The pathogenesis of aciduria in uric acid nephrolithiasis is driven by excessive acid delivery to the kidney and impaired ability of the kidney to buffer the acid jointly cumulating in excessively low urine pH. The underlying pathobiology stems from hepatic and renal steatosis and lipotoxicity. The liver is unable to metabolize fatty acids and in fact adds fatty acids to the circulation. The kidney is handicapped in making its major urinary buffer of H+, ammonia. The combination of this hepatic-renal defect generates and amplifies the aciduria which is the prerequisite in uric acid lithogenesis. Both of the hepatic and renal lesions involve the PPARγ pathways as they are partially alleviated by activators of PPARγ in both animals and humans.