Acute Effect of High Fat Intake on Urinary Acidification Parameters in Uric Acid Stone Formers and Non-stone Forming Controls

Background: The prevalence of uric acid nephrolithiasis (UAN) has increased contemporaneously with obesity and metabolic syndrome in recent decades. The key pathogenic factor in UAN is acidic urine pH (< 5.5), which results from reduced buffering of H+ by ammonia (NH3 + H+ → NH4+). Ammoniagenesis by the renal proximal tubule (PT) consumes amino acids and generates ATP. In this study, we tested whether provision of free fatty acid (FFA) as an alternative energy (ATP) precursor impairs renal ammoniagenesis in uric acid stone formers (UASF) and controls (Ctrl) by substrate competition. Methods: Seven UASF and eight BMI-matched Ctrl were equilibrated on a fixed metabolic diet for 4 days. After sampling fasting urine and blood, subjects received an oral fat load (heavy cream 0.50 ml/kg body weight) hourly for 10 hours. Blood and urine samples were collected every 2 hours during this period. Outcomes: urine acid-base parameters and blood FFA and ketone bodies (KB). Results: Both groups showed significant and similar increases in serum FFA and KB following the fat load. Urine pH (UpH) progressively decreased from 6.6 to 5.6 in the Ctrl group over the 10-hour period (p < 0.001), while UpH started lower (5.3) in the UASF group and remained unchanged over 10 hrs (p=0.59). While the fraction of net acid excretion (NAE) in the form of ammonium (NH4+) (NH4+/NAE) was notably lower in fasting urine in the UASF group compared to Ctrl (p = 0.002), this ratio significantly decreased in both groups during the 10-hour fat load (Ctrl: p < 0.001; UASF: p = 0.01). Conclusion: Acute elevation in serum FFA by an oral fat load leads to a reduction in urine pH and NH4+/NAE in Ctrl, to levels comparable to UASF. These findings are compatible with a substrate switch, whereby high FFA provision in UASF reduces amino acid metabolism and nitrogen provision for ammoniagenesis, resulting in aciduria and predisposition to UAN. Funding: NIDDK Support, Private Foundation Support