Nonsteroidal anti-inflammatory drugs, blood metabolites, and kidney stones: a comprehensive Mendelian randomization study.

Abstract

It remains unclear for the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on kidney stones. This study aimed to investigate the causal relationship between NSAIDs medication usage and the risk of kidney stones, and further determine whether blood metabolites mediate this association. We conducted a two-sample Mendelian randomization (MR) analysis using genetic data from the FinnGen consortium to explore the causal impact of NSAIDs medication usage on kidney stone formation. Furthermore, a two-step MR analysis was performed to assess whether blood metabolites significantly mediate the effects of NSAIDs on kidney stone risk. Genetic variants associated with NSAIDs medication usage or blood metabolites were employed as instrumental variables. The inverse variance weighted (IVW) method serves as the primary analytical approach to assess the causal relationship. We found that NSAIDs usage was causally associated with an increased risk of kidney stones (OR: 1.70, 95% CI: 1.33-2.16, P < 0.001). Additionally, we revealed that the risk of kidney stones was causally affected by 67 blood metabolites, among which NSAIDs usage was causally associated with three metabolites, including β-hydroxyisovaleroylcarnitine level, Mannose level, and Deoxycholic acid 12-sulfate. Furthermore, mediation analysis revealed that β-hydroxyisovaleroylcarnitine partially mediated the effect of NSAIDs usage on kidney stones, accounting for approximately 5.6%. Our study suggests a potentially causal association between NSAIDs medication usage and an increased risk of kidney stones, with blood metabolites possibly mediating this effect. These insights underline the necessity of monitoring blood metabolite levels during NSAIDs therapy, especially in patients at risk for kidney stones. However, further studies are required to validate these findings.