The Effect of Gastric Bypass Surgery on Renal Function and Metabolism

描述（由申请方提供）：由于促炎介质的循环以及潜在的肾脏代谢和血流动力学紊乱，包括肾小球超滤，肥胖患者的肾脏疾病风险增加。这些患者还具有不利的致石性尿代谢特征，例如低尿pH、低柠檬酸尿、高尿酸尿，这使他们易于患肾结石疾病。胃手术，特别是Roux-en-Y-胃旁路术（RYGB），作为一种干预策略正在增加，以促进该人群的体重减轻。尽管理论上在体重减轻过程中获得了控制血糖和高血压的肾脏优势，但高达75%的RYGB患者术后将发展为持续性高尿症，并且一个子集将发展为肾结石、肾钙质沉着症、肾功能受损或甚至由于草酸盐肾病导致的肾衰竭。目前，这些不良肾脏事件背后的机制尚不清楚。 来自RYGB手术的肥胖大鼠模型的初步数据表明，胃旁路术比假手术或成对喂养的肥胖对照组引起更多的肾小球损伤、间质巨噬细胞迁移、骨桥蛋白产生增加。因此，我们假设肥胖是一种低度炎症过程，它放大了肾脏宿主对RYGB相关高尿酸的反应。在这种情况下，肾小球、间质和乳头状细胞长期暴露于大量草酸盐和/或草酸钙晶体，导致产生活性氧、氧化应激、肾损伤和炎症。本申请的目的是为主要研究者提供一个培训环境，以检查RYGB相关高尿酸在肾损伤和肾结石发生中的作用，特别关注肾组织学、转运生理学、组织蛋白质组学和基因组学。我们的具体目标是：1）通过比较代谢谱、促炎介质、组织学、蛋白质表达和聚焦于通路的基因表达谱，进一步表征RYGB手术在饮食诱导的肥胖啮齿动物模型与对照中的肾效应; 2）通过研究肠草酸盐处理的节段性差异和草酸盐定殖对尿草酸盐水平的影响，进一步理解RYGB诱导的高尿酸; 3）比较有和无Randall斑块沉积的人RYGB结石形成者肾乳头尖端的蛋白质和基因表达谱。了解RYGB后高尿酸的机制将有助于了解与肥胖相关的草酸盐肾结石的发病机制。我的K 08计划旨在让我进一步探索肥胖的相关啮齿动物模型，验证最近少数补充奖产生的初步假设，增强我对肠道和肾脏内草酸盐转运的理解，然后，最重要的是，将这些努力转化为人类肾脏组织内的疾病机制。 公共卫生相关性：接受Roux en Y胃旁路术（RYGB）的病态肥胖患者可能会发生持续的术后高尿酸血症，导致肾结石、肾功能受损，肾集合管内草酸钙沉积与炎症和纤维化相关，甚至因草酸盐肾病导致肾衰竭。本申请的目的是为候选人建立一个培训环境，以开发一种动物模型，探索RYGB相关高尿酸在肾损伤和肾结石发生中的肠道和肾脏机制，特别关注肾脏组织学、运输生理学、组织蛋白质组学和基因组学。作为一名在泌尿系结石疾病方面有着良好出版记录的泌尿外科医生，候选人接受了专业培训，以开发结石疾病和肾代谢的手术模型，他的K 08计划旨在让他进一步探索肥胖的相关大鼠模型，以验证最近少数补充奖产生的初步假设，以提高他对肠道和肾脏内草酸盐转运的理解，并将这些努力转化为人类肾脏组织内疾病的机制。

DESCRIPTION (provided by applicant): Obese patients are at increased risk for kidney disease due to circulation of pro-inflammatory mediators and underlying renal metabolic and hemodynamic disturbances, including glomerular hyperfiltration. These patients also have unfavorable lithogenic urinary metabolic profiles, such as low urinary pH, hypocitrituria, hyperuricosuria, that predispose them to kidney stone disease. Gastric operations, in particular Roux-en-Y-gastric bypass (RYGB), are increasing as an interventional strategy to facilitate weight loss in this population. Despite the theoretical renal advantages gained during weight loss for glycemic and hypertension control, up to 75% of RYGB patients will develop sustained hyperoxaluria post-operatively, and a subset will develop kidney stones, nephrocalcinosis, impaired renal function, or even renal failure due to oxalate nephropathy. Currently, the mechanisms behind these adverse renal events are unknown. Preliminary data from an obese rat model of RYGB surgery indicates that gastric bypass causes more glomerular injury, interstitial macrophage migration, increased osteopontin production than sham surgery or pair-fed obese controls. Therefore, we hypothesize that obesity is a low-grade inflammatory process that amplifies renal host responses to RYGB-associated hyperoxaluria. In this setting, glomerular, interstitial, and papillary cells are chronically exposed to high amounts of oxalate and/or calcium oxalate crystals, leading to the production of reactive oxygen species, oxidative stress, renal injury, and inflammation. The objective of this application is to provide a training environment for the principal investigator to examine the role of RYGB-associated hyperoxaluria in the development of renal injury and nephrolithiasis, with special focus on renal histology, transport physiology, tissue proteomics, and genomics. Our specific aims are: 1) To further characterize renal effects of RYGB surgery in a diet-induced obese rodent model versus controls by comparing metabolic profiles, pro-inflammatory mediators, histology, protein expression, and pathway-focused gene expression profiles; 2) To further our understanding of RYGB induced hyperoxaluria by investigating segmental differences in intestinal oxalate handling and the effect of Oxalobacter colonization on urinary oxalate levels; 3) To compare protein and gene expression profiles from renal papillary tips of human RYGB stone formers with and without Randall's plaque deposition. Understanding the mechanisms of hyperoxaluria following RYGB will provide insights into the pathogenesis of oxalate nephrolithiasis associated with obesity. My K08 program is structured to allow me to further explore relevant rodent models of obesity, to validate preliminary hypothesis generated by a recent minority supplement award, to enhance my understanding of oxalate transport within the gut and kidney, and then, most importantly, translate these efforts into mechanisms of disease within human renal tissue. PUBLIC HEALTH RELEVANCE: Morbidly obese patients who undergo Roux en Y gastric bypass (RYGB) may develop sustained post-operative hyperoxaluria that leads to kidney stones, impaired renal function with calcium oxalate deposition within kidney collecting ducts associated with inflammation and fibrosis, or even renal failure due to oxalate nephropathy. The objective of this application is the establishment of a training environment for the candidate to develop an animal model that explores gut and renal mechanisms of RYGB-associated hyperoxaluria in the development of renal injury and nephrolithiasis, with special focus on renal histology, transport physiology, tissue proteomics, and genomics. As a boarded urologic surgeon with a strong track record of publications in urologic stone disease, the candidate is professionally trained to develop a surgical model of stone disease and renal metabolism, and his K08 program is structured to allow him to further explore relevant rat models of obesity, to validate preliminary hypothesis generated by a recent minority supplement award, to enhance his understanding of oxalate transport within the gut and kidney, and to translate these efforts into mechanisms of disease within human renal tissue.