Background: Uric acid (UA) nephrolithiasis affects approximately 10% of kidney stones, with a greater preponderance among patients with obesity and diabetes mellitus. UA lithogenicity is driven by abnormally acidic urine pH. Distinguishing the contribution of intrinsic (e.g., body adiposity) versus external (e.g., dietary) factors to UA stone propensity is challenging due to uncontrolled diets in outpatients in previously published studies. Methods: This compilation of metabolic studies with body composition examined by dual-energy X-ray absorptiometry (DXA) scan, and blood and urine biochemistry collected under a controlled metabolic diet was conducted across three distinct populations: 74 UA stone formers (UASF group), 13 patients with type 2 diabetes mellitus without kidney stones (DM group), and 51 healthy volunteers (HV group). Results: Compared to HV, both UASF and DM exhibited higher levels of net acid excretion (NAE), and significantly lower urine pH and lower proportion of NAE excreted as ammonium (NH4 +/NAE), all under controlled diets. UASF exhibited significantly lower NH4 +/NAE compared with DM. UASFs also showed higher total body and truncal fat compared to controls. Among the HV, lower NH4 +/NAE ratio correlated with higher truncal and total fat. However, this association was abolished in the UASF and DM groups who exhibit a fixed low NH4 +/NAE ratio across a range of body and truncal fat. Conclusion: The findings suggest a dual defect of diet-independent increase in acid production and impaired kidney NH4 + excretion as major contributors to the risk for uric acid stone formation. There is an inverse physiologic association between body fat content and NH4 +/NAE in HV while NH4 +/NAE is persistently low in UASF and DM regardless of body fat representing pathophysiology.