Abstract

OBJECTIVE:: The mechanism explaining the inverse relationship between urinary uric acid and albumin excretion remains unclear. First, we evaluated the impact of candidate SNPs in the urate transporter SLC2A9 gene on the relationship between fractional excretion of uric acid (FEUA) and urinary albumin/creatinine ratio (uACR). Second, we examined urinary uromodulin and sodium excretion as mediators of the relationship between FEUA and uACR. DESIGN AND METHOD:: We analyzed 737 French Canadians from the CARTaGENE cohort, a random sample of the Quebec population aged 40–69 years of 20,004 individuals. French Canadians with available genotyping and urinary data were obtained from a sub-study examining associations between common variants and cardiovascular disease in gender-matched individuals with high and low Framingham Risk Score and vascular rigidity index. We further excluded individuals with an eGFR < 60 ml/min/1.73m2, glycosuria, and use of confounding medication. A spot urine sample was analyzed. Genotyping was performed using the Illumina HumanOmni2.5–8 BeadChips. Two SNPs (rs16890979; rs13129697) were analyzed using an additive model. RESULTS:: Final analyses included 593 individuals (45.5% of men; mean age 54.3 ± 8.6). The rs13129697 G homozygotes within the 1st and 2nd FEUA tertiles had higher estimated mean of uACR compared to those within the 3rd tertile (p = 0.001; p = 0.006, respectively), as well as compared to heterozygotes (p = 0.006; p = 0.005, respectively) and T homozygotes (p = 0.004; p = 0.001, respectively). Contrarily, no difference in uACR by FEUA tertiles was observed in T homozygotes and heterozygotes. In a reference regression model for uACR, an increase in mean blood pressure and plasma glucose, a decrease in FEUA, and female gender were associated with an increase in uACR, whereas carriage of each copy of the rs13129697 T allele was associated with a decrease in uACR. Using the mediation analysis, uromodulin explained 32%, fractional excretion of sodium (FENa) 44%, and uromodulin together with FENa explained 70% of the relationship between FEUA and uACR. Bootstrapping process confirmed the role of both mediators. CONCLUSIONS:: Our data suggest that the relationship of albuminuria with decreased urate excretion may be facilitated by the urate transporter SLC2A9, and mediated by urinary uromodulin, possibly through its effect on sodium reabsorption.