Reliability and validity of the Japanese version of the overall dry skin score in older patients.

BACKGROUND: Dry skin is the most common skin problem, especially in the elderly. However, there is no effective instrument to assess dry skin in Japan. This study aimed to evaluate the reliability and validity of the Japanese version of the overall dry skin score (ODS-J), the gold standard for dry skin assessment. MATERIALS AND METHODS: A cross-sectional study was conducted on 47 patients aged > 65 years. Images of skin on their limbs were captured using a digital camera; both upper and lower limbs were assessed (n = 4/patient). One dermatologist; two wound, ostomy, and continence nurses; and three nursing researchers independently evaluated the images using the ODS-J to assess the intraclass correlation coefficient (ICC) for inter-rater reliability. Stratum corneum hydration (SCH) and transepidermal water loss (TEWL) were the external criteria used to verify concurrent and known-groups validity. RESULTS: In total, 182 sites at which the SCH and TEWL could be measured were evaluated for the ODS-J. The ICC for inter-rater reliability of the six raters was 0.939 (p < 0.001). A higher ODS-J was associated with lower SCH (ρ = -0.374; p < 0.001) and lower TEWL (ρ = -0.287; p < 0.001) values. The ODS-J for the lower legs was significantly higher than that of the forearms (p < 0.001). CONCLUSIONS: The ODS-J showed good inter-rater reliability, concurrent validity, and known-groups validity. It can be used by clinical nurses in Japan to observe patients' skin and is an effective indicator for the evaluation of skin care.

Effectiveness of weak wiping pressure during bed baths in hospitalized older adults: A single-blind randomized crossover trial.

This study evaluated the effectiveness of weak wiping pressure on skin barrier function and patient satisfaction in comparison to ordinary pressure in hospitalized older adults. Forty-seven participants in a general hospital were blindly and randomly assigned a sequence of two bed baths: wiping three times with weak pressure (12-14 mmHg) and ordinary pressure (23-25 mmHg). Transepidermal water loss and stratum corneum hydration were measured before and after the intervention, and patient satisfaction was assessed using a Likert scale. Ordinary pressure significantly decreased skin barrier function compared to weak pressure; however, neither of the pressures caused discomfort. Weak pressure was more effective than ordinary pressure in preventing skin disorders and providing satisfaction. Subgroup cluster analysis showed that ordinary pressure was likely to impair the skin barrier function in older adults with diabetes/dyslipidemia and renal dysfunction. The application of weak pressure during bed baths, especially for these patients, is recommended.

Alcohol consumption and incidence of proteinuria: a retrospective cohort study.

BACKGROUND: Previous studies report conflicting results of a dose-dependent association between alcohol consumption and incidence of chronic kidney disease. Only a few studies have assessed the clinical impact of > 45-65 g/day of critically high alcohol consumption. METHODS: This retrospective cohort study included 88,647 males and 88,925 females with dipstick urinary protein ≤ ± and estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 at their first annual health examinations between April 2008 and March 2010 in Japan. The exposure was the self-reported alcohol consumption. The outcome was proteinuria defined as dipstick urinary protein ≥ 1 + or ≥ 2 +. RESULTS: During median 1.8 years (interquartile range 1.0-2.1) of the observational period, 5416 (6.1%) males and 3262 (3.7%) females developed proteinuria defined as dipstick urinary protein ≥ 1 +. In males, a U-shape association between alcohol consumption and proteinuria was observed in a multivariable-adjusted Poisson regression model [incidence rate ratio (95% confidence interval) of rare, occasional, and daily drinkers with ≤ 19, 20-39, 40-59, and ≥ 60 g/day: 1.00 (reference), 0.86 (0.79-0.94), 0.70 (0.64-0.78), 0.82 (0.75-0.90), 1.00 (0.90-1.11), and 1.00 (0.85-1.17), respectively], whereas a J-shape association was observed in females [1.00 (reference), 0.81 (0.75-0.87), 0.74 (0.64-0.85), 0.93 (0.78-1.11), 1.09 (0.83-1.44), and 1.45 (1.02-2.08), respectively]. Similar associations with dipstick urinary protein ≥ 2 + were shown in males and females. CONCLUSIONS: Moderate alcohol consumption was associated with lower risk of proteinuria in both males and females. Females with ≥ 60 g/day of high alcohol consumption were at higher risk of proteinuria, whereas males were not. Females were more vulnerable to high alcohol consumption, than males.

Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55α contributes to enlargement of infarct size by chronic kidney disease.

Chronic kidney disease (CKD) increases myocardial infarct size by an unknown mechanism. Here we examined the hypothesis that impairment of protective PI3K-PDK1-Akt and/or mTORC-Akt signaling upon reperfusion contributes to CKD-induced enlargement of infarct size. CKD was induced in rats by 5/6 nephrectomy (SNx group) 4 weeks before myocardial infarction experiments, and sham-operated rats served as controls (Sham group). Infarct size as a percentage of area at risk after ischemia/reperfusion was significantly larger in the SNx group than in the Sham group (56.3 ± 4.6 vs. 41.4 ± 2.0%). In SNx group, myocardial p-Akt-Thr308 level at baseline was elevated, and reperfusion-induced phosphorylation of p-Akt-Ser473, p-p70s6K and p-GSK-3ß was significantly suppressed. Inhibition of Akt-Ser473 phosphorylation upon reperfusion by Ku-0063794 significantly increased infarct size in the Sham group but not in the SNx group. There was no difference between the two groups in activities of mTORC2 and PDK1 and protein level of PTEN. However, the PP2A regulatory subunit B55α, which specifically targets Akt-Thr308, was reduced by 24% in the SNx group. Knockdown of B55α by siRNA increased baseline p-Akt-Thr308 and blunted Akt-Ser473 phosphorylation in response to insulin-like growth factor-1 (IGF-1) in H9c2 cells. A blunted response of Akt-Ser473 to IGF-1 was also observed in HEK293 cells transfected with a p-Thr308-mimetic Akt mutant (T308D). These results indicate that increased Akt-Thr308 phosphorylation by down-regulation of B55α inhibits Akt-Ser473 phosphorylation upon reperfusion in CKD and that the impaired Akt activation by insufficient Ser473 phosphorylation upon reperfusion contributes to infarct size enlargement by CKD.

Local Production of Fatty Acid-Binding Protein 4 in Epicardial/Perivascular Fat and Macrophages Is Linked to Coronary Atherosclerosis.

OBJECTIVE: Fatty acid-binding protein 4 (FABP4) is expressed in adipocytes and macrophages, and elevated circulating FABP4 level is associated with obesity-mediated metabolic phenotype. We systematically investigated roles of FABP4 in the development of coronary artery atherosclerosis. APPROACH AND RESULTS: First, by immunohistochemical analyses, we found that FABP4 was expressed in macrophages within coronary atherosclerotic plaques and epicardial/perivascular fat in autopsy cases and macrophages within thrombi covering ruptured coronary plaques in thrombectomy samples from patients with acute myocardial infarction. Second, we confirmed that FABP4 was secreted from macrophages and adipocytes cultured in vitro. Third, we investigated the effect of exogenous FABP4 on macrophages and human coronary artery-derived smooth muscle cells and endothelial cells in vitro. Treatment of the cells with recombinant FABP4 significantly increased gene expression of inflammatory markers in a dose-dependent manner. Finally, we measured serum FABP4 level in the aortic root (Ao-FABP4) and coronary sinus (CS-FABP4) of 34 patients with suspected or known coronary artery disease. Coronary stenosis score assessed by the modified Gensini score was weakly correlated with CS-FABP4 but was not correlated with Ao-FABP4. A stronger correlation (r=0.59, P<0.01) was observed for the relationship between coronary stenosis score and coronary veno-arterial difference in FABP4 level, (CS-Ao)-FABP4, indicating local production of FABP4 during coronary circulation in the heart. Multivariate analysis indicated that (CS-Ao)-FABP4 was an independent predictor of the severity of coronary stenosis after adjustment of conventional risk factors. CONCLUSIONS: FABP4 locally produced by epicardial/perivascular fat and macrophages in vascular plaques contributes to the development of coronary atherosclerosis.

Impact of the Number of Anti-Thrombosis Agents in Hemodialysis Patients: BOREAS-HD2 Study.

BACKGROUND/AIMS: Relationships between the number of anti-thrombosis agents, clinical benefits and adverse events in hemodialysis (HD) patients are unclear. METHODS: All patients on HD in 22 institutes (n = 1,071) were enrolled and followed up for 3 years. After exclusion of patients with missing data, kidney transplantation or retraction of consent during the follow-up period (n = 204), mortality rate and ischemic and hemorrhagic events were compared between different regimens of anti-thrombosis agents. RESULTS: The use of dual or triple antiplatelet (AP) agents (HR:2.03, 95% CI:1.01-4.13, p = 0.04) and the combination of an AP agent and warfarin (WF) (HR:4.84, 95%CI 1.96-11.96, p < 0.001) were associated with an increase in hemorrhagic events compared with no use of anti-thrombosis agents. No anti-thrombosis regimen was associated with a significant change in risk of ischemic stroke. The use of dual or triple AP agents, but not WF, was associated with an increase in cardiovascular mortality (HR:2.48, 95% CI:1.24-4.76, p = 0.01). CONCLUSION: A significant increase in hemorrhagic events by the use of dual or more AP agents and by co-administration of an AP agent and WF in patients on HD should be considered in planning their anti-thrombosis regimen.

Impact of use of angiotensin II receptor blocker on all-cause mortality in hemodialysis patients: prospective cohort study using a propensity-score analysis.

BACKGROUND: It is controversial whether treatment with an angiotensin II receptor blocker (ARB) or a calcium channel blocker (CCB) improves prognosis of hemodialysis (HD) patients. METHODS: This study was designed as a multicenter prospective cohort study. HD patients (n = 1071) were enrolled from 22 institutes in January 2009 and followed up for 3 years. Patients with missing data, kidney transplantation or retraction of consent during the follow-up period (n = 204) were excluded, and 867 patients contributed to analysis of mortality. Propensity score (PS) for use of ARB and that for CCB was calculated using a multiple logistic regression model. RESULTS: ARB and CCB were prescribed in 45.6 and 54.7 % of patients at enrollment. During the 3-year follow-up period, all-cause mortality and cardiovascular mortality rates were 18.8 and 5.1 %, respectively. Kaplan-Meier curves showed that all-cause and cardiovascular mortality rates were lower in the ARB group than in the non-ARB group, though the mortality rates were similar in the CCB group and non-CCB group. In PS-stratified Cox regression analysis, ARB treatment was associated with 34 and 45 % reduction of all-cause death and cardiovascular death, respectively. In PS matching analysis, ARB treatment was associated with a significant reduction (46 % reduction) in the risk of all-cause death. A significant impact of CCB treatment on all-cause or cardiovascular mortality was not detected in PS analysis. CONCLUSIONS: The use of an ARB, but not a CCB, is associated with reduced all-cause and cardiovascular mortalities in patients on HD.

Reduction of circulating FABP4 level by treatment with omega-3 fatty acid ethyl esters.

BACKGROUND: Fatty acid-binding protein 4 (FABP4/A-FABP/aP2) mainly expressed in adipocytes is secreted and acts as an adipokine. Increased circulating FABP4 level is associated with obesity, insulin resistance and atherosclerosis. However, little is known about the modulation of serum FABP4 level by drugs including anti-dyslipidemic agents. METHODS: Patients with dyslipidemia were treated with omega-3 fatty acid ethyl esters (4 g/day; n = 14) containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for 4 weeks. Serum FABP4 level was measured before and after treatment. Expression and secretion of FABP4 were also examined in mouse 3T3-L1 adipocytes treated with EPA or DHA. RESULTS: Treatment with omega-3 fatty acid ethyl esters significantly decreased triglycerides and serum FABP4 level (13.5 ± 1.5 vs. 11.5 ± 1.1 ng/ml, P = 0.017). Change in FABP4 level by omega-3 fatty acids was negatively correlated with change in levels of EPA + DHA (r = -0.643, P = 0.013), EPA (r = -0.540, P = 0.046) and DHA (r = -0.650, P = 0.011) but not change in the level of triglycerides or other fatty acid composition. Treatment of 3T3-L1 adipocytes with EPA or DHA had no effect on short-term (2 h) secretion of FABP4. However, gene expression and long-term (24 h) secretion of FABP4 were significantly reduced by treatment with EPA or DHA. CONCLUSIONS: Omega-3 fatty acids decrease circulating FABP4 level, possibly by reducing expression and consecutive secretion of FABP4 in adipocytes. Reducing FABP4 level might be involved in suppression of cardiovascular events by omega-3 fatty acids.

Reduction of serum FABP4 level by sitagliptin, a DPP-4 inhibitor, in patients with type 2 diabetes mellitus.

Fatty acid binding protein 4 (FABP4), also known as adipocyte FABP or aP2, is secreted from adipocytes in association with lipolysis as a novel adipokine, and elevated serum FABP4 level is associated with obesity, insulin resistance, and atherosclerosis. However, little is known about the modulation of serum FABP4 level by therapeutic drugs. Sitagliptin (50 mg/day), a dipeptidyl peptidase 4 (DPP-4) inhibitor that increases glucagon-like peptide 1 (GLP-1), was administered to patients with type 2 diabetes (n = 24) for 12 weeks. Treatment with sitagliptin decreased serum FABP4 concentration by 19.7% (17.8 ± 1.8 vs. 14.3 ± 1.5 ng/ml, P < 0.001) and hemoglobin A1c without significant changes in adiposity or lipid variables. In 3T3-L1 adipocytes, sitagliptin or exendin-4, a GLP-1 receptor agonist, had no effect on short-term (2 h) secretion of FABP4. However, gene expression and long-term (24 h) secretion of FABP4 were significantly reduced by sitagliptin, which was not mimicked by exendin-4. Treatment with recombinant DPP-4 increased gene expression and long-term secretion of FABP4, and the effects were cancelled by sitagliptin. Furthermore, knockdown of DPP-4 in 3T3-L1 adipocytes decreased gene expression and long-term secretion of FABP4. In conclusion, sitagliptin decreases serum FABP4 level, at least in part, via reduction in the expression and consecutive secretion of FABP4 in adipocytes by direct inhibition of DPP-4.

Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling of the pulmonary artery (PA). Recently, endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) have been disclosed in various types of diseases. Here we examined whether ER stress is involved in the pathogenesis of PAH. Four weeks of chronic normobaric hypoxia increased right ventricular (RV) systolic pressure by 63% compared with that in normoxic controls and induced RV hypertrophy and medial thickening of the PA in C57BL/6J mice. Treatment with 4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced RV systolic pressure by 30%, attenuated RV hypertrophy and PA muscularization, and increased total running distance in a treadmill test by 70% in hypoxic mice. The beneficial effects of 4-PBA were associated with suppressed expression of inflammatory cytokines and ER stress markers, including Grp78 and Grp94 in the activating transcription factor-6 branch, sXbp1 and Pdi in the inositol-requiring enzyme-1 branch and Atf4 in the PKR-like ER kinase branch, and reduced phosphorylation of c-Jun NH2-terminal kinase and eukaryotic translation initiation factor-2α in the lung. The pattern of changes in ER stress and inflammatory markers by 4-PBA in the lung of the PAH model was reproduced in PA smooth muscle cells by chronic stimulation of platelet-derived growth factor-BB or hypoxia. Furthermore, knockdown of each UPR branch sensor activated other branches and promoted proliferation of PA smooth muscle cells. The findings indicate that activation of all branches of the UPR and accompanying inflammation play a major role in the pathogenesis of PAH, and that chemical chaperones are potentially therapeutic agents for PAH.

Elevation of circulating fatty acid-binding protein 4 is independently associated with left ventricular diastolic dysfunction in a general population.

BACKGROUND: Fatty acid-binding protein 4 (FABP4) is expressed in both adipocytes and macrophages. Recent studies have shown secretion of FABP4 from adipocytes and association of elevated serum FABP4 level with obesity, insulin resistance, hypertension, and atherosclerosis. However, little is known about role of FABP4 in cardiac function. METHODS: From the database of the Tanno-Sobetsu Study, data for 190 subjects (male/female: 82/108) who were not treated with any medication and underwent echocardiography in 2011 or 2012 were retrieved for analyses of relationships between serum FABP4 concentration, metabolic markers and parameters of echocardiography. RESULTS: Serum FABP4 level was positively correlated with age, body mass index (BMI), blood pressure (BP), LDL cholesterol, HOMA-R and mean left ventricular (LV) wall thickness (LVWT, males: r = 0.315, females: r = 0.401, p < 0.01) and was negatively correlated with HDL cholesterol, estimated glomerular filtration rate (eGFR) and peak myocardial velocity during early diastole (e'; males: r = -0.434, females: r = -0.353, p < 0.01), an index of LV diastolic function. However, no significant correlation was found between FABP4 level and LV end-diastolic dimension, LV ejection fraction or LV mass index. There were significant correlations of e' with age, BMI, BP, eGFR, brain natriuretic peptide (BNP), FABP4, metabolic markers and LVWT. Multivariate regression analysis adjusted by HOMA-R, BMI, eGFR, BNP or LVWT in addition to age, gender and BP revealed that serum FABP4 concentration was independently correlated with e'. CONCLUSIONS: Elevation of circulating FABP4 may contribute to LV diastolic dysfunction in a general population.

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.

Ectopic expression of fatty acid-binding protein 4 in the glomerulus is associated with proteinuria and renal dysfunction.

BACKGROUND/AIMS: Fatty acid-binding proteins (FABPs) are a family of intracellular lipid chaperones. Among FABPs, FABP1 (liver FABP) is expressed in proximal tubular epithelial cells in the kidney, and urinary FABP1 has been reported to reflect damage of proximal tubular epithelial cells. However, roles of other FABP isoforms in renal pathologies have not been reported. Recently, FABP4 (adipocyte FABP/aP2) was reported to be expressed in peritubular capillaries (PTCs), but not in glomerular capillaries in the normal kidney. We examined the hypothesis that pathological conditions alter the level and localization of FABP4 expression in the kidney, which mediates renal dysfunction. METHODS: A total of 112 consecutive patients who underwent renal biopsy were retrospectively enrolled. Expression of FABP4 protein and mRNA in the kidney was examined by immunohistochemistry and in situ hybridization, respectively. The ratio of FABP4-positive area to total area within glomeruli (G-FABP4-Area), urinary protein level (U-Protein), and change in estimated glomerular filtration rate (eGFR) 1 year after biopsy were examined. RESULTS: FABP4 protein and mRNA were expressed not only in PTCs, but also in endothelial cells and macrophages in the glomerulus. G-FABP4-Area was correlated with U-Protein (r = 0.497, p < 0.001). As a subanalysis, in patients with IgA nephropathy (n = 34), G-FABP4-Area was significantly larger in cases with an endocapillary proliferative lesion, and change in eGFR was negatively correlated with G-FABP4-Area at baseline (r = -0.537, p = 0.008). CONCLUSION: Ectopic FABP4 expression in the glomerulus is induced by renal diseases and is closely associated with proteinuria and renal dysfunction.

U-shaped association between body mass index and proteinuria in a large Japanese general population sample.

BACKGROUND: There is little data on the association between body mass index (BMI) and proteinuria. METHODS: This was a cross-sectional cohort study assessing the association between BMI and proteinuria in a large Japanese population. Using a nationwide health check-up database of 212,251 Japanese aged >20 years with no pre-existing cardiovascular diseases (185,183 men, median age 66 years; 127,068 women, median age 65 years), we examined the association between BMI and proteinuria (≥ 1+ on dipstick). RESULTS: Subjects were divided into 11 subgroups by BMI grading in 1 kg/m(2) intervals from 18.5-27.5 kg/m(2). A BMI of approximately 22 ± 0.5 kg/m(2) was considered optimal for Japanese; therefore, this subgroup was set as a reference when logistic analysis was applied. Age, waist circumference, height, weight, smoking and drinking habits, use of medications such as antihypertensive, antidiabetic, or antihyperlipidemic, as well as proteinuria, estimated glomerular filtration rate (eGFR), chemistry data, and blood pressure levels were significantly different between subgroups in both genders. The odds ratio for proteinuria showed a U-shape in men and women, even after adjustment for significant covariates such as age, waist circumference, systolic blood pressure, eGFR, fasting plasma glucose, triglyceride, low-density lipoprotein, antihypertensive use, antidiabetic use, antihyperlipidemic use, and lifestyle factors (smoking and drinking). Gender differences were also prominent--a BMI <20.4 kg/m(2) was significantly associated with proteinuria in men compared to a BMI <18.4 kg/m(2) in women. On the other hand, a BMI ≥ 25.5 kg/m(2) was also significantly associated with proteinuria in men compared to a BMI ≥ 22.5 kg/m(2) in women. CONCLUSIONS: We found that BMI levels were associated with proteinuria in a U-shaped manner and showed marked gender differences. Health guidance should not only focus on higher BMI subjects, but also on thin subjects, in terms of the prevention of chronic kidney disease.

An association between serum γ-glutamyltransferase and proteinuria in drinkers and non-drinkers: a Japanese nationwide cross-sectional survey.

BACKGROUND: The association between alcohol consumption and chronic kidney disease (CKD), characterized by reduced glomerular filtration rate and proteinuria, is controversial. Recent studies suggest that serum γ-glutamyltransferase (GGT) level, a conventional marker of excessive alcohol consumption, predicts the CKD incidence. Little information is available on the difference in the clinical impact of alcohol consumption and GGT on proteinuria. METHODS: The present cross-sectional survey included 332,296 Japanese people aged ≥40 years in 2008. To examine the associations of GGT and alcohol consumption with proteinuria, 134,600 men and 197,696 women were classified into 20 categories based on GGT quartiles and alcohol consumption categories, and their prevalence rate ratios (PRR) of proteinuria defined as ≥1+ of dipstick urinary protein were calculated after adjusting for clinically relevant factors. RESULTS: Prevalence of proteinuria was 7.5 and 3.7 % in men and women, respectively. In both gender an association between alcohol consumption and proteinuria was in a J-shaped fashion with the lowest PRR of mild drinkers with ≤19 g/day of ethanol consumption, whereas an association between serum GGT level and proteinuria was linear. Compared with rare drinkers in the lowest GGT quartile, the subjects in higher GGT quartiles had a higher probability of proteinuria, irrespective of alcohol consumption. An optimal cutoff level of serum GGT was 43.6 and 23.2 IU/L in men and women, respectively. CONCLUSIONS: The subjects with higher serum GGT level had a higher probability of proteinuria, regardless of alcohol consumption, suggesting that GGT has a clinically greater impact on CKD than alcohol consumption.

Fusion of bone marrow-derived cells with renal tubules contributes to renal dysfunction in diabetic nephropathy.

Although diabetic nephropathy (DN) is a major cause of end-stage renal disease, the mechanism of dysfunction has not yet been clarified. We previously reported that in diabetes proinsulin-producing bone marrow-derived cells (BMDCs) fuse with hepatocytes and neurons. Fusion cells are polyploidy and produce tumor necrosis factor (TNF)-α, ultimately causing diabetic complications. In this study, we assessed whether the same mechanism is involved in DN. We performed bone marrow transplantation from male GFP-Tg mice to female C57BL/6J mice and produced diabetes by streptozotocin (STZ) or a high-fat diet. In diabetic kidneys, massive infiltration of BMDCs and tubulointerstitial injury were prominent. BMDCs and damaged tubular epithelial cells were positively stained with proinsulin and TNF-α. Cell fusion between BMDCs and renal tubules was confirmed by the presence of Y chromosome. Of tubular epithelial cells, 15.4% contain Y chromosomes in STZ-diabetic mice, 8.6% in HFD-diabetic mice, but only 1.5% in nondiabetic mice. Fusion cells primarily expressed TNF-α and caspase-3 in diabetic kidney. These in vivo findings were confirmed by in vitro coculture experiments between isolated renal tubular cells and BMDCs. It was concluded that cell fusion between BMDCs and renal tubular epithelial cells plays a crucial role in DN.

Association between prehypertension and chronic kidney disease in the Japanese general population.

The increased prevalence of chronic kidney disease (CKD) is a consequence of the accumulation of risk factors, one of which is hypertension. Here we assessed the prevalence of CKD according to blood pressure among 232,025 patients in a Japanese nationwide database with a focus on the prevalence and risk factors of CKD in prehypertension. Patients were stratified by blood pressure and included 75,474 with optimal blood pressure (less than 120/80 mm Hg); 59,194 with prehypertension and a normal blood pressure (120-129/80-84 mm Hg) or 46,547 patients with high-normal blood pressure (130-139/85-89 mm Hg); and 50,810 with hypertension (over 140/90 mm Hg without anti-hypertensive drugs). CKD was defined as an estimated glomerular filtration rate of stage 3 or lower or having proteinuria greater than 1+ by a dipstick method. The prevalence of CKD among patients with optimal blood pressure, prehypertension having normal or high-normal blood pressure, and hypertension was 13.9, 15.6, 18.1, and 20.7% in men, and 10.9, 11.6, 12.9, and 15.0% in women, with a significant difference between genders at each strata of blood pressure. In men, but not in women, whose blood pressure was high-normal, the CKD risk was significantly greater (odds ratio 1.11) than those with optimal blood pressure. Obesity (body mass index over 25) was significantly associated with an increased risk of CKD in both men and women (odds ratio 1.43 and 1.26, respectively), and there was an additive effect of obesity and pre-hypertension on CKD risk in men compared with men with optimal blood pressure. Thus, the prevalence of CKD increased with the severity of blood pressure. Prehypertension with high-normal blood pressure, particularly in conjunction with obesity, was found to be an independent risk factor of CKD in men.

Glycohemoglobin not as predictive as fasting glucose as a measure of prediabetes in predicting proteinuria.

BACKGROUND: There is little data on the assessment of prediabetes with proteinuria. METHODS: This is a cross-sectional cohort study assessing prediabetes with proteinuria in a large Japanese population. Using a nationwide health checkup database of 228 778 Japanese aged ≥20 years (median 66 years; 39.3% were men; none had pre-existing cardiovascular disease), we examined the association between prediabetes and proteinuria (≥1+ on dipstick) separately in prediabetes subjects diagnosed with the new hemoglobin A1c (HbA1c) criterion only (PD-A1c), the impaired fasting plasma glucose only (PD-IFG) and fulfilling both criteria (PD-Both). RESULTS: According to the American Diabetes Association's (ADA's) criterion of 5.7-6.4% HbA1c and/or 100-125 mg/dL fasting plasma glucose, 43.8% of the subjects were judged as having prediabetes. Prediabetes subjects were divided into subclasses of PD-A1c (53.7%), PD-IFG (21.7%) and PD-Both (24.5%), respectively. Therefore, 21.7% of prediabetes subjects were missed using the new HbA1c criterion only. Compared with subjects with normal glucose tolerance (as a reference), the odds ratio (OR) [95% confidence interval (95% CI)] for the increased risk of proteinuria (≥1+) in diabetes itself was 2.191 (2.081-2.307) and in whole prediabetes was 1.093 (1.046-1.142); when prediabetes was subdivided, the OR for proteinuria in PD-IFG was 1.217 (1.140-1.300) and that in PD-Both was 1.249 (1.174-1.329), but that in PD-A1c was not significant, even after adjustment for significant covariates, such as age, sex, body mass index, systolic blood pressure, antihypertensive medication, eGFR, lifestyle and lipid profile. CONCLUSIONS: Prediabetes is a significant risk factor for proteinuria compared with completely normal glucose level, and subjects with prediabetes defined using IFG are at significantly higher risk for proteinuria than those defined by HbA1c only.

Cost-effectiveness of chronic kidney disease mass screening test in Japan.

BACKGROUND: Chronic kidney disease (CKD) is a significant public health problem. Strategy for its early detection is still controversial. This study aims to assess the cost-effectiveness of population strategy, i.e. mass screening, and Japan's health checkup reform. METHODS: Cost-effectiveness analysis was carried out to compare test modalities in the context of reforming Japan's mandatory annual health checkup for adults. A decision tree and Markov model with societal perspective were constructed to compare dipstick test to check proteinuria only, serum creatinine (Cr) assay only, or both. RESULTS: Incremental cost-effectiveness ratios (ICERs) of mass screening compared with do-nothing were calculated as ¥1,139,399/QALY (US $12,660/QALY) for dipstick test only, ¥8,122,492/QALY (US $90,250/QALY) for serum Cr assay only and ¥8,235,431/QALY (US $91,505/QALY) for both. ICERs associated with the reform were calculated as ¥9,325,663/QALY (US $103,618/QALY) for mandating serum Cr assay in addition to the currently used mandatory dipstick test, and ¥9,001,414/QALY (US $100,016/QALY) for mandating serum Cr assay and applying dipstick test at discretion. CONCLUSIONS: Taking a threshold to judge cost-effectiveness according to World Health Organization's recommendation, i.e. three times gross domestic product per capita of ¥11.5 million/QALY (US $128 thousand/QALY), a policy that mandates serum Cr assay is cost-effective. The choice of continuing the current policy which mandates dipstick test only is also cost-effective. Our results suggest that a population strategy for CKD detection such as mass screening using dipstick test and/or serum Cr assay can be justified as an efficient use of health care resources in a population with high prevalence of the disease such as in Japan and Asian countries.

Risk factor profiles based on estimated glomerular filtration rate and dipstick proteinuria among participants of the Specific Health Check and Guidance System in Japan 2008.

BACKGROUND: Estimated glomerular filtration rate (eGFR) and albuminuria (proteinuria) are both important determinants of the risk of cardiovascular disease (CVD), end-stage renal disease (ESRD), and mortality. Few studies, however, have examined the risk factor profiles based on eGFR and proteinuria among the general population. METHODS: Data of the newly developed nationwide screening program of the Specific Health Check-up and Guidance System (Tokutei-Kensin) initiated in 2008 were used in this study. The aim of this screening, targeting people 40-74 years of age, was to detect those with metabolic syndrome and to offer those services regarding lifestyle modifications that will lead to the reduction of diabetes mellitus (DM) and DM-related ESRD. Individual records of 580,000 participants in 69 cities and towns and 3 union cohorts throughout Japan were anonymously provided and included in the present study. RESULTS: Details of 332,174 participants (57.3% of the total) with both serum creatinine and dipstick urine test data were analyzed. Mean (SD) age was 63.6 (8.3) years and 40.6% were men. The mean (SD) eGFR was 75.0 (16.2) ml/min/1.73 m(2) and 5.4% had proteinuria. The prevalence of chronic kidney disease (CKD) stage 3, 4, and 5 was 14.2%, 0.2%, and 0.07%, respectively. The prevalence of DM, hypertension, and history of stroke and heart disease was correlated with the combination of eGFR and degree of proteinuria. CONCLUSION: The findings of the present study indicate that CKD and risk factors for CVD are quite common among middle-aged Japanese. CKD classification based on eGFR and proteinuria may be useful for predicting CVD, mortality rate, and ESRD in the Japanese population.