International Journal of Urology
Blackwell Science, LtdOxford, UKIJUInternational Journal of Urology0919-81722005 Blackwell Publishing Asia Pty LtdSeptember 2005129859863Original Article
Kidney stone disease and risk factors for coronary heart diseaseS Hamano
Correspondence: Satoshi Hamano
Chuo-ku, Chiba-city, Chiba 260-0001, Japan. Email:
Received 26 August 2004; accepted 15 March 2005.
, 1-55-8 Miyako-cho,
Kidney stone disease and risk factors for
coronary heart disease
SATOSHI HAMANO, HIROOMI NAKATSU, NORIYUKI SUZUKI, SUSUMU TOMIOKA,
MASASHI TANAKA AND SHINO MURAKAMI
Department of Urology, Asahi General Hospital, Asahi-city, Chiba, Japan
(CHD) risk factors on calcium oxalate (CaOX) stone formation.
: Variables included body mass index (BMI), current alcohol use, smoking habit, hyperten-
sion, hypercholesterolemia, diabetes mellitus, and hyperuricemia. Data sufficient for analysis were
obtained for 181 CaOX stone formers and 187 controls.
: Seven of 181 stone formers (3.9%) had a history of CHD compared with none of 187
control subjects (
0.007). In univariate logistic regression analysis, smoking habit (OR 4.41, 95%
0.0001), hypertension (OR 4.24, 95% CI 2.61–6.91,
olemia (OR 3.03, 95% CI 1.77–5.20,
0.0001) and BMI (OR 1.10, 95% CI 1.04–1.17,
reached statistical significance. In a multivariate logistic regression analysis, smoking habit (OR
4.29, 95% CI 2.68–6.86,
0.0001), hypertension (OR 3.57, 95% CI 2.11–6.07,
hypercholesterolemia (OR 2.74, 95% CI 1.51–5.00,
BMI (OR 1.06, 95% CI 0.99–1.12,
0.09) did not.
: CaOX stone formers are significantly associated with several CHD risk factors,
including smoking habit, hypertension, hypercholesterolemia, and obesity.
: We conducted a case-control study to examine the impact of coronal heart disease
0.001) reached statistical significance, while
calcium oxalate stone, coronary heart disease, nephrolithiasis, risk factor.
Nephrolithiasis is a common painful condition of mul-
(CaOX) is the commonest component of upper urinary
tract calculi in economically developed countries,
including North America, Europe, Australia, and
Many epidemiological factors, including age,
sex, heredity, occupation, body size, social class,
affluence, geographic location, climate, and diet and
fluid intake, have been identified as playing roles in
kidney stone disease.
Our clinical impression was that CaOX stone formers
were at increased risk of experiencing coronary heart
disease (CHD). However, only few attempts have been
and calcium oxalate
made to investigate the associations among urinary
stone disease and CHD.
In October 2000 a 57-year-old man with a previous
history of recurrent CaOX stone disease experienced
acute myocardial infarct. That event prompted the initi-
ation of the present study concerning the risk factors for
CHD among CaOX stone formers. We conducted a
case–control study to assess the impact of the several
CHD risk factors on CaOX stone formation.
Subjects and methods
Cases were 200 patients (137 men, 63 women, M/F 2.2;
aged 40–65 years) who were diagnosed as having upper
urinary stones chiefly composed of CaOX (80% or
more) between January 2001 and March 2003 at our
Subjects without a medical history of nephrolithiasis
or suspected renal colic were sampled randomly from
the individuals who visited our institution for an annual
health check up, and matched for sex and age strata (5-
year interval). Frequency matching with a case–control
ratio of 1:1 was intended in order to increase the power
of the study. Then, control subjects were 200 subjects
(137 men, 63 women, M/F 2.2; aged 40–65 years).
Variables included body mass index (BMI), serum
uric acid, creatinine concentration, total cholesterol, sys-
tolic blood pressure, current alcohol use, smoking habit,
previous history of CHD events, and history of hyper-
tension, hypercholesterolemia, diabetes mellitus (DM),
A 24 h urine collection was not done, and we had no
information regarding the dietary intake.
A total of 32 individuals (19 cases and 13 controls)
were excluded for the following reasons: lack of com-
plete medical records (
6), renal insufficiency (serum
creatinine more than 1.5 mg/dL;
3), chronic urinary tract infection
3), diuretics (
3), history of cancer (
performance status (
2), a high suspicion of hyper-
2), solitary kidney (
tubular acidosis (
1), inflammatory bowel disease
1), and hormone replacement therapy (
because they were considered to have some conditions
predisposing them to calcium-based stone formation.
After exclusion of subjects with above-mentioned con-
ditions, 181 cases (125 men, 56 women, M/F 2.2; mean
7.4 years, range 40–65) and 187 con-
trols (127 men, 60 women, M/F 2.1; mean age
6.6 years, range 40–65) remained for analysis of
these data. Patients and controls were compared accord-
ing to the demographic characteristics, and the presence
of CHD risk factors using
We used univariate and multivariate logistic regres-
sion analyses to access the impacts of different factors
on CaOX stone formation. Difference resulting in
0.05 were considered statistically significant. Only
the statistically significant factors in univariate logistic
regression analysis were included in multivariate logis-
tic regression model to identify the factors that act inde-
pendently. The associations of variables with CaOX
stone formation were estimated with ORs and their 95%
CIs derived from logistic regression analysis. Statistical
analysis was performed with commercially available
Patients and controls were compared according to the
demographic characteristics, and the presence of CHD
risk factors using
priate. The stone formers were significantly associated
with greater BMI (mean
3.7 kg/m ,
0.22 mg/dL vs. 0.74
20.5 mmHg vs.
0.0001), smoking habit (70.2% vs. 25.1%,
0.0001), previous history of CHD events (3.9% vs.
0.007), and history of hypertension (44.7% vs.
0.0001) and hypercholesterolemia (29.8% vs.
0.0001) compared with the controls
Among the stone formers, 98 case subjects (54.1%)
had a unilateral obstructing ureteral calculi when blood
samples were obtained, and 95 (52.5%) were recurrent
stone formers. These findings may be partly attributed
to the slightly increased serum creatinine concentration
in stone formers. Further, there were no abnormal
findings of serum creatinine concentration exceeding
25% above the normal range (0.5–1.2 mg/dL) among
the study population. Therefore, we did not include
serum creatinine concentration in univariate logistic
In univariate logistic regression analysis, smoking
habit (OR 4.41, 95% CI 2.85–6.84,
hypertension history (OR 4.24, 95% CI 2.61–6.91,
0.0001), hypercholesterolemia history (OR 3.03,
95% CI 1.77–5.20,
0.0001) and greater BMI (OR
1.10, 95% CI 1.04–1.17,
significance (Table 2). In multivariate logistic regres-
sion analysis, smoking habit (OR 4.29, 95% CI 2.68–
0.0001), hypertension history (OR 3.57,
95% CI 2.11–6.07,
0.0001), and hypercholester-
olemia history (OR 2.74, 95% CI 1.51–5.00,
0.001) reached statistical significance, while
greater BMI (OR 1.06, 95% CI 0.99–1.12,
did not (Table 3).
-tests if appro-
0.007) reached statistical
Risk factors for CHD are hypertension, hypercholester-
olemia, smoking habit, gender (male), DM, obesity
As established by the seminal study of Iguchi
calcium stone formers ingested large amounts of nutri-
ents, especially animal protein, during the evening
We examined the relationship between kidney
stone disease and risk factors for coronary heart disease,
including body mass index, smoking habit, alcohol
intake, history of hypertension, hypercholesterolemia,
diabetes mellitus, and hyperuricemia since they may
Kidney stone disease and risk factors for coronary heart disease 861
reflect dietary habit and lifestyle of the calcium stone
In the present study, 7 of 181 stone formers (3.9%)
had a history of CHD compared with none of 187 con-
trol subjects (
0.007). However, the mean age of
study population is about 50 years old, and a follow-up
survey for CHD events was not conducted.
The majority of the patients with a history of CHD
may go to the hospital regularly for follow-up of CHD.
Thus, they are not likely to receive health check ups.
Therefore, this is not the firm evidence that CaOX stone
formers are at increased risk for CHD. However, the
results of this study suggest that CaOX stone formers
are strongly associated with several CHD risk factors,
including smoking habit, hypertension, hypercholester-
olemia, and obesity.
In multivariate logistic regression analysis, smoking
habit reached statistical significance (OR 4.29, 95% CI
0.0001). Our findings implicated that
cigarette smoking may be a stronger risk factor of CaOX
stone formation than are hypertension, hypercholester-
olemia, and greater BMI. Cigarette smoking has long
General characteristics of study subjects. (Number (%) or Mean ± SD)
(n = 181)
(n = 187)
Uric acid (mg/dL)
Serum creatinine (mg/dL)*
Total cholesterol (mg/dL)
Systolic blood pressure (mmHg)*
Current alcohol use
Previous history of coronary heart disease*
51.5 ± 7.4
24.8 ± 3.9
5.7 ± 1.5
0.85 ± 0.22
196.8 ± 37.5
128.5 ± 20.5
52.0 ± 6.6
23.7 ± 3.7
5.5 ± 1.5
0.74 ± 0.14
189.9 ± 30.9
118.0 ± 14.3
*P-value <0.05. Body mass index (BMI) was calculated as weight (kg)/height (m)2 to evaluate degree of obesity. History
of hypertension was defined by the presence of any of the following: systolic blood pressure of 140 mmHg or more, diastolic
blood pressure of 90 mmHg or more, or reported use of blood pressure lowering medication. Smoking habits were investigated
with questionnaires and interviews, and subjects were classified as current smokers or non-smokers. History of hypercholes-
terolemia was defined as a total serum cholesterol concentration of 220 mg/dL (5.7 mmol/L) or more, or reported use of lipid
lowering medication. History of hyperuricemia was defined as a serum uric acid of 8.0 mg/dL (5.7 mmol/L) or more, or
reported use of medication for hyperuricemia. History of diabetes mellitus (DM) was defined by the presence of any of the
following: a blood glucose concentration of 140 mg/dL (8.0 mmol/L) or more while fasting, a non-fasting blood glucose
concentration of 200 mg/dL (11.0 mmol/L) or more, use of insulin or an oral hyperglycemic drug, or a physician’s diagnosis
Result of univariate logistic regression analysis
Variables Odds ratio
Current alcohol use
Result of multivariate logistic regression analysis
862S Hamano et al.
been recognized as an important risk factor for CHD.
However, few published study has examined the associ-
ation between smoking and kidney stone disease.
Scott et al. proposed that increased serum cadmium
levels associated with cigarette smoking may be a risk
factor for urinary tract stone formation.7
However, we suggest another idea why smoking
reached statistical significance in the present study. The
rate of stone passage per month is 50% higher in the
summer than in the winter,8 and urine volume is
significantly lower during the summer than the winter
in stone formers.9 Thus, lower urine output is thought to
be an important risk factor for urinary stone formation.
Arginine vasopressin (AVP) has a strong antidiuretic
action. A rise in plasma AVP during the night explains
the known nocturnal decrease in urinary output.10 The
lithogenic risk for CaOX stone was maximal at the end
of the night or during the early morning when urinary
output was minimal.11 Further, Mooser reported that a
significant increases in
(0.8 ± 0.3 pg/mL before and 4.2 ± 4.1 pg/mL after
smoking, P = 0.001) were associated with cigarette
smoking.12 Therefore, cigarette smoking at night may
further decrease urinary output during sleep, and may
be a potential mechanism for CaOX stone formation.
Smoking cessation can be effective to decrease the risk
of calcium stone recurrence.
plasma AVP levels
Hypertension history reached statistical significance in
multivariate logistic regression analysis (OR 3.57, 95%
CI 2.11–6.07, P < 0.0001). Borghi et al. reported that
nephrolithiasis is more frequently found in hyperten-
sive patients than in normotensive subjects and that
higher oxaluria and calciuria as well as supersaturation
of calcium oxalate were more frequently found in
hypertensive males than in normotensive males.13
Quereda et al. reported that untreated hypertensive
patients have a higher prevalence of hypercalciuria
(35% had a urinary calcium/creatinine ratio > 0.20 vs.
20% of treated hypertensives and 2% of control sub-
jects; P < 0.001), that is a common risk factor for cal-
cium stone disease.14
Hypercalciuria and hyperoxaluria associated with
hypertension are noteworthy although the mechanism of
this association is not clearly understood.
significance in multivariate logistic regression analysis
(OR 2.74, 95% CI 1.51–5.00, P = 0.001). In human,
history reached statistical
hypercholesterolemia is generally recognized as a major
risk factor for CHD, but not for nephrolithiasis.4
Osteopontin (OPN) is one of the macromolecules in
CaOX crystallization, and has various effects for nucle-
ation and growth of CaOX crystal formation.15 Konya
et al. reported that OPN enhances the formation and
aggregation of CaOX crystals in the experimental sys-
tem.16 Ohmori et al. showed plasma OPN levels were
found to be associated with the presence and extent of
coronary artery disease.17 Kajikawa et al. reported that
high cholesterol diet induced renal calcification and an
increase in renal OPN-mRNA in rat,18 and proposed that
similarities might exist between renal stone disease and
atherosclerosis in terms of increasing the expression of
OPN in tissues. However, the detailed mechanism is not
yet clarified completely.
The effectiveness of icosapentaenoic acid (EPA) in
lowering serum total cholesterol is now well established.
Konya et al. also reported that some hypercalciuric cal-
cium stone formers experienced significant urinary cal-
cium reduction by taking EPA.19 Further, Yasui et al.
suggested that EPA by reducing urinary calcium might
favorably affect urine composition in a way that possibly
reduces the risk of calcium stone formation.20
The dietary instruction for elimination of hypercho-
lesterolemia or/and treatment by EPA may reduce recur-
rent CaOX stone formation, especially when the patient
is affected by hypercholesterolemia.
In univariate logistic regression analysis, increased BMI
reached statistical significance (OR 1.10, 95% CI 1.04–
1.17, P = 0.007). In multivariate logistic regression
analysis, however, this did not reach statistically
significance (OR 1.06, 95% CI 0.99–1.12, P = 0.09).
This is partly because obesity is significantly associated
with the clustering of many risk factors for CHD, such
as hypertension, hypercholesterolemia, hyperlipidemia,
and resistance/type 2 diabetes.21,21–24 Therefore, obesity
is still considered to be an important risk factor for
CaOX stone formation.
Since men generally have a larger body size and a
threefold higher lifetime risk of stone formation than
women,25,26 body size may be an important risk factor
for CaOX stone formation. Curhan et al. also found
that the prevalence of a stone disease were directly
associated with body weight and body mass index.27
Siener et al. recently demonstrated that obesity is
strongly associated with an elevated risk of stone for-
mation due to an increased urinary excretion of pro-
moters but not inhibitors of calcium oxalate stone
Kidney stone disease and risk factors for coronary heart disease 863
Because BMI is a modifiable risk factor, body weight
control can be effective to decrease the risk of calcium
In the present study, stone formers were significantly
associated with smoking habit, hypertension, hypercho-
lesterolemia and greater BMI, compared with controls.
It has been said that obesity and hypertension are asso-
ciated with increased risk of nephrolithiasis in human
and a high-cholesterol diet induces renal calcifications
in rat. The results of the present study are noteworthy
because CaOX stone formers were strongly associated
with smoking habit and hypercholesterolemia in
humans. Our findings implicated that CHD and kidney
stone disease may share common underlying risk fac-
tors. These findings need to be confirmed by further
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