Obesity and the metabolic syndrome have reached epidemic proportions and uric acid stones are a common health care problem in these individuals. The incidence and prevalence of uric acid stones are escalating with time, imparting a significant burden on quality of life and health care cost. While the epidemiologic link between obesity / metabolic syndrome and uric acid stones is irrefutable, the pathophysiologic link has been elusive. The single most important factor driving uric acid precipitation is unduly low urine pH. We have shown that this stems from an intrinsic renal defect in the utilization of ammonia to buffer protons, with unbuffered protons free to titrate urate to insoluble uric acid and initiate te cascade of lithogenesis. We propose to use a combination of cell culture, animal, and human studies employing some of the latest technologies in magnetic resonance spectroscopy and single-photon emission computed tomography, combined with classical physiology, biochemistry, and molecular biology to test four interrelated hypotheses. 1. There is increased uptake of free fatty acids into the kidney as a result of higher circulating levels as well as preferential transport by the proximal tubule as part of a "conditioning" effect. 2. The increased provision of free fatty acid supplies metabolic substrate for ATP generation hence reducing the consumption of other substrates such as glutamine, which is the principal source of ammoniagenesis by the proximal tubule. This substrate competition, or metabolic switch, can lower the formation of the major urinary buffer ammonia, even in the absence of injury to the proximal tubule. 3. With sustained lipid loading of the proximal tubule that exceeds its oxidative capacity, lipid storage is first activated but with time, toxic lipid metabolites may build up. We have evidence that excess saturated fat, which is prevalent in the Western diet, leads to proximal tubule lipotoxicity manifested as endoplasmic reticulum (ER) leakage/stress, and we propose that defective ammoniagenesis is part of a broader lipotoxic phenotype. We further propose that accumulation of a specific lipid species may be responsible for the toxicity. 4. To test whether proximal tubule steatosis and lipotoxicity in humans have a functional consequence, we will study uric acid stone formers. Having previously shown that thiazolidinediones (TZD) reduce renal steatosis and lipotoxicity and improve ammonium excretion in animals, we have initiated a randomized intervention trial with TZD or placebo in human uric acid stone formers. The interim analysis showed that after 6 months of TZD therapy, stone formers had improved urinary biochemical parameters and reduced propensity for uric acid precipitation. We will continue this trial but add a novel highly sensitive method to non-invasively measure renal fat, testing whether improvement in urinary biochemistry associates with reduction of renal fat. This proposal addresses fundamental concepts of renal tubular lipid biology and lipotoxicity, and clinically will shift the paradigm of uric acid stone therapy from empiric urinary alkalinization to specific reduction in renal fat. We will also introduce cutting-edge human imaging studies for kidney research.
Uric acid kidney stones are a common health care problem particularly in individuals who are overweight, which is escalating in incidence and prevalence with time, thereby imposing a significant burden on quality of life and our health care system. A key reason underlying the formation of uric acid stones is excessive acidity in the urine caused by unknown factors, which we aim to uncover and characterize in this proposal by testing the hypothesis that excessive fat enters the kidney of uric acid stone formers and causes a host of deleterious effects including excessively acidic urine. The understanding of these defects will helps us control and even stop the formation of uric acid kidney stones.
|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|
Showing the most recent 10 out of 31 publications