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Unmarked glass laboratory vessels, a closed notebook, sampling spoon and empty specimen dish illustrating Robinson and colleagues 2026 source research context.

Associations Between Toxic Metal Exposure and Childhood Nephrotic Syndrome

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This prospective cohort study measured total mercury and six other toxic metals (copper, total arsenic, selenium, cadmium, tin, lead) in toenail samples from 298 children with nephrotic syndrome enrolled in the INSIGHT study at SickKids Hospital, Toronto, Canada. The study aimed to test the hypothesis that chronic low-grade metal exposure is a risk factor for childhood nephrotic syndrome outcomes. No significant associations were found between individual or combined toenail metal concentrations and nephrotic syndrome relapses, steroid resistance, frequent relapses, or steroid dependence.

Key numbers

  • Toenail concentrations (mean SD, in micrograms per gram; Table 2):
    • Total mercury (n=298): mean 0.15 (0.31); less than 1% above reference limit (greater than 2 microg/g); 35% (n=104) below method detection limit (MDL) of 0.07 microg/g
    • Copper (n=109): mean 4.73 (5.69); 10% above 20 microg/g reference limit; 7.8% below MDL of 0.18 microg/g
    • Total arsenic (n=109): mean 0.48 (0.31); 0% above 1 microg/g reference limit; 10.2% below MDL of 0.08 microg/g
    • Selenium (n=109): mean 1.09 (0.35); 0% above 3 microg/g reference limit; 48.6% below MDL of 0.12 microg/g
    • Cadmium (n=109): mean 0.08 (0.08); 0% above 0.2 microg/g reference limit; 98.2% below MDL of 0.04 microg/g; fewer than 5% above MDL (reported as less than 5 for privacy)
    • Tin (n=109): mean 1.68 (1.85); 25.7% above 3.8 microg/g reference limit; 74.3% below MDL of 0.38 microg/g
    • Lead (n=109): mean 0.48 (1.85); 18.6% above 0.2 microg/g reference limit; 83.5% below MDL of 0.2 microg/g
  • Reference limits used by the paper (Supplementary Table S2): Mercury 2 and 10 microg/g (WHO normal and toxicity); Cu 20 microg/g; arsenic (As) 1 microg/g; Se 3 microg/g; cadmium (Cd) 0.2 microg/g; tin (Sn) 3.8 microg/g; lead (Pb) 0.2 microg/g.
  • Regression results for relapse rate and other outcomes: no statistically significant associations for individual metals or combined metal mixture (weighted quantile sum analysis). Relative rates and odds ratios all crossed 1.0 (Table 3).
  • Less than 1% (n=5 children, 0.7%) had nail mercury above 2 microg/g (upper limit of normal per WHO guidelines); none had mercury above 10 microg/g (toxicity threshold). 10% of children (n=11) had at least one other toxic metal above reference limits.
  • Blinded quality control samples (n=37, 11% paired replicates) confirmed good laboratory concordance.

Methods (brief)

INSIGHT prospective cohort; children 1-18 at SickKids or community hospitals in the Greater Toronto Area with primary nephrotic syndrome, excluding congenital or secondary nephrotic syndrome. Toenails collected from the first toe before March 2020. Total mercury analyzed in all 298 samples using Milestone Direct Mercury Analysis-80 evo (US EPA method 7473). Six additional metals in 109 samples with sufficient material using ICP-MS (Agilent 7700x; EPA methods 200.8 and 3051A) after digestion in 2 mL concentrated aqua regia diluted to 50 mL. Nails cleaned with acetone rinse then deionized water rinse prior to analysis. Outcomes assessed using negative binomial regression (relapse rate), logistic regression (steroid resistance, frequent relapses, steroid dependence), and weighted quantile sum regression for mixture effects. R statistical software version 4.4.0.

Evidence fitness

This paper provides toenail biomonitoring data for children with an immune-complex kidney disease. The null finding (no significant association between metals and nephrotic syndrome outcomes) is relevant as a contribution to the literature on heavy metals and pediatric kidney disease. The study does not measure metals in food or personal care products. The low proportion of children with detectable cadmium (fewer than 2% above MDL) and the low mean mercury (0.15 microg/g) indicate that this population of Canadian children in a developed-country setting had low heavy metal body burden overall.

Limitations

Only children already diagnosed with nephrotic syndrome were studied; no healthy controls without nephrotic syndrome were included, so this study cannot address whether metal exposure increases risk of developing nephrotic syndrome. Toenail samples were unavailable for 46% of INSIGHT participants (insufficient nail material or enrollment after March 2020 due to COVID-19). The 109 children who could be tested for the full metal panel were slightly older at sample collection than those without sufficient samples.

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