Hyperoxaluria Leading to Tubule Injury and Kidney Stone Disease

描述（由申请人提供）：肾结石疾病是一种严重的健康问题，与严重的疼痛，痛苦和经济成本相关。 5%至15%的人口在70岁时会出现结石症状，其中至少50%的人会复发。迄今为止，尿石症的研究人员一直局限于细胞培养研究或大鼠模型，其中高尿酸是由乙二醇口服给药，这是有毒的多器官或高剂量的腹膜内注射草酸钠诱导。与人类相比，大鼠产生草酸盐结晶和组织或细胞反应所需的诱导尿草酸盐排泄水平被批评为超生理。 我们认为，猪是理想的动物模型，草酸钙晶体和草酸钙结石病的发展。猪肾脏的解剖和生理结构与人类非常相似。厌氧细菌Oxalactiniformigenes在猪肠中将草酸盐降解为甲酸盐，通常会阻止猪患高尿酸症。我们已经成功地获得了无草酸杆菌的猪，并在此首次报道，这些猪表现出尿草酸排泄的显著增加，这是由于口服草酸负荷与富含草酸的人类饮食所经历的类似。我们建议通过给猪喂食富含草酸盐的饮食来诱导高尿酸血症。我们拟研究高尿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，猪喂草酸盐将形成草酸钙结晶和草酸钙结石在他们的尿路中的方式非常相似的man. We还假设，这些高尿酸的猪是理想的适合高尿酸对肾上皮细胞生理学，晶体附着和结石成熟的影响的研究扩展。本基金建议书包含三个具体目标来验证我们的假设：具体目标I：开发一种新的高尿酸猪动物模型;具体目标II：在猪中引发草酸钙晶体形成并确定晶体附着沿着肾单位的位置;具体目标III：在猪中诱导草酸钙结石病并表征结石成熟的过程。 这些特定目的及其相关问题将使我们能够充分描述猪高尿酸的发展以及草酸钙晶体和草酸钙结石的发展。高尿酸猪将在尿石症研究的许多领域的进步和结石病治疗的新治疗方式的设计方面具有巨大的潜力。

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.