Dose–Response Analysis of the Tubular and Glomerular Effects of Chronic Exposure to Environmental Cadmium

Satarug, Soisungwan; Vesey, David A.; Gobé, Glenda C.

doi:10.3390/ijerph191710572

Cited by 5 publications

(5 citation statements)

References 43 publications

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“…In contrast, the BMDL values of E Cd /E cr associated with a 5% eGFR decline could not be reliably determined (U/L ratios of 10 4 –10 5 ). These findings were consistent with data from a conventional dose–response analysis, where an inverse relationship between E Cd and eGFR became statistically significant only when E Cd was normalized to C cr [ 42 ].…”

Section: Discussionsupporting

confidence: 88%

The Validity of Benchmark Dose Limit Analysis for Estimating Permissible Accumulation of Cadmium

Satarug

Vesey

Gobé

et al. 2022

IJERPH

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Cadmium (Cd) is a toxic metal pollutant that accumulates, especially in the proximal tubular epithelial cells of kidneys, where it causes tubular cell injury, cell death and a reduction in glomerular filtration rate (GFR). Diet is the main Cd exposure source in non-occupationally exposed and non-smoking populations. The present study aimed to evaluate the reliability of a tolerable Cd intake of 0.83 μg/kg body weight/day, and its corresponding toxicity threshold level of 5.24 μg/g creatinine. The PROAST software was used to calculate the lower 95% confidence bound of the benchmark dose (BMDL) values of Cd excretion (ECd) associated with injury to kidney tubular cells, a defective tubular reabsorption of filtered proteins, and a reduction in the estimated GFR (eGFR). Data were from 289 males and 445 females, mean age of 48.1 years of which 42.8% were smokers, while 31.7% had hypertension, and 9% had chronic kidney disease (CKD). The BMDL value of ECd associated with kidney tubular cell injury was 0.67 ng/L of filtrate in both men and women. Therefore, an environmental Cd exposure producing ECd of 0.67 ng/L filtrate could be considered as Cd accumulation levels below which renal effects are likely to be negligible. A reduction in eGFR and CKD may follow when ECd rises from 0.67 to 1 ng/L of filtrate. These adverse health effects occur at the body burdens lower than those associated with ECd of 5.24 µg/g creatinine, thereby arguing that current health-guiding values do not provide a sufficient health protection.

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Section: Discussionsupporting

confidence: 88%

The Validity of Benchmark Dose Limit Analysis for Estimating Permissible Accumulation of Cadmium

Satarug

Vesey

Gobé

et al. 2022

IJERPH

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“…The impact of Cd exposure on GFR has long been underestimated due to the common practice of normalizing E Cd to E cr . The comparability of guidelines between populations could be improved by the universal acceptance of a consistent normalization of E Cd to Ccr that eliminates the effect of muscle mass on E cr , thereby giving a more accurate assessment of the severity of Cd nephropathy [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…This tolerable intake level for Cd was derived from a risk assessment model that assumed an increase in excretion of β 2 -microglobulin (β 2 M) (E β2M ) above 300 μg/g creatinine as the point of departure (POD) [ 8 ]. However, we have shown that such an increase in E β2M reflected tubular dysfunction and nephron loss, evident from a reduction in estimated glomerular filtration rate (eGFR) to 60 mL/min/1.73 m 2 or below [ 9 , 10 ]. In effect, a tolerable intake level of Cd derived from the E β2M -based POD is not sufficiently low to be without an impact on human health.…”

Section: Introductionmentioning

confidence: 99%

The NOAEL Equivalent of Environmental Cadmium Exposure Associated with GFR Reduction and Chronic Kidney Disease

Satarug

Djordjevic

Yimthiang

et al. 2022

Toxics

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Cadmium (Cd) is a highly toxic metal pollutant present in virtually all food types. Health guidance values were established to safeguard against excessive dietary Cd exposure. The derivation of such health guidance figures has been shifted from the no-observed-adverse-effect level (NOAEL) to the lower 95% confidence bound of the benchmark dose (BMD), termed BMDL. Here, we used the PROAST software to calculate the BMDL figures for Cd excretion (ECd) associated with a reduction in the estimated glomerular filtration rate (eGFR), and an increased prevalence of chronic kidney disease (CKD), defined as eGFR ≤ 60 mL/min/1.73m2. Data were from 1189 Thai subjects (493 males and 696 females) mean age of 43.2 years. The overall percentages of smokers, hypertension and CKD were 33.6%, 29.4% and 6.2%, respectively. The overall mean ECd normalized to the excretion of creatinine (Ecr) as ECd/Ecr was 0.64 µg/g creatinine. ECd/Ecr, age and body mass index (BMI) were independently associated with increased prevalence odds ratios (POR) for CKD. BMI figures ≥ 24 kg/m2 were associated with an increase in POR for CKD by 2.81-fold (p = 0.028). ECd/Ecr values of 0.38−2.49 µg/g creatinine were associated with an increase in POR for CKD risk by 6.2-fold (p = 0.001). The NOAEL equivalent figures of ECd/Ecr based on eGFR reduction in males, females and all subjects were 0.839, 0.849 and 0.828 µg/g creatinine, respectively. The BMDL/BMDU values of ECd/Ecr associated with a 10% increase in CKD prevalence were 2.77/5.06 µg/g creatinine. These data indicate that Cd-induced eGFR reduction occurs at relatively low body burdens and that the population health risk associated with ECd/Ecr of 2.77−5.06 µg/g creatinine was not negligible.

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“…For C cr -normalized data, kidney tubular dysfunction was defined as (E β2M / C cr ) × 100 ≥ 300 µg/L of filtrate [25]. Microalbuminuria and macroalbuminuria were defined as (E Alb /C cr ) × 100 ≥ 20 and 200 mg/L of filtrate, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Macroalbuminuria was not found in controls, but was present in 11.4-13.3% of those with DM. The overall % of mild and severe tubular dysfunction, defined as (E β2M /C cr ) × 100 ≥ 300 and ≥1000 µg/L filtrate [25] were 66.2%, and 32.4%, respectively. More than half (57.7%) of the ≥10-DM group has severe tubular proteinuria.…”

Section: Characteristics Of the Study Subjectsmentioning

confidence: 98%

Chronic Kidney Disease Induced by Cadmium and Diabetes: A Quantitative Case-Control Study

Yimthiang

Vesey

Pouyfung

et al. 2023

IJMS

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Kidney disease associated with chronic cadmium (Cd) exposure is primarily due to proximal tubule cell damage. This results in a sustained decline in glomerular filtration rate (GFR) and tubular proteinuria. Similarly, diabetic kidney disease (DKD) is marked by albuminuria and a declining GFR and both may eventually lead to kidney failure. The progression to kidney disease in diabetics exposed to Cd has rarely been reported. Herein, we assessed Cd exposure and the severity of tubular proteinuria and albuminuria in 88 diabetics and 88 controls, matched by age, gender and locality. The overall mean blood and Cd excretion normalized to creatinine clearance (Ccr) as ECd/Ccr were 0.59 µg/L and 0.0084 µg/L filtrate (0.96 µg/g creatinine), respectively. Tubular dysfunction, assessed by β2-microglobulin excretion rate normalized to Ccr(Eβ2M/Ccr) was associated with both diabetes and Cd exposure. Doubling of Cd body burden, hypertension and a reduced estimated GFR (eGFR) increased the risks for a severe tubular dysfunction by 1.3-fold, 2.6-fold, and 84-fold, respectively. Albuminuria did not show a significant association with ECd/Ccr, but hypertension and eGFR did. Hypertension and a reduced eGFR were associated with a 3-fold and 4-fold increases in risk of albuminuria. These findings suggest that even low levels of Cd exposure exacerbate progression of kidney disease in diabetics.

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Dose–Response Analysis of the Tubular and Glomerular Effects of Chronic Exposure to Environmental Cadmium

Cited by 5 publications

References 43 publications

The Validity of Benchmark Dose Limit Analysis for Estimating Permissible Accumulation of Cadmium

The Validity of Benchmark Dose Limit Analysis for Estimating Permissible Accumulation of Cadmium

The NOAEL Equivalent of Environmental Cadmium Exposure Associated with GFR Reduction and Chronic Kidney Disease

Chronic Kidney Disease Induced by Cadmium and Diabetes: A Quantitative Case-Control Study

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