Cadmium and Alzheimer's disease mortality in U.S. adults: Updated evidence with a urinary biomarker and extended follow-up time.
ABSTRACT: Cadmium has been linked to impaired cognitive function in adults and may cause behavioral, physiological and molecular abnormalities characteristic of Alzheimer's disease (AD) in animals. Evidence linking cadmium and AD in humans is limited, but supportive. In the most recent epidemiologic study, blood cadmium in U.S. adults was positively associated with elevated AD mortality 7-13 years later. The association between urinary cadmium - an arguably more appropriate biomarker for studying chronic diseases - and AD mortality has not yet been explored. Further study of cadmium and AD mortality in an independent population, with longer follow-up, and stratified by sex is also needed. We sought to answer these questions using the U.S. National Health and Nutrition Examination Survey (NHANES) (1999-2006 cycles) and NHANES III (interviews in 1988-1994) datasets, separately linked to AD mortality as of 2011. We used survey-weighted Cox regression models predicting age at AD death and adjusted for race/ethnicity, sex, smoking status, education and urinary creatinine. An interquartile range (IQR; IQR=0.51ng/mL) increase in urinary cadmium was associated with 58% higher rate of AD mortality (hazard ratio (HR)=1.58, 95% CI: 1.20, 2.09. p-value=0.0009, mean follow-up: 7.5 years) in NHANES 1999-2006 participants. In contrast, in NHANES III participants, an IQR (IQR=0.78ng/mL) increase in urinary cadmium was not associated with AD mortality (HR=0.85, 95% CI: 0.63, 1.17, p-value=0.31, mean follow-up: 13 years). Also in the NHANES III sample however, when the maximum follow-up time was restricted to 12.7 years (i.e. the same as NHANES 1999-2006 participants) and urinary creatinine adjustments were not made, urinary cadmium was associated with elevated AD mortality (HR=1.11, 95% CI: 1.02, 1.20, p-value=0.0086). Our study partially supported an association between cadmium and AD mortality, but the sensitivity of results to follow-up time and creatinine adjustments necessitate cautious interpretation of the association. Further studies, particularly those on toxicological mechanisms, are required to fully understand the nature of the "cadmium-AD mortality" association.
Project description:Environmental and behavioural factors are thought to contribute to all-cause mortality. Here, we develop a method to systematically screen and validate the potential independent contributions to all-cause mortality of 249 environmental and behavioural factors in the National Health and Nutrition Examination Survey (NHANES).We used Cox proportional hazards regression to associate 249 factors with all-cause mortality while adjusting for sociodemographic factors on data in the 1999-2000 and 2001-02 surveys (median 5.5 follow-up years). We controlled for multiple comparisons with the false discovery rate (FDR) and validated significant findings in the 2003-04 survey (median 2.8 follow-up years). We selected 249 factors from a set of all possible factors based on their presence in both the 1999-2002 and 2003-04 surveys and linkage with at least 20 deceased participants. We evaluated the correlation pattern of validated factors and built a multivariable model to identify their independent contribution to mortality.We identified seven environmental and behavioural factors associated with all-cause mortality, including serum and urinary cadmium, serum lycopene levels, smoking (3-level factor) and physical activity. In a multivariable model, only physical activity, past smoking, smoking in participant's home and lycopene were independently associated with mortality. These three factors explained 2.1% of the variance of all-cause mortality after adjusting for demographic and socio-economic factors.Our association study suggests that, of the set of 249 factors in NHANES, physical activity, smoking, serum lycopene and serum/urinary cadmium are associated with all-cause mortality as identified in previous studies and after controlling for multiple hypotheses and validation in an independent survey. Whereas other NHANES factors may be associated with mortality, they may require larger cohorts with longer time of follow-up to detect. It is possible to use a systematic association study to prioritize risk factors for further investigation.
Project description:BACKGROUND:Public health policies such as tobacco control, air pollution reduction, and hazardous waste remediation may have reduced cadmium exposure among U.S. adults. However, trends in urine cadmium, a marker of cumulative cadmium exposure, have not been evaluated. OBJECTIVES:We estimated the trends in urine cadmium concentrations in U.S. adults using data from the National Health and Nutrition Examination Surveys (NHANES) from 1988 to 2008. We also evaluated the impact of changes in the distribution of available cadmium determinants (age, sex, race, education, body mass index, smoking, and occupation) at the population level to explain cadmium trends. METHODS:The study population included 19,759 adults ? 20 years of age with measures of urine cadmium and cadmium determinants. RESULTS:Age-adjusted geometric means of urine cadmium concentrations were 0.36, 0.35, 0.27, 0.27, 0.28, 0.25, and 0.26 µg/g creatinine in 1988-1991, 1991-1994, 1999-2000, 2001-2002, 2003-2004, 2005-2006, and 2007-2008, respectively. The age, sex, and race/ethnicity-adjusted percent reduction in urine cadmium geometric means comparing 1999-2002 and 2003-2008 with 1988-1994 were 27.8% (95% confidence interval: 22.3%, 32.9%) and 34.3% (29.9%, 38.4%), respectively (p-trend < 0.001), with reductions in all participant subgroups investigated. In never smokers, reductions in serum cotinine accounted for 15.6% of the observed reduction. In ever smokers, changes in smoking cessation, and cumulative and recent dose accounted for 17.1% of the observed reduction. CONCLUSIONS:Urine cadmium concentrations decreased markedly between 1988 and 2008. Declining smoking rates and changes in exposure to tobacco smoke may have played an important role in the decline of urine cadmium concentrations, benefiting both smokers and nonsmokers. Cadmium has been associated to several health outcomes in NHANES 1999-2008. Consequently, despite the observed decline, further reduction in cadmium exposure is needed.
Project description:Evidence suggests an association between exposure to cadmium and dysglycemia. To investigate this matter, we examined the relationship between urinary cadmium and prediabetes in the cross sectional National Health and Nutrition Examination Survey (NHANES). NHANES participants for the years 2005 through 2010 aged ? 40 years were included in the analysis. Participants with nephropathy, overt diabetes, or missing required data were excluded. To assess the non-linear relationship between cadmium and Prediabetes, non-parametric logistic regression with B spline expansion of urinary cadmium/creatinine ratio was performed. This analysis revealed a complex non-linear association between higher cadmium levels and prediabetes. This relationship persisted, though with varying magnitudes across smoking groups (never smokers, moderate smokers, heavy smokers). In a conventional logistic regression analysis, this relationship was less evident with significantly increased OR for prediabetes was found in the highest quintile of urine cadmium compared to the lowest quintile in the overall population and in moderate smokers. In an age stratified analysis, a significant linear association was found only in the age groups 60-69 and ? 70. We conclude that there is a significant non-linear, complex relationship between urinary Cd levels, age, smoking habits and odds of prediabetes.
Project description:Urinary cadmium (Cd) concentrations in the Strong Heart Family Study (SHFS) participants are higher than in the general US population. This difference is unlikely to be related to tobacco smoking. We evaluated the association of consumption of processed meats and other dietary products with urinary Cd concentrations in the SHFS, a family-based study conducted in American Indian communities. We included 1725 participants with urine Cd concentrations (standardized to urine creatinine) and food frequency questionnaire data grouped in 24 categories, including processed meat. Median (IQR) urinary Cd concentrations were 0.42 (0.20-0.85) ?g/g creatinine. The age, sex, smoking, education, center, body mass index, and total kcal adjusted geometric mean ratio (GMR) (95%CI) of urinary cadmium concentrations per IQR increase in each dietary category was 1.16 (1.04-1.29) for processed meat, 1.10 (1.00-1.21) for fries and chips, 0.87 (0.80-0.95) for dairy products, and 0.89 (0.82-0.97) for fruit juices. The results remained similar after further adjustment for the dietary categories associated with urinary Cd in the previous model except for fries and chips, which was no longer statistically significant. These findings revealed the potential importance of processed meat products as a dietary source of cadmium.
Project description:Elevated blood homocysteine (Hcy) among middle-aged adults can increase age-related disease risk, possibly through other biochemical and hematological markers. We selected markers for hyperhomocysteinemia among middle-aged adults, studied time-dependent Hcy-marker associations and computed highly predictive indices of hyperhomocysteinemia, with cross-sectional and longitudinal validations. We used data from the National Health and Nutrition Examination Survey (NHANES III, phase 2, nmax = 4000), the NHANES 1999-2006 (nmax = 10,151) and pooled NHANES (cross-sectional validation). Longitudinal validation consisted of mixed-effects linear regression models (Hcy predicting markers' annual rates of change), applied to the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS, n = 227-244 participants, k = 2.4 repeats/participant, Agebase: 30-65 years) data. Machine learning detected nine independent markers for Hcy > 14 µmol/L (NHANES III, phase 2): older age; lower folate and B-12 status; higher serum levels of creatinine, uric acid, alkaline phosphatase, and cotinine; mean cell hemoglobin and red cell distribution widths (RDW); results replicated in the 1999-2006 NHANES [AUC = 0.60-0.80]. Indices combining binary markers increased elevated Hcy odds by 6.9-7.5-fold. In HANDLS, first-visit Hcy predicted annual increase in creatinine, RDW and alkaline phosphatase, with third-visit index (2013-2018) directly predicting Hcy (2004-2009). We provide evidence of the internal and external validity of indices composed of several biomarkers that are strongly associated with elevated Hcy.
Project description:Estimates of chronic kidney disease (CKD) in the United States using the continuous National Health and Nutrition Examination Survey (NHANES) data set 1999-2004 indicate that 13.1% of the population (26.3 million people based on the 2000 census) has CKD stages 1 to 4.We performed sensitivity analyses to highlight assumptions underlying these estimates and illustrate their robustness to varying assumptions.NHANES 1999-2004 was a nationally representative cross-sectional continuous survey of the civilian noninstitutionalized US population. Our sample included participants 20 years and older.Estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m(2) defined from the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation; albuminuria defined as persistence of urinary albumin-creatinine ratio greater than 30 mg/g.We compared prevalence estimates using the MDRD Study equation with 2 other GFR estimating equations (equation 5 by Rule et al from the Mayo Clinic Donors study; Cockcroft-Gault equation adjusted for body surface area and corrected for the bias in the MDRD Study sample), and sex-specific cutoff values to define albuminuria.We found CKD stages 1 to 4 prevalence estimates ranging from 11.7% to 24.9%, a more than 2-fold difference resulting in population estimates of 25.8 million to 54.0 million people using 2006 population estimates. Considering only stages 3 and 4, which are not affected by the choice of cutoff values to define albuminuria, prevalence estimates ranged from 6.3% to 18.6%, resulting in population estimates of 13.7 million to 40.3 million people, a nearly 3-fold difference.NHANES 1999-2004 is a cross-sectional survey and allows for GFR and albumin-creatinine ratio estimates at 1 point in time. NHANES does not account for seniors in long-term care facilities.Although CKD prevalence is high regardless of varying modeling assumptions, different assumptions yield large differences in prevalence estimates.
Project description:BACKGROUND:Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher values. OBJECTIVE:To develop a new estimating equation for GFR: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. DESIGN:Cross-sectional analysis with separate pooled data sets for equation development and validation and a representative sample of the U.S. population for prevalence estimates. SETTING:Research studies and clinical populations ("studies") with measured GFR and NHANES (National Health and Nutrition Examination Survey), 1999 to 2006. PARTICIPANTS:8254 participants in 10 studies (equation development data set) and 3896 participants in 16 studies (validation data set). Prevalence estimates were based on 16,032 participants in NHANES. MEASUREMENTS:GFR, measured as the clearance of exogenous filtration markers (iothalamate in the development data set; iothalamate and other markers in the validation data set), and linear regression to estimate the logarithm of measured GFR from standardized creatinine levels, sex, race, and age. RESULTS:In the validation data set, the CKD-EPI equation performed better than the Modification of Diet in Renal Disease Study equation, especially at higher GFR (P < 0.001 for all subsequent comparisons), with less bias (median difference between measured and estimated GFR, 2.5 vs. 5.5 mL/min per 1.73 m(2)), improved precision (interquartile range [IQR] of the differences, 16.6 vs. 18.3 mL/min per 1.73 m(2)), and greater accuracy (percentage of estimated GFR within 30% of measured GFR, 84.1% vs. 80.6%). In NHANES, the median estimated GFR was 94.5 mL/min per 1.73 m(2) (IQR, 79.7 to 108.1) vs. 85.0 (IQR, 72.9 to 98.5) mL/min per 1.73 m(2), and the prevalence of chronic kidney disease was 11.5% (95% CI, 10.6% to 12.4%) versus 13.1% (CI, 12.1% to 14.0%). LIMITATION:The sample contained a limited number of elderly people and racial and ethnic minorities with measured GFR. CONCLUSION:The CKD-EPI creatinine equation is more accurate than the Modification of Diet in Renal Disease Study equation and could replace it for routine clinical use. PRIMARY FUNDING SOURCE:National Institute of Diabetes and Digestive and Kidney Diseases.
Project description:Cataract is a major cause of visual dysfunction and the leading cause of blindness. Elevated levels of cadmium and lead have been found in the lenses of cataract patients, suggesting these metals may play a role in cataract risk. This study aimed to examine the associations of blood lead, blood cadmium and urinary cadmium with cataract risk. We identified 9763 individuals aged 50 years and older with blood lead and cadmium levels, and a randomly selected subgroup of 3175 individuals with available urinary cadmium levels, from the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2008 (mean age=63years). Participants were considered to have cataract if they self-reported prior cataract surgery in NHANES's vision examination. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using survey logistic regression models. We identified 1737 cataract surgery cases (the weighted prevalence=14.1%). With adjustment for age, race/ethnicity, gender, education, diabetes mellitus, body mass index, cigarette smoking (serum cotinine and pack-years) and urine hydration, every 2-fold increase in urinary cadmium was associated with a 23% higher risk of cataract surgery (OR=1.23, 95% CI: 1.04, 1.46, p=0.021). We found no associations of cataract surgery with blood cadmium (OR=0.97, 95% CI: 0.89, 1.07) and blood lead (OR=0.97, 95% CI: 0.88, 1.06). Mediation analysis showed that for the smoking-cadmium-cataract pathway, the ratio of smoking's indirect effect to the total effect through cadmium was more than 50%. These results suggest that cumulative cadmium exposure may be an important under-recognized risk factor for cataract. However, these findings should be interpreted with a caution because of inconsistent results between urinary cadmium and blood cadmium.
Project description:Analyses of the Third National Health and Nutrition Examination Survey (NHANES III) in 1988 to 1994 found an association of increasing blood lead levels < 10 ?g/dL with a higher risk of cardiovascular disease (CVD) mortality. The potential need to correct blood lead for hematocrit/hemoglobin and adjust for biomarkers for other metals, for example, cadmium and iron, had not been addressed in the previous NHANES III-based studies on blood lead-CVD mortality association. We analyzed 1999 to 2010 NHANES data for 18,602 participants who had a blood lead measurement, were ? 40 years of age at the baseline examination and were followed for mortality through 2011. We calculated the relative risk for CVD mortality as a function of hemoglobin- or hematocrit-corrected log-transformed blood lead through Cox proportional hazard regression analysis with adjustment for serum iron, blood cadmium, serum C-reactive protein, serum calcium, smoking, alcohol intake, race/Hispanic origin, and sex. The adjusted relative risk for CVD mortality was 1.44 (95% confidence interval = 1.05, 1.98) per 10-fold increase in hematocrit-corrected blood lead with little evidence of nonlinearity. Similar results were obtained with hemoglobin-corrected blood lead. Not correcting blood lead for hematocrit/hemoglobin resulted in underestimation of the lead-CVD mortality association while not adjusting for iron status and blood cadmium resulted in overestimation of the lead-CVD mortality association. In a nationally representative sample of U.S. adults, log-transformed blood lead was linearly associated with increased CVD mortality. Correcting blood lead for hematocrit/hemoglobin and adjustments for some biomarkers affected the association.
Project description:American Indian communities are at greater risk of hypertension and cardiovascular disease than the general US population and are exposed to greater cadmium levels. However, cadmium's effect on blood pressure is unclear. This study assesses the association between baseline urinary cadmium and longitudinal changes in blood pressure in American Indian communities. Cadmium was measured in 3047 baseline urine samples from Strong Heart Study participants from three geographic areas. Longitudinal changes in blood pressure across three study visits (1989-1999) were modeled using linear mixed models by baseline log urinary cadmium to creatinine ratio. Hypertension risk was evaluated using interval-censored survival analysis. Higher levels of urinary cadmium at baseline were associated with faster rates of increase in diastolic and systolic blood pressure (P [trend] = .001 and .02, respectively). The estimated change in diastolic and systolic blood pressures per year was 0.18 mm Hg (0.05-0.31) and 0.62 mm Hg (0.37-0.87) in the upper quintile of cadmium level compared with -0.11 mm Hg (-0.24 to 0.02) and 0.21 mm Hg (-0.04 to 0.46) in the lowest, respectively. A one-unit increase in log-transformed urinary cadmium was associated with 10% greater hypertension risk (95% confidence interval: 1.01-1.20). In conclusion, blood pressure of individuals with greater baseline levels of urinary cadmium increased at a faster rate relative to those with lower levels.