Background Long-term cadmium exposure is a risk factor for nephrolithiasis; however, the mechanisms underlying cadmium-mediated nephrolithiasis remain unclear.

Objective To investigate the potential metabolic pathways involved in nephrolithiasis induced by occupational cadmium exposure.

Methods From January to December 2021, workers from a metal smelting plant in Guangdong Province were selected as study subjects. Demographic characteristics, medical history, and lifestyle information were collected through questionnaires. Midstream morning urine and blood samples were collected. Nearest neighbor matching was used to select paired samples. Untargeted metabolomics technology was employed to detect serum metabolite (lipids, amino acids, nucleotides, etc.) levels, while inductively coupled plasma mass spectrometry was used to determine urinary cadmium levels. History of nephrolithiasis was obtained through questionnaire survey, and logistic regression models were constructed to explore factors associated with nephrolithiasis. Core metabolites were identified using volcano plots and elastic net regression analysis. A metabolite-gene regulatory network was constructed using Cytoscape to identify nephrolithiasis-related genes, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was conducted to elucidate nephrolithiasis-associated metabolic pathways.

Results A total of 764 workers met predetermined inclusion and exclusion criteria. Among them, 318 workers were in the nephrolithiasis group (41.62%) and 446 in the control group (58.38%). A representative subset of 70 workers was used for the serum metabolomics analysis, comprising 25 workers in the nephrolithiasis group (35.71%) and 45 in the control group (64.29%). The logistic regression analysis revealed that urinary cadmium was a risk factor for nephrolithiasis in both the total population and the metabolomics subset, showing a positive association with nephrolithiasis occurrence total population: OR(95%CI)=1.22(1.07, 1.38), P=0.01; metabolomics subset: OR(95%CI)=2.38(1.21, 4.70), P=0.01. The volcano plot analysis identified 113 differential metabolites, including 39 significantly upregulated and 74 significantly downregulated metabolites. The elastic net regression analysis of these differential metabolites identified 13 related metabolites at λ=0.0274, where the model achieved optimal performance. These metabolites included acylcarnitine, N-acetylornithine, and spermine. The metabolite-gene regulatory network analysis identified 80 genes regulating the key metabolites. The KEGG pathway enrichment analysis of these genes revealed that lipid and amino acid metabolic pathways may be involved in the cadmium exposure-mediated kidney stone formation process. These pathways included sphingolipid metabolism, glycerate metabolism, arginine biosynthesis, and arginine and proline metabolism, among others.

Conclusion Occupational cadmium exposure is positively associated with nephrolithiasis, and lipid and amino acid metabolic pathways may be involved in the cadmium-mediated process of kidney stone formation.