PREVENTION OF GRAFT FAILURE TO DIETARY N-3 FATTY ACIDS

血液透析患者依赖动静脉（AV）分流， 血管通路，通常通过手术植入血管移植物实现 由膨胀型聚四氟乙烯（ePTFE）组成。不幸的是， 这些AV移植物（AVG）中约有一半在1年内失效，原因是 血管病变形成（VLF）引起的渐进性狭窄。 这 复杂的过程包括1）凝血酶生成，2）血小板活化 血小板衍生生长因子（PDGF）和血栓的分泌 形成，3）单核细胞/巨噬细胞积累和PDGF分泌， 4）血管平滑肌的内膜迁移和增殖 细胞 由于饮食n-3FAs下调许多分子和 细胞相互作用的基础发展甚低频，我们建议， 检验饮食n-3FAs会减少狭窄血栓的假设， 闭塞性移植物失效。 我们在狒狒身上找到了有说服力的证据 饮食n-3FA中断血栓形成和VLF而不损害止血 功能 我们在透析中也有直接的实验证据 AVG狭窄过程中涉及血栓形成的患者， 血栓闭塞，并在镰状细胞患者接受 饮食中的n-3FAs证明了其可行性、可接受性和减少 疼痛发作 我们建议：1.建立有效的抗血栓 n-3FAs的饮食剂量。 在项目的第一年， 将比较0.1 g/kg/d与0.3 g/kg/d的膳食n-3FAs的影响， 24名患者随机分为3组，每组8名 队列，测量血栓形成的替代分子测量， 治疗前和治疗后3个月的炎症和危险因素。 AVG上血小板沉积的差异将使用 用111 In-8-羟基喹啉和定量γ-标记的自体血小板 照相机成像。2.评价饮食中n-FAs对AVG失败的影响 在一个随机的，盲法的，橄榄非对照临床试验中。 期间 在计划余下的三年，我们建议进行一项 在180例透析患者中进行的随机、橄榄油对照、盲法试验 比较饮食n-3FAs与同等对照橄榄油的效果 AVG失败。 膳食n-3FA的剂量为0.1 g/kg/d 或0.3 g/kg/d，取决于其中断AVG的相对功效 血小板沉积 主要结局为AVG失败。 假设 平均每年失败率为50%，治疗获益为50 每年有25%的患者流失，随机抽取180例透析患者， 患者将有90%的能力检测到益处。 二次 要比较的结果是血栓形成的分子标记， 炎症和血管危险因素。

Hemodialysis patients depend on arteriovenous (AV) shunts for angioaccess, usually achieved by surgically implanting vascular grafts composed of expanded polytetrafluroethylene (ePTFE). Unfortunately, approximately half of these AV grafts (AVGs) fail within 1 year due to incremental stenosis arising from vascular lesion formation (VLF). This complex process involves 1) thrombin generation, 2) platelet activation with secretion of platelet-derived growth factor (PDGF) and thrombus formation, 3) monocyte/macrophage accumulation and secretion of PDGF, and 4) intimal migration and proliferation of vascular smooth muscle cells. Since dietary n-3FAs down-regulate many of the molecular and cellular interactions underlying the development of VLF, we propose to test the hypothesis that dietary n-3FAs will reduce stenosing thrombo- occlusive graft failure. We have persuasive evidence in baboons that dietary n-3FAs interrupt thrombosis and VLF without impairing hemostatic function. We also have direct experimental evidence in dialysis patients implicating thrombosis in the processes of AVG stenosis and thrombo-occlusion, and experience in sickle cell patients receiving dietary n-3FAs demonstrating feasibility, acceptance and reduction in pain episodes. We propose to: 1. Establish the effective antithrombotic dose of dietary n-3FAs. During the first year of the project the effects of dietary n-3FAs at 0.1 vs 0.3 g/kg/d will be compared with control olive oil in 24 patients randomly allocated to three 8-patient cohorts, measuring surrogate molecular measures of thrombosis, inflammation and risk factors before and after 3 months of therapy. Differences in platelet deposition on AVGs will be compared using autologous platelets labeled with 111In-oxine and quantitative gamma camera imaging. 2. Evaluate the effects of dietary n-FAs on AVG failure in a randomized, blinded, olive off-controlled clinical trial. During the remaining three years of the project, we propose to carry out a randomized, olive oil-controlled, blinded trial in 180 dialysis patients comparing the effects of dietary n-3FAs vs equivalent control olive oil on AVG failure. The dose of dietary n-3FAs will be either 0.1 g/kg/d or 0.3 g/kg/d, depending on their relative efficacy for interrupting AVG platelet deposition. The primary outcome will be AVG failure. Assuming AVG failure rate of 50 percent per year, treatment benefit of 50 percent, and 25 percent patient loss per year, randomizing 180 dialysis patients will have 90 percent power of detecting a benefit. Secondary outcomes to be compared are molecular markers for thrombosis, inflammation, and vascular risk factors.