Metal Exposure Levels May Explain Cardiovascular-Kidney-Metabolic Stages

Metal and metalloid exposure may be associated with an increased risk of developing cardiovascular-kidney-metabolic (CKM) syndrome, highlighting a rising environmental concern, according to new research.1

“As far as we know, no study to date has been published that comprehensively examines the combined effects of metal exposure on cardiovascular disease, chronic kidney disease, and metabolic-related diseases,” wrote study investigators Shuai Zhang, PhD the deputy director of the male reproductive department at Lianyungang Maternal and Child Health Hospital, and colleagues. “Most existing research focuses on the association between metal exposure and specific diseases.”1

The National Health and Nutrition Examination Survey (NHANES) has monitored the general population of the United States for metal exposure, collected from urine sample analyses. Worldwide > 1,000,000 people are impacted by residual toxic metal particles from current and former mining operations.1,2

The detrimental health impacts of these pollutants are a growing concern for ecological, nutritional, and environmental factors. The association between metal/metalloid levels and CKM syndrome is an area of unexplored research that could provide insight into health outcomes.1,2

In a cross-sectional study leveraging data from NHANES, investigators examined relationships between metal mixtures and CKM syndrome stage, with CKM stage 0 as the reference group to compare differences in urinary metal concentrations.1

CKM stages were defined as follows:

• Stage 0: No identified risk factors for CKM syndrome
• Stage 1: Overweight, dysfunctional obesity, or prediabetes
• Stage 2: The presence of ≥ 1 condition, such as hypertriglyceridemia, hypertension, diabetes, any component of MetS, or moderate to high-risk CKD
• Stage 3: Chronic kidney disease with a very high risk or a predicted 10-year cardiovascular disease risk of ≥ 20%
• Stage 4: Self-reported clinical CVD, including coronary artery disease, angina, myocardial infarction, heart failure, or stroke1

To assess the specific metals driving these associations, investigators examined 9 metal and metalloid species, including barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, and tungsten. Subgroup analyses were conducted by sex, age groups <60 years and ≥60 years, and race. Mediation analysis was conducted to explore how inflammation, oxidative stress, and aging might mediate the link between metal mixtures and CKM syndrome.1

The study’s population included 6650 participants ≥ 20 years of age with complete data on CKM syndrome and metal exposure. There were 814 participants with stage 0 CKM (14.9%), 1122 in stage 1 (18.9%), 3731 in stage 2 (55.6%), and 982 ≥ in the stage 3 (10.6%).1

As the stage of CKM syndrome increased, the average age of participants significantly increased, along with a notable increase in the proportion of males and non-Hispanic black individuals. In stage 1, metal levels of barium, cadmium, cesium, palladium, and titanium were increased. In participants ≥ stage 3, investigators saw increased levels of cobalt, molybdenum, antimony, and tungsten.1

In weighted multinomial logistic regression analysis, increased levels of barium, cobalt, and molybdenum were significantly associated with increased odds of CKM stages ≥3. Participants in CKM stages ≥1 exhibited increased levels of metal exposure, although investigators observed an exception of palladium. They did not report any clear dose-dependent trend in urinary metal levels across different CKM syndrome stages.1

Upon quantile gcomputation regression analysis, the exposure to metal mixtures was significantly associated with the prevalence of stage 1 (Odds Ratio [OR], 2.209; 95% Confidence Interval [CI], 1.78-2.74), and increased urinal metal mixture leveels were associated with increased odds of stage 2 and ≥ stage 3, respectively (OR, 2.242; 95% CI, 1.851-2.715 and OR, 3.401; 95% CI, 2.63-4.399). For every quartile increase, participants in the upper quartiles of urinary metal mixtures had a 2.207-fold increased odds of CKM syndrome (95% CI, 1.835-2.654).1

In the subgroup analysis based on age, participants <60 years of age exhibited increased statistical associations between metal exposure and CKM syndrome, and all metals, except for palladium, were significantly associated with CKM syndrome.1

In mediation analyses, inflammation, measured by serum albumin and alkaline phosphatase, and biological aging, defined by the Klemera-Doubal method (KDM) residuals, partially explained the associations between metal mixture exposure and CKM syndrome across disease stages and overall.1

• Stage 1: serum albumin (12.09%) and KDM residuals (9.15%) explained the association.
• Stage 2: alkaline phosphatase (8.87%), serum albumin (9.14%), and KDM residuals (35.79%) explained the association.
• ≥ stage 3: alkaline phosphatase (8.64%), serum albumin (11.46%), and KDM residuals (23.2%) explained the association.1

“These results improve our understanding of CKM syndrome by suggesting that environmental metal exposure may be associated with CKM stages,” concluded investigators. “However, as NHANES reflects exposure patterns in the U.S. general population, the results are most applicable to community-level environmental exposures and should not be directly extrapolated to high-exposure occupational groups. Further validation through prospective cohort studies and mechanistic research is warranted.”1

References

1. Zhang S, Tang H, Pan L, Zhou M. Association of metal and metalloid exposure with cardiovascular-kidney-metabolic syndrome: mediation by inflammation, oxidative stress, and aging. BMC Public Health. Published online December 12, 2025. doi:https://doi.org/10.1186/s12889-025-25894-0

2. Jomova K, Alomar SY, Nepovimova E, Kuca K, Valko M. Heavy metals: toxicity and human health effects. Archives of Toxicology. 2024;99(1). doi:https://doi.org/10.1007/s00204-024-03903-2