Hydroxycotinine exhibits a stronger association with chronic kidney disease in smokers when compared to cotinine: Evidence from NHANES 2013-2018.

Abstract

Introduction: Smoking is a recognized risk factor for chronic kidney disease (CKD), and cotinine and hydroxycotinine are tobacco metabolites that can be used to quantify smoking. This study evaluated their relationship with CKD in smokers.

Methods: This secondary dataset analysis is based on National Health and Nutrition Examination Survey (NHANES) data from 2013 to 2018. A cross-sectional examination of a subsample of 2930 adult smokers aged ≥20 years was conducted to investigate the relationship between serum cotinine and its metabolite, hydroxycotinine, and CKD. Linear regression, multivariable-adjusted logistic regression, restrictive cubic splines, and subgroup analysis were utilized.

Results: Serum cotinine and hydroxycotinine levels were significantly elevated in CKD patients compared to the non-CKD population (230.00 vs 212.00 ng/mL, p=0.02 for cotinine; 97.30 vs 74.70 ng/mL, p<0.001 for hydroxycotinine). In multivariable-adjusted logistic regression models, cotinine (≥316 ng/mL) showed a positive association solely with renal insufficiency (adjusted odds ratio, AOR=1.53; 95% CI: 1.07-2.17). In contrast, hydroxycotinine (≥124 ng/mL) was independently associated with three CKD indices: CKD diagnosis (AOR=1.61; 95% CI: 1.06-2.43), renal insufficiency (AOR=2.07; 95% CI: 1.33-3.23), and albuminuria (or proteinuria) (AOR=1.61; 95% CI: 1.06-2.43). Restricted cubic spline analyses revealed nonlinear dose-response relationships: hydroxycotinine exhibited broader negative associations with both eGFR and uACR (p<0.001), while cotinine showed threshold-dependent correlations with CKD risk (positive <180 ng/mL, attenuated above). Subgroup analyses further indicated that hydroxycotinine consistently correlated with CKD across demographics (e.g. males, age <60 years, obesity), whereas cotinine's associations were more limited, with no significant interaction effects observed (p for interaction >0.05).

Conclusions: Elevated serum concentrations of cotinine and hydroxycotinine are positively associated with low glomerular filtration rate, albuminuria, and CKD in smokers, with hydroxycotinine demonstrating a stronger correlation. Smoking is established as a heightened risk factor for CKD, thus avoidance or reduction of smoking is strongly recommended.