A high level of thyroid-stimulating hormone is a risk factor for the development of chronic kidney disease in men: a 10-year cohort study.

Hypothyroidism has been reported to be associated with chronic kidney disease (CKD). However, the impact of thyroid-stimulating hormone (TSH) on new onset of CKD and its gender dependence remain undetermined. We investigated the association of serum TSH level and the development of CKD defined by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or positive for urine protein in 28,990 Japanese subjects who received annual health examinations. After excluding subjects with no data for serum TSH, urinalysis and eGFR and those with CKD at baseline, a total of 10,392 subjects (men/women: 6802/3590, mean age: 48 years) were recruited. During a 10-year follow-up, 1185 men (6.7%) and 578 women (2.9%) newly developed CKD. Multivariable Cox proportional hazard models after adjustment of age, body mass index, smoking habit, hypertension, diabetes mellitus, dyslipidemia, ischemic heart disease and eGFR (≥ 90 mL/min/1.73 m2) showed that the hazard ratio (HR) for the development of CKD in the high TSH (> 4.2 mU/L) group was significantly higher than that in the low TSH (≤ 4.2 mU/L) group in men (HR [95% confidence interval]: 1.41 [1.09-1.83]) but not in women (1.08 [0.77-1.51]). There was a significant interaction between sex and the category of TSH level for the development of CKD (p = 0.02). The adjusted HR with a restricted cubic spline increased with a higher level of TSH in men but not in women. In conclusion, a high level of TSH is associated with an increased risk for the development of CKD in men but not in women.

Calculated Small Dense Low-Density Lipoprotein Cholesterol Level is A Predominant Predictor for New Onset of Ischemic Heart Disease.

AIM: A high level of directly measured small dense low-density lipoprotein cholesterol (sdLDL-C) is a strong risk factor for ischemic heart disease (IHD). However, it remains unclear whether estimated sdLDL-C level is a predictor for IHD. We investigated the associations of new onset of IHD with levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides (TG), LDL-C and calculated sdLDL-C by Sampson's equation. METHODS: After exclusion of subjects with IHD or those with TG ≥ 800 mg/dL, a total of 18,176 subjects (men/women: 11,712/6,464, mean age: 46 years) were recruited among 28,990 Japanese individuals who received annual health checkups. RESULTS: During the 10-year follow-up period, 456 men (3.9%) and 121 women (1.9%) newly developed IHD. Multivariable Cox proportional hazard analyses after adjustment of age, sex, obesity, smoking habit, family history of IHD, estimated glomerular filtration rate, hypertension and diabetes mellitus at baseline showed that the hazard ratio (HR) (1.38 [95% confidence interval: 1.03-1.85]) for new onset of IHD in subjects with the 4th quartile (Q4) of sdLDL-C (≥ 42 mg/dL) was significantly higher than that in subjects with the 1st quartile (Q1) (≤ 24 mg/dL) as the reference, though the adjusted HRs in subjects with Q2-Q4 of TC, HDL-C, non-HDL-C, LDL-C and TG were comparable with those in subjects with Q1 of the respective lipid fractions. The adjusted HR with a restricted cubic spline increased with a higher level of calculated sdLDL-C as a continuous value at baseline. CONCLUSIONS: sdLDL-C level calculated by Sampson's equation is a predominant predictor for the development of IHD in a general Japanese population.

An increase in calculated small dense low-density lipoprotein cholesterol predicts new onset of hypertension in a Japanese cohort.

A disorder of lipid metabolism is involved in cardiovascular diseases including hypertension. A high level of small dense low-density lipoprotein cholesterol (sdLDL-C) is a strong risk factor for atherosclerotic cardiovascular disease. However, the association between sdLDL-C and hypertension has not been fully investigated. We investigated the associations between the development of hypertension during a 10-year period and levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides (TG), and LDL-C and sdLDL-C calculated by using the Sampson equations in 28,990 Japanese subjects who received annual health examinations. After exclusion of subjects with missing data, those with hypertension, and those with TG ≥ 800 mg/dL at baseline, a total of 15,177 subjects (men/women: 9374/5803, mean age: 46 years) were recruited. During the 10-year period, 2379 men (25.4%) and 724 women (12.5%) had new onset of hypertension. Multivariable Cox proportional hazard model analyses showed that levels of HDL-C, non-HDL-C, TG and sdLDL-C, but not levels of TC and LDL-C, were independent risk factors for the development of hypertension after adjustment of age, sex, family history of hypertension, systolic blood pressure, obesity, current smoking habit, alcohol drinking habit, estimated glomerular filtration rate, diagnosis of diabetes mellitus and use of lipid-lowering drugs and that the adjusted risk of sdLDL-C (per 1-standard deviation) was highest (hazard ratio [95% confidence interval: 1.09 [1.05-1.13]). The addition of sdLDL-C to traditional risk factors for hypertension significantly improved the discriminatory capability, which was better than that of other lipid fractions. In conclusion, a high level of calculated sdLDL-C predicts the development of hypertension.

Coexistence of Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Kidney Disease Is a More Potent Risk Factor for Ischemic Heart Disease.

Background Metabolic dysfunction-associated fatty liver disease (MAFLD), defined as fatty liver with overweight/obesity, type 2 diabetes, or metabolic abnormalities, is a newly proposed disease. However, it remains unclear whether the coexistence of MAFLD and chronic kidney disease (CKD) is a more potent risk factor for ischemic heart disease (IHD). Methods and Results We investigated the risk of the combination of MAFLD and CKD for development of IHD during a 10-year follow-up period in 28 990 Japanese subjects who received annual health examinations. After exclusion of subjects without data for abdominal ultrasonography or with the presence of IHD at baseline, a total of 14 141 subjects (men/women: 9195/4946; mean age, 48 years) were recruited. During the 10-year period (mean, 6.9 years), 479 subjects (men/women, 397/82) had new onset of IHD. Kaplan-Meier survival curves showed significant differences in rates of the cumulative incidence of IHD in subjects with and those without MAFLD (n=4581) and CKD (n=990; stages 1/2/3/4-5, 198/398/375/19). Multivariable Cox proportional hazard model analyses showed that coexistence of MAFLD and CKD, but not MAFLD or CKD alone, was an independent predictor for development of IHD after adjustment for age, sex, current smoking habit, family history of IHD, overweight/obesity, diabetes, hypertension, and dyslipidemia (hazard ratio, 1.51 [95% CI, 1.02-2.22]). The addition of the combination of MAFLD and CKD to traditional risk factors for IHD significantly improved the discriminatory capability. Conclusions The coexistence of MAFLD and CKD predicts new onset of IHD better than does MAFLD or CKD alone.

Metabolic dysfunction-associated fatty liver disease is associated with an increase in systolic blood pressure over time: linear mixed-effects model analyses.

Metabolic dysfunction-associated fatty liver disease (MAFLD), a new feature of fatty liver (FL) disease that is defined as FL with overweight/obesity, type 2 diabetes mellitus or metabolic dysregulation, has been reported to be associated with the development of diabetes mellitus, chronic kidney disease and cardiovascular disease. However, the association between MAFLD and hypertension remains unclear. We investigated the association between MAFLD and systolic blood pressure (SBP) over a 10-year period in 28,990 Japanese subjects who received annual health examinations. After exclusion of subjects without data for SBP and abdominal ultrasonography at baseline, a total of 17,021 subjects (men/women: 10,973/6048; mean age: 49 years) were recruited. Linear mixed-effects model analyses using diagnoses of FL, nonalcoholic fatty liver disease (NAFLD) or MAFLD and age, sex, SBP, use of anti-hypertensive drugs, levels of uric acid and estimated glomerular filtration rate, family history of hypertension and habits of current smoking and alcohol drinking at baseline as well as the duration of the observation period and the interaction between each covariate and the duration of the observation period showed that the significant association of change in SBP over time with diagnosis of MAFLD (estimate: 0.223 mmHg/year, P < 0.001) was greater than that with diagnoses of FL (estimate: 0.196 mmHg/year, P < 0.001) and NAFLD (estimate: 0.203 mmHg/year, P < 0.001). Furthermore, the rate of increase in SBP over time was higher in subjects with MAFLD than in subjects without FL and subjects with FL who had no MAFLD. In conclusion, MAFLD is significantly associated with an increase in SBP over time. The presence of metabolic dysfunction-associated fatty liver disease (MAFLD) is significantly associated with an increase in systolic blood pressure over time.

Metabolic dysfunction-associated fatty liver disease predicts new onset of chronic kidney disease better than fatty liver or nonalcoholic fatty liver disease.

BACKGROUND: Possible associations of chronic kidney disease (CKD) with fatty liver (FL) and nonalcoholic fatty liver disease (NAFLD) have recently been focused on. Metabolic dysfunction-associated fatty liver disease (MAFLD), defined as FL with overweight/obesity, type 2 diabetes mellitus or metabolic abnormalities, has been proposed as a new feature of chronic liver disease. However, the relationship between MAFLD and new onset of CKD has not been fully addressed. METHODS: We investigated the associations of FL, NAFLD and MAFLD with the development of CKD, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or positive for urinary protein, over a 10-year period in 28 890 Japanese subjects who received annual health examinations. After exclusion of subjects with no data for abdominal ultrasonography and subjects with CKD at baseline, a total of 13 159 subjects (men 8581, women 4578; mean age 48 years) were recruited. RESULTS: The prevalence of FL, NAFLD and MAFLD was 34.6% (men 45.1%, women 15.1%), 32.8% (men 42.7%, women 14.5%) and 32.3% (men 42.4%, women 13.4%), respectively. During the 10-year follow-up period, 2163 subjects (men 1475, women 688) had new onset of CKD. Multivariable Cox proportional hazards model analyses showed that MAFLD [hazard ratio 1.12 (95% confidence interval 1.02-1.26); P = .027] but not FL or NAFLD was an independent risk factor for new onset of CKD after adjustment of age, sex, eGFR, current smoking habit, ischemic heart disease, diabetes mellitus, overweight/obesity, hypertension and dyslipidemia. The addition of MAFLD [continuous net reclassification improvement (NRI) 0.154, integrated discrimination improvement (IDI) 0.0024] to traditional risk factors without metabolic abnormalities significantly improved the discriminatory capacity better than did the addition of FL (NRI 0.138, IDI 0.0018) or NAFLD (NRI 0.132, IDI 0.0017). CONCLUSIONS: MAFLD is modestly and independently associated with new onset of CKD and predicts the risk for development of CKD better than FL or NAFLD.

High fibrosis-4 index predicts the new onset of ischaemic heart disease during a 10-year period in a general population.

Aims: The fibrosis-4 (FIB-4) index, calculated using age, platelet count, and levels of aspartate aminotransferase and alanine aminotransferase, is a non-invasive indicator for the detection of liver fibrosis. Advanced hepatic fibrosis is associated with morbidity and mortality in patients with non-alcoholic fatty liver disease. However, the relationship between liver fibrosis and the development of ischaemic heart disease (IHD) has not fully been addressed. Methods and results: We investigated the association between the FIB-4 index and the new onset of IHD during a 10-year period in a general population of subjects who received annual health examinations (n = 28 990). After exclusion of subjects with missing data and those with a history of IHD at baseline, a total of 13 448 subjects (men/women: 8774/4674, mean age: 48 years) were included. During the 10-year period, 378 men (4.3%) and 77 women (1.6%) had a new onset of IHD. Multivariable Cox proportional hazard models with a restricted cubic spline showed that hazard risk for the development of IHD increased with a higher FIB-4 index at baseline after adjustment of age, sex, fatty liver (FL) determined by ultrasonography, estimated glomerular filtration rate, habits of current smoking and alcohol drinking, family history of IHD, and diagnosis of hypertension, diabetes mellitus and dyslipidaemia. When divided by FL, the FIB-4 index becomes an independent predictor for the development of IHD in subjects with FL but not in those without FL. The addition of the FIB-4 index to traditional risk factors for IHD significantly improved the discriminatory capability. Conclusion: A high level of the FIB-4 index predicts the new onset of IHD during a 10-year period.

High fatty liver index is an independent predictor of ischemic heart disease during a 10-year period in a Japanese population.

AIM: Fatty liver index (FLI), which is calculated by using body mass index, waist circumference and levels of γ-glutamyl transferase and triglycerides, is a validated surrogate marker of nonalcoholic fatty liver disease. We retrospectively investigated the relationship between FLI and the development of ischemic heart disease (IHD) during a 10-year period. METHODS: Among subjects who received annual health checkups (n = 28 990), a total of 18 851 subjects (men/women: 11 659/7192) were enrolled after exclusion of subjects with missing data and those with IHD at baseline. RESULTS: FLI at baseline was significantly higher in men than in women. During the 10-year period, 450 men (3.9%) and 123 women (1.7%) had new onset of IHD determined by a self-reported questionnaire survey. Multivariable Cox proportional hazard models with a restricted cubic spline showed that hazard risk (HR) for the development of IHD increased with a higher FLI at baseline after adjustment of age, sex, current smoking habit, family history of IHD and diagnosis of diabetes mellitus, hypertension, dyslipidemia and chronic kidney disease at baseline. There was no significant interaction between FLI and sex for the adjusted HR. When divided by tertiles of FLI at baseline (T1∼T3), the adjusted risk for development of IHD in the T3 group (HR [95% confidence interval]: 1.34 [1.05-1.71]) was significantly higher than that in the T1 group as the reference. The addition of FLI into traditional risk factors for IHD significantly improved the discriminatory capability. CONCLUSIONS: A high level of FLI is an independent predictor of new onset of IHD during a 10-year period.

Serum uric acid level is associated with an increase in systolic blood pressure over time in female subjects: Linear mixed-effects model analyses.

Whether hyperuricemia is a true risk factor for elevated blood pressure (BP) is controversial, and the sex-specific effects of serum uric acid (SUA) on BP during a follow-up period remain unclear. We investigated whether the association of SUA level with systolic or diastolic BP during a 10-year period differs by sex in a Japanese general population of individuals who received annual health examinations (n = 28,990). After exclusion of subjects who had no BP or SUA data at baseline, a total of 22,994 subjects (male/female: 14,603/8391, age: 47 ± 11 years) were recruited. After adjustment for age; body mass index; BP; SUA level; use of drugs for hyperuricemia and hypertension; diagnosis of diabetes mellitus, dyslipidemia, and chronic kidney disease; family history of hypertension; habits of current smoking and alcohol consumption at baseline; the duration of the observation period; and the interaction between each covariate and the duration of the observation period indicated a significant association of SUA level with change in systolic or diastolic BP over time. There was a significant interaction between sex and SUA level for the change in systolic BP (P = 0.003) but not the change in diastolic BP (P = 0.081). The SUA level at baseline (per 1 mg/dL) was significantly associated with a change in systolic BP over time in females (estimate: 0.073 mmHg/year, P = 0.003) but not in males (estimate: 0.020 mmHg/year, P = 0.160). In conclusion, a high SUA level at baseline is significantly associated with an increase in systolic BP over time in female individuals but not in male individuals.

Elevated Fatty Liver Index Is Independently Associated With New Onset of Hypertension During a 10-Year Period in Both Male and Female Subjects.

Background Fatty liver index (FLI), a predictor of nonalcoholic fatty liver disease, has been reported to be associated with several metabolic disorders. Because of a sex difference in FLI level, we hypothesized that FLI is associated with development of hypertension to a greater extent in men or women. Methods and Results We investigated the relationship between FLI and development of hypertension during a 10-year period in a general population of subjects who received annual health examinations (n=28 990). After exclusion (44.9%) of subjects with missing data and those with hypertension at baseline, a total of 15 965 subjects (men/women: 9466/6499) were included. FLI level was significantly higher in men than in women. During the 10-year period, 2304 men (24.3%) and 745 women (11.5%) had new onset of hypertension. Multivariable Cox proportional hazard models with a restricted cubic spline showed that the hazard ratios (HRs) for development of hypertension after adjustment of age, systolic blood pressure, estimated glomerular filtration rate, habits of smoking and alcohol drinking, family history of hypertension, and diagnosis of diabetes mellitus and dyslipidemia increased gradually with increase in FLI in men and increased rapidly and then slowly with increase in FLI in women. There was a significant interaction between FLI and sex for the risk of hypertension in all of the subjects (P=0.049). The addition of FLI to traditional risk factors significantly improved the discriminatory capability. Conclusions A high level of FLI predicts the development of hypertension in both men and women, although distribution patterns of HRs were different between sexes.

High level of fatty liver index predicts new onset of diabetes mellitus during a 10-year period in healthy subjects.

Fatty liver index (FLI), a predictor of nonalcoholic fatty liver disease, has been reported to be associated with several metabolic disorders. This study aimed to evaluate the relationship between FLI and new onset of diabetes mellitus (DM). We investigated the association of FLI with new onset of DM during a 10-year period in subjects who received annual health examinations (n = 28,990). After exclusion of subjects with DM at baseline and those with missing data, a total of 12,290 subjects (male/female: 7925/4365) who received health examinations were recruited. FLI was significantly higher in males than in females. During the 10-year period, DM was developed in 533 males (6.7%) and 128 females (2.9%). Multivariable Cox proportional hazard models with a restricted cubic spline showed that the risk of new onset of DM increased with a higher FLI at baseline in both sexes after adjustment of age, fasting plasma glucose, habits of alcohol drinking and current smoking, family history of DM and diagnosis of hypertension and dyslipidemia at baseline. When the subjects were divided into subgroups according to tertiles of FLI level at baseline (T1-T3) in the absence and presence of impaired fasting glucose (IFG), hazard ratios after adjustment of the confounders gradually increased from T1 to T3 and from the absence to presence of IFG in both male and female subjects. In conclusion, a high level of FLI predicts new onset of DM in a general population of both male and female individuals.

Fatty liver index is independently associated with deterioration of renal function during a 10-year period in healthy subjects.

A potential link between chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD) has been suggested. We investigated the relationship between fatty liver index (FLI), a noninvasive and simple predictor of NAFLD, and the development of CKD defined as estimated glomerular filtration rate < 60 mL/min/1.73 m2 or positive for urinary protein during a 10-year follow-up period in subjects who received annual health examinations (n = 28,890). After exclusion of CKD at baseline, a total of 14,163 subjects (male/female: 9077/5086) were recruited. During the 10-year period, 1458 males (16.1%) and 737 females (14.5%) had new onset of CKD. Multivariable Cox proportional hazard models with a restricted cubic spline showed that hazard ratios (HRs) of CKD development increased with a higher FLI at baseline in both males and females after adjustment of confounders. When divided by tertiles of FLI level at baseline (T1 ~ T3), the adjusted risk of CKD development in the T3 group (HR [95% confidence interval], male/female: 1.33 [1.16-1.54]/1.33 [1.08-1.63]) was significantly higher than that in both sexes in the T1 group as the reference. The addition of FLI into traditional risk factors significantly improved the discriminatory capability for predicting CKD. In conclusion, a high level of FLI predicts the development of CKD in both sexes in a general population.

Low urine pH predicts new onset of diabetes mellitus during a 10-year period in men: BOREAS-DM1 study.

AIMS/INTRODUCTION: A low level of urine pH (U-pH) has been reported to be associated with metabolic disorders. However, the relationship between the incidence of diabetes mellitus and U-pH has not yet been fully addressed. MATERIALS AND METHODS: We investigated the relationship between U-pH and the development of diabetes mellitus during a 10-year period in a general population of individuals who received annual health examinations in 2006 (n = 28,990). After exclusion of individuals with missing data, and those with diabetes mellitus and/or chronic kidney disease at baseline, a total of 12,476 individuals (men/women: 8,027/4,449) who received health examinations at least once during the period from 2007 to 2016 were recruited. The recruited individuals were divided into four groups according to their U-pH levels: groups of U-pH ≤5.0, 5.5, 6.0 and ≥6.5. RESULTS: During a 10-year period, 521 men (6.5%) and 132 women (3.0%) had new onset of diabetes mellitus. The cumulative incidence of diabetes mellitus was 7.5% (men/women: 9.3%/4.4%) per 100 person-years. The hazard ratios (HRs) in the U-pH ≤5.0 (HR 1.93) and U-pH 5.5 groups (HR 1.46) were significantly higher than that in the U-pH ≥6.5 group as a reference for men, but not for women. After adjustment of age, obesity, fasting glucose, smoking and alcohol drinking habits, family history of diabetes mellitus, and use of drugs for hypertension and dyslipidemia, HR in the U-pH ≤5.0 group (HR 1.39) was significantly higher than that in the U-pH ≥6.5 group for men, but not for women. CONCLUSIONS: Low U-pH predicts new onset of diabetes mellitus in a general population of men.

Association between pancreatic fat and incidence of metabolic syndrome: a 5-year Japanese cohort study.

BACKGROUND AND AIM: Previous cross-sectional studies showed that pancreatic fat was associated with metabolic syndrome. However, no longitudinal study has evaluated whether people with high pancreatic fat are likely to develop future metabolic syndrome. This study investigated the association between baseline pancreatic fat and metabolic syndrome incidence. METHODS: In 2008-2009, 320 participants without metabolic syndrome underwent health checks, which included unenhanced computed tomography, and were followed up annually for 4-5 years. Baseline pancreatic fat amounts were evaluated using a histologically validated method that measured differences between pancreas and spleen attenuations on computed tomography. The participants were divided into low (reference), intermediate, and high pancreatic fat groups based on pancreas and spleen attenuation tertiles. Metabolic syndrome incidence was evaluated annually over a median follow-up period of 4.99 (interquartile range, 4.88-5.05) years, in accordance with the 2009 harmonized criteria. Risk ratios (RRs) for the association between baseline pancreatic fat amounts and metabolic syndrome incidence were estimated using Poisson regression models adjusted for age, sex, body mass index, liver fat, pre-metabolic syndrome, cigarette use, alcohol use, and physical activity. RESULTS: Metabolic syndrome incidence was 30.6% (98/320). Pancreatic fat was associated with an increased incidence of metabolic syndrome, based on a univariate analysis (RRs [95% confidence interval], 3.14 [1.74-5.67] and 3.96 [2.23-7.03] in the intermediate and high pancreatic fat groups, respectively). The association remained statistically significant in the multivariate analysis (RR [95% confidence interval], 2.04 [1.14-3.64] and 2.30 [1.28-4.14] for the same groups, respectively). CONCLUSIONS: Pancreatic fat predicts the future risk of metabolic syndrome.

The impact of elevation of serum uric acid level on the natural history of glomerular filtration rate (GFR) and its sex difference.

BACKGROUND: The impact of elevation of the serum uric acid level (SUA) on the natural history of glomerular filtration rate (GFR) remains controversial. METHODS: If elevation of SUA is a result, rather than a cause, of a decline in GFR, the relationship between SUA and GFR should be the same in the same population over years except for shifts by age-dependent reduction of GFR. We tested this hypothesis using data from two cohorts and a group of allopurinol-treated patients. RESULTS: In Cohort 1 consisting of urban residents aged 40.6 ± 9.0 years (n = 3 446), SUA was inversely correlated with estimated GFR (eGFR) in both men and women, and the slope of the SUA-eGFR relationship was steeper in women than in men. The slopes of the regression lines became significantly steeper after a 6-year interval in both sexes, and the change in the slope was larger in women. A similar sex difference in the SUA-eGFR relationship and 6-year change in the slope were observed in Cohort 2 consisting of rural town residents aged 61.7 ± 12.2 years (n = 404). Multiple regression analyses showed that explanatory factors of eGFR after a 6-year interval were age and SUA at baseline in both cohorts, and partial regression coefficients of SUA were more negative in women than in men. The SUA-eGFR relationship in allopurinol-treated patients (n = 346, 63.5 ± 13.3 years old) was similar to that in Cohort 2. CONCLUSIONS: The results indicate that elevation of SUA accelerates the yearly decline in eGFR and that women are more susceptible to urate-induced decline in eGFR.