Genetically predicted urinary sodium excretion and urolithiasis risk: a two-sample mendelian randomization study

High sodium intake has been linked to kidney stone formation in many observational studies, but these findings may be influenced by dietary habits and fluid intake. Whether urinary sodium itself plays a causal role in urolithiasis remains unclear.

We performed a two-sample Mendelian randomization analysis to examine the association between urinary sodium excretion and urolithiasis risk. Genetic instruments for urinary sodium were obtained from large genome-wide association studies based on the UK Biobank and EBI databases (N > 300,000). Summary statistics for urolithiasis were derived from the FinnGen R12 dataset. The primary analysis was conducted using the inverse variance weighted method, with additional sensitivity analyses including MR-Egger, weighted median, and MR-PRESSO.

Higher genetically predicted urinary sodium excretion was associated with an increased risk of urolithiasis (IVW OR = 2.49, 95% CI: 1.45-4.29, P= 0.00099). Similar results were observed in an independent replication dataset (OR = 2.66, 95% CI: 1.39-5.07, P= 0.0029). There was no evidence of horizontal pleiotropy (MR-Egger intercept P= 0.523), and heterogeneity was low. MR-PRESSO did not detect any significant outliers.

Our findings provide supportive genetic evidence suggesting that higher urinary sodium excretion may contribute to an increased risk of urolithiasis. These results align with current recommendations for dietary sodium restriction in stone prevention.