Hospital-based screening to detect patients with cadmium nephropathy in cadmium-polluted areas in Japan.

BACKGROUND: In health examinations for local inhabitants in cadmium-polluted areas, only healthy people are investigated, suggesting that patients with severe cadmium nephropathy or itai-itai disease may be overlooked. Therefore, we performed hospital-based screening to detect patients with cadmium nephropathy in two core medical institutes in cadmium-polluted areas in Akita prefecture, Japan. METHODS: Subjects for this screening were selected from patients aged 60 years or older with elevated serum creatinine levels and no definite renal diseases. We enrolled 35 subjects from a hospital in Odate city and 22 from a clinic in Kosaka town. Urinary ß2-microglobulin and blood and urinary cadmium levels were measured. RESULTS: The criteria for renal tubular dysfunction and the over-accumulation of cadmium were set as a urinary ß2-microglobulin level higher than 10,000 µg/g cr. and a blood cadmium level higher than 6 µg/L or urinary cadmium level higher than 10 µg/g cr., respectively. Subjects who fulfilled both criteria were diagnosed with cadmium nephropathy. Six out of 57 patients (10.5% of all subjects) had cadmium nephropathy. CONCLUSIONS: This hospital-based screening is a very effective strategy for detecting patients with cadmium nephropathy in cadmium-polluted areas, playing a complementary role in health examinations for local inhabitants. REGISTRATION NUMBER: No. 6, date of registration: 6 June, 2010 (Akita Rosai Hospital), and No. 1117, date of registration: 26 December, 2013 (Akita University).

The Effects of a Workplace Health Promotion Program to Decrease Cadmium Exposure Levels in Nickel-Cadmium Battery Workers.

OBJECTIVE: Cadmium exposure is a common problem in the production of nickel-cadmium batteries. However, keeping the respective legislative occupational and safety policies is essential, but there are problems with compliance. We analysed the effect of strategies to increase compliance with precautions during 20132015 on 59 workers at a nickel-cadmium battery factory. MATERIAL AND METHODS: A health promotion program was implemented in two phases. The first phase included comprehensive education on the importance of appropriate behaviour and changes to the sanitation program. The second phase included renovation of sanitary facilities and modernization of the air exhaust ventilation. RESULTS: The initial median cadmium urinary level in workers was 1.9 µg/g creatinine. After the first phase of interventions, levels dropped to 1.0 µg/g creatinine. After the second phase no significant further decrease was observed. CONCLUSION: Comprehensive education and changes in the sanitation program were able to halve cadmium levels and can be considered a useful and cost-effective preventive tool.

Noninvasive Biomarker Candidates for Cadmium-Induced Nephrotoxicity by 2DE/MALDI-TOF-MS and SILAC/LC-MS Proteomic Analyses.

Cadmium (Cd(2+)) is a major environmental pollutant that induces cytotoxicity by heavy-metal accumulation. Prolonged Cd(2+) exposure leads to cell damage by oxidative stress mainly in the kidneys, a critical organ for detoxification. To identify reliable on invasive protein biomarkers for Cd(2+)-induced nephrotoxicity, we performed 2-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization time of flight mass spectra and stable isotope labeling by amino acids in cell culture/liquid chromatography-mass spectrometry analyses using conditioned media (CM) of HK-2 human kidney epithelial cells treated with CdCl2. Here, we identified heat shock cognate 71 kDa protein isoform1 (HSPA8) and α-enolase (ENO1) as potential biomarker candidates for the evaluation of Cd(2+)-induced nephrotoxicity. Treatment with CdCl2 increased the protein level of HSPA8 in CM and lysates of HK-2 cells. The mRNA level of HSPA8 was also increased by CdCl2 treatment, indicating transcriptional regulation. The level of ENO1 was increased in CM, but not in lysates of CdCl2-treated HK-2 cells. CdCl2 did not affect the mRNA level of ENO1. We provide evidence that the increases of HSPA8 and ENO1 in CM were due to Cd(2+)-induced cell death through oxidative stress. The increases of HSPA8 and ENO1 levels were also detected in CM of HK-2 cells treated with other nephrotoxic agents, such as HgCl2, NaAsO2, cisplatin, amphotericin B, and cyclosporine A. Urine and kidney tissues of CdCl2-treated rats showed increased levels of HSPA8. Taken together, this study identified HSPA8 and ENO1 as noninvasive biomarker candidates by 2 comparative proteomic analyses. These new biomarker candidates may have potential as alternatives to traditional biomarkers for the efficient and sensitive assessment of nephrotoxicity.

Identifying early urinary metabolic changes with long-term environmental exposure to cadmium by mass-spectrometry-based metabolomics.

Cadmium (Cd) is a common environmental pollutant, and urinary Cd (UCd) is generally used as a marker of exposure; however, our understanding on the related urinary metabolic changes caused by Cd exposure is still not clear. In this study, we applied a mass-spectrometry-based metabolomic approach to assess the urinary metabolic changes in human with long-term environmental Cd exposure, aimed to identify early biomarkers to assess Cd nephrotoxicity. Urine samples from 94 female never smokers aged 44-70 with UCd in the range of 0.20-68.67 µg/L were analyzed by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-ToF-MS) and gas chromatography-mass spectrometry (GC-MS). It was found that metabolites related to amino acid metabolism (L-glutamine, L-cystine, L-tyrosine, N-methyl-L-histidine, L-histidinol, taurine, phenylacetylglutamine, hippurate, and pyroglutamic acid), galactose metabolism (D-galactose and myo-inositol), purine metabolism (xanthine, urea, and deoxyadenosine monophosphate), creatine pathway (creatine and creatinine), and steroid hormone biosynthesis (17-α-hydroxyprogesterone, tetrahydrocortisone, estrone, and corticosterone) were significantly higher among those with a UCd level higher than 5 µg/L. Moreover, we noticed that the level of N-methyl-L-histidine had already started to elevate among individuals with a UCd concentration of ≥2 µg/L. The overall findings illustrate that metabolomics offer a useful approach for revealing metabolic changes as a result of Cd exposure.

A biomarker found in cadmium exposed residents of Thailand by metabolome analysis.

First, the urinary metabolic profiling by gas chromatography-mass spectrometry (GC-MS), was performed to compare ten cadmium (Cd) toxicosis cases from a Cd-polluted area in Mae Sot (Thailand) with gender-matched healthy controls. Orthogonal partial list square-discrimination analysis was used to identify new biomarker candidates in highly Cd exposed toxicosis cases with remarkable renal tubular dysfunction. The results of the first step of this study showed that urinary citrate was a negative marker and myo-inositol was a positive marker for Cd toxicosis in Thailand. In the second step, we measured urinary citrate in the residents (168 Cd-exposed subjects and 100 controls) and found significantly lower levels of urinary citrate and higher ratios of calcium/citrate and magnesium/citrate, which are risk factors for nephrolithiasis, in highly Cd-exposed residents. Additionally, this inverse association of urinary citrate with urinary Cd was observed after adjustment for age, smoking and renal tubular dysfunction, suggesting a direct effect of Cd on citrate metabolism. These results indicate that urinary citrate is a useful biomarker for the adverse health effects of Cd exposure in a Thai population with a high prevalence of nephrolithiasis.

[Analysis of clinical features of mild chronic cadmium poisoning induced by different causes].

OBJECTIVE: To analyze the clinical features of mild chronic cadmium poisoning induced by different causes. METHODS: A total of 90 patients with mild chronic cadmium poisoning, who were hospitalized in our center from 2008 to 2011 and had complete clinical data, were divided into two groups according to the causes of poisoning: environmental pollution group (n = 45) and occupational poisoning group (n = 45). The clinical symptoms, signs, laboratory indices, and treatment outcomes of all patients were analyzed. RESULTS: Compared with the environmental pollution group, the occupational poisoning group had more bone pain, less bone injury (based on imaging findings), and significantly increased abnormal rate of urinary retinol-binding protein (RBP) (P < 0.05); there were no significant differences in urinary ß-2 microglobulin (MG) and urinary microalbumin between the two groups (P > 0.05). Urinary cadmium, urinary RBP, and urinary ß-2 MG had no linear correlation between each other in the two groups. Both groups showed significant changes in urinary cadmium levels after treatment (P < 0.05). CONCLUSION: The clinical features of mild chronic cadmium poisoning induced by various causes are different, and active nutritional support therapy plays a positive role in improving prognosis.

Co-exposure to lead increases the renal response to low levels of cadmium in metallurgy workers.

PURPOSE: Research on the effect of co-exposure to Cd and Pb on the kidney is scarce. The objective of the present study was to assess the effect of co-exposure to these metals on biomarkers of early renal effect. METHODS: Cd in blood (Cd-B), Cd in urine (Cd-U), Pb in blood (Pb-B) and urinary renal biomarkers, i.e., microalbumin (µ-Alb), beta-2-microglobulin (ß2-MG), retinol binding protein (RBP), N-acetyl-ß-d-glucosaminidase (NAG), intestinal alkaline phosphatase (IAP) were measured in 122 metallurgic refinery workers examined in a cross-sectional survey. RESULTS AND CONCLUSIONS: The median Cd-B, Cd-U, Pb-B were: 0.8 µg/l (IQR = 0.5, 1.2), 0.5 µg/g creatinine (IQR = 0.3, 0.8) and 158.5 µg/l (IQR = 111.0, 219.3), respectively. The impact of Cd-B on the urinary excretion of NAG and IAP was only evident among workers with Pb-B concentrations ≥ 75th percentile. The association between Cd-U and the renal markers NAG and RBP was also evidenced when Pb-B ≥ 75th percentile. No statistically significant interaction terms were observed for the associations between Cd-B or Cd-U and the other renal markers under study (i.e., µ-Alb and ß2-MG). Our findings indicate that Pb increases the impact of Cd exposure on early renal biomarkers.

Ailing bones and failing kidneys: a case of chronic cadmium toxicity.

Heavy metal toxicity is often caused by occupational exposure. Chronic cadmium toxicity is a significant health concern among workers engaged in zinc smelting, battery production and silver jewellery industries, particularly in developing countries. We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome. He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure. Cadmium has a long biological half-life and there is no effective treatment for people who are exposed to it. Therefore, an early diagnosis and prevention of further exposure are important.

Cadmium exposure induces hematuria in Korean adults.

INTRODUCTION: Toxic heavy metals have adverse effects on human health. However, the risk of hematuria caused by heavy metal exposure has not been evaluated. METHODS: Data from 4701 Korean adults were obtained in the Korean National Health and Nutritional Examination Survey (2008-2010). Blood levels of the toxic heavy metals cadmium, lead, and mercury were measured. Hematuria was defined as a result of ≥+1 on a urine dipstick test. The odds ratios (ORs) for hematuria were measured according to the blood heavy metal levels after adjusting for multiple variables. RESULTS: Individuals with blood cadmium levels in the 3rd and 4th quartiles had a greater OR for hematuria than those in the 1st quartile group: 3rd quartile, 1.35 (1.019-1.777; P=0.037); 4th quartile, 1.52 (1.140-2.017; P=0.004). When blood cadmium was considered as a log-transformed continuous variable, the correlation between blood cadmium and hematuria was significant: OR, 1.97 (1.224-3.160; Ptrend=0.005). In contrast, no significant correlations between hematuria and blood lead or mercury were found in the multivariate analyses. DISCUSSION: The present study shows that high cadmium exposure is associated with a risk of hematuria.

A polymorphism in metallothionein 1A (MT1A) is associated with cadmium-related excretion of urinary beta 2-microglobulin.

OBJECTIVES: Cadmium (Cd) toxicity of the kidney varies between individuals despite similar exposure levels. In humans Cd is mainly bound to metallothioneins (MT), which scavenge its toxic effects. Here we analyzed whether polymorphisms in MT genes MT1A and MT2A influence Cd-related kidney damage. METHODS: In a cross-sectional study N=512 volunteers were selected from three areas in South-Eastern China, which to varying degree were Cd-polluted from a smelter (control area [median Cd in urine U-Cd=2.67 µg/L], moderately [U-Cd=4.23 µg/L] and highly [U-Cd=9.13 µg/L] polluted areas). U-Cd and blood Cd (B-Cd) concentrations were measured by graphite-furnace atomic absorption spectrometry. MT1A rs11076161 (G/A), MT2A rs10636 (G/C) and MT2A rs28366003 (A/G) were determined by Taqman assays; urinary N-Acetyl-beta-(D)-Glucosaminidase (UNAG) by spectrometry, and urinary ß2-microglobulin (UB2M) by ELISA. RESULTS: Higher B-Cd (natural log-transformed) with increasing number of MT1A rs11076161 A-alleles was found in the highly polluted group (p-value trend=0.033; all p-values adjusted for age, sex, and smoking). In a linear model a significant interaction between rs11076161 genotype and B-Cd was found for UNAG (p=0.001) and UB2M concentrations (p=0.001). Carriers of the rs11076161 AA genotype showed steeper slopes for the associations between Cd in blood and natural log-transformed UB2M (ß=1.2, 95% CI 0.72-1.6) compared to GG carriers (ß=0.30, 95% CI 0.15-0.45). Also for UNAG (natural log-transformed) carriers of the AA genotype had steeper slopes (ß=0.55, 95% CI 0.27-0.84) compared to GG carriers (ß=0.018, 95% CI -0.79-0.11). CONCLUSIONS: MT1A rs11076161 was associated with B-Cd concentrations and Cd-induced kidney toxicity at high exposure levels.

Effect of glutathione on the cadmium chelation of EDTA in a patient with cadmium intoxication.

In order to evaluate the efficiency and renal protective effects of glutathione during Ca(++)-EDTA chelation therapy for chronic cadmium intoxication, we measured the renal excretion of cadmium, ß(2)-microglobulin, proteinuria, and hematuria during intravenous administration of glutathione with Ca(++)-EDTA in a 54-year-old patient with chronic cadmium intoxication. We administered 500 mg of Ca(++)-EDTA and 50 mg/kg of glutathione alone or in 1 L of normal saline over the next 24 hours and repeated this over 12 consecutive days. During the first 3 days, the basal levels (only saline administration) were determined; during the second 3 days, Ca(++)-EDTA only was administered, for the third sequence of 3 days, Ca(++)-EDTA with glutathione was provided, and for the last 3 days, glutathione alone was given. One month later, the same protocol was repeated. There were six blood and urine samples to analyze in each group. The blood cadmium level was higher when the EDTA was infused together with glutathione (7.44 ± 0.73 µg/L, p < 0.01) compared to the basal level of 4.6 ± 0.44 µg/L. Also, the renal cadmium excretion was significantly higher in the EDTA with glutathione group than in the basal group (23.4 ± 15.81 µg/g creatinine vs 89.23 ± 58.52 µg/g creatinine, p < 0.01). There was no difference in the protein/creatinine and ß(2)-microglobulin/creatinine ratio in the urine (p > 0.05) among the groups. Furthermore, microhematuria and proteinuria did not develop over the observation period of 6 months. These results suggest that glutathione administration with EDTA might be an effective treatment modality for patients with cadmium intoxication.

Reassessment of the threshold of urinary cadmium by using hybrid approach in a cadmium non-polluted area in Japan.

BACKGROUND AND OBJECTIVES: We applied an updated hybrid approach to estimate the benchmark doses (BMD) and their 95% lower confidence limits (BMDL) for cadmium-induced renal effects as the threshold of urinary cadmium in humans. Using this method, the BMD and BMDL were estimated based on continuous exposure and continuous effect marker, thereby avoiding categorization of subjects, an inevitable outcome of previously used approaches. METHODS: The target subjects were 547 men and 723 women, aged 50 years or older, who lived in a cadmium non-polluted area of Japan. We measured urinary cadmium (U-Cd) as a marker of long-term exposure, and urinary protein, ß2-microglobulin (ß2-MG) and N-acetyl-ß-D-glucosaminidase (NAG) as renal effect markers. BMD and BMDL corresponding to an additional risk (BMR) of 5%, were calculated with the background risk at zero exposure set at 5%. RESULTS AND CONCLUSIONS: The BMDL of U-Cd for renal effect markers were 2.1 (urinary protein), 2.6 (ß2-MG) and 4.1 (NAG) µg/g creatinine in men and 1.5 (urinary protein), 1.4 (ß2-MG) and 3.1 (NAG) µg/g creatinine in women. The BMDLs in the present study may contribute to further discussion on health risk assessment of cadmium exposure, when compared to BMDLs obtained by previously reported methods.

The relationship between the bone mineral density and urinary cadmium concentration of residents in an industrial complex.

BACKGROUND: An association between cadmium exposure and bone mineral density (BMD) has been demonstrated in elderly women, but has not been well studied in youths and men. Some studies report either no or a weak association between cadmium exposure and bone damage. OBJECTIVES: This study was designed to investigate the relationship between the urinary cadmium (U-Cd) levels and BMD of females and males of all ages. METHODS: A total of 804 residents near an industrial complex were surveyed in 2007. U-Cd and BMD on the heel (non-dominant calcaneus) were analyzed with AAS-GTA and Dual-Energy X-ray absorptiometry, respectively. Demographic characteristics were collected by structured questionnaires. Osteoporosis and osteopenia were defined by BMD cut-off values and T-scores set by the WHO; T score>-1, normal; -2.5

Latest status of cadmium accumulation and its effects on kidneys, bone, and erythropoiesis in inhabitants of the formerly cadmium-polluted Jinzu River Basin in Toyama, Japan, after restoration of rice paddies.

PURPOSE: The cadmium-polluted Jinzu River Basin in Toyama, Japan, where nephropathy and itai-itai disease were endemic among resident farmers decades ago, has been almost completely restored. The aim of this study is to investigate whether inhabitants there would still exhibit cadmium accumulation and its effects on kidneys, bones, and erythropoiesis. METHODS: We performed a cross-sectional study of 150 subjects from the polluted area and 144 controls from the same prefecture. Participants included female inhabitants from 34 to 74 years of age who underwent examinations to gather anthropometrical and medical information, obtain rice, blood and urine samples, and measure bone mineral density. RESULTS: Cadmium concentration in rice from the polluted area was lower than the level in the control area. Blood and urinary cadmium and urinary ß(2)-microglobulin levels were higher in subjects from the polluted area than controls, and the urinary ß(2)-microglobulin was independently affected by urinary cadmium. Bone mineral density did not differ between the two areas, but it was affected by renal tubular function in subjects from the polluted area. Serum bone alkaline phosphatase was lower in subjects from the polluted area compared to controls. We detected three cases of cadmium nephropathy among the subjects. One of them suffered from a renal anemia type of itai-itai disease. CONCLUSION: Inhabitants in the formerly polluted area still had high cadmium accumulations and showed a characteristic natural history of chronic cadmium toxicity, indicating that the risk remains for developing nephropathy or itai-itai disease in the future.

Cadmium exposure in association with history of stroke and heart failure.

BACKGROUND: It is unclear whether environmental cadmium exposure is associated with cardiovascular disease, although recent data suggest associations with myocardial infarction and peripheral arterial disease. OBJECTIVE: The objective of this study was to evaluate the association of measured cadmium exposure with stroke and heart failure (HF) in the general population. METHODS: We analyzed data from 12,049 participants, aged 30 years and older, in the 1999-2006 National Health and Nutrition Examination Survey (NHANES) for whom information was available on body mass index, smoking status, alcohol consumption, and socio-demographic characteristics. RESULTS: At their interviews, 492 persons reported a history of stroke, and 471 a history of HF. After adjusting for demographic and cardiovascular risk factors, a 50% increase in blood cadmium corresponded to a 35% increased odds of prevalent stroke [OR: 1.35; 95% confidence interval (CI): 1.12-1.65] and a 50% increase in urinary cadmium corresponded to a 9% increase in prevalent stroke [OR: 1.09; 95% CI: 1.00-1.19]. This association was higher among women [OR: 1.38; 95% CI: 1.11-1.72] than men [OR: 1.30; 95% CI: 0.93-1.79] (p-value for interaction=0.05). A 50% increase in blood cadmium corresponded to a 48% increased odds of prevalent HF [OR: 1.48; 95% CI: 1.17-1.87] and a 50% increase in urinary cadmium corresponded to a 12% increase in prevalent HF [OR: 1.12; 95% CI: 1.03-1.20], with no difference in sex-specific associations. CONCLUSIONS: Environmental exposure to cadmium was associated with significantly increased stroke and heart failure prevalence. Cadmium exposure may increase these important manifestations of cardiovascular disease.

[Clinical and biochemical syndromes of cadmium-induced acute porphyrinopathy].

AIM: To study the specific features of porphyrin metabolic disturbances in cadmium poisoning. MATERIAL AND METHODS: The paper describes a patient who has developed clinical and biochemical syndromes of acute porphyrinopathy after exposure to cadmium-containing paint the vapors. The levels of delta-aminolevulinic acid, porphobilinogen, coproporphyrin, and uroporphyrin in urine and those of coproporphyrin and protoporphyrin in feces were measured. The concentrations of lead, cadmium, and copper were determined in whole blood and urine; selective screening of amino acids for hereditary metabolic diseases was made. RESULTS: The clinical signs of acute porphyrinopathy developed in the patient mimicked those of acute porphyries known by the current classification. The biochemical syndrome more corresponded to lead poisoning. However, the blood and urinary lead levels were not greater than the normal values, but the blood showed a 4-fold increase in cadmium, which seemed to induce porphyrin dysmetabolism.

Urinary excretion of an oxidative stress marker, 8-hydroxyguanine (8-OH-Gua), among nickel-cadmium battery workers.

The relationship between oxidative stress and carcinogenic metals including nickel and cadmium is a matter of interest. To assess the oxidative stress status of workers exposed to nickel and cadmium simultaneously, we determined urinary excretion of 8-hydroxyguanine (8-OH-Gua), a urinary oxidative stress marker. Our subjects were 66 (64 males and 2 females) nickel-cadmium battery workers. Spot urine and blood samples were collected. The levels of cadmium in blood (Cd-B) and nickel in urine (Ni-U) were determined by graphite furnace atomic absorption spectrophotometry. 8-OH-Gua in urine was analyzed using a high performance liquid chromatography-electrochemical detector (HPLC-ECD) system. Data on age, sex, duration of present work and smoking status were also obtained from each subject. Creatinine-adjusted 8-OH-Gua was significantly correlated with age, Ni-U and Cd-B in univariate analysis, while multivariate analysis revealed that Ni-U and Cd-B were significant independent variables and that these two biological exposure indices were positively correlated with 8-OH-Gua. The data were also analyzed in the context of mixture toxicity. The subjects were divided into groups based on median level of Ni-U and Cd-B (2.86 mug/g creatinine and 0.23 mug/dl, respectively). Workers with high Ni-U/high Cd-B (Group IV) had the highest levels of 8-OH-Gua levels (GM (GSD), 21.7(2.0)), followed by those with high Ni-U/low Cd-B (11.5(1.6) Group III), those with low Ni-U/high Cd-B (8.9(1.9) Group II), and those with low Ni-U/low Cd-B (8.5(1.5) Group I). The p values of Students' t-tests between Group I and Group II, III and IV were 0.847, 0.050 and <0.001, respectively. The combined effect of Cd and Ni on the urinary excretion of 8-OH-Gua departed from additivity.

Striking association between urinary cadmium level and albuminuria among Torres Strait Islander people with diabetes.

OBJECTIVES: Indigenous people of the Torres Strait (Australia) have greater potential for cadmium exposure and renal damage than other Australians due to high cadmium in some traditional seafood and a high prevalence of Type 2 diabetes, hypertension, smoking, and obesity. This study explored associations between albuminuria and an index of cadmium exposure (urinary cadmium excretion) in the presence and absence of Type 2 diabetes. RESEARCH DESIGN AND METHODS: Two population-based, cross-sectional studies were undertaken in the Torres Strait to obtain data on body mass index (BMI), blood pressure, chronic disease, smoking, urinary cadmium, and albumin creatinine ratio (ACR). RESULTS: Age- and BMI-adjusted urinary cadmium levels were significantly higher (p<0.01) among people with diabetes and albuminuria (n=22, geometric mean (GM) 1.91 microg Cd/g creatinine) compared to those with diabetes and normal ACR (n=21, GM 0.74 microg Cd/g creatinine). Urinary cadmium was also strongly associated (p<0.001) with ACR among people with diabetes in regression models and remained significant after controlling for age, sex, BMI, smoking status, and hypertension (or continuous systolic and diastolic measurements). CONCLUSIONS: While the study has methodological limitations and the nature of the association is unclear, the striking dose-dependent links between markers of cadmium exposure and of Type 2 diabetic nephropathy highlight the need for further definitive research on the health effects of cadmium in the presence of diabetes.