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.

Public Health Relevance

Uric acid stone disease is strongly associated with obesity and type 2 diabetes, and its prevalence may increase in parallel with the obesity epidemic. This proposal lays the foundation for the novel concept of renal lipotoxicity (fat accumulation within the kidney), 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK081423-04
Application #
8271447
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Kirkali, Ziya
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$334,680
Indirect Cost
$121,508
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Doizi, Steeve; Rodgers, Kathy; Poindexter, John et al. (2016) Assessment of Urinary Inhibitor or Promoter Activity in Uric Acid Nephrolithiasis. J Urol 195:1799-804
Sakhaee, Khashayar; Poindexter, John; Aguirre, Crystal (2016) The effects of bariatric surgery on bone and nephrolithiasis. Bone 84:1-8
Zhang, Dihua; Bobulescu, I Alexandru; Maalouf, Naim M et al. (2015) Relationship between serum uric Acid and bone mineral density in the general population and in rats with experimental hyperuricemia. J Bone Miner Res 30:992-9
Smith, Cynthia R; Poindexter, John R; Meegan, Jennifer M et al. (2014) Pathophysiological and physicochemical basis of ammonium urate stone formation in dolphins. J Urol 192:260-6
Pigna, Federica; Sakhaee, Khashayar; Adams-Huet, Beverley et al. (2014) Body fat content and distribution and urinary risk factors for nephrolithiasis. Clin J Am Soc Nephrol 9:159-65
Curthoys, Norman P; Moe, Orson W (2014) Proximal tubule function and response to acidosis. Clin J Am Soc Nephrol 9:1627-38
Sakhaee, Khashayar (2014) Epidemiology and clinical pathophysiology of uric acid kidney stones. J Nephrol 27:241-5
Bobulescu, Ion Alexandru; Lotan, Yair; Zhang, Jianning et al. (2014) Triglycerides in the human kidney cortex: relationship with body size. PLoS One 9:e101285
Bobulescu, I Alexandru; Maalouf, Naim M; Capolongo, Giovanna et al. (2013) Renal ammonium excretion after an acute acid load: blunted response in uric acid stone formers but not in patients with type 2 diabetes. Am J Physiol Renal Physiol 305:F1498-503
Yoon, Vivienne; Adams-Huet, Beverley; Sakhaee, Khashayar et al. (2013) Hyperinsulinemia and urinary calcium excretion in calcium stone formers with idiopathic hypercalciuria. J Clin Endocrinol Metab 98:2589-94

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