Kidney function may partially mediated the protective effect of urinary uromodulin on kidney stone.

The causal links between urinary uromodulin (uUMOD) and kidney stone disease (KSD) are still not clarified in general population. We assessed their relationships combining 2-sample Mendelian randomization (MR) and multivariable (MVMR) designs among general population of European ancestry. The summary information for uUMOD indexed to creatinine levels (29,315 individuals) and KSD (395,044 individuals) were from 2 independent genome-wide association studies (GWAS). The primary causal effects of exposures on outcomes were evaluated using inverse variance-weighted (IVW) regression model. Multiple sensitivity analyses were also performed. In 2-sample MR, we found that 1-unit higher genetically predicted uUMOD levels were associated with a lower risk of KSD (OR = 0.62; 95% CI 0.55-0.71; P = 2.83E-13). In reverse, we did not find the effect of KSD on uUOMD using IVW (beta = 0.00; 95% CI - 0.06-0.05; P = 0.872) and other sensitivity analyses. In MVMR, uUMOD indexed to creatinine levels were directly associated with the risk of KSD after introducing eGFR, SBP, urinary sodium or all three factors (OR = 0.71; 95% CI 0.64-0.79; P = 1.57E-09). Furthermore, our study supported that the protective effect of uUMOD on KSD may be partially mediated by eGFR (beta = - 0.09; 95% CI - 0.13 to - 0.06; mediation proportion = 20%). Our study supported that the protective effect of genetically predicted higher uUMOD levels on KSD may be partially mediated by eGFR decline, but not via SBP or urinary sodium. uUMOD might be a treatment target in preventing KSD in general population.