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: 8536270
• 负责人: Benjamin K Canales
• 金额: $ 14.35万
• 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/8536270
• 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）：由于促炎介质的循环和潜在的肾脏代谢和血流动力学紊乱，包括肾小球高滤过，肥胖患者患肾脏疾病的风险增加。这些患者也有不利的尿代谢特征，如尿pH值低、低尿量、高尿量，使他们易患肾结石。胃手术，特别是roux -en- y胃旁路手术（RYGB），越来越多地作为一种介入性策略来促进这类人群的减肥。尽管理论上在减肥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患者术后会出现持续的高草酸尿症，一部分患者会出现肾结石、肾钙化症、肾功能受损，甚至由于草酸肾病而导致肾功能衰竭。目前，这些不良肾脏事件背后的机制尚不清楚。