Lifestyle-Related Exposure to Cadmium and Lead is Associated with Diabetic Kidney Disease.
ABSTRACT: BACKGROUND:Environmental factors contributing to diabetic kidney disease are incompletely understood. We investigated whether blood cadmium and lead concentrations were associated with the prevalence of diabetic kidney disease, and to what extent lifestyle-related exposures (diet and smoking) contribute to blood cadmium and lead concentrations. MATERIAL AND METHODS:In a cross-sectional analysis in 231 patients with type 2 diabetes included in the DIAbetes and LifEstyle Cohort Twente (DIALECT-1), blood cadmium and lead concentrations were determined using inductively coupled plasma mass spectrometry. The associations between diet (derived from food frequency questionnaire), smoking and cadmium and lead were determined using multivariate linear regression. The associations between cadmium and lead and diabetic kidney disease (albumin excretion >30 mg/24 h and/or creatinine clearance <60 mL/min/1.73 m2) were determined using multivariate logistic regression. RESULTS:Median blood concentrations were 2.94 nmol/L (interquartile range (IQR): 1.78-4.98 nmol/L) for cadmium and 0.07 µmol/L (IQR: 0.04-0.09 µmol/L) for lead, i.e., below acute toxicity values. Every doubling of lead concentration was associated with a 1.75 (95% confidence interval (CI): 1.11-2.74) times higher risk for albuminuria. In addition, both cadmium (odds ratio (OR) 1.50 95% CI: 1.02-2.21) and lead (OR 1.83 95% CI: 1.07-3.15) were associated with an increased risk for reduced creatinine clearance. Both passive smoking and active smoking were positively associated with cadmium concentration. Alcohol intake was positively associated with lead concentration. No positive associations were found between dietary intake and cadmium or lead. CONCLUSIONS:The association between cadmium and lead and the prevalence of diabetic kidney disease suggests cadmium and lead might contribute to the development of diabetic kidney disease. Exposure to cadmium and lead could be a so far underappreciated nephrotoxic mechanism of smoking and alcohol consumption.
Project description:Evidence suggests that chronic low level cadmium exposure impairs the function of insulin-producing ? cells and may be associated with type-2 diabetes mellitus. Herein, we describe the cadmium content in primary human islets and define the uptake kinetics and effects of environmentally relevant cadmium concentrations in cultured ? cells. The average cadmium content in islets from 10 non-diabetic human subjects was 29 ± 7 nmol/g protein (range 7 to 72 nmol/g protein). Exposure of the ?-cell line MIN6 to CdCl 2 concentrations between 0.1 and 1.0 µmol/L resulted in a dose- and time-dependent uptake of cadmium over 72 h. This uptake resulted in an induction of metallthionein expression, likely enhancing cellular cadmium accumulation. Furthermore, cadmium accumulation resulted in an inhibition of glucose stimulated insulin secretion in MIN6 cells and primary mouse islets. Our results indicate that this impairment in ?-cell function is not due to an increase in cell death or due to an increase in oxidative stress. We conclude that mouse ? cells accumulate cadmium in a dose- and time-dependent manner over a prolonged time course at environmentally relevant concentrations. This uptake leads to a functional impairment of ?-cell function without significant alterations in cell viability, expression of genes important for ?-cell function or increase in oxidative stress.
Project description:Environmental cadmium and lead exposures are widespread, and both metals are nephrotoxic at high exposure levels. Few studies have evaluated the associations between low-level cadmium and clinical renal outcomes, particularly with respect to joint cadmium and lead exposure. The geometric mean levels of blood cadmium and lead were 0.41 microg/L (3.65 nmol/L) and 1.58 microg/dL (0.076 micromol/L), respectively, in 14,778 adults aged >or=20 years who participated in the National Health and Nutrition Examination Survey (1999-2006). After adjustment for survey year, sociodemographic factors, chronic kidney disease risk factors, and blood lead, the odds ratios for albuminuria (>or=30 mg/g creatinine), reduced estimated glomerular filtration rate (eGFR) (<60 mL/minute/1.73 m(2)), and both albuminuria and reduced eGFR were 1.92 (95% confidence interval (CI): 1.53, 2.43), 1.32 (95% CI: 1.04, 1.68), and 2.91 (95% CI: 1.76, 4.81), respectively, comparing the highest with the lowest blood cadmium quartiles. The odds ratios comparing participants in the highest with the lowest quartiles of both cadmium and lead were 2.34 (95% CI: 1.72, 3.18) for albuminuria, 1.98 (95% CI: 1.27, 3.10) for reduced eGFR, and 4.10 (95% CI: 1.58, 10.65) for both outcomes. These findings support consideration of cadmium and lead as chronic kidney disease risk factors in the general population and provide novel evidence of risk with environmental exposure to both metals.
Project description:Elevated red blood cell distribution width (RDW), traditionally an indicator of anemia, has now been recognized as a risk marker for cardiovascular disease incidence and mortality. Experimental and acute exposure studies suggest that cadmium and lead individually affect red blood cell production; however, associations between environmental exposures and RDW have not been explored. We evaluated relationships of environmental cadmium and lead exposures to RDW. We used data from 24,607 participants aged ?20 years in the National Health and Nutrition Examination Survey (2003-2016) with information on blood concentrations of cadmium and lead, RDW and socio-demographic factors. In models adjusted for age, sex, race/ethnicity, education, poverty income ratio, BMI, alcohol consumption, smoking status and serum cotinine, RDW was increasingly elevated across progressively higher quartiles of blood cadmium concentration. A doubling of cadmium concentration was associated with 0.16 higher RDW (95% CI: 0.14, 0.18) and a doubling of lead concentration with 0.04 higher RDW (95% CI: 0.01, 0.06). Also, higher cadmium and lead concentrations were associated with increased odds of high RDW (RDW>14.8%). The associations were more pronounced in women and those with low-to-normal mean corpuscular volume (MCV) and held even after controlling for iron, folate or vitamin B12 deficiencies. In analysis including both metals, cadmium remained associated with RDW, whereas the corresponding association for lead was substantially attenuated. In this general population sample, blood cadmium and lead exposures were positively associated with RDW. The associations may indicate hemolytic or erythropoietic mechanisms by which exposure increases mortality risk.
Project description:Low-level cadmium exposure, resulting in, for example, urinary cadmium <2.0 ?g/g creatinine, is widespread; recent data suggest nephrotoxicity even at these low levels. Few studies have examined the impact of low-level cadmium exposure in workers who are occupationally exposed to other nephrotoxicants such as lead.We evaluated associations of urine cadmium, a measure of cumulative dose, with four glomerular filtration measures and N-acetyl-?-D-glucosaminidase (NAG) in lead workers. Recent and cumulative lead doses were assessed via blood and tibia lead, respectively.In 712 lead workers, mean (SD) blood and tibia lead values, urine cadmium values and estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation were 23.1 (14.1) ?g/dl, 26.6 (28.9) ?g Pb/g bone mineral, 1.15 (0.66) ?g/g creatinine and 97.4 (19.2) ml/min/1.73 m(2), respectively. After adjustment for age, sex, body mass index, urine creatinine, smoking, alcohol, education, annual income, diastolic blood pressure, current or former lead worker job status, new or returning study participant, and blood and tibia lead, higher ln-urine cadmium was associated with higher calculated creatinine clearance, eGFR (? = 8.7 ml/min/1.73 m(2); 95% CI 5.4 to 12.1) and ln-NAG but lower serum creatinine.Potential explanations for these results include a normal physiological response in which urine cadmium levels reflect renal filtration, the impact of adjustment for urine dilution with creatinine in models of kidney outcomes, and cadmium-related hyperfiltration.
Project description:Age-related macular degeneration (AMD) is a complex disease resulting from the interplay of genetic predisposition and environmental exposures, and has been linked to oxidative stress and inflammatory mechanisms. Lead and cadmium can accumulate in human retinal tissues and may damage the retina through oxidative stress, and may thereby play a role in the development of AMD. We examined associations between blood lead, blood cadmium, and urinary cadmium concentrations and the presence of AMD in 5390 participants aged 40 years and older with blood lead and blood cadmium measures and a subsample of 1548 with urinary cadmium measures in the 2005-2008 National Health and Nutrition Examination Surveys. AMD was identified by grading retinal photographs with a modification of the Wisconsin Age-Related Maculopathy Grading System. The weighted prevalence of AMD was 6.6% (n=426). Controlling for age, gender, race/ethnicity, education and body mass index, adults in the highest blood cadmium quartile had higher odds of AMD compared to the lowest quartile (odds ratio [OR], 1.56; 95% CI, 1.02-2.40), with a significant trend across quartiles (p-trend=0.02). After further adjustment for pack-years of cigarette smoking, estimates were somewhat attenuated (OR, 1.43; 95% CI, 0.91-2.27; p-trend=0.08). Similar associations were found with urinary cadmium. The association between urinary cadmium and AMD was stronger in non-Hispanic whites (NHW) than in non-Hispanic blacks (NHB) (OR, 3.31; 95% CI, 1.37-8.01 for levels above versus below the median among NHW; OR,1.45; 95% CI, 0.40-5.32 for levels above versus below the median among NHB; p-interaction=0.03). We found no association between blood lead levels and AMD. Higher cadmium body burden may increase risk of AMD, particularly among non-Hispanic white individuals; however, additional studies are needed before firm conclusions can be drawn.
Project description:<h4>Objectives</h4>Cadmium exposure has been found to be associated with atherosclerotic plaques in the carotid arteries and with circulating levels of the proatherogenic intercellular adhesion molecule-1 (ICAM-1). The research questions were (1) if blood and urinary cadmium levels are associated with low ankle-brachial index (ABI) as a measure of peripheral artery disease in a longitudinal study and (2) if ICAM-1 mediates proatherogenic effects of cadmium exposure.<h4>Design</h4>A prospective, observational cohort study with a 5-year follow-up and an experimental study of cultured human aortic endothelial cells exposed to cadmium.<h4>Setting</h4>Research unit at a university hospital.<h4>Participants</h4>A cohort of 64-year-old women (n=489) recruited by stratified sampling of similarly sized groups with normal, impaired and diabetic glucose tolerance as assessed in a population-based screening examination.<h4>Primary and secondary outcome measures</h4>ABI (ratio of the systolic blood pressures in the tibial and brachial arteries ?0.9 in any artery) in relation to cadmium exposure; ICAM-1 concentrations in the cell culture medium after cadmium incubation.<h4>Results</h4>High (tertile 3 vs 1) concentrations of blood (B-Cd) or creatine-adjusted urinary cadmium (U-Cd) at baseline were found to predict low ABI after adjustment for smoking and other cardiovascular risk factors at baseline. For U-Cd the OR was 2.5 (95% CI 1.1 to 5.8). After exclusion of participants with ultrasound-assessed femoral atherosclerosis at baseline the OR for U-Cd was unchanged, and for B-Cd it was 3.7 (95% CI 1.05 to 13.3). Inclusion of serum ICAM-1 levels did not affect the cadmium-related ORs in multivariate analyses. The experimental study did not show any cadmium-induced increase of the production of ICAM-1 from human endothelial cells.<h4>Conclusions</h4>Cadmium exposure was associated with future peripheral artery disease, supporting the concept that cadmium exposure in the population has proatherogenic effects, although ICAM-1 mediated effects do not seem to be involved.
Project description:Hearing loss is the second most common nonfatal problem affecting the Chinese population. Historical studies have suggested an association between exposure to heavy metals, such as cadmium and lead, and hearing loss. Few studies have investigated this relationship in the general population in China. We conducted a case-control study with 1008 pairs of participants from a cross-sectional epidemiological survey conducted in Zhejiang Province. A self-designed questionnaire was adopted to collect information on demographics, chronic diseases, lifestyles and environmental noise. Pure-tone averages of hearing thresholds at frequencies of 0.5, 1, 2, and 4 kHz were computed. Blood lead and cadmium levels were analyzed with an atomic absorption spectrometer. After adjusting for all other potential confounding factors, compared with the lowest blood cadmium quartile (0.00-0.53 ?g/L), blood cadmium quartile 2 (0.54-0.92 ?g/L), quartile 3 (0.93-1.62 ?g/L) and quartile 4 (1.63-57.81 ?g/L) exhibited significantly elevated risks for hearing loss, with odds ratios of 1.932 (95% CI: 1.356-2.751), 2.036 (95% CI: 1.423-2.914) and 1.495 (95% CI: 1.048-2.133), respectively (P-trend<0.001). However, an association of lead with hearing loss was not found. Young age (less than 60 years), male sex and current smoking were associated with increased blood cadmium concentration. Additionally, a positive association between blood cadmium and lead concentrations was found. Therefore, we conclude that exposure to environmental cadmium may be a risk factor for hearing loss among the general population in China.
Project description:BACKGROUND: Cadmium (Cd), lead (Pb), and mercury (Hg) cause toxicological renal effects, but the clinical relevance at low-level exposures in general populations is unclear. The objective of this study is to assess the risk of developing end-stage renal disease in relation to Cd, Pb, and Hg exposure. METHODS: A total of 118 cases who later in life developed end-stage renal disease, and 378 matched (sex, age, area, and time of blood sampling) referents were identified among participants in two population-based prospective cohorts (130,000 individuals). Cd, Pb, and Hg concentrations were determined in prospectively collected samples. RESULTS: Erythrocyte lead was associated with an increased risk of developing end-stage renal disease (mean in cases 76 ?g/L; odds ratio (OR) 1.54 for an interquartile range increase, 95% confidence interval (CI) 1.18-2.00), while erythrocyte mercury was negatively associated (2.4 ?g/L; OR 0.75 for an interquartile range increase, CI 0.56-0.99). For erythrocyte cadmium, the OR of developing end-stage renal disease was 1.15 for an interquartile range increase (CI 0.99-1.34; mean Ery-Cd among cases: 1.3 ?g/L). The associations for erythrocyte lead and erythrocyte mercury, but not for erythrocyte cadmium, remained after adjusting for the other two metals, smoking, BMI, diabetes, and hypertension. Gender-specific analyses showed that men carried almost all of the erythrocyte lead and erythrocyte cadmium associated risks. CONCLUSIONS: Erythrocyte lead is associated with end-stage renal disease but further studies are needed to evaluate causality. Gender-specific analyses suggest potential differences in susceptibility or in exposure biomarker reliability.
Project description:Gender differences in the association of blood and urine cadmium concentrations with peripheral arterial disease (PAD) were evaluated by using data from 6,456 US adults aged ?40 years who participated in the 1999-2004 National Health and Nutrition Examination Survey. PAD was defined as an ankle-brachial blood pressure index of <0.9 in at least one leg. For men, the adjusted odds ratios for PAD comparing the highest with the lowest quintiles of blood and urine cadmium concentrations were 1.82 (95% confidence interval (CI): 0.82, 4.05) and 4.90 (95% CI: 1.55, 15.54), respectively, with a progressive dose-response relation and no difference by smoking status. For women, the corresponding odds ratios were 1.19 (95% CI: 0.66, 2.16) and 0.56 (95% CI: 0.18, 1.71), but there was evidence of effect modification by smoking: among women ever smokers, there was a positive, progressive dose-response relation; among women never smokers, there was a U-shaped dose-response relation. Higher blood and urine cadmium levels were associated with increased prevalence of PAD, but women never smokers showed a U-shaped relation with increased prevalence of PAD at very low cadmium levels. These findings add to the concern of increased cadmium exposure as a cardiovascular risk factor in the general population.
Project description:BACKGROUND: Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD). METHODS: We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54-5.19) using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease. RESULTS: Study participants were at baseline on average 47±13 years old and 65% were male. Mean±standard deviation of homoarginine concentrations were 2.5±1.1 µmol/L and concentrations were incrementally lower at lower levels of GFR with mean concentrations of 2.90±1.02 µmol/L (GFR>90 ml/min), 2.64±1.06 µmol/L (GFR 60-90 ml/min), 2.52±1.24 µmol/L (GFR 30-60 ml/min) and 2.05±0.78 µmol/L (GFR<30 ml/min), respectively (p?=?0.002). The age- and sex-adjusted risk to reach the renal endpoint was significantly higher by 62% with each decrease by one standard deviation (1.1 µmol/L) of homoarginine (HR 1.62, 95% CI 1.16-2.27, p?=?0.005). This association was independent of proteinuria (HR 1.56, 95% CI 1.11-2.20, p?=?0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95% CI 0.98-1.98, p?=?0.06). CONCLUSIONS: Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations.