Pathogenesis of Idiopathic Uric Acid Nephrolithiasis and Renal Lipotoxicity

特发性尿酸性肾结石的发病机制与肾脂毒性

• 批准号: 8271447
• 负责人: KHASHAYAR SAKHAEE
• 金额: $ 33.47万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271447
• 关键词: 2,4-thiazolidinedione; Accounting; Acids; Ammonium; Animal Model; Animals; Biochemical; Biochemistry; Buffers; Calculi; Cell Culture System; Cell Culture Techniques; Chemistry; Complex; Crystallization; Data; Defect; Deposition; Diagnosis; Disease; Epidemic; Excision; Excretory function; Fatty acid glycerol esters; Forms Controls; Foundations; Growth; Histologic; Human; Individual; Infiltration; Kidney; Kidney Calculi; Magnetic Resonance Spectroscopy; Measures; Metabolic syndrome; Modeling; Nephrectomy; Nephrolithiasis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Patients; Pioglitazone; Precipitation; Predisposition; Prevalence; Production; Publishing; Risk; Role; Solubility; Specimen; Techniques; Testing; Thiazolidinediones; United States; Urate; Uric Acid; Urine; advanced disease; base; human subject; improved; inhibitor/antagonist; novel; organic acid; promoter; urinary

Project Summary Uric Acid (UA) nephrolithiasis constitutes 8-10% of kidney stones in the United States. Our group has previously characterized several distinct features of idiopathic UA nephrolithiasis (IUAN): (1) The principal underlying abnormality is an unduly acidic urine which increases the risk of UA precipitation. (2) The low urine pH is due to the combined effect of increased net acid excretion (NAE) and reduced ammonium (NH4+) excretion. (3) Patients with type 2 diabetes and/or obesity are at increased risk for IUAN. Our preliminary data suggest that (1) renal fat accumulation (steatosis) occurs in humans, and is associated with low NH4+/NAE, (2) steatosis in an animal model is associated with aciduria and impaired NH4+ excretion, features of IUAN, (3) steatosis in a cell culture model results in lipotoxicity which manifests as reduced NH4+ secretion, and (4) low urinary pH is necessary but not sufficient for UA stone formation, suggesting the presence of unknown promoters or the absence of inhibitors of UA crystallization. We hypothesize that three defects are present in UA stone formers: (1) Steatosis of the kidney which impairs renal NH4+ excretion, resulting in an acidic urine at any given acid load. (2) Increased endogenous organic acid production and NAE. (3) In IUAN patients, the lack of a urinary inhibitor and/or the presence of a promoter may additionally account for UA crystallization. Aim 1 of this proposal will determine the functional consequences of renal steatosis by correlating kidney fat content with urinary acid-base parameters in human subjects and in animal models of generalized and kidney- specific lipotoxicity. Aim 2 will evaluate the outcome of reversing renal steatosis in humans, animals, and cell culture systems. Aim 3 will characterize the urinary physicochemical background accounting for the formation of UA stones in IUAN patients using classical physicochemical techniques. This proposal lays the foundation for the novel concept of renal lipotoxicity, identify its pathophysiologic role in uric acid stone formation, characterize the urinary physicochemical background accounting for the formation of uric acid stones, and open new avenues for improved diagnosis and treatment of uric acid nephrolithiasis.

项目总结