The Effect of Gastric Bypass Surgery on Renal Function and Metabolism

说明(申请人提供)：由于促炎介质的循环和潜在的肾脏代谢和血流动力学障碍，包括肾小球高滤过，肥胖患者患肾脏疾病的风险增加。这些患者还具有不利的致石尿代谢谱，如尿液低pH值、低柠檬酸尿、高尿酸尿，这些都是他们容易患肾结石的原因。胃手术，特别是Roux-en-Y胃分流术(RYGB)，作为促进这一人群减肥的一种介入性策略正在增加。尽管从理论上讲，RYGB患者在控制血糖和高血压的体重过程中获得了肾脏优势，但高达75%的RYGB患者会在术后出现持续性的高草酸尿，部分患者会出现肾结石、肾钙沉着、肾功能受损，甚至由于草酸盐肾病而导致的肾功能衰竭。目前，这些不良肾脏事件背后的机制尚不清楚。 RYGB手术肥胖大鼠模型的初步数据表明，与假手术或配对喂养的肥胖对照组相比，胃旁路手术导致更多的肾小球损伤、间质巨噬细胞迁移、骨桥蛋白产生增加。因此，我们假设肥胖是一个低级别的炎症过程，它放大了肾脏宿主对RYGB相关的高草酸尿的反应。在这种情况下，肾小球细胞、间质细胞和乳头细胞长期暴露在大量草酸和/或草酸钙晶体中，导致活性氧的产生，氧化应激，肾脏损伤和炎症。此应用程序的目的是为首席研究人员提供一个培训环境，以检查RYGB相关的高草酸尿在肾损伤和肾结石发生中的作用，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。我们的具体目标是：1)通过比较饮食诱导的肥胖啮齿动物模型和对照组的代谢谱、促炎介质、组织学、蛋白质表达和通路集中的基因表达谱，进一步确定RYGB手术对肾脏的影响；2)通过研究肠道草酸盐处理的分段差异以及草酸杆菌定植对尿草酸水平的影响，进一步了解RYGB诱导的高草酸尿；3)比较有和没有Randall斑块沉积的人RYGB结石患者肾乳头状尖端的蛋白质和基因表达谱。了解RYGB后高草酸尿症的机制将有助于深入了解肥胖相关草酸肾结石的发病机制。我的K08计划是为了让我进一步探索肥胖的相关啮齿动物模型，验证最近的少数人补充剂奖产生的初步假设，增强我对草酸在肠道和肾脏内运输的理解，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胃分流术(RYGB)的病态肥胖患者可能会发展为术后持续的高草酸尿，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，甚至草酸肾病导致的肾功能衰竭。此应用程序的目标是为候选人建立一个动物模型，以探索RYGB相关的高草酸尿在肾脏损伤和肾结石发展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。作为一名注册的泌尿外科医生，在泌尿系结石疾病方面有着良好的发表记录，候选人接受过专业培训，以开发结石疾病和肾脏新陈代谢的外科模型，他的K08计划的结构允许他进一步探索肥胖的相关大鼠模型，验证最近的少数族裔补充剂奖产生的初步假设，以增强他对草酸在肠道和肾脏内转运的理解，并将这些努力转化为人类肾脏组织内的疾病机制。

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.