Cadmium-Induced Proteinuria: Mechanistic Insights from Dose–Effect Analyses
Abstract
:1. Introduction
2. Results
2.1. Descriptive Characteristics of Study Subjects According to eGFR
2.2. Predictors of Protein Excretion
2.3. Predictors of eGFR Deterioration
2.4. Prevalence Odds Ratios for Proteinuria and Low eGFR in Relation to Cadmium Exposure
2.5. Excretion Rates of Various Proteins and Cadmum in the High-Exposure Group
2.6. Correlation Analysis of Age, BMI, and Chemical Constiuents of Urine
3. Discussion
4. Materials and Methods
4.1. Participants
4.2. Collection and Analysis of Blood and Urine Samples
4.3. Estimated Glomerular Filtration Rates and CKD Stratified by the KDIGO Categories
4.4. Normalization of ECd to Ecr and Ccr
4.5. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Parameters | All Subjects n = 405 | eGFR a, mL/min/1.73 m2 | p | ||
---|---|---|---|---|---|
>90, n = 207 | 61–90, n = 147 | ≤60, n = 51 | |||
Low-exposure controls (%) | 46.9 | 84.1 | 10.9 | 0 | <0.001 |
Females (%) | 51.4 | 48.3 | 56.5 | 49.0 | 0.299 |
Smoking (%) | 45.9 | 32.9 | 56.5 | 68.6 | <0.001 |
Diabetes (%) | 2.7 | 0 | 4.8 | 7.8 | 0.001 |
Hypertension (%) | 13.8 | 2.9 | 19.7 | 41.2 | <0.001 |
Age, years | 44.6 ± 16.2 | 33.2 ± 9.9 | 53.2 ± 11.5 | 65.6 ± 10.6 | <0.001 |
eGFR, mL/min/1.73 m2 | 87.3 ± 23.3 | 106.0 ± 10.1 | 75.5 ± 8.2 | 45.4 ± 11.3 | <0.001 |
Plasma creatinine, mg/dL | 0.98 ± 0.29 | 0.84 ± 0.1392 | 0.98 ± 0.14 | 1.50 ± 0.44 | <0.001 |
Urine creatinine, mg/dL | 106 ± 68 | 92 ± 68 | 116 ± 62 | 135 ± 69 | <0.001 |
Plasma total protein, g/dL | 8.04 ± 0.45 | 8.05 ± 0.45 | 7.93 ± 0.47 | − | 0.337 |
Plasma albumin, g/dL | 4.97 ± 0.30 | 4.97± 0.31 | 4.98 ± 0.28 | − | 0.861 |
Urine protein, mg/L | 47.18 ± 150.6 | 5.42 ± 10.33 | 50.83 ± 137.3 | 206.2 ± 307.7 | <0.001 |
Urine protein ≥ 20 mg/L (%) | 28.6 | 3.9 | 45.6 | 80.4 | <0.001 |
Urine Cd, µg/L | 6.54 ± 10.59 | 2.24 ± 8.38 | 9.46 ± 8.22 | 15.6 ± 15.3 | <0.001 |
Normalized to Ecr as Ex/Ecr b | |||||
EProt/Ecr, mg/g creatinine | 43.76 ± 132.57 | 6.52 ± 11.58 | 52.36 ± 141.78 | 170 ± 246 | <0.001 |
EProt/Ecr ≥ 100 mg/g creatinine (%) | 8.6 | 0.5 | 8.8 | 41.2 | <0.001 |
ECd/Ecr, µg/g creatinine | 5.81 ± 7.64 | 2.14 ± 5.43 | 8.95 ± 7.06 | 11.69 ± 9.20 | <0.001 |
Normalized to Ccr as Ex/Ccr c | |||||
(EProt/Ccr) × 100, mg/L filtrate | 60.2 ± 236.5 | 5.32 ± 9.00 | 51 ± 134 | 310 ± 568 | <0.001 |
(EProt/Ccr) × 100 ≥ 20 mg/L (%) | 30.6 | 3.9 | 49 | 86.3 | <0.001 |
(ECd/Ccr) × 100, µg/L filtrate | 6.21 ± 9.00 | 1.70 ± 4.55 | 8.67 ± 6.85 | 17.44 ± 14.17 | <0.001 |
Independent Variables/ Factors | Urinary Excretion of Protein a | |||||
---|---|---|---|---|---|---|
All subjects, n = 405 | Males, n = 197 | Females, n = 208 | ||||
β b | p | β | p | β | p | |
Age, years | 0.263 | <0.001 | 0.222 | 0.028 | 0.260 | 0.011 |
Log [(ECd/Ccr) × 105], µg/L filtrate | 0.252 | <0.001 | 0.376 | <0.001 | 0.179 | 0.050 |
Diabetes | −0.039 | 0.353 | 0.012 | 0.831 | −0.097 | 0.114 |
Sex | 0.078 | 0.107 | − | − | − | − |
Hypertension | −0.065 | 0.152 | −0.116 | 0.069 | −0.002 | 0.974 |
Smoking | −0.075 | 0.150 | 0.007 | 0.911 | −0.152 | 0.040 |
Adjusted R2 | 0.306 | <0.001 | 0.371 | <0.001 | 0.259 | <0.001 |
Independent Variables/ Factors | eGFR, mL/min/1.73 m2 a | |||||
---|---|---|---|---|---|---|
All Subjects, n = 405 | Males, n = 197 | Females, n = 208 | ||||
β b | p | β | p | β | p | |
Age, years | −0.558 | <0.001 | −0.603 | <0.001 | −0.504 | <0.001 |
Log [(ECd/Ccr) × 105], µg/L filtrate | −0.266 | <0.001 | −0.178 | 0.012 | −0.334 | <0.001 |
Diabetes | 0.034 | 0.256 | 0.048 | 0.246 | 0.033 | 0.441 |
Sex | −0.049 | 0.155 | − | − | − | − |
Hypertension | 0.084 | 0.010 | 0.158 | 0.001 | 0.012 | 0.790 |
Smoking | −0.043 | 0.247 | −0.061 | 0.168 | 0.016 | 0.750 |
Adjusted R2 | 0.650 | <0.001 | 0.681 | <0.001 | 0.635 | <0.001 |
Parameters | Number of Subjects | Proteinuria a | Low eGFR b | ||
---|---|---|---|---|---|
POR (95% CI) | p | POR (95% CI) | p | ||
Age, years | 405 | 0.923 (0.897, 0.949) | <0.001 | 0.888 (0.854, 0.924) | <0.001 |
Diabetes | 11 | 0.726 (0.181, 2.916) | 0.652 | 0.582 (0.119, 2.861) | 0.506 |
Sex (females) | 208 | 1.030 (0.539, 1.971) | 0.928 | 0.775 (0.336, 1.787) | 0.550 |
Hypertension | 56 | 0.498 (0.244, 1.017) | 0.055 | 0.363 (0.159, 0.826) | 0.016 |
Smoking | 186 | 0.778 (0.398, 1.520) | 0.462 | 1.271 (0.523, 3.092) | 0.597 |
ECd/Ccr × 100, µg/L filtrate | |||||
0.04–2.71 | 203 | Referent | |||
2.72–8.28 | 102 | 1.252 (0.670, 2.341) | 0.482 | 4.579 (1.116, 18.79) | 0.035 |
8.29–63 | 100 | 4.575 (1.880, 11.13) | 0.001 | 5.109 (2.093, 12.47) | <0.001 |
Parameters | All Subjects n = 215 | eGFR a, mL/min/1.73 m2 | p | ||
---|---|---|---|---|---|
>90, n = 33 | 61–90, n = 131 | ≤60, n = 51 | |||
Age, years | 57.0 ± 11.1 | 49.4 ± 9.4 | 55.6 ± 9.6 | 65.6 ± 10.6 | <0.001 |
BMI, kg/m2 | 21.4 ± 3.6 | 21.2 ± 3.2 | 21.3 ± 3.5 | 21.7 ± 4.3 | 0.822 |
eGFR, mL/min/1.73 m2 | 71.6 ± 19.4 | 100.4 ± 8.3 | 74.6 ± 8.2 | 45.4 ± 11.3 | <0.001 |
Plasma creatinine, mg/dL | 1.07 ± 0.35 | 0.79 ± 0.13 | 0.98 ± 0.14 | 1.50 ± 0.44 | <0.001 |
Urine creatinine, mg/dL | 118.4 ± 62.2 | 99.1 ± 53.1 | 116.8 ± 60.2 | 135.2 ± 69.4 | 0.054 |
Plasma to urine creatinine ratio | 0.0125 ± 0.0096 | 0.0116 ± 0.0097 | 0.0118 ± 0.0094 | 0.0148 ± 0.0098 | 0.034 |
Urine Cd, µg/L | 11.85 ± 12.28 | 11.18 ± 18.70 | 10.56 ± 8.05 | 15.61 ± 15.31 | 0.079 |
Urine β2M, mg/L | 4.92 ± 17.43 | 0.20 ± 0.36 | 1.18 ± 4.02 | 17.57 ± 32.31 | <0.001 |
Urine α1M, mg/L | 13.09 ± 18.68 | 5.66 ± 6.17 | 8.37 ± 7.91 | 30.04 ± 30.31 | <0.001 |
Urine albumin, mg/L | 25.57 ± 70.59 | 7.62 ± 7.29 | 22.64 ± 76.57 | 44.72 ± 73.74 | <0.001 |
Urine protein, mg/L | 85.4 ± 199.1 | 14.9 ± 22.6 | 56.2 ± 144.6 | 206.2 ± 307.7 | <0.001 |
Normalized to Ecr as Ex/Ecr b | |||||
ECd/Ecr, µg/g creatinine | 10.43 ± 8.02 | 10.26 ± 10.35 | 9.98 ± 6.79 | 11.69 ± 9.20 | 0.641 |
Eβ2M/Ecr, mg/g creatinine | 4.87 ± 16.55 | 0.23 ± 0.37 | 1.66 ± 9.72 | 16.13 ± 27.49 | <0.001 |
Eα1M/Ecr, mg/g creatinine | 11.34 ± 15.00 | 5.78 ± 4.95 | 7.53 ± 6.30 | 24.72 ± 24.57 | <0.001 |
EAlb/Ecr, mg/g creatinine | 23.21 ± 55.07 | 10.47 ± 15.68 | 20.71 ± 59.50 | 37.88 ± 57.23 | <0.001 |
EProt/Ecr, mg/g creatinine | 78.25 ± 174.96 | 16.73 ± 24.54 | 57.98 ± 149.26 | 170.13 ± 246.01 | <0.001 |
Eβ2M/Ecr, µg/g creatinine (%) | |||||
<100 | 36.7 | 51.5 | 43.5 | 9.8 | <0.001 |
100–999 | 37.7 | 42.4 | 42.0 | 23.5 | <0.001 |
1000 | 25.6 | 6.1 | 14.5 | 66.7 | <0.001 |
EAlb/Ecr, mg/g creatinine (%) | |||||
<30 | 84.2 | 93.9 | 88.5 | 66.7 | <0.001 |
30–300 | 15.3 | 0.1 | 10.7 | 33.3 | <0.001 |
>300 | 0.5 | 0 | 0.8 | 0 | 0.017 |
Normalized to Ccr as Ex/Ccr c | |||||
(ECd/Ccr) × 100, µg/L filtrate | 11.27 ± 9.89 | 8.10 ± 9.06 | 9.67 ± 6.60 | 17.44 ± 14.17 | <0.001 |
(Eβ2M/Ccr) × 100, mg/L filtrate | 7.74 ± 29.06 | 0.18 ± 0.28 | 1.82 ± 11.58 | 27.82 ± 52.20 | <0.001 |
(Eα1M/Ccr) × 100, mg/L filtrate | 15.00 ± 28.25 | 4.46 ± 3.59 | 7.45 ± 6.63 | 41.20 ± 48.68 | <0.001 |
(EAlb/Ccr) × 100, mg/L filtrate | 29.06 ± 75.93 | 7.50 ± 9.83 | 20.23 ± 56.82 | 65.68 ± 119.75 | <0.001 |
(EProt/Ccr) × 100, mg/L filtrate | 109.9 ± 316.8 | 13.0 ± 19.1 | 56.3 ± 141.0 | 310.2 ± 568.2 | <0.001 |
Variables | Age | BMI | ECd/Ccr | EProt/Ccr | EAlb/Ccr | Eβ2M/Ccr | Eα1M/Ccr |
---|---|---|---|---|---|---|---|
Age | |||||||
BMI | −0.248 *** | ||||||
ECd/Ccr | 0.778 *** | −0.050 | |||||
EProt/Ccr | 0.516 *** | −0.133 | 0.507 *** | ||||
EAlb/Ccr | 0.320 *** | −0.120 | 0.152 * | 0.546 *** | |||
Eβ2M/Ccr | 0.421 *** | −0.184 ** | 0.430 *** | 0.508 *** | 0.537 *** | ||
Eα1M/Ccr | 0.368 *** | −0.164 * | 0.364 *** | 0.508 *** | 0.653 *** | 0.825 *** | |
Creatinine | 0.152 ** | 0.084 | 0.169 ** | 0.217 *** | −0.024 | −0.067 | 0.015 |
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Satarug, S.; Vesey, D.A.; Gobe, G.C. Cadmium-Induced Proteinuria: Mechanistic Insights from Dose–Effect Analyses. Int. J. Mol. Sci. 2023, 24, 1893. https://doi.org/10.3390/ijms24031893
Satarug S, Vesey DA, Gobe GC. Cadmium-Induced Proteinuria: Mechanistic Insights from Dose–Effect Analyses. International Journal of Molecular Sciences. 2023; 24(3):1893. https://doi.org/10.3390/ijms24031893
Chicago/Turabian StyleSatarug, Soisungwan, David A. Vesey, and Glenda C. Gobe. 2023. "Cadmium-Induced Proteinuria: Mechanistic Insights from Dose–Effect Analyses" International Journal of Molecular Sciences 24, no. 3: 1893. https://doi.org/10.3390/ijms24031893
APA StyleSatarug, S., Vesey, D. A., & Gobe, G. C. (2023). Cadmium-Induced Proteinuria: Mechanistic Insights from Dose–Effect Analyses. International Journal of Molecular Sciences, 24(3), 1893. https://doi.org/10.3390/ijms24031893