This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this project is to elucidate pathophysiologic basis of gouty diathesis and uric acid nephrolithiasis. Gouty diathesis is a descriptive term applied to a syndrome characterized by uric acid nephrolithiasis, varying degrees of renal uric acid retention, and dyslipidemia. Uric acid precipitation in the urine is secondary to acidic urine pH, which renders the uric acid insoluble but the cause of the acidic urine pH is unknown. We have shown that the acidic urine pH is secondary to defects in urinary ammonium excretion' the major urinary buffer. Furthermore, the reduced urinary ammonium can be correlated with the degree of peripheral insulin resistance. The study hypothesis: That a manifestation of insulin resistance in the kidney is impaired ammonium excretion. The reduction of urinary ammonium excretion can be due to decreased insulin action on the kidney per se or secondary to the elevated free fatty acid levels associated with insulin resistance. although the reduced ammonium excretion is insufficient to disturb acid-base balance, it is sufficient to lower urinary pH and cause uric acid precipitation. This 'renal insulin resistance' is part of the syndrome of gouty diathesis and contributes directly to uric acid precipitation.
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