Associations between smoke exposure and kidney stones: results from the NHANES (2007–2018) and Mendelian randomization analysis

PURPOSE: It is currently controversial whether smoke exposure is associated with the risk of kidney stones. Herein, publicly available databases were combined to explore relationships with the risk of nephrolithiasis in terms of smoking status and serum cotinine concentrations. MATERIALS AND METHODS: First, we conducted an observational study using data from 2007 to 2018, based on the National Health and Nutrition Examination Survey (NHANES) database. Univariate analysis, multivariate logistic regression, trend testing, restricted cubic spline (RCS), and multiple imputation (MI) were the main analytical methods of our study. Then, A Mendelian randomization (MR) analysis was performed to explore the causal relationship between serum cotinine and nephrolithiasis. Genetic instruments for serum cotinine and pooled data for kidney stones were derived from publicly available large-scale genome-wide association studies (GWAS). Inverse-variance weighting (IVW) was the primary method for our MR analysis. RESULTS: A total of 34,657 and 31,352 participants were included in the observational study based on smoking status and serum cotinine concentrations, respectively. Under full adjustment of covariates, current smokers had an increased risk of kidney stones compared to non-smokers [OR = 1.17 (1.04–1.31), P = 0.009, P for trend = 0.010]. Compared with serum cotinine of <0.05 ng/ml, serum cotinine levels of 0.05–2.99 ng/ml [OR = 1.15 (1.03–1.29), P = 0.013] and ≥3.00 ng/ml [OR = 1.22 (1.10–1.37), P < 0.001] were observed to have a higher risk of nephrolithiasis (P for trend < 0.001). In addition, a non-linear relationship between log2-transformed serum cotinine and the risk of nephrolithiasis was found (P for non-linearity = 0.028). Similar results were found when serum cotinine (log(2) transformation) was used as a continuous variable [OR = 1.02 (1.01–1.03), P < 0.001] or complete data was used to analyze after MI. In the MR analysis, genetically predicted high serum cotinine was causally related to the high risk of nephrolithiasis [IVW: OR = 1.09 (1.00–1.19), P = 0.044]. CONCLUSION: Current smoking and high serum cotinine concentrations may be associated with an increased risk of kidney stones. Further research is needed to validate this relationship and explore its underlying mechanisms.