The Effect of Gastric Bypass Surgery on Renal Function and Metabolism

胃绕道手术对肾功能和代谢的影响

• 批准号: 8631157
• 负责人: Benjamin K Canales
• 金额: $ 0.11万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-23 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631157
• 关键词: Acute; Adverse effects; Affect; Animal Model; Area; Award; Bacteria; Basic Science; Blood Circulation; Body Weight decreased; Bypass; Calcium Oxalate; Calculi; Cardiovascular system; Cells; Chronic Kidney Failure; Clinical Investigator Award; Clinical Sciences; Colon; Comorbidity; Data; Deposition; Development; Diabetes Mellitus; Diet; Disease; End stage renal failure; Enteral; Environment; Event; Excretory function; Failure; Fibrosis; Functional disorder; Gastric Bypass; Gene Expression; Genomics; Goals; Histology; Human; Hyperoxaluria; Hypertension; Immune response; Impaired Renal Function; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Intervention; Intestinal Bypasses; Intestines; Kidney; Kidney Calculi; Kidney Diseases; Kidney Failure; Learning; Literature; Long-Term Effects; Malabsorption Syndromes; Metabolic; Metabolism; Minority; Modeling; Molecular; Molecular Profiling; Nature; Nephrocalcinosis; Nephrolithiasis; Obesity; Operative Surgical Procedures; Oxalates; Oxalobacter; Oxidative Stress; Papillary; Pathogenesis; Pathway interactions; Patients; Pattern; Permeability; Physiology; Population; Postoperative Period; Principal Investigator; Process; Production; Proteomics; Publications; Rattus; Reactive Oxygen Species; Renal Tissue; Renal function; Reporting; Risk; Rodent Model; Role; Sleep Apnea Syndromes; Small Intestines; Solubility; Stomach; Structure; Surgical Models; Technology; Time; TimeLine; Tissues; Training; Translating; Urologic Surgeon; absorption; bariatric surgery; body system; collecting tubule structure; feeding; glycemic control; hemodynamics; human data; hypertension control; improved; insight; interstitial; kidney metabolism; macrophage; medical complication; migration; operation; osteopontin; protein expression; public health relevance; sham surgery; urinary; urologic

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.

描述（由申请人提供）：肥胖患者由于促炎性介质的循环以及潜在的肾脏代谢和血液动力学障碍（包括肾小球过滤）而患肾脏疾病的风险增加。这些患者还具有不利的岩性泌尿代谢特征，例如低尿液pH值，低尿性，高尿尿液，使它们容易患上肾脏石头疾病。胃部操作，尤其是Roux-en-Y-Gastric旁路（RYGB），它是一种介入的策略，以促进该人群的体重减轻。尽管在血糖和高血压控制的体重减轻期间获得了理论上的肾脏优势，但多达75％的RYGB患者将在术后持续持续性高氧化脂蛋白，并且子集将发展肾脏结石，肾上腺素病，肾功能受损，肾功能受损，甚至是由于肾上腺素肾上腺素而导致的肾衰竭。当前，这些不良肾脏事件背后的机制尚不清楚。 来自肥胖大鼠RYGB手术模型的初步数据表明，胃旁路会导致更多的肾小球损伤，间质巨噬细胞迁移，骨桥蛋白的产生增加，而不是假手术或配对的肥胖对照。因此，我们假设肥胖症是一种低级炎症过程，可以扩增肾脏对RYGB相关的高氧尿症的肾脏反应。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，肾脏损伤和炎症。该应用的目的是为主要研究者提供一个训练环境，以检查与RYGB相关的高氧核酸盐在肾脏损伤和肾石石症发展中的作用，并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。我们的具体目的是：1）通过比较代谢谱，促炎性介体，组织学，蛋白质表达和以途径为中心的基因表达谱，进一步表征了RYGB手术在饮食引起的肥胖啮齿动物模型与对照中的肾脏影响； 2）通过研究肠道肠道处理的节段差异以及草杆菌定殖对草酸尿液水平的影响，我们对RYGB诱导的高黄油尿症的理解； 3）比较有或没有兰德尔的斑块沉积的人类rygb石材形成器的肾乳头状尖端的蛋白质和基因表达谱。了解RYGB后高氧化尿液的机制将提供有关与肥胖相关的草酸根肾石岩症发病机理的见解。我的K08计划的结构是使我能够进一步探索肥胖的相关啮齿动物模型，以验证最近的少数族裔补充剂奖所产生的初步假设，以增强我对肠道和肾脏中草酸盐的理解，然后将这些努力转化为人类肾脏组织内疾病机制。