Hepatic Steatosis and Elevated Acid Load in Uric Acid Stone Formers: Evidence for a Hepato-Renal Axis

Background: Uric acid (UA) nephrolithiasis is characterized by persistently elevated net acid excretion (NAE) and low urine pH and seen mostly in individuals with obesity and metabolic syndrome. While the mechanisms underlying this aciduria remain incompletely understood, hepatic steatosis and elevated concentration of circulating free fatty acids (FFAs) have been suggested as potential contributors. Methods: Twenty-one UASF and eighteen matched non-stone formers (NSF) were placed under a fixed 5-day metabolic diet. 24-hour urine and fasting blood samples were collected. Hepatic fat content was quantified by magnetic resonance imaging. Results: UASF and NSF were comparable in age, sex, and body mass index. Compared to NSF, UASF exhibited significantly lower 24-hour urine pH (5.4 vs. 6.0, p<0.001), higher NAE, and a lower fraction of NAE excreted as ammonium (NH4+/NAE: 0.71 vs. 0.89, p=0.008). Hepatic fat content was markedly higher in UASF (12.9% vs. 3.7%, p<0.001) and positively correlated with NAE (r = 0.48, p = 0.04). Serum FFA was higher in UASF (0.71 vs. 0.57 mEq/L) and positively correlated with liver fat in UASF. The association between liver fat and NAE was attenuated after adjusting for serum FFAs (p = 0.07). Conclusion: This is the first study to implicate hepatic steatosis in the pathogenesis of UA nephrolithiasis. The strong association between liver fat and NAE suggests that hepatic steatosis contributes to the aciduria in UASF. Elevated FFAs, a hallmark of hepatic and visceral adiposity, at least in part contribute to hepatic steatosis and the greater NAE , possibly by promoting a metabolic substrate shift from amino acids to fatty acids, which could enhance organic acid generation but also impair renal ammoniagenesis by limiting amino acid availability. These findings support the presence of a hepato-renal metabolic axis in UA stone disease, in which hepatic steatosis and FFA-driven metabolic dysfunction contribute to persistent aciduria and UA stone formation. Funding: NIDDK Support