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

Abstract

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 (log₂ 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.

Keywords: Mendelian randomization; NHANES; kidney stone; serum cotinine; smoking status.

Figure 1

Flowchart of sample selection from NHANES (2007–2018).

Figure 2

Flowchart of Mendelian Randomization analysis. MR, Mendelian randomization; GWAS, genome-wide association study; MR-PRESSO, MR-Pleiotropy RESidual Sum and Outlier; IVW, inverse-variance weighting; MR-RAPS, MR-robust adjusted profile score.

Figure 3

Restricted cubic spline (RCS) analysis of log2-transformed serum cotinine and odds ratio of kidney stone disease based on Model 3. OR, odds ratio; CI, confidence interval; KSD, kidney stone disease.

Figure 4

Mendelian randomization analysis to explore the causal association between serum cotinine and kidney stones. Bold and red dots indicate that there is statistical significance (P < 0.05). MR, Mendelian randomization; IVW-FE, inverse-variance weighting with fixed-effect model; MR-RAPS, MR-robust adjusted profile score.

Figure 5

Scatter plot for THE causal effect of serum cotinine on kidney stones. MR, Mendelian randomization; SNP, single nucleotide polymorphism; KSD, kidney stone disease.