BACKGROUND: Kidney stone disease affects approximately 10% of individuals in their lifetime and is frequently recurrent. The disease is linked to obesity, but the mechanisms mediating this association are uncertain. METHODS: Associations of adiposity and incident kidney stone disease were assessed in the UK Biobank over a mean of 11.6 years/person. Genome-wide association studies and Mendelian randomization (MR) analyses were undertaken in the UK Biobank, FinnGen, and in meta-analysed cohorts to identify factors that affect kidney stone disease risk. RESULTS: Observational analyses on UK Biobank data demonstrated that increasing central and general adiposity are independently associated with incident kidney stone formation. Multivariable MR, using meta-analysed UK Biobank and FinnGen data, established that risk of kidney stone disease increases by ∼22% per one standard deviation increase in body mass index (BMI, a marker of general adiposity) independent of waist-to-hip ratio (WHR, a marker of central adiposity) and per one standard deviation increase of WHR independent of BMI. Genetic analyses indicate that higher WHR, but not higher BMI, increases risk of kidney stone disease by elevating adjusted serum calcium concentrations (β=0.12mmol/L); WHR mediates 14-19% of its effect on kidney stone risk in this way. CONCLUSIONS: Our study indicates that visceral adipose depots elevate serum calcium concentrations, resulting in increased risk of kidney stone disease. These findings highlight the importance of weight loss in individuals with recurrent kidney stones and suggest that therapies targeting adipose depots may affect calcium homeostasis and contribute to prevention of kidney stone disease.
J Am Soc Nephrol