Metabolic syndrome, the simultaneous occurrence. Original Investigation

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1 Original Investigation Association Between Metabolic Syndrome and the Presence of Kidney Stones in a Screened Population In Gab Jeong, MD, PhD, 1 Taejin Kang, MD, 1 Jeong Kyoon Bang, MD, 1 Junsoo Park, MD, 1 Wansuk Kim, MD, 1 Seung Sik Hwang, MD, PhD, 2 Hong Kyu Kim, MD, PhD, 3 and Hyung Keun Park, MD, PhD 1 Background: Components of metabolic syndrome have been associated with kidney stone disease, but little evidence is available to support a relationship between metabolic syndrome and kidney stone development in healthy large screened populations. Study Design: Cross-sectional analysis. Setting & Participants: Data were obtained from 34,895 individuals who underwent general health screening tests between January 2006 and December 2006 at the Asan Medical Center. Predictor: Metabolic syndrome was defined according to criteria established by the National Cholesterol Education Program Adult Treatment Panel III, American Heart Association, and National Heart, Lung, and Blood Institute. Outcomes & Measurements: The presence of kidney stones was evaluated using computed tomography or ultrasonography. Results: Of all those screened, 839 (2.4%) had radiologic evidence of kidney stones and metabolic syndrome was diagnosed in 4,779 (13.7%). The multivariable-adjusted OR for kidney stones increased with an increasing quintile of waist circumference and systolic/diastolic blood pressure (P 0.001). Age, sex, hypertension, and metabolic syndrome status were independent risk factors for kidney stones. The presence of metabolic syndrome had an OR of 1.25 (95% CI, ) for kidney stone prevalence. In participants with hypertension, the OR for the presence of kidney stones was 1.47 (95% CI, ) compared with that for participants without hypertension after adjustment for other variables. Limitations: Cross-sectional design, absence of stone composition. Conclusion: Metabolic syndrome is associated with a significantly increased risk of kidney stone development. Our findings suggest the need for interventional studies to test the effects of preventing and treating metabolic syndrome on the risk of kidney stone development. Am J Kidney Dis. 58(3): by the National Kidney Foundation, Inc. INDEX WORDS: Kidney calculi; metabolic syndrome X; mass screening. Metabolic syndrome, the simultaneous occurrence of hyperglycemia, hyperlipidemia, hypertension, and visceral obesity, is a chronic disease associated with high mortality. In addition, this condition substantially increases the risk of developing cardiovascular diseases and type 2 diabetes. 1 In the United States, the prevalence of metabolic syndrome is 24% in men and 23.4% in women, increasing at ages years to 43.5% in both sexes. 2 In Korea, 19.9% of men and 23.7% of women meet the metabolic syndrome criteria established by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). 3 Kidney stone disease is common throughout the world, with a lifetime cumulative incidence of symptomatic nephrolithiasis ranging from 5%-10%. 4 The prevalence of kidney stones has increased in recent years. In American adults, the lifetime occurrence of kidney stones increased significantly by 37% in and again in Concurrent with the westernization of Asian culture, kidney stone formation has increased recently in Asian countries. 5 The origin of kidney stones is multifactorial, with epidemiologic studies showing that male sex, race/ethnicity, age, climate, occupation, and obesity are associated with kidney stone formation. 6,7 Obesity and components of metabolic syndrome have been associated with nephrolithiasis, 7-12 and several studies have suggested that metabolic syndrome is linked directly to the formation of kidney stones Although the exact pathophysiologic mechanisms underlying the association between metabolic syndrome and nephrolithiasis are unclear, met- From the 1 Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul; 2 Department of Social and Preventive Medicine, Inha University School of Medicine, Incheon; and 3 Health Screening and Promotion Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. Received August 27, Accepted in revised form March 22, Originally published online May 27, Address correspondence to Hyung Keun Park, MD, PhD, Department of Urology, Asan Medical Center, Pungnap 2 dong, Songpa-gu, Seoul , Korea. hkpark@amc.seoul.kr 2011 by the National Kidney Foundation, Inc /$36.00 doi: /j.ajkd Am J Kidney Dis. 2011;58(3):

2 Jeong et al abolic syndrome has been associated with changes in urinary constituents, including lower urinary ph, decreased citrate excretion, and increased uric acid and calcium excretion, leading to increased risks of uric acid and calcium stone formation. 13,16,17 To date, little evidence has been available to support a relationship between metabolic syndrome and kidney stone development in healthy screened populations. Preventative health care intervention may be improved by studying the relationship between metabolic syndrome and kidney stone formation in a screened population. Determining common modifiable risk factors for the development of kidney stones might uncover new strategies for treatment and prevention. We therefore investigated the association of metabolic syndrome with kidney stone formation in a large screened population. METHODS Study Participants We retrospectively analyzed medical records of 34,895 individuals who visited the Health Promotion Center of the Asan Medical Center for routine health checkups between January 2006 and December Our health screening program includes anthropometric measurements (height, weight, and waist circumference), blood tests (complete blood cell count, basic chemistry, serologic tests, blood coagulation test, thyroid function tests, and assays for tumor markers), stool/urine analyses, abdominal ultrasonography and/or computed tomography (CT), gastrofiberscopy, chest radiography, pulmonary function tests, and electrocardiography. The study protocol was approved by the Institutional Review Board of the Asan Medical Center. Exposure Measures Weight, waist circumference, and blood pressure were measured after an overnight fast, and a blood sample was drawn. Plasma fasting glucose, serum total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured using enzymatic methods with an autoanalyzer (Toshiba 200-FR; Toshiba Medical System Co, Ltd, Metabolic syndrome was defined according to the criteria established in 2005 by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), American Heart Association, and National Heart, Lung, and Blood Institute. 18 For the criteria for metabolic syndrome, abdominal obesity was defined as waist circumference 90 cm in men and 80 cm in women, according to the World Health Organization Asia-Pacific obesity criteria. 19 Metabolic syndrome was diagnosed in those who satisfied at least 3 of the following 5 criteria: waist circumference 80 cm in women and 90 cm in men, triglyceride concentration 150 mg/dl or undergoing treatment for hypertriglyceridemia, HDL cholesterol concentration 40 mg/dl in men and 50 mg/dl in women or undergoing treatment for low HDL-C level, blood pressure 130/85 mm Hg or undergoing treatment for hypertension, and fasting plasma glucose level 100 mg/dl or undergoing treatment for hyperglycemia. Outcome Measures The presence of kidney stones was the outcome of our analysis. We retrospectively reviewed radiology records of all participants and recorded kidney stones as present if they were detected using abdominal ultrasonography (n 27,884; IU-22 ultrasound unit; Philips Medical Systems, philips.com) or CT (n 7,091; SOMATOM Sensation 16; Siemens AG, stone size did not matter and we even counted cases for which patients did not require treatment. Ultrasonographic examinations were conducted by one of several clinically experienced radiologists at our Health Promotion Center, and an ultrasonographic diagno- Table 1. Baseline Demographic Characteristics No. of Metabolic Syndrome Components Present Characteristics Total P Age (y) Age category y 5,228 (15.0) 3,142 (22.9) 1,196 (11.9) 558 (8.7) 261 (7.7) 62 (5.1) 9 (5.0) y 11,438 (32.8) 5,178 (37.8) 3,269 (32.7) 1,815 (28.4) 857 (25.4) 284 (23.4) 35 (19.1) y 12,263 (35.1) 4,211 (30.8) 3,787 (37.8) 2,423 (37.8) 1,323 (39.1) 458 (37.7) 61 (33.3) 60 y 5,966 (17.1) 1,169 (8.5) 1,757 (17.6) 1,611 (25.1) 940 (27.8) 411 (33.8) 78 (42.6) Sex Male 20,790 (59.6) 6,604 (48.2) 6,419 (64.1) 4,481 (69.9) 2,407 (71.2) 785 (64.6) 94 (51.4) Female 14,105 (40.4) 7,096 (51.8) 3,590 (35.9) 1,926 (30.1) 974 (28.8) 430 (35.4) 89 (48.6) Waist circumference (cm) Triglycerides (mg/dl) HDL cholesterol (mg/dl) Blood pressure (mm Hg) Systolic Diastolic Fasting glucose (mg/dl) Note: Continuous variables given as mean standard deviation; categorical variables are number (percentage). Conversion factors for units: cholesterol in mg/dl to mmol/l, ; glucose in mg/dl to mmol/l, ; triglycerides in mg/dl to mmol/l, Abbreviation: HDL, high-density lipoprotein. 384 Am J Kidney Dis. 2011;58(3):

3 Metabolic Syndrome and Kidney Stone Table 2. Agreement Between Diagnostic Tests for the Detection of Kidney Stones in Participants Who Had Both CT and US Kidney Stone on US Yes Total Kidney stone on CT Yes 239 (3.3) 20 (0.3) 259 (3.6) No 109 (1.6) 6,723 (94.8) 6,832 (96.4) Total 348 (4.9) 6,743 (95.1) 7,091 (100) Note: N 7,091. Values shown are number (percentage). Abbreviations: CT, computed tomography; US, ultrasonography. sis of kidney stones required demonstration of any hyperechoic structure causing acoustic shadowing. The CT diagnosis of kidney stones was established by visualization of a highattenuation structure ( 100 Hounsfield units) in the kidney. Statistical Analyses We performed inter-rater reliability analysis using the statistic to determine the agreement between CT and ultrasonography in 7,091 participants who underwent both CT and ultrasonography. The prevalence of metabolic syndrome and individual components thereof and the numbers of metabolic syndrome components present (0, 1, 2, or 3) were determined for the overall study sample. Mean values for continuous demographic and metabolic variables were calculated relative to the presence of kidney stones. The statistical significance of differences among these variables was assessed using Mann-Whitney U test and 2 test. Crude and multivariable-adjusted odds ratios (ORs) of kidney stone presence were calculated using logistic regression models with age, sex, metabolic syndrome components, and metabolic syndrome status as input factors. The best-fitting model was judged according to the Akaike information criterion (AIC), and the model with the lowest AIC was considered to be the best-fitting model. The AIC was used to select the most parsimonious model. 20 All P values were 2 tailed, and P 0.05 was defined as statistically significant. All statistical analysis was performed using Stata, version 10.1 (Stata- Corp). No RESULTS Baseline demographic characteristics of the 34,895 participants are listed in Table 1. In the study population, 59.6% were men and 67.9% were aged years. As the number of metabolic syndrome components increased, waist circumference, triglyceride concentration, blood pressure, and fasting blood glucose level increased, whereas HDL cholesterol level decreased. A total of 839 participants (2.4% of the population) had radiologic evidence of kidney stones. Of the 7,091 participants who underwent CT and ultrasonography, 368 (5.2%) had kidney stones detected using CT or ultrasonography. Of the 7,091 participants who underwent both CT and ultrasonography, was 0.78 (P 0.001), for excellent agreement (Table 2). Of 839 participants with kidney stones, a single stone was found in 638 (76.0%); 2 stones, in 107 (12.8%); 3 stones, in 53 (6.3%); 4 stones, in 38 (4.5%); and 5 stones, in 3 participants (0.4%). Mean number of kidney stones per person was 1.4. Mean kidney stone size was 6.5 mm (median, 6; range, 1-27). Characteristics of kidney stones by the number of metabolic syndrome component fulfilled are listed in Table 3.As the number of metabolic syndrome components increased, the frequency of kidney stones increased regardless of the diagnostic test used. Overall, 4,779 (13.7%) participants were given a diagnosis of metabolic syndrome. The criterion for increased blood pressure was fulfilled in 30.5% of participants and was the most common of the 5 metabolic syndrome components (increased triglycerides, 27.2%; increased waist circumference, 24.2%; low HDL cholesterol, 15.4%; and impaired glucose tolerance, 13.7%). A total of 61% of participants fulfilled at least one criterion of metabolic syndrome. Table 4 lists crude and multivariable-adjusted ORs for kidney stones according to quintile of the 5 metabolic syndrome components. Crude and multivariableadjusted ORs for kidney stones increased with increasing quintile of waist circumference (P 0.001) and systolic and diastolic blood pressure (P and P 0.001, respectively). When each of the 5 meta- Table 3. Characteristics of Kidney Stone by Number of Metabolic Syndrome Components Fulfilled No. of Metabolic Syndrome Components Present Characteristics Total P No. of participants 34,895 13,700 10,009 6,407 3,381 1, Presence of kidney stone by diagnostic test Total 839 (2.4) 240 (1.8) 245 (2.4) 177 (2.8) 131 (3.9) 38 (3.1) 8 (4.4) Detected by US 675 (1.8) 198 (1.8) 191 (2.4) 137 (2.7) 112 (4.1) 31 (3.3) 6 (4.2) Detected by CT 164 (1.5) 42 (1.5) 54 (2.7) 40 (3.1) 19 (3.0) 7 (2.5) 2 (5.1) No. of kidney stones per person Size of the largest kidney stone (mm) Note: Categorical variables are shown as number (percentage), continuous variables as mean standard deviation. Abbreviations: CT, computed tomography; US, ultrasonography. Am J Kidney Dis. 2011;58(3):

4 Jeong et al Table 4. Crude and Multivariable-Adjusted ORs for Kidney Stone by Quintile of the 5 Metabolic Syndrome Components Total No. Cases of Stones No. (%) Crude OR (95% CI) P Adjusted OR (95% CI) a P Waist circumference Quintile 1 ( 72 cm) 7, (1.4) 1.00 (reference) 1.00 (reference) Quintile 2 (73-78 cm) 7, (1.8) 1.26 ( ) 0.98 ( ) Quintile 3 (79-83 cm) 7, (2.5) 1.74 ( ) 1.13 ( ) Quintile 4 (84-88 cm) 5, (3.2) 2.31 ( ) 1.42 ( ) Quintile 5 ( 89 cm) 6, (3.4) 2.44 ( ) 1.48 ( ) Triglycerides Quintile 1 ( 69 mg/dl) 6, (2.0) 1.00 (reference) 1.00 (reference) Quintile 2 (70-92 mg/dl) 6, (1.9) 0.94 ( ) 0.79 ( ) Quintile 3 ( mg/dl) 6, (2.7) 1.36 ( ) 1.06 ( ) Quintile 4 ( mg/dl) 6, (2.6) 1.31 ( ) 0.97 ( ) Quintile 5 ( 171 mg/dl) 6, (3.0) 1.51 ( ) 1.07 ( ) HDL cholesterol Quintile 1 ( 44 mg/dl) 7, (3.0) 1.00 (reference) 1.00 (reference) Quintile 2 (45-51 mg/dl) 6, (2.5) 0.84 ( ) 0.89 ( ) Quintile 3 (52-58 mg/dl) 6, (2.4) 0.80 ( ) 0.90 ( ) Quintile 4 (59-67 mg/dl) 6, (2.1) 0.69 ( ) 0.84 ( ) Quintile 5 ( 68 mg/dl) 6, (2.0) 0.65 ( ) 0.88 ( ) Systolic BP Quintile 1 ( 105 mm Hg) 7, (1.5) 1.00 (reference) 1.00 (reference) Quintile 2 ( mm Hg) 7, (2.3) 1.50 ( ) 1.27 ( ) Quintile 3 ( mm Hg) 6, (2.3) 1.52 ( ) 1.19 ( ) Quintile 4 ( mm Hg) 7, (2.8) 1.89 ( ) 1.40 ( ) Quintile 5 ( 131 mm Hg) 6, (3.2) 2.18 ( ) 1.58 ( ) Diastolic BP Quintile 1 ( 66 mm Hg) 7, (1.6) 1.00 (reference) 1.00 (reference) Quintile 2 (67-71 mm Hg) 6, (2.2) 1.35 ( ) 1.15 ( ) Quintile 3 (72-76 mm Hg) 7, (2.1) 1.33 ( ) 1.07 ( ) Quintile 4 (77-82 mm Hg) 6, (2.7) 1.72 ( ) 1.31 ( ) Quintile 5 ( 83 mm Hg) 6, (3.6) 2.27 ( ) 1.64 ( ) Fasting glucose Quintile 1 ( 85 mg/dl) 6, (2.0) 1.00 (reference) 1.00 (reference) Quintile 2 (86-91 mg/dl) 7, (2.0) 1.00 ( ) 0.89 ( ) Quintile 3 (92-96 mg/dl) 6, (2.2) 1.15 ( ) 0.94 ( ) Quintile 4 ( mg/dl) 6, (2.8) 1.46 ( ) 1.12 ( ) Quintile 5 ( 104 mg/dl) 6, (3.1) 1.57 ( ) 1.09 ( ) Note: Conversion factors for units: cholesterol in mg/dl to mmol/l, ; glucose in mg/dl to mmol/l, ; triglycerides in mg/dl to mmol/l, Abbreviations: BP, blood pressure; CI, confidence interval; HDL, high-density lipoprotein; OR, odds ratio. a Adjusted for age and sex. bolic components was analyzed as a continuous variable, systolic and diastolic blood pressure (P and P 0.001, respectively), waist circumference (P 0.001), and triglyceride concentration (P 0.02) were independent risk factors for kidney stones after adjustment for age and sex. HDL cholesterol and fasting blood glucose levels were not associated independently with risk of kidney stones (P 0.3 and P 0.7, respectively). Table 5 lists crude and multivariable-adjusted ORs of kidney stone presence associated with age, sex, hypertension, and metabolic syndrome status. We selected this as the best-fitting model because it had the lowest AIC value. Age was significantly positively associated with the OR for kidney stone development. The presence of metabolic syndrome ( 3 criteria) was associated with a 71% increased OR of kidney stone prevalence compared with the absence of metabolic syndrome. After adjustment for age, sex, and the presence of hypertension, this OR decreased to 1.25 (95% confidence interval [CI], ). Compared with men, women had a multivariable OR for the presence of kidney stones of 0.56 (95% CI, ). In participants with hypertension, the OR for the presence of kidney stones was 1.47 (95% CI, ) compared with those without hypertension 386 Am J Kidney Dis. 2011;58(3):

5 Metabolic Syndrome and Kidney Stone Table 5. Crude and Multivariable-Adjusted ORs of the Association Between Kidney Stone Presence and Metabolic Syndrome Status Total No. Cases of Stones No. (%) Crude OR (95% CI) P Adjusted OR (95% CI) a P Age category y 5, (1.2) 1.00 (reference) 1.00 (reference) y 11, (2.0) 1.62 ( ) ( ) y 11, (3.0) 2.45 ( ) ( ) y 5, (2.4) 2.44 ( ) ( ) Sex Male 20, (3.0) 1.00 (reference) 1.00 (reference) Female 13, (1.6) 0.52 ( ) ( ) Hypertension No 23, (1.9) 1.00 (reference) 1.00 (reference) Yes 10, (3.5) 1.86 ( ) ( ) Metabolic syndrome No 29, (2.2) 1.00 (reference) 1.00 (reference) Yes 4, (3.7) 1.71 ( ) ( ) 0.02 Note: Criteria for metabolic syndrome were used as defined by the National Cholesterol Education Program Adult Treatment Panel III, American Heart Association, National Heart, Lung, and Blood Institute statement. 18 Abbreviations: CI, confidence interval; OR, odds ratio. a Multivariable adjusted. after adjustment for other variables. The diagnostic test for detecting kidney stones was not associated significantly with the detection of kidney stones (crude OR, 0.94 for CT vs ultrasonography; 95% CI, ; P 0.5). After adjustment for age, sex, hypertension, and the presence of metabolic syndrome, diagnostic testing was not associated with the OR of the presence of kidney stones (multivariable-adjusted OR, 0.95; 95% CI, ; P 0.5). DISCUSSION In our large screened population, metabolic syndrome was associated with a significantly increased risk of kidney stone presence after adjustment for other confounding variables. We also showed that metabolic syndrome is associated with risk of kidney stones in addition to already known independent metabolic risk factors, such as hypertension. Our results are consistent with those of an earlier study, which found a significant association between metabolic syndrome and echographic evidence of nephrolithiasis in an inpatient white population referred to the hospital for any reason. 14 However, our present study is the first to show such an association in a large screened population of healthy Asian men. Although the detailed mechanisms responsible for the association of metabolic syndrome with kidney stone development are unclear, the syndrome has been associated with a self-reported history of kidney stones. In a study of 14,870 participants in the Third National Health and Nutrition Examination Survey (NHANES III), the presence of 4-5 traits of metabolic syndrome was associated with an approximately 2-fold increase in self-reported kidney stone disease. 15 We also found that hypertension was associated positively with risk of kidney stones after adjustment for patient age, sex, and the presence of metabolic syndrome. Compared with normotensive patients, the multivariable OR for kidney stones in hypertensive patients was To date, several epidemiologic studies have analyzed the association between hypertension and nephrolithiasis. In cross-sectional studies, it has been reported that nephrolithiasis is more frequent in hypertensive patients than in those who are normotensive, but the pathologic link between hypertension and stone disease remains to be clarified In addition, some prospective studies reported the risk of stones in hypertensive patients. 10,22,25 Although previous studies have suggested that the prevalence of kidney stones is amplified by diabetes mellitus, especially in those with uric acid nephrolithiasis, our data do not support a possible association between diabetes and kidney stones. 8,26,27 In our study, fasting blood glucose level, which was analyzed as either a categorical or continuous variable, was not an independent risk factor for kidney stones after adjustment for patient age and sex. It is difficult to directly compare our results with those of studies conducted in Western countries. Differences in racial/ ethnic variables, age distribution, frequency of nephrolithiasis, methods of detection of nephrolithiasis (ie, electronic data based or self-reported questionnaires vs a radiologic diagnosis), and study populations may have affected results of analyses. Therefore, addi- Am J Kidney Dis. 2011;58(3):

6 Jeong et al tional studies are needed to determine whether diabetes is an independent risk factor for the formation of calcium stones. Our findings have important implications for clinical care and public health because metabolic syndrome is so common. If metabolic syndrome and the presence of kidney stones are associated, stone development may be prevented by lifestyle modification and subsequent resolution of metabolic syndrome. Our study was strengthened by the large size of the screened cohort population and the use of standardized clinical and laboratory covariates. However, the study was limited by our inability to measure and analyze stone composition. In addition, it was difficult to define the duration of any metabolic risk factor because a substantial number of individuals with such risk factors may be undiagnosed and the duration of risk factors may reflect the extent of medical surveillance. Last, because our study was not longitudinal, we could not determine whether a causal relationship existed between metabolic syndrome or obesity and kidney stone development. In conclusion, we found that metabolic syndrome was a strong and independent risk factor for kidney stone formation. This association suggests that kidney stones may be a systemic disorder representing the interaction of multiple metabolic risk factors. These results argue for interventional studies to examine the effects of prevention and treatment of metabolic syndrome on the risk of kidney stone development. ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests. REFERENCES 1. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365(9468): Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey. 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