Omega-3 Fatty Acid Administration In Dialysis Patients

描述（由申请人提供）：目前美国有30多万患者接受慢性透析治疗，这些患者的预期寿命仅为普通人群的1/3至1/6。慢性炎症是血液透析患者中非常普遍的疾病，是该患者住院和死亡的一个强有力的独立预测因子。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，可导致一种独特形式的蛋白质和能量营养不良，可称为“尿毒症消耗”。目前，还没有确定的干预措施来改善透析患者慢性炎症的不良影响。Omega-3脂肪酸是正常生长发育所必需的，并已被证明对冠状动脉疾病、高血压、关节炎、炎症性疾病和癌症有影响。研究表明，补充omega-3脂肪酸，特别是EPA，可能会减少促炎细胞因子的产生和/或减轻与心血管疾病、关节炎和炎症性肠病相关的症状。EPA也被证明可以通过下调癌症患者骨骼肌中泛素-蛋白体通路关键调控组分的基因表达来减弱蛋白质分解。本拨款申请的总体目标是研究补充EPA在改善尿毒症炎症状态和与该疾病状态相关的肌肉蛋白分解代谢中的作用。我们假设，如果给药3个月，EPA将改善慢性尿毒症炎症和与尿毒症相关的肌肉蛋白分解。我们将进行一项随机、安慰剂对照试验，在慢性炎症血液透析患者中给予EPA超过3个月，通过以下目的来验证这些假设：具体目标1：通过测量促炎细胞因子生产能力、急性期反应和血浆促炎细胞因子浓度来确定EPA给药对炎症状态的影响。具体目标2：利用稳定同位素方法（主要结果测量）和血清营养生物标志物浓度，确定EPA给药对蛋白质代谢的影响，这些蛋白质代谢是通过全身和肌肉蛋白质周转率测量的。

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.