Anti-Inflammatory Interventions in Maintenance Hemodialysis Patients

描述（由申请人提供）：目前有超过40万人在美国接受维持性血液透析（MHD）。这组患者的死亡率高得令人无法接受。大多数死亡是由于心血管疾病，其次是感染性并发症和蛋白质能量浪费。降低MHD患者死亡率的策略，包括针对传统心血管危险因素（如他汀类药物）的策略，在很大程度上是无效的。炎症与动脉粥样硬化性心血管疾病和蛋白质-能量消耗的发病机制有关。炎症状态的生物标志物，如 C反应蛋白（hsCRP）和白细胞介素-6（IL-6）在MHD患者中升高，也是该患者人群心血管事件和死亡率的可靠预测因子。虽然抗炎干预措施，特别是特异性抗细胞因子疗法已成功用于治疗炎症性肠病、银屑病和类风湿性关节炎患者，虽然已报道了改善2型糖尿病血糖控制和β细胞功能的令人鼓舞的研究，但在MHD患者中使用这些干预措施的研究有限。我们的研究小组已经进行了一系列研究，调查MHD患者中多种抗炎治疗的可行性，安全性和有效性，包括白细胞介素-1受体拮抗剂（IL-1 ra），鱼油（EPA+DHA），维生素E（γ-生育酚），α-硫辛酸（ALA）和CoEnyzme Q10，研究范围从14例患者到300例患者。我们已经表明，在这些干预措施中，IL-1 ra和鱼油疗法对炎症标志物如hsCRP和TNF-α具有最显著的有益作用。 IL- 6;而维生素E和ALA治疗不影响这些患者的炎症状态。本资助申请是针对最近的NIDDK RFA DK-12-010（降低血液透析患者发病率和死亡率的新型干预措施-安全性和其他早期研究）提交的，其总体目的是通过U 01合作机制研究维持性血液透析患者中有前景的药理学和透析干预措施的安全性、可行性和有效性。我们的具体目标是：1）通过两项单独的随机临床试验，在维持性血液透析患者中测试IL-1 ra和鱼油在6个月内对炎症生物标志物的疗效; 2）通过两项单独的随机临床试验，在维持性血液透析患者中测试IL-1 ra和鱼油在6个月内的安全性和耐受性; 3）建立研究者和透析设施的协作网络，以有效和快速地招募受试者，用于维持性血液透析患者的试点和可行性研究。本申请的最终目标是获得研究设计的关键要素和适当的干预措施，用于随后在MHD患者中进行的全面随机对照临床试验，以测试严格的临床结局，包括发病率和死亡率。

DESCRIPTION (provided by applicant): There are currently more than 400,000 people undergoing maintenance hemodialysis (MHD) in the United States program. The mortality in this group of patients is unacceptably high. A majority of the deaths are due to cardiovascular diseases, followed by infectious complications and protein-energy wasting. Strategies to reduce the mortality of MHD patients, including those directed at traditional cardiovascular risk factors such as statins, have largely been ineffective. Inflammation has been implicated in the pathogenesis of atherosclerotic cardiovascular disease and protein-energy wasting. Biomarkers of the inflammatory state such as C-reactive protein (hsCRP) and interleukin-6 (IL-6) are elevated in MHD patients and are also robust predictors of cardiovascular events and mortality in this patient population. While anti-inflammatory interventions, especially specific anti-cytokin therapies have been used successfully to treat patients with inflammatory bowel disease, psoriasis and rheumatoid arthritis, and while encouraging studies have been reported in improving glycemic control and beta cell function in type 2 diabetes, there are only limited studies using these interventions in MHD patients. Our investigative group has performed a series of studies investigating the feasibility, safety, and efficacy of a number of anti-inflammatory therapies in MHD patients, including Interleukin-1 receptor antagonist (IL-1ra), Fish Oil (EPA+DHA), Vitamin E (gamma-tocopherol), alpha lipoic acid (ALA) and CoEnyzme Q10 in studies ranging from 14 patients to 300 patients. We have shown that amongst these interventions, IL-1ra and Fish Oil therapies have the most significant beneficial effects on inflammatory markers, such as hsCRP and IL- 6; whereas Vitamin E and ALA therapies do not influence inflammatory state in these patients. This grant application is submitted in response to the recent NIDDK RFA DK-12-010 (Novel Interventions to Reduce Morbidity and Mortality of Hemodialysis Patients - Safety and Other Early Phase Studies) and has the overarching aim of studying the safety, feasibility and efficacy of promising pharmacological and dialytic interventions in maintenance hemodialysis patients through a U01 collaboration mechanism. Our specific aims are 1) To test the efficacy of IL-1ra and Fish Oil on inflammatory biomarkers over 6 months through two separate randomized clinical trials in maintenance hemodialysis patients; 2) To test the safety and tolerability of IL-1ra and Fish Oil over 6 months through two separate randomized clinical trials in maintenance hemodialysis patients; 3) Create a collaborative network of investigators and dialysis facilities for efficient and swift subject recruitment for pilot and feasibility studies in maintenance hemodialysis patients. The ultimate goal of this application is to obtain critical elements of the study design and suitable interventin for a subsequent full-scale randomized controlled clinical trial in MHD patients testing rigorous clinical outcomes including morbidity and mortality.