积和 皮肤导致局部和全身炎症，导致MHD患者对胰岛素代谢影响的抵抗 病人。我们将通过检测组织钠含量和净蛋白质平衡(主要结果)来实现这一目标， 60例MHD患者炎症和常量营养素(葡萄糖和氨基酸)处理率的标志物 与年龄、性别、种族和体重指数相匹配的30个频率的对照组没有肾脏疾病。特定的 目的2：验证通过调整血液透析处方来清除组织钠的假设 改善MHD患者的代谢环境和蛋白质能量消耗。我们将通过一个 调整透析液钠浓度的交叉随机临床试验(138mEq/L 与132mEq/L，每4周)在以下设置中去除10%的基线骨骼肌钠含量 通过饮食稳定的钠摄入量。我们的主要结果将是净蛋白质平衡、炎症和 常量营养素处置率。如果成功，我们提议的研究将对临床产生巨大的影响。 在MHD患者中的实践，因为拟议的干预方案将很容易获得，并可以 最终导致住院和死亡率的改善，并对退伍军人的健康产生重大影响 关心并为退役军人管理部的研究使命做出重要贡献。

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.