Serum Gamma-Glutamyltransferase, Daily Alcohol Consumption, and the Risk of Chronic Kidney Disease: The Kansai Healthcare Study.

BACKGROUND: Serum gamma-glutamyltransferase has been recognized as the risk factor of cardiovascular and metabolic diseases. However, the association between serum gamma-glutamyltransferase and the risk of chronic kidney disease is not well known, and no prospective studies have examined separately the relationship of serum gamma-glutamyltransferase with the risk of proteinuria versus that of low estimated glomerular filtration rate (eGFR). METHODS: We prospectively followed 9,341 Japanese men who did not have low eGFR, proteinuria, or diabetes, and did not take antihypertensive medications at entry for the analysis of proteinuria, and we followed 9,299 men for the analysis of low eGFR. We defined "persistent proteinuria" as proteinuria detected two or more times consecutively and persistently as ≥1+ on urine dipstick at the annual check-up until the end of follow-up. Low eGFR was defined as eGFR <60 mL/min/1.73 m2. RESULTS: During the 11-year observation period, 151 men developed persistent proteinuria and 1,276 men developed low eGFR. In multivariate models, the highest quartile (≥71 IU/L) of serum gamma-glutamyltransferase was independently related to the development of persistent proteinuria (hazard ratio 3.39; 95% confidence interval, 1.92-5.97) compared with the lowest quartile (≤25 IU/L). In joint analysis of alcohol consumption and serum gamma-glutamyltransferase, non-drinkers in the highest tertile (≥58 IU/L) of serum gamma-glutamyltransferase had the highest risk of persistent proteinuria. However, there was no association between serum gamma-glutamyltransferase and low eGFR. CONCLUSION: In middle-aged Japanese men, elevated serum gamma-glutamyltransferase was independently associated with future persistent proteinuria, but not with low eGFR.

Habitual Alcohol Intake Modifies Relationship of Uric Acid to Incident Chronic Kidney Disease.

BACKGROUND: Previous studies showed that higher serum uric acid levels increased the risk of chronic kidney disease (CKD), but moderate alcohol consumption decreased it. The comparative importance of serum uric acid levels and habitual alcohol consumption as risk factors for CKD remain undefined. We therefore evaluated the relationship of baseline serum uric acid level in combination with daily alcohol consumption to the incidence of CKD. METHODS: A prospective cohort study of 9,116 middle-aged nondiabetic -Japanese men without CKD nor proteinuria who were not taking antihypertensive medications nor urate-lowering medications at entry. CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m2. We investigated the relationship of baseline serum uric acid level in combination with daily alcohol consumption to the incidence of CKD during an 11-year observation period. Daily alcohol consumption was classified into 4 groups: nondrinkers, light drinkers (0.1-23.0 g ethanol/day), moderate drinkers (23.1-46.0 g ethanol/day), and heavy drinkers (≥46.1 g ethanol/day). Cox proportional hazards models were used in multivariate analysis. RESULTS: During the 79,361 person-years follow-up period, a total of 1,230 subjects developed CKD. In multivariate models, higher serum uric acid levels increased risk of CKD; and moderate daily alcohol consumption decreased the risk. Multiple-adjusted hazard ratios of CKD were 1.38 (95% CI 1.11-1.70), 1.58 (95% CI 1.28-1.95), 2.27 (95% CI 1.86-2.77), and 3.12 (95% CI 2.56-3.81) for quintile 2, quintile 3, quintile 4, and quintile 5 of serum uric acid levels, respectively, compared with quintile 1, and that for moderate drinkers was 0.55 (95% CI 0.46-0.66) compared with nondrinkers. In the joint analysis of alcohol consumption and serum uric acid, moderate drinkers with the lowest tertile of serum uric acid levels had the lowest risk of CKD, but nondrinkers with the highest tertile of serum uric acid levels had the highest risk of CKD. CONCLUSIONS: Serum uric acid level and daily alcohol consumption were independently associated with the risk of CKD. Nondrinkers with the highest serum uric acid level had the highest risk of CKD.

Design and validation of a novel estimator of visceral adipose tissue area and comparison to existing adiposity surrogates.

AIMS: Visceral adiposity measured by computed tomography (CT) as intra-abdominal fat area (IAFA) predicts metabolic diseases. Existing adiposity surrogates have not been systematically compared to a regression-based model derived in individuals of Japanese ancestry. We developed and validated a method to estimate IAFA in individuals of Japanese ancestry and compared it to existing adiposity surrogates. METHODS: We assessed age, BMI, waist circumference (WC), fasting lipids, glucose, smoking status, grip strength, mid-thigh circumference (MTC), humeral length, leg length, and IAFA by single-slice CT at the umbilicus for 622 Japanese Americans. We used stepwise linear regression to predict IAFA and termed the predicted value the Estimate of Visceral Adipose Tissue Area (EVA). For men, the final model included age, BMI, WC, high-density lipoprotein cholesterol (HDLc), glucose, and MTC; for women, age, BMI, WC, HDLc, low-density lipoprotein cholesterol, glucose, and MTC. We compared goodness-of-fit (R2) from linear regression models and mean-squared errors (MSE) from k-fold cross-validation to compare the ability of EVA to estimate IAFA compared to an estimate by Després et al., waist-to-height ratio, WC, deep abdominal adipose tissue index, BMI, lipid accumulation product, and visceral adiposity index (VAI). We classified low/high IAFA using area under receiver-operating characteristic curves (AUROC) for IAFA dichotomized at the 75th percentile. RESULTS: EVA gave the least MSE and greatest R2 (men: 1244, 0.61; women: 581, 0.72). VAI gave the greatest MSE and smallest R2 (mean 2888, 0.08; women 1734, 0.14). CONCLUSIONS: EVA better predicts IAFA in Japanese-American men and women compared to existing surrogates for adiposity.

The Association Between Metabolically Healthy Obesity and the Risk of Proteinuria: The Kansai Healthcare Study.

BACKGROUND: Metabolically healthy obesity seems to be a unique phenotype for the risk of cardiometabolic diseases. However, it is not known whether this phenotype is associated with the risk of proteinuria. METHODS: Study subjects were 9,185 non-diabetic Japanese male workers aged 40-55 years who had no proteinuria, an estimated glomerular filtration rate ≥60 mL/min/1.73 m2, no history of cancer, and no use of antihypertensive or lipid-lowering medications at baseline. Obesity was defined as body mass index ≥25.0 kg/m2. Metabolic health was defined as the presence of no Adult Treatment Panel III components of the metabolic syndrome criteria, excluding waist circumference, and metabolic unhealth was defined as the presence of one or more metabolic syndrome components, excluding waist circumference. "Consecutive proteinuria" was considered positive if proteinuria was detected twice consecutively as 1+ or higher on urine dipstick at annual examinations to exclude chance proteinuria as much as possible. RESULTS: During the 81,660 person-years follow-up period, we confirmed 390 cases of consecutive proteinuria. Compared with metabolically healthy non-obesity, metabolically healthy obesity was not associated with the risk of consecutive proteinuria (multiple-adjusted hazard ratio [HR] 0.86; 95% confidence interval [CI], 0.37-1.99), but metabolically unhealthy non-obesity with ≥2 metabolic syndrome components (HR 1.77; 95% CI, 1.30-2.42), metabolically unhealthy obesity with one component (HR 1.71; 95% CI, 1.12-2.61), and metabolically unhealthy obesity with ≥2 metabolic syndrome components (HR 2.77; 95% CI, 2.01-3.82) were associated with an increased risk of consecutive proteinuria. CONCLUSIONS: Metabolically healthy obesity did not increase the risk of consecutive proteinuria in Japanese middle-aged men.

Blood pressure components and the risk for proteinuria in Japanese men: The Kansai Healthcare Study.

BACKGROUND: We examined prospectively which of the four blood pressure (BP) components (systolic BP [SBP], diastolic BP [DBP], pulse pressure [PP], and mean arterial pressure [MAP]) was best in predicting the risk of proteinuria. METHODS: This prospective study included 9341 non-diabetic Japanese middle-aged men who had no proteinuria and an estimated glomerular filtration rate ≥60 mL/min/1.73 m2 and were not taking antihypertensive medications at entry. Persistent proteinuria was defined if proteinuria was detected two or more times consecutively and persistently at the annual examination until the end of follow-up. We calculated the difference in values of Akaike's information criterion (ΔAIC) in comparison of the BP components-added model to the model without them in a Cox proportional hazards model. RESULTS: During the 84,587 person-years follow-up period, we confirmed 151 cases of persistent proteinuria. In multiple-adjusted models that included a single BP component, the hazard ratios for persistent proteinuria for the highest quartile of SBP, PP, and MAP were 3.11 (95% confidence interval [CI], 1.79-5.39), 1.87 (95% CI, 1.18-2.94), and 2.21 (95% CI, 1.33-3.69) compared with the lowest quartile of SBP, PP, and MAP, respectively. The hazard ratio for the highest quartile of DBP was 2.69 (95% CI, 1.65-4.38) compared with the second quartile of DBP. Of all models that included a single BP component, those that included SBP alone or DBP alone had the highest values of ΔAIC (14.0 and 13.1, respectively) in predicting the risk of persistent proteinuria. CONCLUSIONS: Of all BP components, SBP and DBP were best in predicting the risk of persistent proteinuria in middle-aged Japanese men.

Relationship between cumulative exposure to 1,2-dichloropropane and incidence risk of cholangiocarcinoma among offset printing workers.

OBJECTIVES: This study aimed to evaluate the relationship between cumulative exposure to 1,2-dichloropropane (1,2-DCP) and incidence risk of cholangiocarcinoma among workers in the offset proof-printing section of a small printing company in Osaka, Japan. METHODS: We identified 95 workers of a printing company (78 men and 17 women) who had been exposed to 1,2-DCP between 1987 and 2006, and calculated the standardised incidence ratio (SIR) of cholangiocarcinoma from 1987 to 2012. We estimated cumulative exposure to 1,2-DCP and calculated SIRs in four exposure categories. We also calculated incidence rate ratios (RRs) adjusted by sex, age, calendar year and dichloromethane (DCM) exposure for three exposure categories using Poisson regression analysis. RESULTS: Cumulative exposures to 1,2-DCP ranged from 32 to 3433 ppm-years (mean, 851 ppm-years) and the SIR was 1171 (95% CI 682 to 1875). In the analysis of the four exposure categories, SIRs increased significantly in the three highest exposure categories, but not in the lowest category. Adjusted RRs in the middle and high exposure categories were 14.9 (95% CI 4.1 to 54.3) and 17.1 (95% CI 3.8 to 76.2), respectively, in the analysis without lag time, and were 11.4 (95% CI 3.3 to 39.6) and 32.4 (95% CI 6.4 to 163.9), respectively, in the analysis with a 5-year lag. The trend analysis revealed a significant increase in RR in association with increasing cumulative exposure to 1,2-DCP. DCM exposure was not significantly associated with the development of cholangiocarcinoma. CONCLUSIONS: The present study demonstrated an exposure-response relationship between exposure to 1,2-DCP and the development of cholangiocarcinoma.

Investigation of Spatial Clustering of Biliary Tract Cancer Incidence in Osaka, Japan: Neighborhood Effect of a Printing Factory.

BACKGROUND: In 2013, an unusually high incidence of biliary tract cancer among current or former workers of the offset color proof printing department of a printing company in Osaka, Japan, was reported. The purpose of this study was to examine whether distance from the printing factory was associated with incidence of biliary tract cancer and whether incident biliary tract cancer cases clustered around the printing factory in Osaka using population-based cancer registry data. METHODS: We estimated the age-standardized incidence ratio of biliary tract cancer according to distance from this printing factory. We also searched for clusters of biliary tract cancer incidence using spatial scan statistics. RESULTS: We did not observe statistically significantly high or low standardized incidence ratios for residents in each area categorized by distance from the printing factory for the entire sample or for either sex. The scan statistics did not show any statistically significant clustering of biliary tract cancer incidence anywhere in Osaka prefecture in 2004-2007. CONCLUSIONS: There was no statistically significant clustering of biliary tract cancer incidence around the printing factory or in any other areas in Osaka, Japan, between 2004 and 2007. To date, even if some substances have diffused outside this source factory, they do not appear to have influenced the incidence of biliary tract cancer in neighboring residents.

Relationship Between Alcohol Drinking Pattern and Risk of Proteinuria: The Kansai Healthcare Study.

BACKGROUND: Moderate alcohol consumption has been reported to be associated with a decreased risk of cardiometabolic diseases. Whether drinking pattern is associated with the risk of proteinuria is unknown. METHODS: Study subjects were 9154 non-diabetic Japanese men aged 40-55 years, with an estimated glomerular filtration rate ≥60 mL/min/1.73 m(2), no proteinuria, and no use of antihypertensive medications at entry. Data on alcohol consumption were obtained by questionnaire. We defined "consecutive proteinuria" as proteinuria detected twice consecutively as 1+ or higher on urine dipstick at annual examinations. RESULTS: During the 81 147 person-years follow-up period, 385 subjects developed consecutive proteinuria. For subjects who reported drinking 4-7 days per week, alcohol consumption of 0.1-23.0 g ethanol/drinking day was significantly associated with a decreased risk of consecutive proteinuria (hazard ratio [HR] 0.54; 95% confidence interval [CI], 0.36-0.80) compared with non-drinkers. However, alcohol consumption of ≥69.1 g ethanol/drinking day was significantly associated with an increased risk of consecutive proteinuria (HR 1.78; 95% CI, 1.01-3.14). For subjects who reported drinking 1-3 days per week, alcohol consumption of 0.1-23.0 g ethanol/drinking day was associated with a decreased risk of consecutive proteinuria (HR 0.76; 95% CI, 0.51-1.12), and alcohol consumption of ≥69.1 g ethanol/drinking day was associated with an increased risk of consecutive proteinuria (HR 1.58; 95% CI, 0.72-3.46), but these associations did not reach statistical significance. CONCLUSIONS: Men with frequent alcohol consumption of 0.1-23.0 g ethanol/drinking day had the lowest risk of consecutive proteinuria, while those with frequent alcohol consumption of ≥69.1 g ethanol/drinking day had an increased risk of consecutive proteinuria.

Association of Visceral Fat and Liver Fat With Hyperuricemia.

OBJECTIVE: To examine cross-sectionally whether intraabdominal fat area (IAFA), i.e., visceral fat, and liver fat assessed by computed tomography (CT) are independently associated with hyperuricemia. METHODS: Subjects were 801 Japanese men not taking antidiabetic, antihypertensive, or urate-lowering medications, without any history of renal disease, cardiovascular disease, or cancer, and with serum creatinine <1.5 mg/dl. Abdominal, thoracic, and thigh fat areas were measured by CT. Total fat area (TFA) was the sum of these fat areas. Total subcutaneous fat area (TSFA) was TFA minus IAFA. Liver fat was assessed by liver-to-spleen (L/S) ratio measured by CT. Hyperuricemia was defined as serum uric acid level >7.0 mg/dl. Its association with adiposity was tested using logistic regression. RESULTS: The prevalence of hyperuricemia was 19.6% (157 men). Both greater IAFA and lower L/S ratio were independently associated with hyperuricemia in models that simultaneously included IAFA and L/S ratio: multiple-adjusted odds ratios of hyperuricemia for quintiles 3, 4, and 5 of IAFA were 2.16 (95% confidence interval [95% CI] 1.02-4.59), 2.41 (95% CI 1.13-5.16), and 4.00 (95% CI 1.81-8.85), respectively, compared to quintile 1, and the L/S ratios for quintiles 3, 2, and 1 were 2.34 (95% CI 1.16-4.75), 2.15 (95% CI 1.06-4.34), and 2.79 (95% CI 1.35-5.76), respectively, compared to quintile 5. Both IAFA and L/S ratio remained significant even after adjusting for abdominal subcutaneous fat area, TFA, TSFA, body mass index, or waist circumference. Of all fat measurements, IAFA had the strongest association with hyperuricemia by Akaike's information criteria. CONCLUSION: Greater amounts of both visceral fat and liver fat were independently associated with hyperuricemia.

Risk of bile duct cancer among printing workers exposed to 1,2-dichloropropane and/or dichloromethane.

OBJECTIVES: We conducted a retrospective cohort study to examine the risk of bile duct cancer among current and former workers in the offset color proof printing department at a printing company in Osaka, Japan. METHODS: Standardized incidence ratios (SIRs) between January 1, 1985, and December 31, 2012, were estimated for the cumulative years of exposure to two chemicals, dichloromethane (DCM) and 1,2-dichloropropane (1,2-DCP), using the national incidence level as a reference. In addition, we examined risk patterns by the calendar year in which observation started. RESULTS: Among 106 workers with a total of 1,452.4 person-years of exposure, 17 bile duct cancer cases were observed, resulting in an estimated overall SIR of 1,132.5 (95% confidence interval (CI): 659.7-1,813.2). The SIR was 1,319.9 (95% CI: 658.9-2,361.7) for those who were exposed to both DCM and 1,2-DCP, and it was 1,002.8 (95% CI: 368.0-2,182.8) for those exposed to 1,2-DCP only. SIRs tended to increase according to years of exposure to 1,2-DCP but not DCM when a 5-year lag time was assumed. The SIRs were higher for the cohorts in which observation started in 1993-2000, particularly in cohorts in which it started in 1996-1999, compared with those in which it started before or after 1993-2000. CONCLUSIONS: We observed an extraordinarily high risk of bile duct cancer among the offset color proof printing workers. Elevated risk may be related to cumulative exposure to 1,2-DCP, but there remains some possibility that a portion of the risk is due to other unidentified substances.

Drinking pattern and risk of chronic kidney disease: the kansai healthcare study.

BACKGROUND/AIMS: The association between alcohol consumption and the risk of chronic kidney disease (CKD) has been reported. What is not known is whether drinking pattern combined with the weekly frequency of alcohol consumption and the quantity per drinking day is associated with the risk of CKD. METHODS: We enrolled 9,112 Japanese nondiabetic men aged 40 to 55 years with absence of proteinuria, an estimated glomerular filtration rate (eGFR) of 60 ml/min/1.73 m(2) or higher, and not on antihypertensive medications at baseline. CKD was defined if eGFR was <60 ml/min/1.73 m(2). The weekly frequency classification was nondrinkers, 1-3 drinking days/week, or 4-7 drinking days/week. The quantity consumed per drinking day was classified as 0.1-23.0 g ethanol/drinking day, 23.1-46.0 g ethanol/drinking day, 46.1-69.0 g ethanol/drinking day, and ≥69.1 g ethanol/drinking day. RESULTS: During the 79,099 person-years, 1,253 subjects developed CKD. Compared to nondrinkers, those who consumed 23.1-46.0 or 46.1-69.0 g ethanol/drinking day on 4-7 drinking days/week had a decreased risk of CKD (multiple-adjusted hazard ratio (HR) 0.62 (0.52-0.74) and 0.76 (0.59-0.97), respectively). The association between the quantity per drinking day and the incidence of CKD was U-shaped among each category of the weekly frequency. HRs within similar categories of quantity per drinking day were lower in the 4-7 drinking days/week group than in the 1-3 drinking days/week group. CONCLUSION: Among middle-aged Japanese men, the people who drank middle-range quantity, specifically who drank 4-7 days/week, had lower risk of CKD than nondrinkers.

Sleep duration and the risk of future lipid profile abnormalities in middle-aged men: the Kansai Healthcare Study.

BACKGROUND: Although short sleep duration has been reported to be associated with future cardiometabolic diseases, it is not fully understood whether sleep duration is prospectively associated with the risk of each lipid profile abnormality. METHODS: Subjects were nondiabetic Japanese, 40-55 years of age, who were not taking oral lipid-lowering medications: for the incidence of low high-density lipoprotein cholesterol (HDL-C), 7627 men with an HDL-C level ≥ 40 mg/dL; for high triglycerides, 6973 men with a triglyceride level <200 mg/dL; for high low-density lipoprotein cholesterol (LDL-C), 7273 men with an LDL-C level <160 mg/dL; for high non-HDL-C, 7415 men with a non-HDL-C level <190 mg/dL; and for high total cholesterol (TC), 7196 men with a TC level <240 mg/dL. Lipid profile abnormalities were defined according to the Adult Treatment Panel III guidelines of the National Cholesterol Education Program. RESULTS: During the 6-year observation period, there were 1022 cases of low HDL-C. Multiple-adjusted hazard ratios for low HDL-C were 0.79 (95% confidence interval, 0.64-0.97) for sleep durations of 5 to <7 h and 0.62 (0.46-0.83) for ≥ 7 h compared with <5 h. There were 1473 cases of high triglycerides. Multiple-adjusted hazard ratios for high triglycerides were 0.81 (0.68-0.98) for sleep durations of 5 to <7 h and 0.90 (0.72-1.13) for ≥ 7 h compared with <5 h. However, no association between sleep duration and the risk of future high LDL-C, non-HDL-C, or TC was observed. CONCLUSIONS: Moderate and/or long sleep durations decreased the risk of future low HDL-C and high triglycerides.

Case series of 17 patients with cholangiocarcinoma among young adult workers of a printing company in Japan.

BACKGROUND: An outbreak of cholangiocarcinoma occurred among workers in the offset color proof-printing department at a printing company in Japan. The aim of this study was to clarify the characteristics of the patients with cholangiocarcinoma. METHODS: This was a retrospective study conducted in 13 Japanese hospitals between 1996 to 2013. The clinicopathological findings of cholangiocarcinoma developed in 17 of 111 former or current workers in the department were investigated. Most workers were relatively young. RESULTS: The cholangiocarcinoma was diagnosed at 25-45 years old. They were exposed to chemicals, including dichloromethane and 1,2-dichloropropane. The serum γ-glutamyl transpeptidase activity was elevated in all patients. Dilated intrahepatic bile ducts without tumor-induced obstruction were observed in five patients. The cholangiocarcinomas arose from the large bile ducts. The precancerous or early cancerous lesions, such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile ducts, as well as non-specific bile duct injuries, such as fibrosis, were observed in various sites of the bile ducts in all eight patients for whom operative specimens were available. CONCLUSIONS: The present results showed that cholangiocarcinomas occurred at a high incidence in relatively young workers of a printing company, who were exposed to chemicals including chlorinated organic solvents.

Serum butyrylcholinesterase and the risk of future type 2 diabetes: the Kansai Healthcare Study.

OBJECTIVE: Butyrylcholinesterase is synthesized in the liver. The serum butyrylcholinesterase level has been cross-sectionally reported to be higher in patients with diabetes, hyperlipidaemia, obesity and fatty liver than in those without them. It is not known whether serum butyrylcholinesterase is associated with the risk of future type 2 diabetes. DESIGN: A prospective cohort study. PARTICIPANTS: A total of 8470 Japanese men aged 40-55 years without type 2 diabetes at baseline. MEASUREMENTS: Type 2 diabetes was diagnosed if a fasting plasma glucose (FPG) level was ≥7·0 mmol/l, if a HbA1 c level was ≥6·5% or if participants were taking oral hypoglycaemic medication or insulin. RESULTS: During the 42,227 person-years of follow-up, 868 cases had developed type 2 diabetes. Serum butyrylcholinesterase was significantly positively correlated with body mass index (BMI), FPG, alanine aminotransferase (ALT), γ-glutamyltransferase (GGT) and triglycerides (TG), whereas negatively with high-density lipoprotein (HDL) cholesterol. In Cox proportional hazards models, after adjusting for age, BMI, FPG, alcohol consumption, smoking habit, walk to work, regular leisure-time physical activity and family history of diabetes, the highest quartile (398-806 IU/l) of serum butyrylcholinesterase increased the risk of type 2 diabetes compared with the lowest quartile (56-311 IU/l) [hazard ratio (HR) 1·41 (95% confidence interval (CI), 1·14-1·74)]. After further adjusting for ALT and GGT, this association remained [HR 1·40 (95% CI, 1·13-1·73)]. Furthermore, this association was significant independent of TG and HDL cholesterol. CONCLUSIONS: Elevated serum butyrylcholinesterase was independently associated with an increased risk of future type 2 diabetes.