Kidney stone disease and risk factors for coronary heart disease
Satoshi Hamano md, 1-55-8 Miyako-cho, Chuo-ku, Chiba-city, Chiba 260-0001, Japan. Email: email@example.com
Abstract Background: We conducted a case-control study to examine the impact of coronal heart disease (CHD) risk factors on calcium oxalate (CaOX) stone formation.
Methods: Variables included body mass index (BMI), current alcohol use, smoking habit, hypertension, hypercholesterolemia, diabetes mellitus, and hyperuricemia. Data sufﬁcient for analysis were obtained for 181 CaOX stone formers and 187 controls.
Results: Seven of 181 stone formers (3.9%) had a history of CHD compared with none of 187 control subjects (P = 0.007). In univariate logistic regression analysis, smoking habit (OR 4.41, 95% CI 2.85–6.84, P < 0.0001), hypertension (OR 4.24, 95% CI 2.61–6.91, P < 0.0001), hypercholesterolemia (OR 3.03, 95% CI 1.77–5.20, P < 0.0001) and BMI (OR 1.10, 95% CI 1.04–1.17, P = 0.007) reached statistical signiﬁcance. In a multivariate logistic regression analysis, smoking habit (OR 4.29, 95% CI 2.68–6.86, P < 0.0001), hypertension (OR 3.57, 95% CI 2.11–6.07, P < 0.0001), and hypercholesterolemia (OR 2.74, 95% CI 1.51–5.00, P = 0.001) reached statistical signiﬁcance, while BMI (OR 1.06, 95% CI 0.99–1.12, P = 0.09) did not.
Conclusions: CaOX stone formers are signiﬁcantly associated with several CHD risk factors, including smoking habit, hypertension, hypercholesterolemia, and obesity.
Nephrolithiasis is a common painful condition of multifactorial ethiopathogenesis,1 and calcium oxalate (CaOX) is the commonest component of upper urinary tract calculi in economically developed countries, including North America, Europe, Australia, and Japan.1,2 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.1
Our clinical impression was that CaOX stone formers were at increased risk of experiencing coronary heart disease (CHD). However, only few attempts have been made to investigate the associations among urinary stone disease and CHD.3
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 initiation 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 institution.
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, systolic blood pressure, current alcohol use, smoking habit, previous history of CHD events, and history of hypertension, hypercholesterolemia, diabetes mellitus (DM), and hyperuricemia.
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 complete medical records (n = 6), renal insufﬁciency (serum creatinine more than 1.5 mg/dL; n = 5), liver insufﬁciency (n = 3), chronic urinary tract infection (n = 3), diuretics (n = 3), history of cancer (n = 3), poor performance status (n = 2), a high suspicion of hyperparathyroidism (n = 2), solitary kidney (n = 2), renal tubular acidosis (n = 1), inﬂammatory bowel disease (n = 1), and hormone replacement therapy (n = 1) because they were considered to have some conditions predisposing them to calcium-based stone formation.1 After exclusion of subjects with above-mentioned conditions, 181 cases (125 men, 56 women, M/F 2.2; mean age ± SD: 51.5 ± 7.4 years, range 40–65) and 187 controls (127 men, 60 women, M/F 2.1; mean age ± SD: 52.0 ± 6.6 years, range 40–65) remained for analysis of these data. Patients and controls were compared according to the demographic characteristics, and the presence of CHD risk factors using χ2 or Mann–Whitney U-tests if appropriate.
We used univariate and multivariate logistic regression analyses to access the impacts of different factors on CaOX stone formation. Difference resulting in P < 0.05 were considered statistically signiﬁcant. Only the statistically signiﬁcant factors in univariate logistic regression analysis were included in multivariate logistic regression model to identify the factors that act independently. 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 software.
Patients and controls were compared according to the demographic characteristics, and the presence of CHD risk factors using χ2 or Mann–Whitney U-tests if appropriate. The stone formers were signiﬁcantly associated with greater BMI (mean ± SD: 24.8 ± 3.9 kg/m2 vs. 23.7 ± 3.7 kg/m2, P = 0.0007), higher creatinine concentration (0.85 ± 0.22 mg/dL vs. 0.74 ± 0.14 mg/dL, P < 0.0001), systolic blood pressure (128.5 ± 20.5 mmHg vs. 118.0 ± 14.3 mmHg, P < 0.0001), smoking habit (70.2% vs. 25.1%, P < 0.0001), previous history of CHD events (3.9% vs. 0%, P = 0.007), and history of hypertension (44.7% vs. 16%, P < 0.0001) and hypercholesterolemia (29.8% vs. 12.2%, P < 0.0001) compared with the controls (Table 1).
Table 1. General characteristics of study subjects. (Number (%) or Mean ± SD)
|Age (years)|| 51.5 ± 7.4|| 52.0 ± 6.6||0.44 matched|
|BMI*|| 24.8 ± 3.9|| 23.7 ± 3.7||0.0007|
|Uric acid (mg/dL)|| 5.7 ± 1.5|| 5.5 ± 1.5||0.11|
|Serum creatinine (mg/dL)*|| 0.85 ± 0.22|| 0.74 ± 0.14||<0.0001|
|Total cholesterol (mg/dL)||196.8 ± 37.5||189.9 ± 30.9||0.080|
|Systolic blood pressure (mmHg)*||128.5 ± 20.5||118.0 ± 14.3||<0.0001|
|Current alcohol use||106 (59%)||102 (55%)||0.44|
|Smoking habit*||127 (70.1%)|| 47 (25.1%)||<0.0001|
|Previous history of coronary heart disease*|| 7 (3.9%)|| 0||0.007|
| Hypertension*|| 81 (44.7%)|| 30 (16%)||<0.0001|
| Hypercholesterolemia*|| 54 (29.8%)|| 23 (12.2%)||<0.0001|
| Diabetes mellitus|| 19 (10.4%)|| 11 (5.8%)||0.11|
| Hyperuricemia|| 20 (11%)|| 15 (8%)||0.47|
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 regression analysis.
In univariate logistic regression analysis, smoking habit (OR 4.41, 95% CI 2.85–6.84, P < 0.0001), hypertension history (OR 4.24, 95% CI 2.61–6.91, P < 0.0001), hypercholesterolemia history (OR 3.03, 95% CI 1.77–5.20, P < 0.0001) and greater BMI (OR 1.10, 95% CI 1.04–1.17, P = 0.007) reached statistical signiﬁcance (Table 2). In multivariate logistic regression analysis, smoking habit (OR 4.29, 95% CI 2.68–6.86, P < 0.0001), hypertension history (OR 3.57, 95% CI 2.11–6.07, P < 0.0001), and hypercholesterolemia history (OR 2.74, 95% CI 1.51–5.00, P = 0.001) reached statistical signiﬁcance, while greater BMI (OR 1.06, 95% CI 0.99–1.12, P = 0.09) did not (Table 3).
Table 2. Result of univariate logistic regression analysis
|BMI*||1.10 (1.04–1.17)|| 0.007|
|Current alcohol use||1.18 (0.78–1.78)|| 0.43|
|Smoking habit*||4.41 (2.85–6.84)||<0.0001|
|Diabetes mellitus||1.88 (0.87–4.06)|| 0.11|
|Hyperuricemia||1.42 (0.71–2.88)|| 0.32|
Table 3. Result of multivariate logistic regression analysis
|Smoking habit*||4.29 (2.68–6.86)||<0.0001|
|Hypercholesterolemia*||2.74 (1.51–5.00)|| 0.001|
|BMI||1.06 (0.99–1.12)|| 0.09|
Risk factors for CHD are hypertension, hypercholesterolemia, smoking habit, gender (male), DM, obesity etc.4,5
As established by the seminal study of Iguchi et al. calcium stone formers ingested large amounts of nutrients, especially animal protein, during the evening meal.6 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 reﬂect dietary habit and lifestyle of the calcium stone formers.
In the present study, 7 of 181 stone formers (3.9%) had a history of CHD compared with none of 187 control subjects (P = 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, hypercholesterolemia, and obesity.
In multivariate logistic regression analysis, smoking habit reached statistical signiﬁcance (OR 4.29, 95% CI 2.68–6.86, P < 0.0001). Our ﬁndings implicated that cigarette smoking may be a stronger risk factor of CaOX stone formation than are hypertension, hypercholesterolemia, and greater BMI. Cigarette smoking has long been recognized as an important risk factor for CHD. However, few published study has examined the association 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 plasma AVP levels (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.
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 hypertensive 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 subjects; P < 0.001), that is a common risk factor for calcium stone disease.14
Hypercalciuria and hyperoxaluria associated with hypertension are noteworthy although the mechanism of this association is not clearly understood.
Hypercholesterolemia history reached statistical signiﬁcance in multivariate logistic regression analysis (OR 2.74, 95% CI 1.51–5.00, P = 0.001). In human, 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 nucleation and growth of CaOX crystal formation.15 Konya et al. reported that OPN enhances the formation and aggregation of CaOX crystals in the experimental system.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 calcium stone formers experienced signiﬁcant urinary calcium 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 hypercholesterolemia or/and treatment by EPA may reduce recurrent 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 formation due to an increased urinary excretion of promoters but not inhibitors of calcium oxalate stone formation.28
Because BMI is a modiﬁable risk factor, body weight control can be effective to decrease the risk of calcium stone recurrence.
In the present study, stone formers were signiﬁcantly associated with smoking habit, hypertension, hypercholesterolemia and greater BMI, compared with controls. It has been said that obesity and hypertension are associated 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 factors. These ﬁndings need to be conﬁrmed by further prospective study.