Omega-3 Fatty Acid Administration In Dialysis Patients

描述(申请人提供)：目前美国有30多万名患者正在接受慢性透析治疗，这些患者的预期寿命仅为普通人群的三分之一至六分之一。慢性炎症是血液透析患者中的一种高度流行的疾病，是这类患者住院和死亡的强大独立预测因子。研究表明，促炎细胞因子是导致肌肉萎缩的炎症反应的主要介质，会导致一种独特的蛋白质和能量营养不良，可被称为尿毒症衰竭。目前，还没有既定的干预措施来减轻透析患者慢性炎症的不良影响。Omega-3脂肪酸对正常生长和发育是必不可少的，已被证明影响冠状动脉疾病、高血压、关节炎、炎症性疾病和癌症。研究表明，补充omega-3脂肪酸，特别是与EPA一起补充，可能会减少促炎细胞因子的产生和/或缓解与心血管疾病、关节炎和炎症性肠道疾病相关的症状。EPA还被证明通过下调癌症患者骨骼肌中泛素-蛋白酶体途径关键调节成分基因表达的增加来减弱蛋白质的分解。这项赠款申请的总体目标是检查补充EPA在改善尿毒症炎症状态以及与此疾病状态相关的肌肉蛋白质分解代谢方面的作用。我们推测，如果给药3个月，EPA将改善与尿毒症相关的慢性尿毒症炎症和肌肉蛋白分解。我们将在慢性炎症血液透析患者中进行一项随机、安慰剂对照试验，并在3个月内给予EPA，以检验这些假说，目的如下：具体目标1：确定EPA给药对炎症状态的影响，通过以下指标衡量：促炎细胞因子产生能力、急性时相反应和血浆促炎细胞因子浓度。具体目标2：利用稳定同位素方法学(主要结果指标)和血清营养生物标志物浓度，通过全身和肌肉蛋白质周转来确定EPA对蛋白质代谢的影响。 公共卫生相关性：慢性血液透析患者存活率低的最重要因素之一是一种被称为尿毒症消瘦的营养不良，其表现为肌肉质量的进行性丧失。慢性炎症在透析患者中也很常见，并与尿毒症的消瘦有关。我们建议测试抗炎治疗(在这种情况下是欧米茄-3脂肪酸)是否可以减少透析患者的炎症和肌肉损失。

DESCRIPTION (provided by applicant): There are currently more than 300,000 patients receiving chronic dialysis therapy in the United States and the life expectancy for these patients are only 1/3 to 1/6 of those for the general population. Chronic inflammation, a highly prevalent condition in hemodialysis patients, is a powerful independent predictor of hospitalization and death in this patient population. Studies have suggested that pro-inflammatory cytokines, the primary mediators of inflammatory response leading to muscle wasting lead to a unique form of protein and energy malnutrition, which can be termed "uremic wasting". Currently, there are no established interventions to ameliorate the adverse effects of chronic inflammation in dialysis patients. Omega-3 fatty acids are essential for normal growth and development and have been shown to influence coronary artery disease, hypertension, arthritis, inflammatory disorders, and cancer. Studies have shown that omega-3 fatty acid supplementation, particularly with EPA, may reduce pro-inflammatory cytokine production and/or alleviate symptoms related to cardiovascular disease, arthritis, and inflammatory bowel disease. EPA has also been shown to attenuate protein breakdown by downregulating the increased gene expression of key regulatory components of the ubiquitin-proteosome pathway in skeletal muscle of patients with cancer. The overall goal of this grant application is to examine the role of EPA supplementation in ameliorating the inflammatory state of uremia and the related muscle protein catabolism associated with this disease state. We hypothesize that if administered for a period of 3 months, EPA will improve the chronic uremic inflammation and the muscle protein breakdown associated with uremia. We will conduct a randomized, placebo-controlled trial with administration of EPA over 3 months in chronically inflamed hemodialysis patients to test these hypotheses by the following aims: Specific Aim 1: To determine the effects of EPA administration on the inflammatory state as measured by: Pro- inflammatory cytokine production capacity, acute phase response and plasma pro-inflammatory cytokine concentrations. Specific Aim 2: To determine the effects of EPA administration on protein metabolism as measured by whole body and muscle protein turnover utilizing stable isotope methodology (primary outcome measure) and serum concentrations of nutritional biomarkers. PUBLIC HEALTH RELEVANCE: One of the most important factors responsible for the poor survival of chronic hemodialysis patients is a form of malnutrition termed as "uremic wasting", which is manifested by progressive loss of muscle mass. Chronic inflammation is also common in dialysis patients and has been linked to uremic wasting. We propose to test if reducing inflammation with an anti-inflammatory treatment (Omega-3 fatty acids in this case) will reduce inflammation and muscle loss in dialysis patients.