Is uric acid excretion a possible cause of kidney damage? A cross-sectional study of CHARLS and CHNS with Mendelian randomization verification.

BACKGROUND AND OBJECTIVES: To explore whether uric acid excretion (UAE) causes kidney damage. MATERIALS AND METHODS: Cross-sectional analyses were conducted using the China Health and Retirement Longitudinal Study (CHARLS), with external validation in the China Health and Nutrition Survey (CHNS). The relationship between fractional excretion of uric acid (FEUA) and estimated glomerular filtration rate (eGFR) decline was assessed using univariate and multivariate logistic regression analysis. Six sets of TSMR analyses were performed for verification using FEUA, Urinary uric acid clearance (UACL), renal-under-excretive and renal-overload type gout, SLC2A9 increase, SLC22A11 decrease related single-nucleotide polymorphisms (SNPs). Cochran's Q test, MR-Egger intercept, power calculation, and sample overlap analysis were performed. RESULTS: Logistic regression analysis revealed that FEUA was significantly, independently associated with eGFR decline adjusting for confounders (OR=1.218, 95%CI: 1.176∼1.262, P<0.001). FEUA decrease was causally associated with eGFR increase (Wald Ratio method: β = 0.003, 95% CI: 0.002∼0.004, P= 1.456E-8). UACL increase achieved a borderline causality with eGFR decline (IVW method: β = -0.545, 95% CI: -1.095∼0.005, P= 0.052). SLC2A9 increase was causally associated with eGFR decline (Wald Ratio method: β = -0.007, 95% CI: -0.008∼-0.006, P= 2.754E-4). SLC22A11 decrease was causally associated with eGFR increase (Wald Ratio method: β = 0.005, 95% CI: 0.004∼0.006, P= 0.018). CONCLUSIONS: This study demonstrated that FEUA is positively associated with eGFR decline and a greater UAE burden harms the kidney, whereas an increase in renal UA excretory ability protects it, underscoring the importance of early detection of FEUA or UACL or renal UA transporters capacity to benefit kidney protection in people prone to kidney damage.