Elevated Cadmium Exposure Associated with Hypertension, Diabetes and Chronic Kidney Disease, in the Population of Cadmium-Contaminated Area

Abstract

Cadmium exposure is one major risk factors associated with both renal tubular dysfunction and cardiovascular disease. In the present study, we examined the association of increased urinary cadmium excretion with chronic kidney disease (CKD), hypertension (HT) and type-2 diabetes mellitus (T2DM) of 535 study residents of 13 cadmium-contaminated villages. Elevated urinary cadmium excretion was associated with increased risk of hypertension and T2DM. This study suggests that CKD induced by cadmium might also increase the risk of hypertension and T2DM in populations of environmentally contaminated area. INTRODUCTION There is a link between cadmium (Cd) exposure and all-cause mortality in populations exposed to relatively high Cd levels, including individuals in Cd contaminated areas as well as occupational-workers

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International Journal of Toxicological and Pharmacological Research 2015; 7(1); 50-56
ISSN: 0975-5160
Research Article
*Author for Correspondence
Elevated Cadmium Exposure Associated with Hypertension, Diabetes
and Chronic Kidney Disease, in the Population of Cadmium-
Contaminated Area
Surapon Tangvarasittichai,*1 Sukumarn Niyomtam,2 Suwadee Meemark, 1
Patchanrin Pingmuangkaew,3 Prapa Nunthawarasilp4
1 Chronic Diseases Research Unit, Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan
University, Phitsanulok 65000, Thailand
2 Clinical Pathology, Naresuan University Hospital, Faculty of Medicine, Naresuan University, Phitsanulok 65000,
Thailand
3 Department of Community Occupational Family Medicine, Faculty of Medicine, Naresuan University, Phitsanulok
65000,Thailand
4 Department of Public Health Foundation, Faculty of Public Health, Burapha University, Chonburi 20131, Thailand
Available Online: 1st February, 2015
ABSTRACT
Cadmium exposure is one major risk factors associated with both renal tubular dysfunction and cardiovascular disease. In
the present study, we examined the association of increased urinary cadmium excretion with chronic kidney disease (CKD),
hypertension (HT) and type-2 diabetes mellitus (T2DM) of 535 study residents of 13 cadmium-contaminated villages.
Elevated urinary cadmium excretion was associated with increased risk of hypertension and T2DM. This study suggests
that CKD induced by cadmium might also increase the risk of hypertension and T2DM in populations of environmentally
contaminated area.
Keywords: Cadmium exposure, hypertension, type 2 diabetes, renal tubular dysfunction, chronic kidney disease
INTRODUCTION
There is a link between cadmium (Cd) exposure and all-
cause mortality in populations exposed to relatively high
Cd levels, including individuals in Cd contaminated areas
as well as occupational-workers 1. Previous studies have
suggested that Cd is associated with renal dysfunction,
renal stones and cardiovascular disease 2-5. Associations
between Cd exposure and these outcomes would
potentially be important, because kidney disease and
certain cardiovascular conditions such as hypertension are
also significant in the etiology of diabetes. Cd exposure is
pervasive but modifiable, while hypertension and diabetes
are important sources of morbidity and mortality.
Occupational studies found a positive correlation between
increased urinary Cd with blood pressure among Cd
workers 6. In the many studies, researchers have reported
conflicting results; while a few studies have described an
association between Cd exposure with elevated blood
pressure 7-9, others have suggested no association 10 or even
a negative association 11. Additionally, the associations
differed by gender 4, 11 and smoking status 9.
Cd is an important nephrotoxic pollutant that increases
risks to expose populations in many parts of the world 12-
14. Cd accumulates in the epithelial cells of the proximal
tubule of the kidney, causing a generalized dysfunction of
the proximal tubule characterized by polyuria, low
molecular weight proteinuria and glucosuria 15-17. Cd may
play a role in the development and progression of diabetes
and diabetes-related kidney disease. Population in Cd
contaminated areas have high rate of hypertension and
diabetes.
The present study evaluated the association between
elevated Cd exposure with CKD concomitant with
increased hypertension and diabetes in residents of Cd
contaminated villages in rural northern Thailand. The Cd
contamination resulted from two creeks running through a
zinc mine. The runoff affected crops, including rice and
vegetables grown in these areas, which were found to have
elevated Cd levels. Residents were exposed to Cd by
consuming contaminated foods, vegetables, drinking water
and smoking. They were deemed to be at high risk of the
Cd toxicity 13, 14. We hypothesize that Cd may play a role
in the development and progression of hypertension,
diabetes and diabetes-related kidney disease.
MATERIALS AND METHODS
Study population
This cross-sectional study was based on health evaluation
of a total 535 subjects who were 30 years or older. Two
hundred fifty eight subjects (mean age 55.32±12.07 years;
87 men and 171 women) and who had urinary Cd ≥5.0
g/g creatinine were randomly selected from 13 Cd

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contaminated villages (during January 2010–January
2011) and 277 subjects of non-Cd polluted village located
in the same province were selected as the control group.
All participants are from each study area had been
residents for over 30 years. A questionnaire survey was
conducted by trained health workers about demographic
characteristics, occupational history, residency time,
medical history of diabetes, hypertension, renal diseases,
cancer and alcohol consumption. We excluded 64 cases
with known-end stage renal failure, cancer, infection
and/or any life threatening diseases from the study. The
study protocol was approved by the Ethic Committees of
Naresuan University (51-02-04-0043). All subjects
provided written informed consent and they all agreed to
participate and to provide blood and urine samples for their
health check.
Blood pressure (BP) measurement
The BP was taken after the participants were seated and
rested for 5 minutes. BP was measured twice at 5 minutes
intervals with a digital blood pressure monitor, ES-P 110
(Terumo Cooperation, Japan). The average of the two
measurements was used for data analysis. Hypertension
was defined as an average BP ≥140/90 mmHg or if the
participant was taking antihypertensive medications or had
been diagnosed with hypertension.
Blood and urine samples collection
Fasting venous blood was collected from all participants.
Plasma glucose (Glu) and blood urea nitrogen (BUN) were
measured by using enzymatic colorimetric method; serum
and urine creatinine (CT) concentration was estimated
based on the Jaffe reaction procedures with a Hitachi 912
auto-analyzer (Roche Diagnostic, Switzerland) at the
laboratory of Medical Technology, Faculty of Allied
health Sciences. Diabetes was defined as a fasting glucose
concentration of ≥126 mg/dl, a non-fasting glucose
Table 1 Comparison of general characteristics of the elevated Cd exposure with non-Cd exposure control population
Parameter
Non Cd exposure (n=277)
Cd exposure (n=258)
p- value
Age (yr)
54.07 ± 9.88
55.32 ± 12.07
0.189
Systolic BP (mmHg)
121.0(113.0-127.5)
130.0(120.0-138.3)
<0.001
Diastolic BP (mmHg)
80.0(73.0-82.5)
80.0(70.0-88.0)
0.081
BMI (kg/m2)
23.96 ± 3.97
22.14 ± 3.83
<0.001
Cd (µg/g CT)
0.7(0.4-1.3)
8.3(6.4-10.7)
<0.001
NAG (U/g CT)
1.56(1.02-2.90)
3.91(2.44-7.82)
<0.001
U-Protein (mg/g CT)
89.6(63.8-121.9)
134.8(84.5-233.6)
<0.001
U-Cal (mg/g CT)
84.5(52.9-114.6)
131.6(91.2-188.5)
<0.001
eGFR (ml/min/1.73 m2)
71.0(60.0-84.0)
56.2(45.0-66.1)
<0.001
Glucose (mg/dl)
86.0(82.0-92.3)
85.0(80.0-92.0)
0.172
BUN (mg/dl)
11.0(11.0-12.0)
13.3(10.9-16.8)
<0.001
CT (mg/dl)
0.9(0.8-1.0)
0.9(0.8-1.1)
0.005
Smoking
28(10.1%)
142(55.0%)
<0.001
Alcohol drinking
28(10.1%)
120(46.5%)
<0.001
Hypertension
51 (18.4%)
88(34.1%)
<0.001
Type 2 diabetes
11(3.9%)
19(7.4%)
0.046
Data are mean±SD or median (interquartile range) for variables with a skewed distribution and n (%) P values are
given for comparisons between non-exposure and Cd exposure groups tested with t test, non-parametric and Chi
square tests
Table 2 Comparison of general characteristics of the elevated Cd-exposure-man with Cd-exposure-women
Parameter
Cd exposed men (n=87)
Cd exposed women (n=171)
p- value
Age (yr)
55.99 ± 13.61
54.99 ± 11.24
0.530
Systolic BP (mmHg)
125.0(120.0-135.0)
130.0(120.0-140.0)
0.150
Diastolic BP (mmHg)
80.0(70.0-86.0)
80.0(73.0-90.5)
0.148
BMI (kg/m2)
21.74 ±3.26
22.34 ±4.09
0.204
Cd (µg/g CT)
8.0(6.5-10.1)
8.2(6.4-11.3)
0.440
NAG (U/g CT)
4.45(2.58-8.78)
3.72(2.39-6.24)
0.027
U-Protein (mg/g CT)
130.1(86.3-233.5)
138.0(83.5-234.0)
0.564
U-Cal (mg/g CT)
139.6(105.2-187.6)
129.3(80.0-191.0)
0.218
eGFR (ml/min/1.73 m2)
57.9(45.2-67.6)
55.8(44.1-66.0)
0.459
Glucose (mg/dl)
87.0(81.0-93.0)
84.0(79.0-92.0)
0.092
BUN (mg/dl)
14.4(11.4-17.1)
12.3(10.8-16.3)
0.055
CT (mg/dl)
1.1(1.0-1.2)
0.9(0.8-1.0)
<0.001
Smoking
76(87.4%)
66(38.6%)
<0.001
Alcohol drinking
71(81.6%)
49(28.7%)
<0.001
Hypertension
29(33.3%)
59(34.5%)
0.890
Type 2 diabetes
7(8.0%)
26(15.2%)
0.118

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concentration of ≥200 mg/dl, a self-reported physician
diagnosis, or medication use. Urine samples were collected
in polyethylene bottles after physical examination,
anthropometric measurements and blood taken. A 30-ml of
urine sample from each subject was divided into three
aliquots (5-10 ml each) one was used for microscopic
analysis and other aliquots were frozen and stored at −20
◦C for later analysis of cadmium, protein, N-acetyl-β-D-
glucosaminidase (NAG) and U-CT.
Cadmium concentration determination
Blood Cd is a marker of current exposure because it
appears to reflect body burden from long-term retention of
Cd in kidney and liver while urinary Cd is a marker of
cumulative exposure 18, 19. We used urinary Cd
concentration as a marker in this study. Urinary Cd
concentration was determined by a graphite tube atomic-
absorption spectrometer (Varian Model AA280Z, USA) at
the Bangkok-Pathology Laboratory, a private reference
clinical laboratory. Standards of low concentrations were
freshly prepared by serial dilution with 20% (w/v) nitric
acid. Bio-Rad lymphocheck urine control and Seronorm
trace elements urine control (Nycomed As, Oslo, Norway)
were performed for quality control of urine metal
determination. Diammonium hydrogen phosphate was
used as matrix modifier. Cd was measured at 228.8 nm by
standard addition method. Cd concentration in urine was
expressed after correction for creatinine concentrations.
The within-run assay coefficients of variation ranged from
2.8% to 13.6%. Additionally, in an external quality
assurance program from the External Quality Assessment
Scheme of Medical Sciences center of Thailand, laboratory
measures were within 10% of reference means for urinary
Cd (r2 = 0.97).
Renal function
All participants had clinically normal renal function,
defined as a serum creatinine concentration below 159.12
mol/l (1.8 mg/dl) and serum BUN concentration below
7.14 mmol/l (20 mg/dl). Estimated glomerular filtration
rate (eGFR) was calculated by Cockroft-Gault formula,
which incorporates age, body weight and sex 20. The
formula is as: eGFR = [(140-age) * Weight (kg) *
constant]/ serum creatinine (mol/l), where constant is
1.23 for men and 1.04 for women; serum creatinine in
mol/l. Five eGFR stages were used: Stage I was normal
eGFR (90ml/min/1.73 m2); Stage II was mildly eGFR
(60-89 mL/min/1.73 m2); Stage III was moderately eGFR
(30-59 ml/min/1.73 m2); Stage IV was severely eGFR (<30
ml/min/ 1.73 m2), and Stage V was end-stage renal disease:
eGFR (<15 ml/min/1.73 m2). An eGFR lower than 60
ml/min/1.73 m2 (moderately eGFR) was defined as chronic
kidney disease (CKD) 21. Urinary NAG assay was as
described by Horak et al. 22. Briefly, NAG in urine reacts
with substrate (p-nitrophenyl-N-acetyl- β -D-
glucosaminide) in sodium citrate buffer (pH 4.4) at 37 ºC.
NAG then liberates p-nitrophenylate ion. Then, adding 2-
amino-2-methyl-1-propanol (AMP) buffer (pH 10.25) into
Table 3 Bivariate correlation of all variables in population of elevated Cd exposure and hypertension
Correlation between parameters
Correlation coefficient
r
p- value
Cd/g CT
Cal/g CT
0.280
<0.001
NAG/g CT
0.251
<0.001
U-Protein/g CT
0.272
<0.001
eGFR
-0.187
0.040
NAG/g CT
Age
0.267
<0.001
Cal/g CT
0.532
<0.001
U-Protein/g CT
0.675
<0.001
eGFR
-0.584
<0.001
BUN
0.190
0.002
CT
0.190
0.002
U-Protein/g CT
Age
0.338
<0.001
BMI
-0.131
0.035
Cal/g CT
0.459
<0.001
eGFR
-0.535
<0.001
Glu
0.223
<0.001
BUN
0.178
0.004
CT
0.178
0.004
U-Cal/g CT
eGFR
-0.334
<0.001
Diastolic BP
0.139
0.026
eGFR
Age
-0.577
<0.001
BMI
0.430
<0.001
Glu
-0.218
<0.001
BUN
-0.305
<0.001
CT
-0.339
<0.001

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the reaction and measured the reaction product by
spectrophotometry at 405 nm. The within–run and
between-run coefficient of variation for NAG assay in
control material assay was 3.14% and 4.11% (n=10).
Urinary protein concentration was measured with the
Kingsbury–Clark method. Urinary CT concentration was
based on the Jaffe reaction. Urinary-calcium (U-Cal)
concentration was determined based on the the
colorimetric assay with o-cresolphthalein complexone to
form purple color of calcium-o-cresolphthalein complex
(Roche Diagnostic, Switzerland).
Statistical analysis
Categorical data are presented as percentages, and
continuous data are presented as mean± standard deviation
(SD) or median and interquartile range for non-normally
distributed data, and tested by using Shapiro-Wilk test. A
Student’s t-test was used to analyze the differences for
normally distributed data and Mann-Whitney U-test was
used to analyze the differences for non-normally
distributed data. Correlations between cadmium exposure
index with renal toxicity (urinary levels of protein
markers), hypertension and diabetes were analyzed with
Spearman’s rho correlation test. Odds ratios (OR) from
logistic regression analyses were used to estimate the risk
of hypertension and diabetes, proteinuria, calciurea, NAG
and CKD that was associated with elevated urinary
cadmium excretion. The results of all statistical analyses
were evaluated for statistical significance using p-value
<0.05 and the 95% confidence intervals (CI). All analysis
was performed using the SPSS computer program version
13.0 (SPSS, Chicago, IL).
RESULTS
General and anthropometric characteristics
A total samples of 258 residents (aged 55.32 ± 12.07 years)
who lived in the Cd contaminated villages more than 30
years and 277 residents (aged 54.07 ± 9.88 years) in the
non-Cd contaminated villages participated as control in
this study. Of the participants, 204 (38.1%) were male [87
(42.6%) were exposed] and 331 (61.9%) were female [171
(51.7%) were exposed]. The characteristics of the study
group and control group are shown in Table 1 and 2.
Residents of the Cd contaminated villages were
significantly lower in BMI, higher in smoking, alcohol
consumption, hypertension and type 2 diabetes. Cd
exposed men were also significantly higher in smoking and
drinking than women, while their HT and DM were not
significantly different (Table 2). The results demonstrated
that residents of the Cd contaminated villages were lower
in BMI, despite higher alcohol consumption (more
calories) and smoking. The inference is that increased
incidence of HT and DM were not a result of BMI.
Cadmium, renal toxicity and hypertension
Residents of Cd exposed villages had significantly higher
urinary Cd, Systolic BP, NAG, urine protein, urine
calcium, BUN, CT, and lower eGFR than control residents
(p<0.05). We also compared the clinical characteristics of
the Cd exposed patients with hypertension with non-
hypertension (data not shown). Patients with hypertension
were significantly older (longer exposure), had more
severe renal tubular dysfunction, higher Cd exposed,
decreased eGFR, higher glucose, BUN and CT levels than
patients without hypertension (p<0.05). Cd exposed men
were also significantly higher in NAG/g CT and CT than
women (p<0.001). Overall, these results indicate that
residents of the Cd contaminated villages were at risk for
subclinical CKD, renal insufficiency and higher BP.
In bivariate correlation
Urinary Cd showed the positive correlation with U-Cal/g
CT (r =0.280, p<0.001), NAG/g CT (r =0.251, p<0.001),
U-Protein/g CT (r =0.272, p<0.001) and eGFR (r =-0.187,
p=0.040) and the correlation of the other variables is
shown in Table 3.
Multivariate analysis
Multiple logistic regression analyses were used to test for
association between elevated urinary Cd with hypertension
and diabetes after adjusting for their covariates. The risk of
hypertension OR = 2.06 (95% confidence interval (CI):
1.12-3.79) and the risk for diabetes OR = 3.02 (95% CI:
1.23-7.38) after adjusting for CKD, U-Protein/g CT, U-
Cal/g CT, BMI, drinking, smoking, age and gender as
shown in Table 4. These results demonstrate that elevated
Cd exposure is associated with increased risk for both
hypertension and diabetes.
DISCUSSION
Our present study demonstrated the possible association
between elevated urinary Cd level with hypertension and
diabetes concomitant with CKD after adjusting for various
covariates. This may reflect an increased number of HT
and diabetes patients in this population. Many studies
reported that environmental Cd exposure related to the
development of renal tubular dysfunction and to the
pathogenesis of arterial hypertension 7, 9, 10. Nakagawa and
Nishijo 23 reported the positive associations of blood Cd
and urinary Cd with BP in general population. In our
present study, we also found the association of elevated
urinary Cd with hypertension and diabetes. The risk of
hypertension and diabetes was stronger when renal tubular
dysfunction or CKD and hypercalciuria which suggested
that the major effects on hypertension may occur via
Table 4: Association of elevated Cd exposure with
hypertension and diabetes after adjusting for their
covariates in the study populations
Variables
Elevated urine cadmium excretion
OR
95% CI
P-value
Hypertension
2.06
1.12-3.79
0.019
Diabetes
3.02
1.23-7.38
0.016
CKD
3.80
1.91-7.59
<0.001
U-Protein/g CT
1.00
1.00-1.27
0.304
U-Cal/g CT
1.01
1.00-1.01
<0.001
BMI
0.94
0.87-1.01
<0.001
Alcohol drinking
7.09
3.64-13.79
<0.001
Smoking
7.04
3.58-13.83
<0.001
Gender
5.73
2.89-11.32
<0.001
Age
0.94
0.91-0.97
<0.001
Model after adjusted with diabetes, CKD, U-Protein/g
CT, Cal/g CT, BMI, alcohol drinking, smoking, gender,
age

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nephrotoxicity 24. Increased excretion of NAG in urine or
lower eGFR could be observed in individuals with elevated
Cd exposure, as shown in Table 1. Both urinary NAG and
eGFR markers were more sensitive than CT, so may be
used as early biomarkers of renal tubular dysfunction and
CKD. For residents in these areas, dietary intake and
cigarette smoking were the likely sources of Cd exposure.
Smoking is associated with increased Cd levels because
cigarettes (local cigarettes) contain Cd taken up by the
tobacco plant 18, 25. In non-smokers and non-drinker
drinking, staple food is the primary source of exposure 18.
Our study demonstrated that Cd exposured men have
greater likelihood of smoking, drinking and more severe
renal tubular dysfunction than the women who were Cd
exposed, as shown in Table 2. These look like gender-
effect in statistical analysis.
Four biological mechanisms that link Cd exposure with
hypertension have been proposed. (i) One mechanism may
relate to the nephrotoxicity of Cd 7, 8, 24. Cd–
metallothionein complex in blood filters through
glomerular membrane to renal tubular cells 26, 27. The
complex enters to lysosomes of the renal cells and releases
the Cd into the cytosol and degraded the metallothionein
into amino acids. Free Cd can injure the renal tubules and
cause glomerular damage 28. This injury can induce salt
retention, volume overload, and eventually hypertension 24
same as in our results. (ii) A second possibility is that, Cd
induced hypertension is at least partly associated with
impairment of intracellar Ca2+ homeostasis 29. It was
known that Cd acted as a calcium channel blocker
competing with Ca2+ ions for membrane receptor sites and
also increased the permeability of cellular membranes to
Ca2+ ions 30. It had been postulated that Cd could increase
sodium and water retentions, which were important factors
controlling the development of hypertension. Retention of
intracellular sodium was associated with intracellar Ca2+
concentration. The elevation of intracellular Ca2+
concentration affected an increase in vascular tone and
subsequently elevated blood pressure. As in our study, Cd
induced nephrotoxicity caused increased urinary excretion
and decreased re-absorption of the major protein and Ca2+
may effect in this mechanism. Elevated urinary calcium
excretion 31 and use of loop diuretics in treating
hypertension may also increased urinary calcium
excretion, which could precede the onset of hypertension
32. (iii) The third pathway is based upon animal and
in vitro studies; Cd may increase BP through vascular
effects by decreased endothelial nitric oxide synthase in
blood vessels, which suppresses acetylcholine-induced
vascular relaxation inducing hypertension 33. These
include the formation of reactive oxygen species,
promotion of lipid peroxidation, depletion of glutathione
(GSH), disruption of sulfhydryl homeostasis and down-
regulation of nitric oxide 9, 34. (iv) Approximately one-
fourth of renovascular hypertension subjects show high
levels of angiotensin II, a vasoconstrictor 35. Angiotensin
II receptor binding sites are located in the brain at sites
involved with sympathetic nerve activity via baroreflex
regulation 35, 36. Cd has been demonstrated to inhibit
angiotensin-converting enzyme (ACE) at low, medium,
and high doses without a dose–response effect induced
hypertension in rats 36. It is well recognized that people
with hypertension have an increased risk of developing
diabetes, even when untreated. It is also recognized that
this risk can be further influenced by antihypertensive
therapy. A long-term study of hypertensive patients from
Sweden developed diabetes during 25 years follow-up by
using multivariate Cox regression analysis demonstrated
that BMI, triglycerides level and treatment with -blockers
were positively related with diabetes complication 37.
In bivariate correlation, this study showed no correlations
between continuous variables of urinary Cd and fasting
blood glucose, although some animal studies have
demonstrated a possible link between Cd exposure and
increasing fasting blood glucose levels or pancreas
dysfunction 12,38, 39. Many studies have found positive
correlations between urinary Cd and prevalence of
impaired fasting glucose and diabetes 40, 41. Experimental
studies in rodents have indicated that Cd may cause
damage of pancreatic β-cells, impaired insulin production
and is diabetogenic, which might explain why Cd exposure
could lead to diabetes 12,39,42. Cd exposure is a risk factor
for cardiovascular disease, hypertension and diabetes,
increasing morbidity and mortality in the future. Cd
contamination still exists in the areas we studied, and the
growing concern about environmental exposure to Cd
provided the impetus for the implementation of national
surveillance and ongoing assessment of the exposure to Cd
in the residents of Cd contaminated areas. Environmental
protection by the government and education on healthy
lifestyle will be needed to protect from further exposure.
Limitation of the present study is that we only studied in
the participants with high Cd exposure (≥5.0 µg/g
creatinine) at the Cd contamination area, and it is difficult
to infer the resulting conditions to exposures in the general
population. The advantage is that we were able to examine
the general population with high Cd exposure and show
increasing risk of hypertension and diabetes.
CONCLUSION
Elevation of Cd exposure is associated with increased risk
for hypertension and diabetes probably caused by Cd
induced tubular dysfunction and/or CKD.
ACKNOWLEDGEMENT
We sincerely thank Naresuan University for financial
support, the provincial governor of Tak for the permission
to research in Mae Sot District and all co-workers for their
technical assistance. We especially thank those who
participated and donated blood samples for this study.
Finally we sincerely thank Asst. Prof. Dr. Ronald A.
Markwardt, Faculty of Public Health, Burapha University,
for his critical reading and correcting of the manuscript.
CONFLICT OF INTEREST
None
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