Abstract
Objectives: Metabolic syndrome (MtS) and kidney stone are two common aging diseases with male dominant. This is the first study regarding the potential impact of MtS and its components on kidney stone in aging Chinese population.
Methods: A total of 694 males with a mean age of 55.6 years were enrolled. The definition of MtS was according to the modified criteria developed by the Bureau of Health Promotion in Taiwan. Subjects were classified as having a disease of kidney stones according to diagnosis by a physician with available medical records or evidence from ultrasonography judged by an investigator of urologist.
Results: Using age-adjusted multivariate logistic regression analysis, our results showed that subjects with kidney stone had significantly higher prevalence of MtS (p = 0.04, OR = 1.74, 95% CI: 1.0 1–3.00). The presence of MtS had significant correlation with kidney stone (p = 0.01, OR = 1.83, 95% CI: 1.1 4–2.93), which were associated with the increment of MtS components (p < 0.01). After adjusting for age and testosterone level, abnormal blood pressure (BP) was the most significantly independent component of MtS for kidney stone among the MtS components (p < 0.01, OR = 2.81, 95% CI: 1.46–5.39).
Conclusions: In aging Taiwanese males, the presence of MtS and its components are strongly associated with kidney stone. Abnormal BP is the most significant risk component of MtS for kidney stone.
Introduction
The metabolic syndrome (MtS) refers to a complex entity consisting of multiple interrelated factors including insulin resistance (IR), central obesity, dyslipidemia, and atherosclerotic disease, appearing to affect approximately 10–40% of adult populations worldwide [Citation1]. It has been a main public health concern in the twenty-first century due to the rapidly increasing prevalence in recent years and its utility as a predictor of cardiovascular disease (CVD) risk [Citation2]. Nowadays, kidney stone is also a common disease that may cause significant health care burden. The prevalence is between 5 and 20% in different countries. Also, the recurrence rates are variable and can be up to 50–75% within 10 years [Citation3].
The pathogenetic mechanisms of kidney stone are complex and involve both metabolic and environmental conditions. Although some of these conditions have a well-defined role in the etiologic pathway, the causative mechanisms for most patients with kidney stone are multifactorial and are poorly understood. However, much like MtS, the prevalence of kidney stone is increasing throughout the world. Also, recent papers have described the potential association between kidney stone and CVD [Citation4]. As such, there is increasing evidence that these parallel relationships between MtS and kidney stone might be linked.
MtS and kidney stone are two aging diseases with male dominant. Recent studies have indicated the closed association of androgen with MtS and kidney stone in males [Citation5,Citation6]. Although previous studies suggested the association of two conditions, some limitations still remained in assessing the connection between both disorders because of not completely controlling the effects of potential confounders (e.g., testosterone level) in aging male population. In terms of epidemiology, the expression of MtS is highly variable among ethnicities [Citation7]. Studies about this issue mainly appeared for western ethnicities to date; however, data from Asian populations were very limited. This is the first study regarding the potential impact of MtS and its components on kidney stone in aging Chinese population. Our objectives were to identify the possible associations between MtS and kidney stone in aging Taiwanese males and to explore the potential impact of MtS components on kidney stone.
Methods
We conducted a population-based study with a total of 694 Taiwanese men. All subjects were volunteers older than 40 years and underwent a free health screening in our institution. The screening was open to the general male population living in the city of Kaohsiung. The Institutional Review Board of our hospital approved the study. All subjects provided informed consent before their participation was allowed.
Investigators have taken all subjects complete medical and surgical histories. Detailed physical examinations, including weight, height, blood pressure and ultrasonography for kidneys, were also performed. Fasting blood samples were taken for biochemical analysis and hormone profiling. Body mass index (BMI) (kg/m2) was calculated as body weight divided by the square of body height.
Subjects were defined as alcohol drinkers, cigarette smokers or betel nut chewers if they had regularly consumed any alcoholic beverage ≥1 times per week, had smoked ≥10 cigarettes per week, or had chewed ≥7 betel quids per week, respectively, for at least 6 months [Citation8]. Hypertension was defined as a systolic pressure of ≧140 mmHg or diastolic pressure of ≧90 mmHg. DM was diagnosed when the FBG was ≧126 mg/dL. Hyperlipidemia was defined as a total cholesterol level ≧200 mg/dL or triglycerides level ≧200 mg/dL [Citation9]. Individuals diagnosed as previously having hypertension, DM, or hyperlipidemia, but were under control with regular medication were also included.
MtS was defined using the modified criteria developed by the Bureau of Health Promotion in Taiwan. Participants were defined as having MtS if they met at least 3 of the 5 following criteria [Citation10]: patients were defined as having MtS by the presence of at least three of five of the following criteria: waist circumference (WC) ≥ 90 cm, high-density lipoprotein (HDL) cholesterol <40 mg/dL, triglyceride (TG) ≥ 150 mg/dL, blood pressure (BP) ≥ 130/85 mm Hg or diagnosed hypertension on therapy and fasting blood glucose (FBG) > 100 mg/dL or have a diagnosis of type 2 DM.
Subjects were classified as having a disease of kidney stones if they met one or more of the following criteria: (a) characteristic clinical findings diagnosed by a physician with available medical records; (b) evidence of kidney stones from ultrasonography judged by an investigator (urologist); (c) operative history of stones removal from kidney.
Subjects with apparent causes for kidney stones including ureteropelvic junction obstruction, polycystic renal disease, renal malformations, chronic kidney disease, prolonged immobility, primary thyroid or parathyroid disorders and those with systemic diseases such as gout, neoplasms were excluded in the study.
Statistical analysis
The frequencies of clinical variables between the different groups were compared according to MtS and kidney stone prevalence using the Chi-square test The Student t-test was used to compare quantitative variables between groups. Multivariate logistic regression analysis was used to determine the independent factors influencing MtS and kidney stone. Odds ratios (ORs) were also calculated in multivariate logistic regression analysis. A two-sided p < 0.05 was considered statistically significant. All statistical operations were performed using Statistical Package of the Social Sciences software version 15(SPSS Inc., Chicago, IL).
Results
showed the demographics and laboratory data of the study subjects. The mean (range) age of 639 participants was 55.6 (43–83) years. The characteristics of subjects with and without MtS are summarized in . The associations between qualitative variables and MtS were evaluated with univariate analysis, revealing that the frequencies of smoking, drinking, CVD and kidney stone were significantly greater in patients with MtS (p < 0.05). Among the quantitative variables, age, BMI and testosterone were significantly different between patients without and with MtS. A further multiple logistic regression analysis for all significant variables in univariate analysis was used to define the independent risk factors for MtS; indicating that CVD (p = 0.04, OR = 2.95, 95% CI: 1.40–6.20), kidney stone (p = 0.04, OR = 1.74, 95% CI: 1.0 1–3.00), age (p < 0.01, OR = 1.09, 95% CI: 1.04–1.14) and BMI (p < 0.01, OR = 1.54, 95% CI: 1.42–1.67) were the most independent risk factors for MtS.
Table 1. Demographic characteristics of subjects (N = 694).
Table 2. Results of univariate analysis of the association between variables and MtS.
showed the clinical characteristics of subjects according to kidney stone. Univariate analysis pointed out that there were significantly greater frequencies of betel nut chewers, CVD, MtS, hypertension and hyperlipidemia in subjects with kidney stone (p < 0.05). Among the quantitative variables, age was significantly different between subjects with and without kidney disease (p < 0.05). In the further multiple logistic regression analysis, MtS (p = 0.01, OR = 1.83, 95% CI: 1.14–2.93), hypertension (p = 0.04, OR = 1.64, 95% CI: 1.00–2.71) and hyperlipidemia (p < 0.01, OR = 2.50, 95% CI: 1.50–4.16) were the three most significant variables correlating to kidney stone.
Table 3. Results of univariate analysis of the association between variables and kidney stone.
In , subjects were grouped in accordance with the number of MtS components they had. The results showed that the more number of MtS components, the higher prevalence of kidney stone from 14.2% with three components to 18.4% with four components to 30.4% with five components (p <0.01). To evaluate the statistical effect of individual MtS component on kidney stone, the prevalence of kidney stone was compared according with components of MtS one by one. We found the three components including abnormal BP, abnormal TG and abnormal HDL had significant impact on kidney stone prevalence in univariate analysis. After adjusting OR of age and testosterone, results of multivariate logistic regression analysis indicated that abnormal BP (p < 0.01, OR = 2.81, 95% CI: 1.46–5.39) was the most significant element of MtS on kidney stone ().
Table 4. The prevalence of kidney stone regarding to MtS and the number of MtS components.
Table 5. Mutivariate logistic regression analysis of MtS components for kidney stone.
Discussions
The MtS has gained increasing attention in recent years because of its association with growingly common pathophysiologic states such as CVD, type 2 DM and chronic renal disease (CKD) [Citation2,Citation11]. IR is at the core of the MtS. MtS and IR are mutually independent risk factors for CVD, and this association recently extends to kidney stone as well [Citation4]. In 2010, Rule et al. [Citation12] enrolled 5081 incident kidney stone patients and 14 144 matched control subjects. They found that patients with kidney stone have a 38% increased risk for myocardial infarction (MI). The risk for MI in stone formers remained elevated even when adjusted for other metabolic risk factors and CKD. In 2011, Domingos and Serra [Citation13] further confirmed the relationship between kidney stone and CVD through a study performed in over 23 000 adult subjects from the 4th Portuguese National Health Survey. Their results showed that kidney stone patients have a higher prevalence of MI (OR = 1.338) and stroke (OR = 1.330) compared with controls. More recently, Reiner et al. [Citation14] analyzed data among participants in the CARDIA study, and demonstrated that young adults with a history of kidney stone had a higher prevalence of subclinical atherosclerosis.
A growing evidences now have shown the association between kidney stone disease and variety of metabolic risk factors of CVD, such as hypertension, DM and obesity [Citation15,Citation16], suggesting that kidney stone is likely a complex systemic illness linked to the MtS. However, the specific mechanisms of these associations are not clear. One of the putative explanations for MtS driven kidney stone rests in IR and subsequent defective renal ammoniogenesis, which is insulin mediated at proximal tubule, resulting in alterations of urine acidification and low urine pH [Citation17]. Systemic acidosis ensues which can then result in bone demineralization-mediated hypercalciuria as well as renal citrate reabsorption and subsequent hypocitraturia. The lowering urine pH also leads to acid crystal deposition that can be attached to an exposed site of interstitial calcium phosphate the renal papilla, otherwise known as Randall’s plaque [Citation18]. Another feature of MtS, along with IR, is chronic inflammation. Recent studies have shown that early processes of kidney stone formation involve the inflammatory response, including expression of inflammatory molecules such as monocyte chemoattractant protein 1 and macrophage infiltration [Citation19]. Thus, chronic inflammatory status might be another plausible explanation for increased kidney stone in MtS.
However, MtS does not manifest itself uniformly in all populations. Although studies investigating the associations between MtS and kidney stone are appearing for Caucasian subjects, there are still limited data in Asian populations. In 2011, Jeong et al. [Citation20] reported that the presence of MtS had an OR of 1.25 (95% CI, 1.03–1.50) for kidney stone prevalence evaluated using computed tomography or ultrasonography in individuals who underwent health screening in Korea. In 2013, Kohjimoto et al. [Citation15] examined the effects of metabolic components on kidney stone disease in Japanese population. They found that there was a significant and stepwise increase of recurrent and/or multiple stones proportions from 57.7% with 0 MtS components to 73.3% with four components (p < 0.001). The odds of disease severity in patients with four components was 1.8-fold greater than subjects with 0 traits (OR, 1.78; 95% CI, 1.22–2.66). Above two studies suggested the links of MtS to kidney stone. However, the effects of potential confounders for both MtS and kidney stone (e.g. testosterone level in male population) were not completely controlled to determine the independent associations with each other. This is the first study regarding the potential impact of MtS and its components on kidney stone in aging Chinese population. In our study, the independent associations of MtS (p = 0.01, OR = 1.83) and kidney stone (p = 0.04, OR = 1.74) were also demonstrable in aging Taiwanese males after controlling confounders of both conditions. Our data further showed that the prevalence of kidney stone is associated with the increment of MtS components number (p < 0.01).
Although MtS seems to be an important risk factor for kidney stone, it is unclear which component of MS is more important for the occurrence of kidney stone. Previous studies showed that certain components of MtS have differing effects on the risk of kidney stone disease. Masterson et al. indicated patients with HDL values <45 for men and <60 for women had an increased risk for kidney stone disease on multivariate analysis (OR = 1.27, p = 0.024). In Turkey, Itoh et al. [Citation21] demonstrated that kidney stone patients had elevated TG levels compared to controls. With regard to obesity, Taylor et al. [Citation22] reported that WC, BMI and weight gain increased the risk of kidney stone formation in prospective analyses of three large cohort studies with over 46 years follow-up in the United States. Meanwhile, a positive association between DM and kidney stone disease also showed in these three large cohorts [Citation16]. However, in a study by Kohjimoto et al. in Japan [Citation15], they did not find a significant correlation between MtS components and severity of kidney stone disease, except for hypertension and dyslipidemia. These controversial results suggested that the relationship between MtS and kidney stone may not be clear-cut, and may be selective for certain components in different populations. In the present study, we investigated the effects of MtS components on kidney stone separately, and found that the three components including abnormal BP, abnormal TG, and abnormal HDL had significant impact on kidney stone prevalence. After adjusting OR of age and testosterone level, a logistic regression analysis identified that abnormal BP was the most significant risk component of MtS for kidney stone disease (OR = 2.81, p < 0.01).
Although bidirectional associations between HTN and nephrolithiasis have been reported [Citation23,Citation24], evidence of an association between hypertension and kidney stone disease remains inconsistent. Two longitudinal studies with follow-up of 8 years showed that hypertensive patients had a significantly increased incidence of kidney stone disease [Citation23,Citation25]. In contrast, Madore et al. [Citation26,Citation27] reported that the occurrence of incident kidney stone disease seemed independent of the diagnosis of hypertension in two large prospective studies. However, hypertension, one of the most important CVD risk factors, has been suggested to be a significant predictor of kidney stone disease [Citation23,Citation25]. Hence, such a relationship could explain why kidney stone formers have an increased CVD morbidity. Several studies describe lithogenic urine parameters in association with hypertension. Specifically, hypertension has been found in association with low pH, low citrate and high calcium excretion in kidney stone formers [Citation17,Citation28]. Another possible mechanism has also been proposed recently. As observed, reduced bone mass is a frequent finding in kidney stone formers [Citation29]. Several studies reported an inverse relationship between bone density and abnormal arterial stiffness partly related to vessel calcifications that is also a strong predictor of CVD mortality [Citation30].
In summary, this study has demonstrated that the presence of MtS is strongly associated with kidney stone and that abnormal BP is the most independent predictor of MtS for kidney stone in aging Taiwanese males. Our results provide another view regarding the potential impact of MtS and its components on kidney stone in comparison with previous investigations in different ethnicities. In addition, these findings give significant insight into the importance of interplay among MtS, hypertension in the development of CVD, and the relationship to kidney stone, consolidating the idea that a routine survey for MtS in patients with kidney stone can be feasible and effective in early detecting cardiovascular risk markers. However, there are still some limitations affecting our current findings needed to be addressed. First, our study is cross-sectional. Data on the association among the conditions are represented by epidemiological studies that might not allow definitive conclusions about causal links between MtS and kidney stone. Second, some of kidney stone cases were self-reported. Participants may have kidney stone disease without self awareness or clinical diagnosis. This may lead to potential misclassification and are likely to be random with respect to case status. Third, lacking of functional investigations and stone information (e.g. composition and duration of onset) in relation to those of the comorbid conditions, our study cannot provide further evidence about the possible mechanisms by which the MtS has a potential impact on kidney stone.
Declaration of interest
The authors report that they have no conflicts of interest in this study.
Acknowledgements
The authors thank Ms. Chao-Shih Chen for her help to hold the healthy screening and Ms. Kai-Lin Huang for editing this manuscript.
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