MONOCYTE PHENOTYPES AND MORBIDITY IN UREMIA

在观察到的白细胞的众多体外功能异常中， 从肾衰竭患者中分离，单核细胞功能障碍具有 预测临床显著感染事件的最大能力， vivo. 这些单核细胞功能异常中的许多类似于那些 观察到营养不足。 因为透析与某些 膜导致单核细胞衍生的细胞因子的异常释放 它对中间代谢有分解作用， 建议透析本身可能会刺激发展， 营养不良 因此，我们认为， 单核细胞是感染和营养的关键决定因素， 透析患者的发病率。 我们认为， 与这种过度风险相关的单核细胞可以在体外定义， 将提供患者患病前的危险标记。 此外，本发明还 定义这样的表型将允许体外分析 单核细胞定向调节细胞因子纠正 功能异常 根据这些目标，我们提出了一个前瞻性的， 交叉研究，其中患者在由以下组成的膜上透析： 铜原烷、醋酸纤维素、聚丙烯腈和聚砜。 在6个月内分离单核细胞进行表型分析 的透析;单核细胞表型将基于 程序性细胞死亡的动力学，以及它们精心选择 营养相关的细胞因子、促炎脂质和反应性 氧物种，介导细胞毒性，并作为抗原发挥作用 呈递细胞 异常的单核细胞表型将与 患者结局，由感染性并发症定义，包括 尿素动力学建模的营养参数，选择的血浆水平 蛋白质、体内免疫学评估和饮食史。

Of the numerous in vitro functional abnormalities observed for leukocytes isolated from patients with renal failure, monocyte dysfunction has the greatest capacity to predict a clinically significant infectious event in vivo. Many of these monocyte functional abnormalities resemble those observed with inadequate nutrition. Because dialysis with certain membranes results in the abnormal release of monocyte-derived cytokines which have a catabolic effect on intermediary metabolism, it has been suggested that dialysis per se may be provocative for the development of malnutrition. Therefore, we suggest that the functional phenotype of the monocyte is a critical determinant of infectious and nutritional morbidity in dialysis patients. We propose that the phenotype of monocyte associated with this excessive risk can be defined in vitro and will provide a premorbid marker of the patient at risk. Further, defining such a phenotype will permit an in vitro analysis of the capacity of monocyte-directed regulatory cytokines to correct the abnormal function. Pursuant to these aims, we propose a prospective, cross-over study in which patients are dialyzed on membranes composed of cuprophane, cellulose acetate, polyacrylonitrile, and polysulfone. Monocytes will be isolated for phenotypic analysis during the six months of dialysis on each membrane; monocyte phenotyping will be based upon the kinetics of programmed cell death, and their capacity to elaborate select nutritionally relevant cytokines, proinflammatory lipids and reactive oxygen species, to mediate cytotoxicity, and to function as antigen presenting cells. The abnormal monocyte phenotypes will be correlated with patient outcome, defined by infectious complications and inclusive nutritional parameters of urea kinetic modelling, plasma levels of select proteins, in vivo immunologic assessment, and dietary history.