Kidney function decline and kidney stone risk: cohort and Mendelian randomization analyses

To investigate the association and potential causal effect of kidney function decline on kidney stone disease (KSD).

We evaluated linear and non-linear associations between kidney function decline-assessed by estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD)-and KSD using individual-level data from the UK Biobank and summary genome-wide association study (GWAS) data. Analyses included prospective cohort models, one-sample Mendelian randomization (MR), two-sample MR, genetic correlation analyses, and identification of shared single-nucleotide polymorphisms (SNPs).

Individuals with lower baseline eGFR_cys had an increased risk of KSD during a mean follow-up of 13.9 years. However, longitudinal decline in eGFR over time (ΔeGFR_cys) was associated with a reduced risk of KSD (HR 0.80, 95% CI 0.67-0.95). Mendelian randomization analyses showed that genetically predicted lower eGFR (one-sample: OR 0.70, 95% CI 0.63-0.78; two-sample: OR 0.78, 95% CI 0.71-0.85) and CKD (one-sample: OR 0.73, 95% CI 0.65-0.81; two-sample: OR 0.89, 95% CI 0.83-0.97) were associated with a lower risk of KSD. Genetic correlation analyses suggested shared genetic influences between kidney function traits and KSD (eGFR: r_g = 0.11; CKD: r_g = -0.11). Several shared loci related to calcium homeostasis were identified.

Kidney function decline appears to be associated with a reduced risk of KSD. Combined observational and genetic analyses support shared biological pathways linking these conditions, although further studies are needed to clarify the underlying mechanisms.