Isoflavones:Acute Response in Chronic Renal Failure

描述（由申请人提供）：高达40%的ESRD患者患有 从慢性炎症过程，目前不适合特定的 治疗，并与高发病率和死亡率。高循环 促炎细胞因子的水平和产生是这一过程的重要组成部分。 持续的急性期反应，据信它们会加剧许多 终末期肾病的临床表现，包括肾性骨营养不良。像在所有 其他炎症过程已经经历了更广泛的研究， 核因子，核因子κ B（NF κ B）承诺是一个关键的 这种急性相反应的细胞中间体，既是调解人， 炎症细胞因子作用的靶点。在目前对代理人的搜索中， 可能能够否定正在进行的急性期反应的终末期肾病，大豆 染料木黄酮和大豆苷元已成为潜在的有用的。这些 大豆酮存在于许多大豆食品中， 营养补充剂，并受到越来越多的关注，由于其 生物学特性和作为治疗剂的潜力。抑制作用 对酪氨酸激酶和NF-κ B活性的影响， 细胞因子的产生和氧化应激的作用已经通过这种方法得到证实。 小组和许多其他调查人员，他们可能是高度相关的 肾衰竭人群。此外，我们最近发现， 终末期肾病患者食用大豆食品会导致非常高的血胆固醇水平， 耐受性良好。 我们的工作假设是，在慢性肾衰竭中， 内源性和外源性因素触发急性期反应并激活 NF κ B和促炎细胞因子的产生， 大豆异黄酮抑制NF κ B活化和细胞因子产生， 阻断正在进行的急性期反应，并在临床上产生积极影响 ESRD疾病活动的相关参数。 本提案的具体目标是进行一项随机、双盲 在血液透析患者中进行饮食干预试验，以确定： 1.有临床症状的终末期肾病患者对大豆异黄酮的膳食摄入 持续的急性期反应减少了促炎性细胞因子的产生， 细胞因子TNF-α，IL-1和IL-6在外周血中，从而改变 这些细胞因子及其拮抗剂sTNF RI、sTNF RII和 IL-1ra。 2.大豆异黄酮抑制炎症细胞因子的产生 与疾病的临床相关参数改善相关 活动，包括改善急性期反应的血液标志物，以及 代谢性骨病标志物的血液水平降低。 3.摄入大豆异黄酮抑制外周血NF-κ B活性 终末期肾病患者的单核细胞，以与 细胞因子水平和疾病的临床参数。

DESCRIPTION (provided by applicant): Up to 40 percent of ESRD patients suffer from a chronic inflammatory process which is not currently amenable to specific treatment and is associated with high morbidity and mortality. High circulating levels and production of pro-inflammatory cytokines are essential part of this ongoing acute-phase response and they are believed to exacerbate many of the clinical manifestations of ESRD, including renal osteodystrophy. Like in all other inflammatory processes that have undergone more extensive investigation, the nuclear factor, Nuclear Factor Kappa-B (NFKB) promises to be a critical cellular intermediate of this acute-phase response and to be both mediator and target of inflammatory cytokine effects. In the current search for agents that may be able to negate the ongoing acute-phase response of ESRD, the soy isoflavones genistein and daidzein have emerged as potentially useful. These isoflavones are present in many soyfoods, are available as over-the-counter nutritional supplements and have received growing attention due to their biological properties and potential as therapeutic agents. Inhibitory effects of the isoflavones on tyrosine kinase and NFKB activity, on inflammatory cytokine production and on oxidative stress have been demonstrated by this group and by many other investigators and they may be highly relevant to the renal failure population. Additionally, we have found recently that intake of soy food by ESRD patients results in very high blood levels of isoflavones and it is well tolerated. It is our working hypothesis that in chronic renal failure a variety of endogenous and exogenous factors trigger acute-phase response with activation of NFKB and production of pro-inflammatory cytokines, and that intervention with soy isoflavones inhibits NFKB activation and cytokines production, thus blocking the ongoing acute-phase response and affecting positively clinically relevant parameters of disease activity in ESRD. Specific objective of this proposal is to conduct a randomized, double-blinded dietary intervention trial in hemodialysis patients to determine whether: 1. Dietary intake of the soy isoflavones by ESRD patients with clinical signs of ongoing acute-phase response decreases the production of the proinflammatory cytokines TNF-alpha, IL-1 and IL-6 in peripheral blood, thus changing the balance between these cytokines and their antagonists sTNF RI, sTNF RII, and IL-1ra. 2. Suppression of inflammatory cytokine production by soy isoflavones is associated with improvement of clinically relevant parameters of disease activity, including improvement of blood markers of acute-phase response, and decreased blood levels of markers of metabolic bone disease. 3. Intake of soy isoflavones suppresses NF-KB activity in peripheral blood monocytic cells of ESRD patients, in a manner consistent with change of cytokine levels and of clinical parameters of disease.