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DOI： 10.1007/s00774-023-01478-z

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OBJECTIVE: Alcohol drinking and tobacco smoking have impacts on lifestyle-related diseases, but their association with dementia remains a debated topic. This study aimed to examine longitudinal associations between alcohol consumption, smoking, and dementia risk in middle-aged and older Japanese people. METHODS: This study used a cohort design with an 8-year follow-up. Participants were community-dwelling Japanese people (N = 13,802) aged 40-74 years. The baseline survey, including a self-administered questionnaire, was conducted in 2011-2013. Predictors were alcohol consumption and tobacco smoking. The outcome was incident dementia obtained from a long-term care insurance database. Covariates were demographics, lifestyle factors, body mass index, general health status, and history of stroke, diabetes, and depression. RESULTS: Participant mean age was 59.0 years. The 1-149, 150-299, and 300-449 g ethanol/week groups had significantly lower adjusted hazard ratios (HRs) (0.62, 0.59, and 0.47, respectively) compared with the reference group, with no significant linear association. HRs increased toward 1 when past-drinkers and those with poor health status and a disease history were excluded (0.80, 0.66, and 0.82, respectively). Higher smoking levels were dose-dependently associated with a higher HR (adjusted P for trend = 0.0105), with the ≥20 cigarettes/day group having a significantly higher adjusted HR (1.80). Heavy drinkers (≥449 g ethanol/week) with smoking habits, but not those without smoking habits, had higher dementia risk (P for interaction = 0.0046). CONCLUSION: Light-to-moderate alcohol consumption is associated with decreased dementia risk, and smoking is dose-dependently associated with increased dementia risk, with an interaction between high alcohol consumption and smoking on dementia risk.

DOI： 10.1016/j.maturitas.2023.107788

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AIM: Despite global efforts in public health campaigns concerning chronic kidney disease (CKD), awareness of the condition remains low. We evaluated CKD awareness and related factors to identify an effective way to raise awareness. METHODS: This study assessed laboratory-confirmed CKD and self-reported CKD using a population-based cohort (baseline from 2012 to 2014, age ≥40 years) in Niigata, Japan. Self-reported CKD was obtained at a 5-year follow-up survey and laboratory-confirmed CKD was diagnosed when an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or dipstick urinary protein ≥1+ was observed in at least two health check-ups during the 5-year period. CKD awareness was defined as a match between laboratory-confirmed and self-reported CKD. The association between characteristics and CKD awareness was tested by multivariable logistic regression analysis with adjustment for eGFR and other potential confounders. RESULTS: The analytic population comprised 7472 individuals (mean age, 65.6 years old, 51.2% women) and 19.4% with laboratory-confirmed CKD. The sensitivity and specificity of the survey question concerning self-reported CKD were 12.4% and 98.2%, respectively. Among the participants with laboratory-confirmed CKD, significant factors associated with CKD awareness were male sex (adjusted odds ratio [95% confidence interval], 1.81 [1.27, 2.59]), a history of urinary tract stone (1.86 [1.06, 3.26]), age (0.97 [0.95, 0.99]), and married status (0.66 [0.44, 0.99]). CONCLUSION: Our findings suggest that known lifestyle-related diseases that could cause CKD are not associated with CKD awareness independently of kidney function and that a sex-dependent approach may help to raise CKD awareness in community-dwelling Japanese adults.

DOI： 10.1111/nep.14170

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BACKGROUND: The association between body mass index (BMI) and dementia risk is heterogeneous across age groups and might be influenced by sex. OBJECTIVE: This study aimed to clarify sex differences in the association between BMI and dementia risk in community-dwelling people. METHODS: This cohort study with an 8-year follow-up targeted 13,802 participants aged 40-74 years at baseline in 2011-2013. A self-administered questionnaire requested information on body size, including height, weight, and waist circumference (the values of which were validated by direct measurement), socio-demographics, lifestyle, and disease history. BMI was calculated and categorized as < 18.5 (underweight), 18.5-20.6 (low-normal), 20.7-22.7 (mid-normal), 22.8-24.9 (high-normal), 25.0-24.9 (overweight), and≥30.0 kg/m2 (obese). Incident cases of dementia were obtained from the long-term care insurance database. A Cox proportional hazards model was used to calculate multivariable-adjusted hazard ratios (HRs). RESULTS: The mean age of participants was 59.0 years. In men, higher BMI was associated with lower dementia risk (fully-adjusted p for trend = 0.0086). In women, the association between BMI and dementia risk was U-shaped; the "underweight," "low-normal," and "overweight" groups had a significantly higher risk (fully-adjusted HR = 2.12, 2.08, and 1.78, respectively) than the reference ("high-normal" group). These findings did not change after excluding dementia cases which occurred within the first four years of the follow-up period. CONCLUSION: Overweight/obese women, but not men, had an increased risk of dementia, suggesting that sex differences in adiposity might be involved in the development of dementia.

DOI： 10.3233/JAD-230294

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BACKGROUND: Association between vitamin D levels and the occurrence of depression are not always consistent. The present cohort study aimed to determine this association in older adults, using a method for measuring vitamin D levels which is more accurate than those used in previous studies. METHODS: Participants were 3447 individuals aged 40-74 years without depressive symptoms at baseline who participated in the 5-year follow-up survey. The baseline investigation, including a self-administered questionnaire survey and blood collection, was conducted in 2011-2013. Plasma 25-hydroxyvitamin D (25[OH]D) levels were measured, and divided into overall quartiles summed up by sub-quartiles and stratified by age, sex, and season. The outcome was depressive symptoms determined by the CES-D (11-item, cut-off score of 6/7) 5 years later. Covariates were demographics, lifestyles, baseline CES-D score, and disease history. RESULTS: Mean plasma 25(OH)D levels were 58.0 nmol/L in men and 45.7 in women (P < 0.0001), and cumulative incidences of depressive symptoms were 249/1577 (15.8 %) in men and 313/1870 (16.7 %) in women (P = 0.4526). The lower 25(OH)D quartile group had higher adjusted ORs in men and women combined (P for trend = 0.0107) and women (P for trend = 0.0003), but not in men. Adjusted ORs of the lowest quartile group were significantly higher than the highest group in men and women combined (OR = 1.39, 95 % CI: 1.06-1.81) and women (OR = 1.89, 95 % CI: 1.31-2.72). LIMITATION: Depressive symptoms were self-reported. CONCLUSIONS: Low vitamin D levels were associated with a high risk of depressive symptoms, especially in women. Women are thus considered a major target for preventing vitamin D deficiency to address depression.

DOI： 10.1016/j.jad.2022.12.104

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DOI： 10.1186/s11556-022-00306-z

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AIMS: Megalin, a proximal tubular endocytosis receptor, is excreted in urine in two forms: ectodomain (A-megalin) and full-length (C-megalin). We explored whether urinary megalin levels can be used as independent prognostic biomarkers in the progression of diabetic kidney disease (DKD). METHODS: The associations between baseline urinary A-megalin/creatinine (Cr) and/or C-megalin/Cr levels and the subsequent estimated glomerular filtration rate (eGFR) slope were analyzed using a generalized estimating equation. Patients were categorized into higher or lower groups based on the optimal cutoff values, obtained from a receiver operating characteristic curve, of the two forms of urinary megalin. RESULTS: We retrospectively analyzed 188 patients with type 2 diabetes. The eGFR slopes of the higher A-megalin/Cr and higher C-megalin/Cr groups were - 0.904 and -0.749 ml/min/1.73 m2/year steeper than those of the lower groups, respectively. Moreover, the eGFR slope was -1.888 ml/min/1.73 m2/year steeper in the group with both higher A- and higher C-megalin/Cr than in the other group. These results remained significant when adjusted for known urinary biomarkers (albumin, α1-microglobulin, β2-microglobulin, and N-acetyl-β-d-glucosaminidase). CONCLUSIONS: Urinary A- and C-megalin/Cr levels are likely to be prognostic biomarkers in the progression of DKD independent of other urinary biomarkers.

DOI： 10.1016/j.jdiacomp.2022.108312

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BACKGROUND: Falls are important causes of injury and mortality in older people, and associated medical costs can be enormous. Physical activity (PA) is a potential preventive factor for falls. However, few studies have examined the effect of different types of PA on fall prevention. This study aimed to evaluate the association between PA levels and the incidence of recurrent falls by type of PA in middle-aged and older people. METHODS: This cohort study targeted 7,561 community-dwelling individuals aged 40-74 years who did not experience recurrent falls in the year before baseline. Information on PA levels, demographics, body size, lifestyle, and fall/disease history was obtained using a self-administered questionnaire in the baseline survey. Levels of total PA, leisure-time PA, and non-leisure-time PA (occupation, commuting, and housework) were estimated using metabolic equivalent (MET) scores (MET-h/day; hours spent on a given activity per day multiplied by its MET intensity). PA levels were categorized into four groups. Falls were recorded as none, once, or twice or more (recurrent falls). The outcome of the study was the incidence of recurrent falls in the past year before a survey conducted 5 years after the baseline survey. Logistic regression analyses were performed to calculate odds ratios for recurrent falls. RESULTS: Higher total PA and non-leisure-time PA levels were associated with a higher risk of recurrent falls (P for trend = 0.0002 and 0.0001, respectively), with the highest total PA and non-leisure-time PA groups having a significantly higher adjusted OR (1.96 [95%CI:1.33-2.88] and 2.15 [95%CI:1.48-3.14], respectively) relative to the lowest group (reference). As for leisure-time PA, the medium group had a significantly lower adjusted OR (0.70 [95%CI:0.49-0.99]) relative to the reference group. By sex, the adjusted OR in the medium leisure-time PA group was significantly lower relative to the reference group in women (0.50 [95%CI: 0.29-0.85]) but not in men. CONCLUSIONS: Medium level leisure-time PA reduces the risk of recurrent falls in middle-aged and older people, whereas higher level non-leisure-time PA is associated with a higher risk of recurrent falls.

DOI： 10.1186/s11556-022-00300-5

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OBJECTIVE: Although physical activity (PA) in late life is considered a preventive factor for dementia, effects of different types of PAs on the development of dementia in early old age are unclear. This study aimed to determine the effect of leisure-time and non-leisure-time PAs on dementia risk in middle-aged and older adults during an 8-year follow-up. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: Participants were 13,773 community-dwelling individuals aged 40-74 years who completed the baseline self-administered questionnaire survey of the Murakami cohort study in 2011-2013. METHODS: Main predictors were leisure-time and non-leisure-time (commute, occupational work, and housework) PAs as assessed by MET score (MET-hour/d). The outcome was newly developed dementia determined using a long-term care insurance database. Covariates included demographics, lifestyle, body size, disease history, and PA level. Hazard ratios (HRs) were calculated using Cox proportional hazards models. RESULTS: Mean age of participants was 59.0 (SD 9.3) years. Higher levels of leisure-time PA were associated with lower HRs (adjusted P for trend <.001), with all tertiles having significantly lower HRs (low: 0.71, 95% CI 0.51-0.99; medium: 0.59, 95% CI 0.43-0.81; high: 0.55, 95% CI 0.41-0.75) relative to the reference (zero). Higher quartiles of non-leisure-time PA were associated with lower adjusted HRs for dementia (adjusted P for trend < .001), with the second-fourth quartiles having significantly lower HRs (second: 0.73, 95% CI 0.54-0.98; third: 0.59, 95% CI 0.43-0.81; fourth: 0.55, 95% CI 0.41-0.75) relative to the lowest quartile. These associations were robust regardless of sex and age group. CONCLUSIONS AND IMPLICATIONS: Both leisure-time and non-leisure-time PAs are independently and robustly associated with a reduced risk of dementia.

DOI： 10.1016/j.jamda.2022.01.053

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Several studies have reported an association between sarcopenia and depression. Their results, however, are inconsistent, partly due to small sample sizes and lack of consideration of important confounders. The present study aimed to cross-sectionally examine this association in community-dwelling people in Japan. This study used baseline data from the Yuzawa cohort study (age ≥ 40 years), with the final analysis population comprising 2,466 participants. A self-administered questionnaire was used to elicit information related to sarcopenia, depressive symptoms, demographic characteristics, anthropometrics, disease history, and lifestyles. Sarcopenia was diagnosed using SARC-F, a validated questionnaire including components of Strength, Assistance in walking, Rising from a chair, Climbing stairs, and Falls. Depressive symptoms were assessed using the 11-item version of the Center for Epidemiologic Studies Depression Scale (CES-D). For depressive symptoms, prevalence ratios (PRs) were calculated, and odds ratio (ORs) were obtained using simple and multiple logistic regression analyses. Mean age of participants was 61.7 years (standard deviation = 11.8), and 10.5% and 34.7% had sarcopenia and depressive symptoms, respectively. Sarcopenic individuals had a significantly higher PR (2.00), unadjusted OR (3.67), and adjusted OR (4.96) compared to non-sarcopenic individuals, with an estimated adjusted PR of 2.7. There was a significant dose-dependent association between SARC-F scores and depressive symptoms in sarcopenic individuals (adjusted P for trend = 0.0028). In conclusion, sarcopenia and depressive symptoms were robustly associated in community-dwelling, middle-aged and older people in Japan. However, the direction of this association is unclear, and a future cohort study will be needed to determine causality.

DOI： 10.1620/tjem.2022.J024

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BACKGROUND: Although metabolic syndrome traits are risk factors for chronic kidney disease, few studies have examined their association with urinary biomarkers. METHODS: Urinary biomarkers, including A-megalin, C-megalin, podocalyxin, albumin, α1-microglobulin, β2-microglobulin, and N-acetyl-β-D-glucosaminidase, were cross-sectionally assessed in 347 individuals (52.7% men) with a urine albumin-to-creatinine ratio (ACR)  < 300 mg/g in a health checkup. Metabolic syndrome traits were adopted from the National Cholesterol Education Program (third revision) of the Adult Treatment Panel criteria modified for Asians. RESULTS: Participants had a mean body mass index, estimated glomerular filtration rate (eGFR), and median ACR of 23.0 kg/m2, 74.8 mL/min/1.73 m2, and 7.5 mg/g, respectively. In age- and sex-adjusted logistic regression analysis, A-megalin and albumin were significantly associated with the clustering number of metabolic syndrome traits (3 or more). After further adjustment with eGFR, higher quartiles of A-megalin and albumin were each independently associated with the clustering number of metabolic syndrome traits (adjusted odds ratio for A-megalin: 1.30 per quartile, 95% CI 1.03-1.64; albumin: 1.42 per quartile, 95% CI 1.12-1.79). CONCLUSIONS: Both urinary A-megalin and albumin are associated with the clustering number of metabolic syndrome traits. Further research on urinary A-megalin is warranted to examine its role as a potential marker of kidney damage from metabolic risk factors.

DOI： 10.1186/s13098-021-00779-5

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INTRODUCTION: The urinary sodium-to-potassium ratio is an indicator of dietary sodium intake and has been associated with reduced kidney function. However, less is known about its association with albuminuria, the other key component of chronic kidney disease, in the community-dwelling adult population. We examined the association of the spot urinary sodium-to-potassium ratio with albuminuria and compared spot urinary and dietary sodium-to-potassium ratios. METHODS: We quantified the association of the urinary sodium-to-potassium ratio with albuminuria in 6,274 Japanese adults (aged 40-97 years; 50.9% women) based on spot urine samples. We performed linear and logistic regression modeling to account for potential confounders. Elevated albuminuria was defined as a spot urinary albumin-to-creatinine ratio (ACR) ≥30 mg/g. We secondarily evaluated the dietary sodium-to-potassium ratio based on a food-frequency questionnaire. RESULTS: The median spot urinary and dietary sodium-to-potassium ratios were 2.70 (interquartile interval, 1.87-3.83) and 1.50 (1.21-1.84), respectively. The median ACR was 11.0 (6.0-24.0) mg/g. In a multivariable linear regression model, the spot urinary sodium-to-potassium ratio (per increment) was significantly associated with the natural logarithm of the ACR (regression coefficient, 0.023 [95% confidence interval {95% CI}, 0.007-0.038]). This result was consistent in a multivariable logistic regression model (adjusted odds ratio, 1.08 [95% CI: 1.04-1.12]). The corresponding estimates for the dietary sodium-to-potassium ratio were 0.139 (95% CI: 0.087-0.191) and 1.28 (95% CI: 1.14-1.45), respectively. CONCLUSIONS: Both spot urinary and dietary sodium-to-potassium ratios were associated with elevated albuminuria in community-dwelling Japanese adults. Our findings further support the potential usefulness of the spot urinary sodium-to-potassium ratio as an indicator of sodium intake and suggest a link between sodium intake and kidney damage.

DOI： 10.1159/000526277

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INTRODUCTION: Secular changes in hip fracture incidence have been reported in the last few decades in Japan, but whether long-term bone mineral density (BMD) is also changing is unclear. This study aimed to determine whether BMD of Japanese women has changed over time. METHODS: Subjects were 10,649 adult women who underwent BMD measurement in a health check-up population in Niigata, Japan, between 1995 and 2013. BMD of the distal, non-dominant forearm was measured by dual-energy X-ray absorptiometry. Demographic information and BMI were also obtained. Secular trends were determined by linear regression analysis. RESULTS: BMD of subjects in their 40's decreased significantly in the age-adjusted model (P for trend=0.0162), but not in the age- and BMI-adjusted model (P for trend=0.2171). BMD of subjects in their 50's decreased marginally in the age-adjusted model (P for trend=0.0535), but not in the age- and BMI-adjusted model (P for trend=0.6601). BMDs of subjects in their 30's and 60's did not significantly change, while BMIs of subjects in their 40's-60's decreased significantly. CONCLUSIONS: A secular decrease in BMD, partly attributed to decreases in BMI, was observed in middle-aged Japanese women from 1995 to 2013. Measures to help maintain suitable BMI will be necessary to prevent a decrease in BMD among women.

DOI： 10.5387/fms.2021-10

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BACKGROUND: Income inequality has dramatically increased worldwide, and there is a need to re-evaluate the association between socio-economic status (SES) and depression. Relative contributions of household income and education to depression, as well as their interactions, have not been fully evaluated. This study aimed to examine the association between SES and depressive symptoms in Japanese adults, focusing on interactions between education and household income levels. METHODS: This cross-sectional study used data from baseline surveys of two cohort studies. Participants were 38,499 community-dwelling people aged 40-74 years who participated in baseline surveys of the Murakami cohort study (2011-2012) and Uonuma cohort study (2012-2015) conducted in Niigata Prefecture, Japan. Information regarding marital status, education level, household income, occupation, activities of daily living (ADL), and history of cancer, myocardial infarction, stroke, and diabetes was obtained using a self-administered questionnaire. Depressive symptoms were examined using the Center for Epidemiologic Studies Depression Scale (CES-D). Logistic regression analysis was used to obtain odds ratios (ORs). Covariates included age, sex, marital status, education, household income, occupation, ADL, and disease history. RESULTS: Individuals with higher education levels had lower ORs (adjusted P for trend = 0.0007) for depressive symptoms, independently of household income level. The OR of the university-or-higher group was significantly lower than that of the junior high school group (adjusted OR = 0.79). Individuals with lower household income levels had higher ORs (adjusted P for trend< 0.0001) for depressive symptoms, independently of education level. The type of occupation was not associated with depressive symptoms. In subgroup analyses according to household income level, individuals with higher education levels had significantly lower ORs in the lowest- and lower-income groups (adjusted P for trend = 0.0275 and 0.0123, respectively), but not in higher- and highest-income groups (0.5214 and 0.0915, respectively). CONCLUSIONS: Both education and household income levels are independently associated with the prevalence of depressive symptoms, with household income levels showing a more robust association with depressive symptoms than education levels. This suggests that a high household income level may offset the risk of depressive symptoms from having a low education level.

DOI： 10.1186/s12889-021-12168-8

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OBJECTIVES: Coffee, green tea, and caffeine are potential preventive factors for dementia, but the underlying evidence is insufficient. This study aimed to examine associations between the consumption of coffee, green tea, and caffeine and dementia risk in middle-aged and older people. METHODS: This was a cohort study with an 8.0-year follow-up. Participants were community-dwelling individuals (n = 13,757) aged 40-74 years. A self-administered questionnaire survey was conducted in 2011-2013. Predictors were the consumption of coffee/green tea, from which caffeine consumption was estimated. The outcome was incident dementia obtained from the long-term care insurance database. Covariates were demographic factors, body mass index, physical activity, energy, smoking, drinking, and disease history. Adjusted hazard ratios (HRs) were calculated using Cox proportional hazards models. HRs were also calculated using a Cox model with delayed entry. RESULTS: The number of dementia cases during the study period was 309. Participants with higher coffee consumption had lower HRs (adjusted p for trend = 0.0014), with the fifth quintile (≥326 ml/day) having a significantly lower HR (0.49, 95% confidence interval [CI]: 0.30-0.79) than the first quintile (<26 ml/day, reference). Similarly, participants with higher caffeine consumption had a significantly lower HR (adjusted p for trend = 0.0004) than the reference. The Cox model with delayed entry yielded similar results. These associations were significant in men, but not in women. Moreover, participants who consumed 2-2.9 cups/day and ≥3 cups/day of coffee had lower HRs (0.69, 95% CI: 0.48-0.98 and 0.53, 95% CI: 0.31-0.89, respectively) than those who consumed 0 cup/day. The association between green tea consumption and reduced dementia risk was significant (adjusted p for trend = 0.0146) only in the 60-69 years age subgroup. CONCLUSIONS: High levels of coffee and caffeine consumption were significantly associated with a reduced dementia risk in a dose-dependent manner, especially in men. Moreover, coffee consumption of ≥3 cups/day was associated with a 50% reduction in dementia risk.

DOI： 10.1111/jgs.17407

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AIMS: A prior meta-analysis found that obesity (body mass index [BMI] ≥ 30 kg/m2 ) was associated with a high fall risk, while being overweight (BMI≥25, <30 kg/m2 ) was associated with the lowest fall risk. However, whether these associations hold true for East Asians is unknown. This study aimed to assess the association between BMI and incidence of recurrent falls in Japanese aged 40-74 years. METHODS: This 5-year follow-up cohort study involved 7538 community-dwelling individuals who did not experience recurrent falls in the year before the baseline study. Information on demographics, body size, lifestyle, and disease history was obtained using a self-administered questionnaire. BMI was categorized as <18.5 (underweight), 18.5-20.6 (low-normal), 20.7-22.7 (mid-normal, reference), 22.8-24.9 (high-normal), and ≥ 25.0 kg/m2 (overweight). The outcome was recurrent falls reported, and fall history in the previous year was recorded as none, once, or twice or more (recurrent falls). RESULTS: Mean BMI was 23.5 kg/m2 (SD 2.9) for men and 22.7 kg/m2 (SD 3.2) for women. The adjusted odds ratio (OR) for recurrent falls in the BMI ≥25 group was significantly higher (1.41, 95%CI: 1.02-1.93) than that in the reference group. The adjusted OR in the BMI ≥25 group was significantly higher than that in the reference group for the age ≥ 60 subgroup (1.62, 95%CI: 1.09-2.40), but not for the age < 60 subgroup (OR = 1.04, 95%CI: 0.60-1.80). CONCLUSIONS: Being overweight may be a risk factor for recurrent falls in community-dwelling older Japanese. Further studies are needed to determine the underlying mechanism. Geriatr Gerontol Int 2021; 21: 498-505.

DOI： 10.1111/ggi.14167

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Although dietary Ca, vitamin D and vitamin K are nutritional factors associated with osteoporosis, little is known about their effects on incident osteoporotic fractures in East Asian populations. This study aimed to determine whether intakes of these nutrients predict incident osteoporotic fractures. We adopted a cohort study design with a 5-year follow-up. Subjects were 12 794 community-dwelling individuals (6301 men and 6493 women) aged 40-74 years. Dietary intakes of Ca, vitamin D and vitamin K were assessed with a validated FFQ. Covariates were demographic and lifestyle factors. All incident cases of major osteoporotic limb fractures, including those of the distal forearm, neck of humerus, neck or trochanter of femur and lumbar or thoracic spine were collected. Hazard ratios (HR) for energy-adjusted Ca, vitamin D and vitamin K were calculated with the residual method. Mean age was 58·8 (sd 9·3) years. Lower energy-adjusted intakes of Ca and vitamin K in women were associated with higher adjusted HR of total fractures (Pfor trend = 0·005 and 0·08, respectively). When vertebral fracture was the outcome, Pfor trend values for Ca and vitamin K were 0·03 and 0·006, respectively, and HR of the lowest and highest (reference) intake groups were 2·03 (95 % CI 1·08, 3·82) and 2·26 (95 % CI 1·19, 4·26), respectively. In men, there were null associations between incident fractures and each of the three nutrient intakes. Lower intakes of dietary Ca and vitamin K were independent lifestyle-related risk factors for osteoporotic fracture in women but not men. These associations were robust for vertebral fractures, but not for limb fractures.

DOI： 10.1017/S0007114520001567

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<title>Abstract</title>Physical activity is associated with subjective well-being. In rural communities, however, physical activity may be affected by environmental factors (e.g., nature and socioecological factors). We examined the association of two physical activities in rural life (farming activity and snow removal) with subjective well-being in terms of happiness and <italic>ikigai</italic> (a Japanese word meaning purpose in life). In this cross-sectional study, we analysed data collected from community-dwelling adults aged ≥ 40 years in the 2012–2014 survey of the Uonuma cohort study, Niigata, Japan. Happiness (<italic>n</italic> = 31,848) and <italic>ikigai</italic> (<italic>n</italic> = 31,785) were evaluated with respect to farming activity from May through November and snow removal from December through April by using an ordinal logistic regression model with adjustments for potential confounders. The analyses were conducted in 2019. Among the participants who reported some farming or snow-removal time, median farming and snow-removal time (minutes per day) was 90.0 and 64.3 for men and 85.7 and 51.4 for women, respectively. Ordinal logistic regression analysis showed that longer time farming was associated with greater happiness and <italic>ikigai</italic> in men (adjusted odds ratio for first vs. fourth quartile: happiness = 1.17, 95% confidence interval [CI] = 1.01, 1.35; <italic>ikigai</italic> = 1.29, 95% CI = 1.10, 1.50), and also in women (adjusted odds ratio for first vs. fourth quartile: happiness = 1.17, 95% CI = 1.001, 1.36; <italic>ikigai</italic> = 1.42, 95% CI = 1.20, 1.67). More snow-removal time was inversely associated with happiness and with <italic>ikigai</italic> in women only (adjusted odds ratio for first vs. fourth quartile: happiness = 0.75, 95% CI = 0.67, 0.85; <italic>ikigai</italic> = 0.78, 95% CI = 0.69, 0.88). Our findings showed that physical activity in rural life was associated with happiness and with <italic>ikigai</italic>, and gender differences were observed in their associations with more snow-removal time. These results may be useful in helping to identify people in rural communities who are vulnerable in terms of psychological well-being.

DOI： 10.1057/s41599-021-00723-y

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The COVID-19 pandemic might affect many aspects of the community and a range of psychiatric risk factors due to life changes, including people's behaviors and perceptions. In this study, we aim to identify specific life changes that correlate with psychological distress within the social context of the COVID-19 pandemic in Japan. In July 2020, workers (company employees and civil servants) in Japan were recruited from local institutions that had not had any confirmed COVID-19 cases as well as neighborhoods that had only a few cases. Participants completed a COVID-19 mental health survey (N = 609; 66.9% male). Psychological distress was identified based on Kessler-6 scores (≥13). Life changes were assessed by an open-ended question about life changes in participants and their family, workplace, and community due to the COVID-19 pandemic. A convergent mixed-method approach was used to compare the context of perceived life changes in participants with psychological distress and those without. As a result, 8.9% of participants had psychological distress, and sex and age categories were different between those with psychological distress and those without. Among the participants who responded to the open-ended question, the biggest life change was "staying at home," and the next biggest life changes were "event cancellations" and "increased workload" in participants with psychological distress, and "no changes" and "mask-wearing" in those without psychological distress, respectively. Regarding emotional/perceptual changes, "stress," "fear," and "anger" were more frequently reported by participants with psychological distress than those without (P <0.001). By integrating these findings, we identified themes focusing on vulnerable characteristics related to psychological distress. This study may provide a source in society for mediating psychological distress during a pandemic.

DOI： 10.1371/journal.pone.0256481

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Little is known about predictors of decline in vitamin D status (vitamin D decline) over time. We aimed to determine demographic and lifestyle variables associated with vitamin D decline by sufficiently controlling for seasonal effects of vitamin D uptake in a middle-aged to elderly population. Using a longitudinal study design within the larger framework of the Murakami Cohort Study, we examined 1044 individuals aged between 40 and 74 years, who provided blood samples at baseline and at 5-year follow-up, the latter of which were taken on a date near the baseline examination (±14 d). Blood 25-hydroxyvitamin D (25(OH)D) concentrations were determined with the Liaison® 25OH Vitamin D Total Assay. A self-administered questionnaire collected demographic, body size and lifestyle information. Vitamin D decline was defined as the lowest tertile of 5-year changes in blood 25(OH)D (Δ25(OH)D) concentration (<6·7 nmol/l). Proportions of those with vitamin D decline were 182/438 (41·6 %) in men and 166/606 (27·4 %) in women (P < 0·0001). In men, risk of vitamin D decline was significantly lower in those with an outdoor occupation (P = 0·0099) and those with the highest quartile of metabolic equivalent score (OR 0·34; 95 % CI 0·14, 0·83), and higher in those with 'university or higher' levels of education (OR 2·92; 95 % CI 1·04, 8·19). In women, risk of vitamin D decline tended to be lower with higher levels of vitamin D intake (Pfor trend = 0·0651) and green tea consumption (Pfor trend = 0·0025). Predictors of vitamin D decline differ by sex, suggesting that a sex-dependent intervention may help to maintain long-term vitamin D levels.

DOI： 10.1017/S0007114520001580

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BACKGROUND: Kidney dysfunction is associated with sarcopenia. Estimated glomerular filtration rate based on cystatin C (eGFRcys), an alternative to creatinine-based measures of kidney function eGFR, is not affected by muscle mass. Given that the association of eGFRcys with muscle weakness would be limited, we examined the association in older adults with normal or compromised kidney function. METHODS: This cross-sectional study involved 594 community-dwelling Japanese adults aged ≥40 years living in Yuzawa, Japan. Serum creatinine, cystatin C, and handgrip strength were concurrently measured at a health-check examination in 2015. eGFR was calculated according to the equation developed for the Japanese population using creatinine and cystatin C. Associations of eGFRcys and eGFRcreat with low grip strength (men, <26 kg and women, <18 kg) were analyzed using logistic regression models adjusted to control for potential confounders. RESULTS: Participants (mean age, 74.9 years) included 319 women and 109 individuals with low grip strength. Mean eGFRcys was 75.2 (SD 18.6) mL/min/1.73 m 2. Pearson's correlation coefficients of handgrip strength for eGFRcys and eGFRcreat were 0.19 (P < 0.001) and -0.04 (P = 0.281), respectively. Multivariate logistic regression analysis showed the adjusted odds ratio (OR) of low grip strength for the highest versus lowest quartile of eGFRcys value was 2.46 (95% confidence interval, 1.03-5.86; P-trend = 0.026); whereas the comparative adjusted OR for eGFRcreat was 0.67 (95% confidence interval, 0.34-1.32). CONCLUSION: Low kidney function as assessed by eGFRcys was associated with muscle weakness in community-dwelling Japanese older adults.

DOI： 10.1093/gerona/glaa240

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BACKGROUND: Evidence for primary prevention of chronic kidney disease (CKD) is insufficient. The population-based prospective Uonuma CKD cohort study aims to explore associations of lifestyle and other risk factors with CKD. We report here the study design and baseline profiles. METHODS: All 67,322 residents aged ≥40 years in Minamiuonuma City, Uonuma City, and Yuzawa Town, Niigata Prefecture, Japan and 11,406 participants who attended local health-check examinations were targeted for baseline questionnaire and biochemical sampling, respectively. Information was gathered from 43,217 (64.2%) questionnaires and 8,052 (70.6%) biochemical samples; 6,945 participants consented to both questionnaire and biochemical sampling at baseline, conducted between fiscal years 2012 and 2015. Participants provided information regarding sociodemographic, lifestyle, and self-reported outcomes. Urine albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were measured. The primary outcome is CKD based on self-report and biochemical/clinical diagnosis. RESULTS: Mean age of questionnaire respondents was 63.3 (standard deviation [SD], 12.5) years for men and 64.3 (SD, 13.3) years for women. Among participants who submitted urine samples, median ACR was 10.0 (interquartile range [IQR], 5.0-24.0) mg/g for men and 13.0 (IQR, 7.7-27.0) mg/g for women, and median eGFR was 73.6 mL/min/1.73 m2 (IQR, 63.5-84.5) for men and 73.5 mL/min/1.73 m2 (IQR, 64.4-83.5) for women. ACR 30 mg/g or more was found in 1,741 participants (21.7%) and eGFR <60 mL/min/1.73 m2 in 1,361 participants (16.9%). CONCLUSION: The Uonuma CKD cohort study was established to investigate the impact of lifestyle on CKD development and to provide data for preventing the onset and progression of CKD.

DOI： 10.2188/jea.JE20180220

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BACKGROUND: Specific components of physical activity, such as vigorous exercise and heavy occupational work, are known to increase the risk of chronic low back pain (CLBP) and chronic knee pain (CKP), but impacts of other components are less known. This study aimed to assess the relationship between total physical activity and risk of CLBP and CKP from a public health perspective. METHODS: Participants were 7,565 individuals, aged 40-74 years, who did not have CLBP or CKP, and who participated in the 5-year follow-up survey. A self-administered questionnaire was used to obtain information on demographics, body size and lifestyle (including physical activity) in the baseline survey in 2011-2013, and on CLBP and CKP using Short Form 36 (SF-36) in the follow-up survey. Sitting, standing, walking and strenuous work for occupational activity were assessed for total physical activity, and walking slowly, walking quickly, light to moderate exercise and strenuous exercise were assessed for leisure-time physical activity using metabolic equivalent hours/day (METs score). RESULTS: Mean age of participants was 60.1 years (SD, 8.8). Participants with higher METs scores had a significantly higher risk of CKP (p for trend = 0.0089, OR of 4th quartile = 1.29, 95% CI: 1.04-1.59 vs. 1st quartile), but not CLBP. An intermediate leisure-time METs score was associated with a lower risk of CLBP (OR = 0.75, 95%CI: 0.61-0.92 vs. 0 METs-group). CONCLUSIONS: A high level of total physical activity may increase the risk of CKP, whereas an intermediate level of leisure-time physical activity may decrease the risk of CLBP, in middle-aged and elderly individuals. SIGNIFICANCE: Evidence on the longitudinal association between total physical activity and CLBP and CKP in middle-aged and elderly people is lacking. We conducted a cohort study to assess this association, and found that high levels of total physical activity increased risk of CKP, and intermediate levels of leisure-time physical activity decreased risk of CLBP. This suggests that the effect of physical activity on chronic pain differed by pain site.

DOI： 10.1002/ejp.1535

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Positive associations between vitamin D levels and hand grip strength have been reported worldwide, but the results are not consistent and few studies on East Asian populations have been published. The aim of this study was to determine whether such an association is present in a community-dwelling Japanese population, including elderly and middle-aged individuals. This study used a cross-sectional design. Participants were 492 community-dwelling individuals aged ≥ 40 years living in Yuzawa Town, Japan. The health check examination was conducted in 2015, and serum 25-hydroxyvitamin D [25(OH)D, an index of vitamin D levels], and hand grip strength were measured. Covariates were serum albumin concentration, body mass index, and physical activity level. The associations of serum 25(OH)D concentrations with hand grip strength and low grip strength (< 26 kg for men and < 18 kg for women) were analyzed using analysis of covariance and multiple logistic regression. Mean (standard deviation) age and serum 25(OH)D were 75.4 (9.0) years and 30.9 (9.1) ng/mL, respectively. The prevalence of serum 25(OH)D < 20, 20-29, and ≥ 30 ng/mL was 7.3%, 37.8%, and 54.9%, respectively. Mean hand grip strength in the 25(OH)D < 20 ng/mL group was significantly lower than that in the ≥ 30 ng/mL group (adjusted P ≤ 0.001). The 25(OH)D < 20 ng/mL group was significantly more likely to have low grip strength than the 25(OH)D ≥ 30 ng/mL group (odds ratio = 4.12). In conclusion, low serum 25(OH)D concentration (< 20 ng/mL) is associated with low grip strength in an older Japanese population.

DOI： 10.1007/s00774-019-01040-w

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BACKGROUND: A large earthquake can cause extreme stress and may adversely affect cognitive function in humans. We aimed to examine a possible association between psychological distress and incident dementia after the 2004 Niigata-Chuetsu earthquake in Japan. METHODS: This is a retrospective cohort study followed participants for 10-12 years. Subjects were 6,012 residents in 2005, 5,424 in 2006, and 5,687 in 2007 (age ≥40 years) living in Ojiya city who participated in the annual health check examinations after the 2004 Niigata-Chuetsu earthquake. Psychological distress was assessed using the Kessler Psychological Distress Scale (K10), and individuals with a K10 score ≥10 were considered to have psychological distress. Incident dementia cases were identified from a long-term care insurance database of the local government during the follow-up period. We evaluated hazard ratios (HRs) of psychological distress for incident dementia in each year, unadjusted and adjusted for covariates, including sex, age, occupation, BMI, and property damage of residential area. RESULTS: The average age of the subjects was 64.6 years in 2005, 64.6 in 2006, and 65.2 in 2007. Adjusted HRs were significantly higher (HR = 1.20-1.66) in the psychological distress group than in the reference group in each year. In particular, adjusted HR was high (HR = 2.89) in those with psychological distress in all three years (2005-2007). CONCLUSION: Psychological distress, especially persistent distress, is a risk factor for incident dementia in victims of large disasters.

DOI： 10.1016/j.jad.2019.08.041

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BACKGROUND: Dietary acid load has been suggested to mediate the progression of chronic kidney disease (CKD). However, it is unclear what kinds of foods are actually associated with dietary acid load in patients with CKD. The self-administered diet history questionnaire (DHQ), which semi-quantitatively assesses the dietary habits of Japanese individuals through 150 question items, can estimate average daily intake of various foods and nutrients during the previous month. Using the DHQ, we investigated the association of dietary acid load with CKD progression. We also analyzed the kinds of food that significantly affect dietary acid load. METHODS: Subjects were 96 outpatients with CKD (average estimated glomerular filtration rate [eGFR], 53.0 ± 18.1 ml/min/1.73 m2) at Niigata University Hospital, who had completed the DHQ in 2011. We calculated net endogenous acid production (NEAP) from potassium and protein intake evaluated by the DHQ in order to assess dietary acid load. CKD progression was assessed by comparing eGFR between 2008 and 2014. RESULTS: NEAP was not correlated with protein intake (r = 0.088, p = 0.398), but was negatively correlated with potassium intake (r = - 0.748, p < 0.001). Reduction in eGFR from 2008 to 2014 was estimated to be significantly greater in patients with higher NEAP (NEAP > 50.1 mEq/day, n = 45) than in those with lower NEAP (NEAP ≤50.1 mEq/day, n = 50) by 5.9 (95% confidence interval [95%CI], 0.1 to 11.6) ml/min/1.73 m2. According to multiple logistic regression analysis, higher NEAP was significantly associated with lower intake of fruits (odds ratio [OR], 6.454; 95%CI, 2.19 to 19.00), green and yellow vegetables (OR, 5.18; 95%CI, 1.83 to14.66), and other vegetables (OR, 3.87; 95%CI, 1.29 to 11.62). CONCLUSIONS: Elevated NEAP could be a risk factor for CKD progression. Low intake of fruits and vegetables would increase dietary acid load and might affect the progression of renal dysfunction in Japanese CKD patients.

DOI： 10.1186/s12882-019-1591-8

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OBJECTIVES: Modifiable risk factors for knee osteoarthritis (OA) have not been studied in detail. This study aimed to determine lifestyle-related modifiable factors of symptomatic knee osteoarthritis in an East Asian population. STUDY DESIGN: This 5-year cohort study involved 11,091 individuals (age range 40-72 years) living in the Murakami region of Niigata, Japan, who did not have a history of knee OA. At baseline, information on sociodemographic characteristics, body size, lifestyle, and living condition was obtained using a self-administered questionnaire. MAIN OUTCOME MEASURES: Incident symptomatic knee OA observed at hospitals and orthopaedic clinics in the five years to 2016. Clinical grades of knee OA were based on the Kellgren-Lawrence scale. P for trend was assessed to examine linear associations between predictors and the outcome in multiple logistic regression analysis. RESULTS: The mean age of participants was 58.1 (SD 9.3) years. The number of cases of grade 2 or more incident knee OA was 429. In men, older age (P for trend < 0.0001), higher BMI (P for trend < 0.0001), higher METs score (P for trend = 0.0150), less smoking (P for trend = 0.0249), and lower green tea consumption (P for trend = 0.0437) were associated with incident knee OA. In women, older age (P for trend < 0.0001), higher BMI (P for trend < 0.0001), and alcohol consumption (P = 0.0153) were associated with incident knee OA. CONCLUSIONS: Several lifestyle-related factors were found to be associated with incident knee OA and exhibited sex-dependent differences. In particular, higher consumption of green tea was associated with a lower incidence of knee OA in men.

DOI： 10.1016/j.maturitas.2019.06.013

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BACKGROUND: Acid-base imbalance might promote the progression of chronic kidney disease (CKD), but whether nutrient-derived dietary acid load increases the risk of albuminuria or even high normoalbuminuria is unclear. METHODS: A Japanese cohort comprising 3250 men and 3434 women aged 40-97 years with urine albumin-to-creatinine ratio (ACR) < 33.9 mg/mmol or estimated glomerular filtration rate ≥ 15 ml/min/1.73 m2 were assessed. We performed a cross-sectional evaluation of the association between net endogenous acid production (NEAP), estimated as dietary protein to potassium content ratio, and the presence of high normoalbuminuria (ACR: 1.13-3.38 mg/mmol) or microalbuminuria. RESULTS: Median NEAP was 43.4 (interquartile range (IQR): 34.2-53.4) mEq/day in men and 35.0 (IQR: 27.7-43.6) mEq/day in women. Median ACR was 1.11 (IQR: 0.57-2.49) mg/mmol in men and 1.47 (IQR: 0.82-2.83) mg/mmol in women. In multivariate analysis, the adjusted odds ratio of the highest versus lowest NEAP quartile for microalbuminuria was 1.47 (95% confidence interval (CI): 1.08-1.99) in men and 1.54 (95% CI: 1.11-2.14) in women. For high normoalbuminuria or microalbuminuria, the adjusted odds ratio was 1.28 (95% CI: 1.02-1.59) in men and 1.39 (95% CI: 1.11-1.74) in women. From nutrient composition analysis, subjects with the highest potassium intake, but not protein intake, had lower adjusted odds ratios for the presence of microalbuminuria than those in the lowest quartile for potassium intake. CONCLUSIONS: Higher NEAP was associated with albuminuria and its association might negatively relate to potassium intake in an adult Japanese population.

DOI： 10.1186/s12882-019-1352-8

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BACKGROUND: Age-related musculoskeletal diseases are becoming increasingly burdensome in terms of both individual quality of life and medical cost. We intended to establish a large population-based cohort study to determine environmental, lifestyle, and genetic risk factors of musculoskeletal and other age-related diseases, and to clarify the association between vitamin D status and such diseases. METHODS: We targeted 34,802 residents aged 40-74 years living in areas of northern Niigata Prefecture, including Sekikawa Village, Awashimaura Village, and Murakami City (Murakami region). The baseline questionnaire survey, conducted between 2011 and 2013, queried respondents on their lifestyle and environmental factors (predictors), and self-reported outcomes. Plasma 25-hydroxyvitamin D (25[OH]D) concentration, an indicator of vitamin D status, was determined with the Liaison® 25OH Vitamin D Total Assay. The primary outcome of this study was osteoporotic fracture; other outcomes included age-related diseases including knee osteoarthritis, perception of chronic pain, dementia, and long-term care insurance use. Mean ages of men and women were 59.2 (SD = 9.3, N = 6907) and 59.0 (SD = 9.3, N = 7457) years, respectively. From the blood samples provided by 3710 men and 4787 women, mean 25(OH)D concentrations were 56.5 (SD = 18.4) nmol/L (22.6 ng/mL) and 45.4 (SD = 16.5) nmol/L (18.2 ng/mL), respectively. DISCUSSION: Follow-up surveys are planned every 5 years for 15 years, and incident cases of our targeted diseases will be followed at hospitals and clinics in and nearby the cohort area. We anticipate that we will be able to clarify the association between vitamin D status and multiple disease outcomes in a Japanese population.

DOI： 10.1186/s12199-018-0715-2

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Purpose: Epidemiological profiles of chronic low back and knee pain have not been studied extensively. This study aimed to determine the prevalence of and potential risk factors associated with chronic low back and knee pain in middle-aged and elderly Japanese. Methods: This cross-sectional study involved 14,217 community-dwelling individuals aged 40-74 years living in the Murakami area of Japan. A self-administered questionnaire was used to obtain information regarding marital status, education level, occupation, household income, and body size. Participants also reported current chronic pain, if any, by site and degree of severity, using the verbal rating scale of the Short Form 36. Results: The prevalence of moderate-very severe chronic pain was 9.7% in the low back, 6.7% in the knee, 13.9% in either the low back or knee, and 2.6% in both the low back and knee. Multivariate analysis revealed that lower education level, lower income, and manual occupation in men and older age and higher body mass index in women were significantly associated with a higher prevalence of chronic low back pain. In both sexes, older age, lower education level, and higher body mass index were significantly associated with a higher prevalence of knee pain. Regarding sex differences, adjusted ORs of chronic pain of the low back and knee for women were 0.85 (95% CI 0.75-0.97) and 1.27 (95% CI 1.09-1.49), respectively. Conclusion: Nearly 14% of middle-aged and elderly individuals had moderate-very severe chronic pain of the low back or knee, and this pain was associated with many demographic factors, including sex, age, education level, household income, occupation, and body size.

DOI： 10.2147/JPR.S184746

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AIM: Evidence for the association between dialysis treatment and cognitive decline is limited. The present study aimed to determine whether dialysis treatment is associated with cognitive decline in adult outpatients of a general hospital in Japan. METHODS: This was a cross-sectional substudy of the Project in Sado for Total Health (PROST). Total Health PROST targeted adult outpatients of a general hospital in Sado City, Niigata, Japan. Among 753 patients (mean age 68.1 ± 11.6 years) analyzed, 66 received dialysis. Cognitive state was evaluated using the Mini-Mental State Examination, and those with a Mini-Mental State Examination score <24 were considered "cognitively declined." The prevalence of cognitive decline was compared by odds ratios calculated with multiple logistic regression analysis. Variables included in the analyses were dialysis, age, sex and self-reported histories of hypertension, diabetes, stroke and ischemic heart disease. RESULTS: Of the 66 dialysis patients, 24 (36.4%) showed cognitive decline, whereas 172 (25.0%) of 687 non-dialysis patients showed cognitive decline. The age and sex-adjusted odds ratio for cognitive decline in dialysis patients was 2.57 (95% confidence interval 1.43-4.61), relative to non-dialysis patients. The odds ratio remained significant (odds ratio 2.69, 95% confidence interval 1.49-4.88) even after adjusting for all covariates. CONCLUSION: The prevalence of cognitive decline was high in dialysis patients relative to non-dialysis patients among outpatients of a general hospital in Japan. Geriatr Gerontol Int 2017; 17: 1584-1587.

DOI： 10.1111/ggi.12937

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BACKGROUND: Albuminuria is a biomarker for chronic kidney disease and an independent predictor of cardiovascular and all-cause mortality. A recent meta-analysis concluded that these risks increase with urinary albumin concentration, even when below the microalbuminuria threshold. Thus, minimizing urinary albumin may be a valuable therapeutic goal regardless of disease status. METHODS: We investigated the benefits and safety of a 12-week lifestyle modification program including diet and combined aerobic and resistance exercise for reducing albuminuria in 295 normoalbuminuric or microalbuminuric Japanese adults, including 30 with type 2 diabetes mellitus (T2DM), 104 with metabolic syndrome (MS), and 145 with hypertension (HT). RESULTS: In the study population, the urinary albumin:creatinine ratio (UACR) was reduced significantly (ΔUACR -3.8 ± 16.8 mg/g, P < 0.001) with no change in estimated glomerular filtration rate (eGFR) (ΔeGFR -0.4 ± 7.4 mL/min/1.73 m(2), P = 0.343). The reduction in UACR was associated with decreased fasting plasma glucose (P < 0.05). The UACR was also reduced in the T2DM, MS, and HT groups with no change in eGFR. Reduced UACR was associated with decreased fasting plasma glucose in the MS group and decreased systolic blood pressure in the HT group. The UACR was also reduced in 46 subjects using renin-angiotensin system inhibitors with no change in eGFR. CONCLUSIONS: Our 12-week lifestyle modification program reduced UACR, maintained eGFR, and improved multiple fitness findings in Japanese subjects including T2DM, MS, and HT patients.

DOI： 10.1007/s10157-015-1103-5

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OBJECTIVE: Megalin, an endocytic receptor in proximal tubule cells, is involved in the mechanisms of albuminuria in diabetic nephropathy (DN). To develop efficient novel biomarkers associated with the pathogenesis of DN, we investigated urinary megalin excretion in type 2 diabetes. RESEARCH DESIGN AND METHODS: Sandwich enzyme-linked immunosorbent assay systems were established with monoclonal antibodies against the NH(2) (amino [A]-megalin assay) and COOH (C-megalin assay) termini of megalin to analyze urinary forms of megalin in 68 patients with type 2 diabetes. RESULTS: The A-megalin assay mainly detected a megalin ectodomain form in the soluble urinary fraction, whereas the C-megalin assay identified a full-length form in both soluble and insoluble fractions. Urinary C-megalin levels were significantly high in patients with normoalbuminuria, were elevated in line with increased albuminuria, and showed a better association with estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73 m(2)) than did urinary albumin. In contrast, urinary A-megalin levels were increased in patients with normo- and microalbuminuria but not in those with macroalbuminuria. Urinary C-megalin levels were also positively associated with plasma inorganic phosphate and negatively with hemoglobin levels in those showing no features of bleeding and not taking vitamin D analogs, phosphate binders, or erythropoiesis-stimulating agents. CONCLUSIONS: Urinary full-length megalin excretion as measured by the C-megalin assay is well associated with reduced eGFR and linked to the severity of DN, phosphate dysregulation, and anemia, whereas urinary excretion of megalin ectodomain as measured by the A-megalin assay may be associated with distinctive mechanisms of earlier DN in type 2 diabetes.

DOI： 10.2337/dc11-1684

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Expression and function of megalin, an endocytic receptor in proximal tubule cells (PTCs), are reduced in diabetic nephropathy, involved in the development of proteinuria/albuminuria. Lipopolysaccharide (LPS) is chronically increased in diabetic sera, by the mechanism called metabolic endotoxemia. We investigated low-level LPS-mediated signaling that regulates megalin expression in immortalized rat PTCs (IRPTCs). Incubation of the cells with LPS (10 ng/ml) for 48 h suppressed megalin protein expression and its endocytic function. TNF-α mRNA expression was increased by LPS treatment, and knockdown of the mRNA with siRNA inhibited LPS-mediated downregulation of megalin mRNA expression at the 24-h time point. Incubation of IRPTCs with exogenous TNF-α also suppressed megalin mRNA and protein expression at the 24- and 48-h time points, respectively. MEK1 inhibitor PD98059 competed partially but significantly TNF-α-mediated downregulation of megalin mRNA expression. Collectively, low-level LPS-mediated TNF-α-ERK1/2 signaling pathway is involved in downregulation of megalin expression in IRPTCs.

DOI： 10.1016/j.bbrc.2011.02.118

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Megalin plays a critical role in the endocytosis of albumin and other filtered low-molecular-weight proteins. Here we studied the interaction between megalin and Disabled-2 (Dab2), an adaptor protein that binds to the cytoplasmic domain of megalin and appears to control its trafficking. We co-immunoprecipitated megalin and Dab2 from cultured proximal tubule cells and identified the proteins by liquid chromatography and tandem mass spectrometry. We found two proteins associated with the megalin/Dab2 complex, nonmuscle myosin heavy chain IIA (NMHC-IIA) and beta-actin. Subcellular fractionation followed by sucrose velocity gradient separation showed that megalin, Dab2, and NMHC-IIA existed as a complex in the same endosomal fractions. In vitro pull-down assays demonstrated that NMHC-IIA was bound to the carboxyl-terminal region of Dab2, but not to megalin's cytoplasmic domain. We then transfected COS-7 cells with plasmids that induced the expression of Dab2, NMHC-IIA, and the megalin minireceptor, a truncated form of megalin. Co-immunoprecipitation studies showed that the minireceptor and NMHC-IIA co-immunoprecipitated only with Dab2. Furthermore, the uptake of (125)I-lactoferrin, an endocytic ligand of megalin, by rat yolk sac-derived megalin-expressing L2 cells was inhibited by blebbistatin, a specific inhibitor of nonmuscle myosin II. Our study shows that NMHC-IIA is functionally linked to megalin by interaction with Dab2 and is likely involved in megalin-mediated endocytosis in proximal tubule cells.

DOI： 10.1038/ki.2009.85

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Impairment of proximal tubular endocytosis of glomerular-filtered proteins including albumin results in the development of proteinuria/albuminuria in patients with chronic kidney disease. However, the mechanisms regulating the proximal tubular function are largely unknown. This study aimed to investigate the role of angiotensin II type 1A receptor (AT(1A)R)- and insulin-mediated signaling pathways in regulating the expression of megalin, a multiligand endocytic receptor in proximal tubule cells (PTCs). Opossum kidney PTC-derived OK cells that stably express rat AT(1A)R but are deficient in endogenous angiotensin II receptors (AT(1A)R-OK cells) were used for this study. Treatment of the cells with angiotensin II suppressed mRNA and protein expression of megalin at 3- and 24-h incubation time points, respectively. Cellular uptake and degradation of albumin and receptor-associated protein, megalin's endocytic ligands were suppressed 24 h after angiotensin II treatment. The AT(1A)R-mediated decrease in megalin expression was partially prevented by ERK inhibitors. Insulin competed with the AT(1A)R-mediated ERK activation and decrease in megalin expression. Inhibitors of phosphatidylinositol 3-kinase (PI3K), a major component of insulin signaling, also suppressed megalin expression, and activation of the insulin receptor substrate (IRS)/PI3K system was prevented by angiotensin II. Collectively the AT(1A)R-mediated ERK signaling is involved in suppressing megalin expression in the OK cell line, and insulin competes with this pathway. Conversely, the insulin-IRS/PI3K signaling, with which angiotensin II competes, tends to stimulate megalin expression. In conclusion, there is AT(1A)R- and insulin-mediated competitive signaling cross talk to regulate megalin expression in cultured PTCs.

DOI： 10.1210/en.2008-0886

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Serum levels of cystatin C, an endogenous cysteine proteinase inhibitor, are often used as an indicator of glomerular filtration rate. Although it is known that cystatin C is filtered by glomeruli and metabolized in proximal tubule cells (PTC), the precise molecular mechanism underlying this process is undetermined. Using quartz-crystal microbalance analyses, we demonstrate that cystatin C binds directly to megalin, an endocytic receptor in PTC, in a Ca(+)-dependent manner. We also find that cystatin C is endocytosed specifically via megalin in rat yolk sac epithelium-derived L2 cells which share a variety of characteristics with PTC. Finally, in vivo studies using kidney-specific megalin knockout mice provide evidence that megalin mediates proximal tubular uptake of cystatin C. We conclude that megalin is an endocytic receptor of cystatin C in PTC.

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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