Anti-Inflammatory Interventions in Maintenance Hemodialysis Patients

描述(申请人提供)：目前美国有超过40万人正在接受维持性血液透析(MHD)。这类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，包括针对他汀类药物等传统心血管危险因素的策略，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)和白介素6(IL-6)在MHD患者中升高，也是该患者群体心血管事件和死亡率的有力预测指标。虽然抗炎干预，特别是特定的抗细胞因子疗法已经成功地用于治疗炎症性肠病、牛皮癣和类风湿性关节炎患者，虽然有报道称在改善2型糖尿病的血糖控制和β细胞功能方面有令人鼓舞的研究，但在MHD患者中使用这些干预措施的研究有限。我们的研究小组进行了一系列研究，探讨了一些抗炎疗法在MHD患者中的可行性、安全性和有效性，包括白细胞介素1受体拮抗剂(IL-1ra)、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名患者到300名患者。我们已经证明，在这些干预措施中，IL-1ra和鱼油疗法对炎症标记物，如hsCRP和IL-6有最显著的有益影响；而维生素E和ALA疗法对这些患者的炎症状态没有影响。这项赠款申请是对最近的NIDDK RFA DK-12-010(降低血液透析患者发病率和死亡率的新干预措施-安全性和其他早期研究)的响应，其总体目标是通过U01合作机制研究有希望的药物和透析干预措施在维持性血液透析患者中的安全性、可行性和有效性。我们的具体目标是1)通过两个单独的随机临床试验，测试IL-1ra和鱼油在6个月内对维持性血液透析患者炎症生物标志物的疗效；2)通过两个单独的随机临床试验，测试IL-1ra和鱼油在6个月内对维持性血液透析患者的安全性和耐受性；3)创建研究人员和透析设施的协作网络，为维持性血液透析患者的试点和可行性研究高效、快速地招募受试者。这项应用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，以便随后在MHD患者中进行全面的随机对照临床试验，测试严格的临床结果，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.