Latent association between low urine pH and low body weight in an apparently healthy population.

Low urine pH, a plausible predictor for chronic kidney disease and metabolic disorders, is often observed in obese individuals. However, the association between low urine pH and low body weight is equivocal. We examined clinical parameters including urine pH and body mass index (BMI) in a cross-sectional study of 3629 apparently healthy Japanese adults aged 25-80 years who underwent a health-screening check-up. Urine pH was lower and the prevalence of proteinuria was significantly higher in subjects with BMI of ≥ 27.0 kg/m(2) compared with those with BMI of 21.0-22.9 kg/m(2). By contrast, hematuria was more prevalent in subjects with BMI of ≤ 20.9 kg/m(2). Logistic regression analysis showed that BMI of ≥ 27.0 kg/m(2) was significantly associated with low urine pH (≤ 5.5), which remained significant after adjustment for relevant confounders including age, sex, proteinuria, estimated glomerular filtration rate, urine density, hematuria, smoking status, and daily alcohol drinking. However, the association disappeared after further adjustment for serum uric acid. In contrast, the association between low urine pH and BMI of ≤ 19.0 kg/m(2) was significant after adjustment for age and sex and rather strengthened by the further adjustment for serum uric acid. In conclusion, low urine pH may be independently associated with low BMI. However, the underlying mechanisms of low urine pH in low body weight may differ from those in high body weight.

The association of serum sodium and chloride levels with blood pressure and estimated glomerular filtration rate.

BACKGROUND: High serum sodium (sNa) concentrations may be associated with hypertension, which deteriorates kidney function. However, it is equivocal whether high sNa concentrations are associated with impaired kidney function independently of blood pressure (BP) or serum chloride (sCl). Therefore, we addressed this issue in an apparently healthy population. METHODS: Clinical variables including estimated glomerular filtration rate (eGFR) were examined in 3603 men and women (aged 25-75 years) who underwent health-screening check-ups. sNa concentrations were classified into five categories. RESULTS: Most parameters, including age and BP, increased with increasing sNa, whereas eGFR decreased. Logistic regression analysis showed that, compared with low-normal sNa (≤ 140 mEq/l), high sNa (≥ 144 mEq/l) was significantly associated with elevated BP (≥ 130/85 mmHg) even after adjustment for blood hematocrit, eGFR, serum potassium (sK) concentration and sCl. The highest sNa category was significantly associated with reduced eGFR (< 60 ml/min/1.73 m(2)) independently of elevated BP. Unlike adjustment for sK, adjustment for sCl strengthened the association between high sNa and elevated BP but attenuated the association between high sNa and reduced eGFR. CONCLUSIONS: These results suggest that high sNa concentrations, even within the normal range, are independently associated with elevated BP and impaired kidney function. These associations may be substantially modified by sCl.

Serum uric acid is an independent predictor of metabolic syndrome in a Japanese health screening population.

Serum levels of uric acid (UA) are associated with metabolic syndrome (MetS). However, no study has been aimed to investigate whether baseline UA is a predictor of MetS in a Japanese population. The multivariable adjusted hazard ratios (HRs) of MetS through 3 years were calculated for each 1 SD increase in baseline UA, for the higher quartiles of baseline UA compared with the lowest quartile, and for baseline hyperuricemia defined as ≥7.0 mg/dl for men and ≥6.0 mg/dl for women in apparently healthy 1,606 men aged 51.7 ± 9.4 years and 953 women aged 51.6 ± 9.4 years who visited a medical check-up center in Japan. The HRs (95 % confidence interval; p value) were 1.282 (1.097-1.499; 0.002) in men and 1.354 (1.041-1.762; 0.024) in women for 1 SD increase in baseline UA, 2.206 (1.344-3.620; 0.002) in men and 3.110 (1.121-8.627; 0.029) in women for the highest quartile of baseline UA compared with the lowest quartile, and 1.900 (1.376-2.622; <0.001) in men and 2.088 (1.040-4.190; 0.038) in women for baseline hyperuricemia adjusting for the pre-existing components of MetS, age, smoking, drinking, physical activity, use of antihypertensive, antihyperlipidemic, and antidiabetic medications and histories of coronary heart disease and stroke. However, no significant association was found between longitudinal changes in UA and incident MetS. Baseline UA is an independent predictor of MetS in a Japanese health screening population.

Overweight and high-sensitivity C-reactive protein are weakly associated with kidney stone formation in Japanese men.

OBJECTIVES: To investigate longitudinal relationships between obesity/inflammation and kidney stone formation in a population where obesity is not prevalent. METHODS: Using Cox regression models, associations between kidney stone formation and body mass index, waist circumference, high-sensitivity C-reactive protein and other possible risk factors were retrospectively examined in a health screening Japanese population including 1726 men and 992 women. RESULTS: During 4 years of follow up (mean 3.2 years), kidney stones were formed in 238 men (34.5 per 1000 person-years) and 82 women (20.7 per 1000 person-years). In men, when the possible risk factors were separately examined as continuous parameters, body mass index (P = 0.030) and waist circumference (P = 0.025) were significantly, and log C-reactive protein (P = 0.092) were marginally, associated with kidney stone formation. However, none of these parameters was independently associated with kidney stone formation after fully adjusted. In women, none of the aforementioned three parameters was associated with kidney stone formation. As a categorical parameter, the higher two quintiles of C-reactive protein were significantly associated with kidney stone formation compared with the lower two quintiles in men (P = 0.026). CONCLUSIONS: Overweight and C-reactive protein are weakly associated with kidney stone formation in Japanese men. Inflammation might be an underlying mechanism of the association between obesity and kidney stone formation.

The association between obesity and acute myocardial infarction is age- and gender-dependent in a Japanese population.

Controversies concerning the association between obesity and acute myocardial infarction (AMI) are still ongoing in Japan. We investigated the association between obesity defined by body mass index of 25 kg/m(2) or higher and AMI by a case-control study using data from 1199 AMI cases and 4056 apparently healthy controls. The analysis was performed in age- and sex-matched samples of 621 case-control pairs younger than 80 years and in crude samples aged 40-79 years divided into 10-year age groups. Prevalence of obesity, diabetes, current smoking, hypertension, and hypercholesterolemia were compared between cases and controls, and a multivariable odds ratio (OR) of AMI was calculated for each risk factor in various age groups. The OR (95 % confidence interval (CI)) of AMI for obesity was 1.63 (1.23-2.17), P = 0.0008 in men younger than 80 years; 2.65 (1.41-5.00), P = 0.0025 in women younger than 80 years; 2.23 (1.46-3.41), P = 0.0002 in men aged 59 years or younger; 1.34 (0.90-2.01), P = 0.1510 in men aged 60-79 years; and 2.98 (1.56-5.71), P = 0.0010 in women aged 60-79 years using paired samples. The OR (95 % CI) of AMI for obesity was 4.92 (2.53-9.58), P < 0.0001 in men aged 40-49 years; 1.54 (1.07-2.21), P = 0.0197 in men aged 50-59 years; 1.07 (0.69-1.66), P = 0.7717 in men aged 60-69 years; 2.24 (1.20-4.20), P = 0.0118 in men aged 70-79 years; 2.48 (1.12-5.48), P = 0.0245 in women aged 60-69 years; and 3.05 (1.46-6.37), P = 0.0029 in women aged 70-79 years using crude samples. The association between obesity and AMI was age- and gender-dependent in a Japanese population.

Hypobilirubinemia might be a possible risk factor of end-stage kidney disease independently of estimated glomerular filtration rate.

BACKGROUND/AIMS: The relationship between serum total bilirubin (TB) and estimated glomerular filtration rate (eGFR) is controversial and there is no report on the association between TB and end-stage kidney disease (ESKD). METHODS: We examined the cross-sectional association between TB and eGFR and investigated whether TB can predict ESKD with multivariable logistic regression adjusted for age, sex, and baseline eGFR using hospital-based data. RESULTS: The geometric mean TB of patients with eGFR ≥ 90 mL/min/1.73 m2 (S1), 8960 mL/min/1.73 m2 (S2), 59-30 mL/min/1.73 m2 (S3), 29-15 mL/min/1.73 m2 (S4), and < 15 mL/min/1.73 m2 (S5 = ESKD) was 0.55 mg/dL, 0.59 mg/dL, 0.56 mg/dL, 0.47 mg/dL, and 0.36 mg/dL (all p<0.0001 except for S1 vs. S3 where p=0.3726), respectively excluding patients with hyperbilirubinemia (TB > 1.24 mg/dL). The odds ratio (95% confidence interval) of incident ESKD for each 0.1 mg/dL increase in TB and hypobilirubinemia defined as TB ≤ 0.34 mg/dL were 0.92 (0.80-1.07) (p=0.2804) and 3.51 (1.56-7.88) (p=0.0023), respectively in patients with baseline eGFR ≥ 15 mL/min/1.73 m2 and 0.59 (0.37-0.95) (p=0.0283) and 6.03 (1.63-22.30) (p=0.0071), respectively in patients with baseline eGFR 29-15 mL/min/1.73 m2. CONCLUSIONS: Hypobilirubinemia might be a possible risk factor of ESKD.

A possible cross-sectional association of serum total bilirubin with coronary heart disease and stroke in a Japanese health screening population.

Bilirubin is a potent antioxidant, and serum total bilirubin (TB) is reported to be negatively associated with cardiovascular disease (CVD). There has been no report on the association between TB and CVD prevalence in Japanese. The aim of the study is to examine the association between TB and CVD prevalence in a Japanese health screening population. Prevalence of CVD was studied in 3,375 Japanese men and 2,069 Japanese women. Odds ratios (ORs) of each higher quintile of TB using the lowest quintile as the reference in men and of each higher tertile of TB using the lowest tertile as the reference in women were calculated for coronary heart disease (CHD) and stroke adjusting for age, liver function tests, smoking, physical activity, and alcohol consumption. The ORs [95% confidence intervals (CIs)] for CHD and stroke of the 2nd, 3rd, 4th, and 5th quintiles of TB were 0.63 (0.37-1.07) and 0.49 (0.24-1.00), 0.45 (0.22-0.90) and 0.65 (0.28-1.51), 0.69 (0.39-1.20) and 0.37 (0.15-0.87), and 0.61 (0.34-1.09) and 0.40 (0.18-0.92), respectively in men. The ORs (95% CIs) for CHD and stroke of the 2nd and 3rd tertiles of TB were 1.32 (0.49-3.54) and 0.35 (0.13-0.93), and 1.26 (0.44-3.62) and 0.34 (0.13-0.93), [corrected] respectively in women. Low TB was associated with the higher prevalence of CHD and stroke in men and with the higher prevalence of stroke in women among a Japanese health screening population.

Lymphocyte count was significantly associated with hyper-LDL cholesterolemia independently of high-sensitivity C-reactive protein in apparently healthy Japanese.

The aim of this study was to investigate the association between leukocyte subtype counts and hyper-LDL cholesterolemia, hypertriglyceridemia, and hypo-HDL cholesterolemia. Logistic regressions using hyper-LDL cholesterolemia, hypertriglyceridemia, and hypo-HDL cholesterolemia as a dependent variable and total leukocyte, basophil, eosinophil, neutrophil, lymphocyte, and monocyte counts as an independent variable were calculated adjusting for age, body mass index (BMI), high-sensitivity C-reactive protein (hs-CRP), smoking, drinking, and physical activity in apparently healthy Japanese men (1,803) and women (1,150). The odds ratio (OR) of hyper-LDL cholesterolemia for total leukocyte, eosinophil, and lymphocyte counts, the OR of hypertriglyceridemia for total leukocyte, eosinophil, neutrophil, and lymphocyte counts, and the OR of hypo-HDL cholesterolemia for total leukocyte, neutrophil, and lymphocyte counts were significant in men, and the OR of hyper-LDL cholesterolemia, for lymphocyte count, and the OR of hypo-HDL cholesterolemia for eosinophil count were significant in women. Lymphocyte count was significantly associated with hyper-LDL cholesterolemia independently of hs-CRP in apparently healthy Japanese.

Bilirubin is negatively associated with hemoglobin a(1c) independently of other cardiovascular risk factors in apparently healthy Japanese men and women.

BACKGROUND: Serum total bilirubin (TB) is a potent antioxidant and may be a negative risk factor of cardiovascular disease. In non-diabetic adults, hemoglobin A(1c) (HbA(1c)), but not fasting plasma glucose, is an independent risk factor of cardiovascular disease. METHODS AND RESULTS: Linear regression using TB as a dependent variable and cardiovascular risk factors, including HbA(1c), as independent variables, linear regression using HbA(1c) as a dependent variable and other cardiovascular risk factors, including TB, as independent variables, and logistic regression using the highest decile (≥ 5.4%) of HbA(1c) as a dependent variable and TB and other cardiovascular risk factors as independent variables were performed for 893 apparently healthy male smokers, 1,607 male nonsmokers, and 1,680 women. The standardized regression coefficient of HbA(1c) for TB and that of TB for HbA(1c) was -0.12 (P = 0.007) and -0.06 (P = 0.02), respectively, in the smokers, -0.20 (P < 0.0001) and -0.07 (P < 0.0001), respectively, in the nonsmokers, and -0.21 (P < 0.0001) and -0.14 (P < 0.0001), respectively, in the women. The odds ratio of 1 SD increment in TB for HbA(1c) ≥ 5.4% was not significant in the smokers, 0.67 (P = 0.002) in the nonsmokers, and 0.55 (P<0.0001) in the women. CONCLUSIONS: Bilirubin was negatively associated with HbA(1c) independently of other cardiovascular risk factors in apparently healthy Japanese men and women. The association was weak in male smokers.

Reproducibility of high-sensitivity C-reactive protein as an inflammatory component of metabolic syndrome in Japanese.

BACKGROUND: Cutoff points for high-sensitivity C-reactive protein (hs-CRP) as a component of metabolic syndrome (MetS) in Japanese have been proposed as 0.40-0.45 mg/L for men and 0.25-0.35 mg/L for women. However, there are some concerns about the reproducibility of hs-CRP. METHODS AND RESULTS: Reproducibility of hs-CRP as a component of MetS was examined using receiver-operating characteristic (ROC) curves for diagnosing MetS in 1,274 men and 673 women whose serum levels of hs-CRP were measured twice at annual health screening tests. The Spearman's correlation coefficient between baseline hs-CRP and hs-CRP at the next year's test was 0.68 in men and 0.71 in women. The area under the ROC curves of baseline hs-CRP, hs-CRP at the next year's test, and the mean of the 2 hs-CRP tests for diagnosing baseline MetS were 0.71, 0.71, and 0.72, respectively, in men and 0.75, 0.74, and 0.74, respectively, in women. Optimal cutoff points of baseline hs-CRP, hs-CRP at the next year's test, and the mean of 2 tests for diagnosing baseline MetS were all 0.40 mg/L in men and 0.35 mg/L in women. CONCLUSIONS: The serum level of hs-CRP was stable enough for use as a measure of the inflammatory component of MetS, and the optimal cutoff point of hs-CRP was 0.40 mg/L for men and 0.35 mg/L for women in a Japanese health-screening population.

Significance of heart rate in the prevalence of metabolic syndrome and its related risk factors in Japanese.

BACKGROUND: Autonomic dysfunction is thought to be an important mechanism of metabolic syndrome (MetS), but there has not been a study on the direct association between MetS and heart rate (HR) in Japanese. METHODS AND RESULTS: The association between MetS and HR was examined using medical check-up data from 1,880 men and 1,079 women. HR was significantly higher in MetS subjects than in non-MetS subjects in both men and women (P<0.0001 in men, P<0.001 in women). The prevalence of MetS increased linearly through the quartiles of HR in both men and women. HR was significantly correlated with MetS-related risk factors other than uric acid in men and other than uric acid, body mass index, waist circumference, and high-density lipoprotein cholesterol in women. CONCLUSIONS: The prevalence of MetS increased linearly with the increase in HR among Japanese men and women, and HR was significantly correlated with MetS-related risk factors.

The metabolic syndrome as a concept of adipose tissue disease.

The metabolic syndrome is a constellation of interrelated metabolic risk factors that appear to directly promote the development of diabetes and cardiovascular disease. However, in 2005, the American Diabetes Association and the European Association for the Study of Diabetes jointly stated that no existing definition of the metabolic syndrome meets the criteria of a syndrome, and there have been endless debates on the pros and cons of using the concept of this syndrome. The controversy may stem from confusion between the syndrome and obesity. Obesity is an epidemic, essentially contagious disease caused by an environment of excess nutritional energy and reinforced by deeply rooted social norms. The epidemic of obesity should be prevented or controlled by social and political means, similar to the approaches now being taken to combat global warming. The diagnosis of metabolic syndrome is useless for this public purpose. The purpose of establishing criteria for diagnosing metabolic syndrome is to find individuals who are at increased risk of diabetes and cardiovascular disease and who require specific therapy including diet and exercise. The syndrome may be an adipose tissue disease different from obesity; in that case, it would be characterized by inflammation clinically detected through systemic inflammatory markers such as high-sensitivity C-reactive protein and insulin resistance reflecting histological changes in adipose tissue. However, many problems in defining the optimal diagnostic criteria remain unresolved.

Historical perspectives of the metabolic syndrome.

The metabolic syndrome (MetS) or insulin resistance syndrome is a constellation of obesity-related metabolic derangements predisposing to type 2 diabetes and cardiovascular disease. In 1998, WHO defined the first criteria of MetS. Three years later, the user-friendly National Cholesterol Education Program criteria of MetS were proposed. Different criteria were issued by the International Diabetes Federation in 2005, making abdominal obesity a necessary component. Several international societies, including The International Diabetes Federation, jointly adopted the revised National Cholesterol Education Program criteria as harmonizing criteria of MetS in 2009. WHO warned the next year that MetS has limited practical utility as a management tool. Adipose tissue inflammation has been shown to be a fundamental mechanism of metabolic derangements, associated with ectopic lipid deposit and mitochondrial dysfunction in skeletal muscle and the liver.

LDL cholesterol was more strongly associated with percent body fat than body mass index and waist circumference in a health screening population.

AIMS: To compare correlations between changes in cardiovascular risk factors and those in obesity indices and to compare associations with incident hyper-LDL cholesterolemia among obesity indices. METHODS: Correlation coefficients were calculated between 7-year changes in cardiovascular risk factors and those in body mass index (BMI), waist circumference (WC) and percent body fat (PBF) in 634 men and 396 women who used no antihypertensive, antidiabetic or antihyperlipidemic drugs. Odds ratios of incident hyper-LDL cholesterolemia after 7 years were calculated for BMI, WC and PBF in 738 men and 388 women. RESULTS: There were no significant differences in the correlations with 7-year changes in cardiovascular risk factors between 7-year changes in BMI and WC. The correlation with 7-year change in LDL cholesterol was stronger for that in PBF than that in BMI or WC (p=0.021 or 0.089, respectively in men and 0.022 or 0.020, respectively in women). The correlations with 7-year changes in log triglycerides, HDL cholesterol and log high-sensitivity CRP were stronger for those in BMI and WC than that in PBF in men. Incident hyper-LDL cholesterolemia after 7 years was significantly associated with PBF, but not BMI or WC, in men after adjusted for age and other covariates. However, the association was not significant after further adjusted for LDL cholesterol. CONCLUSIONS: The correlation with 7-year change in LDL cholesterol was stronger for that in PBF than that in BMI or WC. Incident hyper-LDL cholesterolemia was significantly associated with PBF, but not with BMI or WC, in men.

Ketonuria may be associated with low serum amylase independent of body weight and glucose metabolism.

CONTEXT: Ketonuria, which reflects a preferential combustion of lipids relative to carbohydrates, is often observed in lean rather than obese people. Clinical studies have shown that individuals with diabetes and/or obesity predispose to have low serum amylase (LSA). OBJECTIVE: To investigate the association between ketonuria and LSA. METHODS: We examined ketonuria assessed by dipstick urinalysis and clinical parameters including serum amylase in 3638 Japanese people aged 25-79 years who underwent a health-screening checkup. RESULTS: There was an inverse relationship between body mass index (BMI) and serum amylase. The lowest serum amylase was observed in obese subjects (BMI ≥ 25.0 kg/m2) with positive ketonuria. Logistic regression analysis showed that ketonuria was significantly associated with LSA (<50 IU/L), which was not altered by the adjustments for relevant confounders including age, sex, BMI, and HbA1c. CONCLUSIONS: Current results suggest a relative unavailability of carbohydrates for energy production in individuals with LSA.

Gender differences in correlations among cardiovascular risk factors.

BACKGROUND: Although the clustering of a few specific cardiovascular risk factors is known as the metabolic syndrome, sex-specific differences in correlations among risk factors have not been thoroughly examined. OBJECTIVE: The analysis was undertaken to detect gender differences in correlations among cardio-vascular risk factors. METHODS: Correlations among age, body mass index, systolic and diastolic blood pressures, and serum levels of fasting blood sugar (FBS), triglycerides (TG), high- and low-density lipoprotein cholesterol, high-sensitivity C-reactive protein (CRP), and uric acid were analyzed in apparently healthy Japanese men and women with TG<400 mg/dL and FBS<126 mg/dL. RESULTS: Among the 136 men and 136 women examined, the frequency of significant correlations was marginally higher in women than in men: 28/45 correlations versus 17/45 correlations, respectively (P=0.017). Of a total of 45 possible correlations, 5 were marginally or significantly stronger in women, whereas no correlations among these risk factors were marginally or significantly stronger in men (P=0.021). These gender differences were considerably attenuated after adjustment for age. However, a significant sex-specific difference was observed in the correlation between TG and rank transformation of CRP, even after adjustment for age (P<0.01). CONCLUSIONS: Correlations among cardiovascular risk factors were marginally stronger in women than in men. These results suggest that the existence of 1 additional risk factor may increase the risk of cardiovascular disease more steeply in women than in men.

Cross-Sectional and Longitudinal Associations between Serum Bilirubin and Prediabetes in a Health Screening Population.

OBJECTIVES: Longitudinal associations between total bilirubin (TB) and prediabetes have not been reported. This study investigated cross-sectional and longitudinal associations between TB and prediabetes. METHODS: Cross-sectional associations between TB and prediabetes were investigated in 3681 nondiabetic subjects. Longitudinal associations between TB and prediabetes over 6 years were investigated in 2149 subjects who were normoglycemic at baseline. Prediabetes was defined as fasting plasma glucose (FPG) levels of ≥5.6 mmol/L or glycated hemoglobin levels of ≥5.7% excluding diabetes. RESULTS: The prevalence of prediabetes was 25.4%, and the cumulative incidence of prediabetes during 6 years was 25.5% in a Japanese health screening population. Prevalent prediabetes was significantly associated with the quintiles of TB in nonsmoking men (trend, p<0.001) and women (trend, p=0.012), but not in smoking men (trend, p=0.689). Incident prediabetes was not significantly associated with the quintiles of TB, while it was positively associated with 1 standard deviation increase in TB in nonsmoking men (hazard ratio [95% confidence interval]; 1.21 [1.07 to 1.37], p=0.002). CONCLUSIONS: TB levels were significantly inversely associated with prevalent prediabetes in nonsmokers, but not in smokers, whereas an inverse association between TB levels and incident prediabetes seemed to be unlikely.

Low Vital Capacity Was Associated with Incident Diabetes in a Japanese Health Screening Population in Whom Obesity Was Not Prevalent.

OBJECTIVES: There have been few studies regarding the relationship between respiratory function and incident diabetes in East Asian populations in whom obesity is not prevalent. METHODS: This is a 6-year follow-up study in a Japanese health-screening population that included 1874 men and 1093 women. Using Cox regression models, hazard ratios (HRs) of incident diabetes for percent vital capacity (%VC) and forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC) were calculated. Diabetes was defined as simultaneous fasting plasma glucose (FPG) ≥7.0 mmol/L and glycated hemoglobin (A1C) ≥6.5% or use of antidiabetic medications. RESULTS: During the 6-year follow-up period (mean of 4.8 years), 71 men (3.8%) and 18 women (1.7%) developed diabetes. The HRs (95% confidence intervals [CIs]) of incident diabetes for each 1 SD increase in %VC and the lowest tertile of %VC compared with the highest tertile were 0.81 (0.66 to 1.00) (p=0.045) and 1.78 (1.01 to 3.16) (p=0.048), respectively, adjusted for sex, age, body mass index, antihypertensive drug use and A1C levels. After further adjustment for log high-sensitivity C-reactive protein, the HRs (95% CI) of incident diabetes for each 1 SD increase in %VC and the lowest tertile of %VC were 0.82 (0.67 to 1.01) (p=0.063) and 1.69 (0.95 to 3.01) (p=0.073), respectively. The association between FEV1/FVC and incident diabetes was not significant. CONCLUSIONS: %VC, but not FEV1/FVC, was significantly associated with incident diabetes in a Japanese health-screening population in whom obesity was not prevalent.