The association between low-concentration heavy metal exposure and chronic kidney disease risk through α-klotho Original paper

What was studied?

The association between low-concentration heavy metal exposure and chronic kidney disease (CKD) risk through α-klotho was studied in this original research article. This analysis specifically explored how cadmium, mercury, lead, and thallium—identified as priority pollutants via machine-learning screening—relate to CKD risk, with α-klotho positioned as a mechanistic mediator. The investigators leveraged NHANES 2007–2016 data and advanced modeling approaches, including Bayesian kernel machine regression (BKMR), to evaluate metal mixtures rather than single-exposure models. Because microbiome signatures often intersect with toxin-response phenotypes such as inflammation, oxidative stress, and renal metabolic shifts, understanding how toxic metals perturb α-klotho is clinically relevant for any microbiome-focused biomarker database.

Who was studied?

A total of 2,415 U.S. adults aged 40–79 years were analyzed from NHANES cycles spanning 2007–2016 The association between lowconc…. Participants included 1,997 non-CKD controls and 418 individuals with CKD, defined by reduced estimated glomerular filtration rate or albuminuria. Baseline characteristics showed that CKD participants were older, had higher BMI, and had greater prevalence of diabetes and hypertension. Urinary concentrations of Cd, Hg, Pb, and Tl were quantified using ICP-MS, while α-klotho was measured via ELISA. The population’s low-level exposure setting provides meaningful insight applicable to environmental-health and microbiome-health interface research.

Most important findings

The study found that heavy metals, particularly Cd, Tl, Pb, and Hg, ranked highest among 51 pollutants screened for CKD risk contribution. Machine-learning SHAP analysis (page 5) highlighted cadmium and thallium as the strongest predictors. Logistic and BKMR models revealed a notable pattern: cadmium exposure increased CKD risk, whereas thallium and lead exhibited inverse associations, potentially reflecting reduced urinary excretion in impaired renal function rather than protective effects. Hg showed no significant direct association with CKD, but higher Hg correlated positively with α-klotho, suggesting biological interaction. α-Klotho itself strongly associated with lower CKD risk and partially mediated the mercury–CKD link (≈34.5% mediation; page 11). These findings align with known microbial and host-metabolic disturbances tied to oxidative stress pathways—where shifts in microbial taxa and metabolites such as short-chain fatty acids are known to modify oxidative and inflammatory tone.

Key implications

This study underscores that even low-level metal exposures can influence CKD risk through pathways relevant to oxidative stress, endocrine regulation, renal tubular integrity, and α-klotho biology. For microbiome-focused clinicians, α-klotho serves as a central integrator of systemic oxidative burden—conditions strongly modifiable by gut microbial composition. These findings reinforce the need to evaluate environmental toxins alongside microbiome data when building precision-medicine signatures. Moreover, the differential behavior of metals within mixture models demonstrates the importance of multivariate environmental assessment rather than single-toxin frameworks, particularly when identifying clinically meaningful microbial–host interaction signatures.

Citation

Liu S, Wang H, Cao Y, et al. The association between low-concentration heavy metal exposure and chronic kidney disease risk through α-klotho.Scientific Reports. 2025;15:11320. doi:10.1038/s41598-025-96016-4