Hyperoxaluria Leading to Tubule Injury and Kidney Stone Disease

描述(由申请人提供)：肾结石是一种严重的健康问题，与巨大的疼痛、痛苦和经济成本有关。到70岁时，5%至15%的人口将出现结石的症状发作，其中至少50%的人将复发疾病。到目前为止，尿石症研究人员仅限于细胞培养研究或高草酸尿症大鼠模型，其中高草酸尿症是由口服乙二醇会对多个器官有毒或通过高剂量草酸钠腹腔注射诱导的。与人类相比，大鼠产生草酸盐结晶尿和组织或细胞反应所需的诱导尿草酸排泄水平被批评为超生理学。 我们认为猪是建立草酸钙结晶性尿症和草酸钙结石动物模型的理想动物模型。猪肾脏的解剖学和生理学与人类非常相似。厌氧细菌草酸杆菌在猪的肠道中将草酸降解为甲酸盐，通常会阻止猪变得高草酸。我们已经成功地获得了不含草酸杆菌的猪，并首次报告了这些猪由于口服草酸盐负荷而显着增加了尿草酸排泄，这与人类摄入富含草酸盐的饮食所经历的结果相似。我们建议通过饲喂富含草酸的饲料来诱发猪的高草酸尿症。我们建议研究高草酸对猪肾脏生理的影响及其对草酸钙晶体附着和结石成熟的影响。 我们假设，喂食草酸盐的猪将以非常类似于人类的方式在它们的尿路中形成草酸钙结晶和草酸钙结石。我们还假设，这些高草酸尿猪非常适合扩展研究高草酸尿对肾上皮细胞生理、晶体附着和结石成熟的影响。这项资助提案包含三个具体目标来验证我们的假设：具体目标一：建立一种新的高草酸尿酸猪动物模型。具体目标二：启动猪的草酸钙结晶并确定沿肾的晶体附着位置。具体目标三：在猪中诱发草酸钙结石疾病并描述结石成熟的过程。 这些特定的目标和相关的问题将使我们能够全面描述猪的高草酸尿症的发展以及草酸钙晶体尿和草酸钙结石的发展。高草酸猪在尿石症研究的许多领域以及在设计治疗结石疾病的新治疗方式方面将具有巨大的潜力。

DESCRIPTION (provided by applicant): Kidney stone disease is a substantial health problem associated with significant pain, suffering, and economic costs. 5% to 15% of the population will have a symptomatic episode of a stone by the age of 70 and at least 50% of these individuals will have recurrent disease. To date, urolithiasis researchers have been limited to cell culure studies or a rat model where hyperoxaluria is induced by either ethylene glycol oral administration that is toxic to multiple organs or by high dose intraperitoneal sodium oxalate injection. The levels of induced urinary oxalate excretion in the rat needed to produce oxalate crystalluria and tisssue or cell response are criticized as being supraphysiologic compared to man. We propose that the pig is ideal for the development of an animal model of calcium oxalate crystalluria and calcium oxalate stone disease. The anatomy and physiology of the pig kidney is very similar to man. The anerobic bacteria Oxalobacter formigenes degrades oxalate to formate in the pig gut and normally stops the pig from becoming hyperoxaluric. We have successfully obtained Oxalobacter formigenes free pigs and report here for the first time that these pigs demonstrated a significant increase in urinary oxalate excretion as the result of an oral oxalate load similar to that experienced by man ingesting an oxalate rich diet. We propose to induce hyperoxaluria in the pig by feeding them an oxalate rich diet. We propose to study the effect of hyperoxaluria on pig kidney physiology and its impact on calcium oxalate crystal attachment and stone maturation. We hypothesize that pigs fed oxalate will form calcium oxalate crystalluria and calcium oxalate stones in their urinary tract in a manner very similar to man. We also hypothesize that these hyperoxaluric pigs are ideally suited for the extension of studies on the effect of hyperoxaluria on renal epithelial cell physiology, crystal attachment and stone maturation. This grant proposal contains three Specific Aims that test our hypotheses:Specific Aim I: To develop a new hyperoxaluric pig animal model.Specific Aim II: To initiate calcium oxalate crystalluria in the pig and to identify the site of crystal attachment along the nephron.Specific Aim III: To induce calcium oxalate stone disease in the pig and to characterize the process of stone maturation. These Specific Aims and their associated questions will allow us to fully describe the development of hyperoxaluria in the pig and the development of calcium oxalate crystalluria and calcium oxalate stones. The hyperoxaluric pig will have great potential in the advancement of many areas of urolithiasis research and in the design of new therapeutic modalities for the treatment of stone disease.