Table 2.

Epidemiological studies of exposure to metals (other than lead) and kidney function biomarkers.

Reference and Country	Age, % male	Study Design	N	Outcome Ascertainment	Biomarker Assessment	Exposure Levels	Effect size (95% CI)	Adjustment factors
Studies of Cadmium exposures
Weaver et al., 2014 Mexico	Mean age of 14.0 years, 51.2% male	Cross-sectional	512	eGFR using serum creatinine and cystatin C measurement	Urine Cadmium Thallium Uranium (ICPMS)	Mean (SD) μg/L: Cadmium: 0.34 (0.37) Thallium: 0.35 (0.20) Uranium: 0.07 (0.14)	Mean difference in creatinine eGFR per doubling of: Cadmium: 3.1 (1.4, 4.8) Thallium: 3.6 (1.8, 5.3) Uranium: 1.1 (−0.2, 2.3)	Age, sex, BMI, maternal education, income, smoking, systolic BP, blood lead, urine creatinine
Swaddiwudhipong et al., 2015 Thailand	Mean age of 9.3 years, 48.3% male	Cross-sectional	594	Urine β2MG levels and total protein levels	Urine and blood cadmium (AAS)	Geometric mean: 0.54 μg/g creatinine	OR of β2MG ≥ 200 μg/g: Middle/low tertile of urine cadmium: 2.06 (1.15, 3.68) High/low tertile of urine cadmium: 2.28 (1.28, 4.04) OR of urine protein ≥ 100 μg/g: Middle/low tertile of urine cadmium: 1.25 (0.82, 1.92) High/low tertile of urine cadmium: 1.39 (0.91–2.13)	Age, sex, blood lead
De Burbure et al., 2006 France, Poland, Czech Republic	Age range 8.5–12.3 years, 49.2% male	Cross-sectional	804	Urine RBP, β2MG, and NAG levels	Blood and urine cadmium and mercury (AAS)	Geometric mean (SD) of blood cadmium in Unexposed males in France: 0.46 (1.40) μg/L Exposed males in France: 0.52 (1.40) μg/L Unexposed females in France: 0.47 (1.38) μg/L Exposed females in France: 0.5 (1.25) μg/L Unexposed males in Poland: 0.07 (1.85) μg/L Exposed males in Poland: 0.19 (2.36) μg/L Unexposed females in Poland: 0.08 (2.25) μg/L Exposed females in Poland: 0.19 (2.58) μg/L Unexposed males in Czech Republic 0.20 (1.47) μg/L Exposed males in Czech Republic: 0.29 (1.73) μg/L Unexposed females in Czech Republic: 0.20 (1.43) μg/L Exposed females in Czech Republic: 0.24 (1.62) μg/L Geometric mean (SD) of urine mercury in of Unexposed males in France: 0.99 (4.93) μg/g Exposed males in France: 0.92 (6.60) μg/g Unexposed females in France: 0.89 (5.20) μg/g Exposed females in France: 1.19 (5.78) μg/g Unexposed males in Poland: 0.06 (1.51) μg/g Exposed males in Poland: 0.06 (1.61) μg/g Unexposed females in Poland: 0.05 (1.59) μg/g Exposed females in Poland: 0.06 (1.53) μg/g Unexposed males in Czech Republic 0.26 (2.81) μg/g Exposed males in Czech Republic: 0.13 (3.59) μg/g Unexposed females in Czech Republic 0.32 (3.14) μg/g Exposed females in Czech Republic: 0.18 (2.50) μg/g	Mean difference (p-value) in urine RBP per unit increase in blood Cd: 0.06 (< 0.001) Mean difference in urine NAG per increase in blood Cd: 0.053 (0.004) Mean difference (p-value) in urine RBP per unit increase in urine Cd: 0.097 (< 0.001) Mean difference in urine NAG per increase in urine Cd: 0.017 (< 0.03) Mean difference (p-value) in serum B2MG per unit increase in urine Hg: −0.023 (0.02) Mean difference in urine NAG per increase in urine Hg: 0.215 (0.03)	Models for cadmium: Urine creatinine, blood lead x urine mercury, urine mercury x blood cadmium, urine mercury Models for mercury: Urine creatinine, blood lead x urine mercury, urine mercury x blood cadmium, blood cadmium
Chan et al., 2012 China (Hong Kong)^a	Age range 1–21 years, 48.5% male	Cross-sectional	2209	Urine albumin levels	Blood and urine lead and cadmium (ICPMS)	Range of urine cadmium: < 0.30–29.26 nmol/L Range of blood cadmium: Smokers: < 0.27–39.27 nmol/L Non-smokers: < 0.27–36.94 nmol/L	Correlation coefficient between urine albumin and blood cadmium: −0.014 Correlation coefficient between urine albumin and urine cadmium: 0.119	None
Hossny et al., 2001 Egypt	Age range: 0–18 years 49.3% male	Cross-sectional	405	Urine A1M	Blood cadmium (AAS)	Geometric mean (SD) of blood cadmium in Neonates: 0.92 (1.9) μg/L Infants: 1.33 (1.5) μg/L Preschool: 1.11 (1.6) μg/L Primary school: 1.34 (1.6) μg/L Adolescents: 1.24 (1.5) μg/L	In primary school aged children and adolescents, those who were A1M positive had higher blood Cd than those without A1M (p > 0.05 in school aged children and p < 0.01 in adolescents)	Age
Fels et al., 1998 Poland^b	Mean age of 9.9 years in unexposed, 10.6 years in exposed, 64.2% male	Cross-sectional	112	Urine total protein, albumin, NAG, RBP, and β2MG levels	Blood and urine lead and cadmium (AAS)	Mean (SD) of blood cadmium in unexposed: 0.55 (0.18) μg/L Mean (SD) of blood cadmium in exposed: 0.69 (0.23) μg/L Mean (SD) of urine cadmium in unexposed: 0.40 (0.24) μg/L Mean (SD) of urine cadmium in exposed: 0.49 (0.35) μg/L	Median (Range) of urine NAG in unexposed: 2.1 (0.9, 4.8) U/g Median (Range) of urine NAG in exposed: 1.9 (0.6, 8.1) U/g Median (Range) of urine β2MG in unexposed: 37 (4, 764) μg/g Median (Range) of urine β2MG in exposed: 89 (5, 1145) μg/g Median (Range) of urine RBP in unexposed: 42 (11, 207) μg/g Median (Range) of urine RBP in exposed: 46 (7, 183) μg/g Median (Range) of urine total protein in unexposed: 34 (0, 127) mg/g Median (Range) of urine total protein in exposed: 34 (0, 212) mg/g Median (Range) of urine albumin in unexposed: 6 (0.1, 35) mg/g Median (Range) of urine albumin in exposed: 7 (0.3, 47) mg/g	None
Noonan et al., 2002 ^c United States	Age range of 6–17 years, 55.3% male	Cross-sectional	159	NAG, AAP, albumin, and β2MG levels	Urine cadmium (AAS)	Geometric mean (95% confidence interval) of urine cadmium in females: 0.08 (0.07, 0.10) μg/g creatinine Geometric mean (95% confidence interval) of urine cadmium in females: 0.07 (0.06, 0.08) μg/g creatinine	Spearman correlation coefficients (95% confidence interval) between urine cadmium and NAG (U/L): 0.09 (−0.07, 0.24) Spearman correlation coefficients (95% confidence intervals) between urine cadmium and albumin (mg/L): 0.03 (−0.12, 0.19) Spearman correlation coefficients (95% confidence intervals) between urine cadmium and AAP (U/L): 0.15 (0.00, 0.30, 0.19) Spearman correlation coefficients (95% confidence intervals) between urine cadmium and β2MG(mg/L) −0.01 (−0.20, 0.19)	Urine creatinine, age, sex
Studies of Mercury exposures
DeRouen et al., 2006 Woods et al., 2008 Geier et al., 2013 Portugal	Age range 8–12 years at baseline, 54% male Mean (SD) age 10.09 (1.0) and 58% male	Randomized trial (amalgam vs composite)	507 Geier: 344/447^d	Urine albumin levels (Woods et al) Grier: urine GST-α and GST-π levels	Urine Mercury (AAS) Geier et al. score derived from number of amalgams, BMI, age, gender	Mean urine mercury of 1.8 μg/g at baseline, 3.2 μg/g after 2 years Mercury levels significantly higher in amalgam group Geier et al. mean (SD) urine mercury of 8.51 (9.5)	No significant difference in creatinine adjusted urine albumin by treatment year (DeRouen et al., 2006) Mean difference in urine albumin per log-increase in mercury: 1.29 (1.15, 1.45) (Woods et a 2008) Grier: Mean difference (SE) in urine GST-α per increase in restorations: 0.0047 (0.002) Mean difference (SE) in urine GST-π per increase in restorations: 0.0042 (0.002)	Age, gender, race, age at baseline, urine creatinine (Woods et al., 2008) Grier: urine mercury, porphyrin measures, gender, race, blood lead, and GST-α and GST-π levels
Bellinger et al., 2006 Barregard et al., 2008 United States	Mean (SD) age of 7.9 (1.3) years and 50.9% male in amalgam group Mean (SD) age of 7.9 (1.4) years and 41.6% male in amalgam group	Randomized trial (amalgam vs composite)	534	Urine albumin levels (Bellinger et al., 2006) Urine albumin, γ-GT, A1M, NAG levels (Barregard et al., 2008)	Urine and hair mercury (AAS)	Mean (SD) hair mercury of 0.4(0.5) μg/g in amalgam group at baseline Mean (SD) hair mercury of 0.4(0.5) μg/g in composite group at baseline	Adjusted OR (95%CI) of albuminuria comparing amalgam to composite group: 1.8 (1.1, 2.9) (Barregard et al., 2008)	Randomization stratum, age, sex, race, socioeconomic status, basiline hair mercury, baseline blood lead, lean body mass, time of urine collection, creatinine concentration, storage time
Studies of Arsenic exposures
Hawkesworth et al., 2013 Skroder et al., 2015 Bangladesh	Mother-child pairs 52.7% male Mean age mothers 26.7 y	Cohort (children assessed at 4.5 years) Cross-sectional (Skroder et al)	2012: 1334 2015: 1106	eGFR levels via Cystatin-C formula^e	Urine Arsenic (Hydride generation atomic absorption) Urine Arsenic, Cadmium, Selenium (ICP-MS)	Median (10th, 90th) maternal urine As (μg/l) 80 (24, 383) at 8 weeks of pregnancy Median (5^th, 95^th) of child urine arsenic: 51 (16, 364) μg/L urine cadmium: 0.22 (0.08, 0.63) μg/L urine selenium: 13(6.0–26) μg/L	Mean difference in child’s eGFR −14.2 (−32.2, 3.7) per unit increase in maternal As; Mean difference in child’s eGFR −0.29 (−0.86, 0.28) per 100 μg/L increase in arsenic Mean difference in child’s eGFR −1.8 (−3.4, −0.071) per 0.5 μg/L increase in cadmium Mean difference in child’s eGFR 0.34 (−0.76, 1.4) per 10 μg/L increase in selenium	Age, sex, parental wealth index, height at age 4.5, season of birth Age, sex, birth weight, season of birth, weight for age z-score, maternal BMI, parity, SES, arsenic, cadmium and selenium (depending on model)
Studies of Manganese exposures
Nascimento et al., 2016 Brazil	Mean (SD) age 8.6 (0.3) in rural and 10.4 (0.3) in urban, 50.7% male	Cross-sectional (urban vs rural)	63	Urine albumin and NAG levels	Blood, hair, drinking water manganese (ICPMS)	Median (min, max) Manganese in rural children: blood: 32.0 (28.0, 44.0) μg/L hair 1.5 (0.19, 11.5) μg/g drinking water: 6.0 (1.0, 16.7) μg/L Urban children: blood: 19.0 (14.0, 31.0) μg/L hair 1.5 (0.09, 0.98) μg/g drinking water 1.0 (1.0, 3.0) μg/L	Significant difference in mean (SE) in urine albumin levels between rural and urban children 11.3 (1.5)mg/g in rural children and 7.0 (1.4) mg/g in urban children P < 0.05 Significant difference in mean (SE) of urine NAG levels between rural and urban children 5.2 (0.4) mg/g in rural children and 3.4 (0.2) mg/g in urban children P < 0.05	None

RBP: retinol binding protein, eGFR: estimated glomerular filtration rate, GFR: glomerular filtration rate, β2MG: β-2-microglobulin, A1M: α-1-microglobulin, NAG: N-acetyl-β-D-glucosaminidase, AAP: alanine aminopeptidase, ASV: Anodic Stripping Voltammetry, AAS: atomic absorption spectroscopy, ICPMS: inductively coupled plasma mass spectrometry

Footnote about Chan et al. (2012): study also measures lead – see Table 1 for lead results.

Footnote about Fels et al. (1998): study also measures lead – see Table 1 for lead results.

Noonan et al., results only reported for individuals aged 6–17 years.

N = 344 for GSTα, N = 447 for GSTπ.

Formula from Grubb et al., “Simple cystatin C-based prediction equations for glomerular filtration rate compared with the modification of diet in renal disease prediction equation for adults and the Schwartz and the Counahan-Barratt prediction equations for children.” Clin Chem 2005 51:1420–31.