Metabolic dysfunction-associated fatty liver disease as a mediator of urolithiasis risk: evidence from...

Introduction: The rising prevalence of urolithiasis and metabolic dysfunction-associated fatty liver disease (MAFLD) has become a significant concern within urology and hepatology, respectively. Emerging studies reveal a compelling association between these conditions, yet the underlying relationship remains poorly understood. This study aims to investigate the connection between urolithiasis and MAFLD within the Chinese population and leverages Mendelian Randomization (MR) analysis to explore potential causal links between the two diseases, shedding light on new avenues for both prevention and treatment. Methods: This cross-sectional study included 98,232 Chinese participants and employed logistic regression models and subgroup analyses to assess the association between MAFLD and urolithiasis. For the MR analysis, genetic instruments from genome-wide association studies served as instrumental variables. Bidirectional MR was conducted to investigate the potential causal relationship between genetically predicted MAFLD and urolithiasis. Additionally, multivariable MR and mediation analysis were used to assess both the direct effect of MAFLD on urolithiasis and any mediating pathways involved. Results: In a cohort of 98,232 Chinese participants, 10.1% (9,928) had urolithiasis, and 26.7% (26,217) had MAFLD. MAFLD was positively associated with urolithiasis, with an unadjusted odds ratio (OR) of 1.563 (95% CI, 1.495-1.633), an adjusted OR in model 1 of 1.204 (95% CI, 1.146-1.265), and an adjusted OR in model 2 of 1.137 (95% CI, 1.079-1.199). Subgroup analysis showed consistent associations across most subgroups, except for a significant interaction between MAFLD and triglyceride (TG) levels (p for interaction < 0.05). Bidirectional MR analysis suggested that genetically predicted MAFLD increased the risk of urinary stone disease, while no significant causal effect was observed from urolithiasis to MAFLD. Furthermore, multivariable MR and mediation analyses highlighted MAFLD as a key mediator in kidney stone formation driven by obesity and type 2 diabetes. Conclusions: This study demonstrates a causal link between MAFLD and an increased risk of urolithiasis, supported by both epidemiological and genetic evidence. Furthermore, MAFLD serves as a significant mediator in the pathway from obesity and type 2 diabetes to urolithiasis development.