PATHOPHYSIOLOGY OF AIDS GLOMERULOPATHY

艾滋病肾小球病的病理生理学

• 批准号: 3241238
• 负责人: BRYAN David MYERS
• 金额: $ 30.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-15 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3241238
• 关键词: AIDS; albuminuria; autoimmune disorder; biopsy; cyclosporines; cytokine; dextrans; disease /disorder model; glomerular filtration; human immunodeficiency virus 1; human subject; immunochemistry; interferons; laboratory mouse; laboratory rat; monoclonal antibody; nephrosclerosis; nephrotic syndrome; renal glomerulus; renal toxin; surface antigens; tissue /cell culture; urinalysis

A chronic glomerular injury has been described in patients with AIDS. To determine its incidence we will screen urine of 500 AIDS patients with a sensitive immunochemical technique for subclinical as well as overt elevation of albuminuria. Twenty-five AIDS patients with heavy proteinuria will then be examined with physiologic, morphometric and cell biologic techniques to elucidate the pathogenesis and extent of the glomerular injury. Because the idiopathic nephrotic syndrome (INS) is associated with a similar alteration of glomerular epithelial cells with or without focal and segmental glomerulosclerosis, 25 patients with INS will be examined in identical fashion. Fractional clearances of uncharged dextrans of graded size and of anionic dextran sulfate will be used to define the magnitude of injury to the size- and charge-selective barriers in the glomerular filter. Morphometric determinations, including glomerular filtration surface area and epithelial filtration slit density will be correlated with lowered GFR and ultrafiltration capacity (Kf). Monoclonal antibodies will be used to determine levels of various cytokines in supernates of cultured lymphocytes, so as to relate such levels to the magnitude of glomerular injury. Recombinant interferons and other selected cytokines will be infused into the Munich Wistar rat and micropuncture and morphometric techniques used to determine whether the foregoing human glomerular injuries can be replicated. Rat kidney will also be examined with monoclonal antibodies to identify cytokine- mediated alteration of expression on renal cells of MHC and other antigens, and these alterations will be sought for in human biopsy material. To define the course of the injury, differential solute clearances and cytokine levels will be repeated before and after an attempt to inhibit the latter with cyclosporine, and then at regular intervals over a 5 year period. The filtration data will be analyzed with a model that treats the glomerular capillary wall as a heteroporous membrane with an effective concentration of fixed negative charges. The membrane parameters derived from serial examinations will be used to monitor the injury and define either remission of irrevocable progression. By obtaining a more guantitative description of AIDS-related glomerulopathy, we hope to determine whether it represents a non-specific or unique injury to glomerular epithelial cells, perhaps mediated by cytokines. Enhancement of our understanding of its pathogenesis and pathophysiology could lead to the development of efficacious therapy.

慢性肾小球损伤已被描述在患者 艾滋病 为了确定其发病率，我们将筛查500 艾滋病患者采用敏感的免疫化学技术， 亚临床以及明显的白蛋白尿升高。 二十五 有大量蛋白尿的艾滋病患者将接受 生理学、形态学和细胞生物学技术， 阐明肾小球损伤的发病机制和程度。 由于原发性肾病综合征（INS）与 肾小球上皮细胞有类似的改变， 无局灶性和节段性肾小球硬化，25例 将以相同的方式检查INS。 部分清除率 不带电荷的葡聚糖和阴离子葡聚糖 硫酸盐将被用来定义伤害的大小- 和肾小球滤过器中的电荷选择性屏障。 形态测定，包括肾小球滤过 表面积和上皮滤过狭缝密度 与GFR和超滤能力（Kf）降低相关。 单克隆抗体将用于测定各种 培养的淋巴细胞上清液中的细胞因子，以便 肾小球损伤的程度。 重组 干扰素和其他选定的细胞因子将被注入到 慕尼黑Wistar大鼠及显微穿刺和形态计量学 用于确定上述人类是否 肾小球损伤可以复制。 大鼠肾脏也将 用单克隆抗体检测细胞因子， 介导的肾细胞MHC和其他 抗原，这些改变将在人类活检中寻找。 材料 为了确定损伤的过程，微分溶质 清除率和细胞因子水平将重复之前和之后， 尝试用环孢霉素抑制后者，然后在 在5年的时间内定期进行。 过滤数据将是 用一个模型分析，该模型将肾小球毛细血管壁视为 一种具有有效浓度的 固定负电荷。 膜参数由 一系列检查将用于监测损伤，并确定 缓解或不可撤销的进展。 通过获得更多 定量描述艾滋病相关的肾小球疾病，我们希望 以确定它是否代表非特异性或独特的伤害 肾小球上皮细胞，可能通过细胞因子介导。 提高我们对其发病机制的认识， 病理生理学可能导致有效的 疗法