桑原 政成

OBJECTIVE: This study was conducted to identify whether higher fasting blood glucose levels is predictive of hypertension by a large-scale longitudinal design. METHODS: We conducted a retrospective 5-year cohort study using the data from 13 201 Japanese individuals who underwent annual medical examinations in 2004 and were reevaluated 5 years later. This study included individuals without diabetes or hypertension between ages 30 and 85 years in 2004. The cumulative incidences of hypertension over 5 years in each 10 mg/dl of fasting blood glucose levels were calculated. Moreover, we examined risk factors and calculated odds ratios (ORs) for developing hypertension after adjustments for age, sex, BMI, smoking and drinking habits, dyslipidemia, chronic kidney disease, serum uric acid, and fasting blood glucose levels by logistic regression analyses. RESULTS: We analyzed 10 157 participants (age: 48.9 ± 10.7 years; 43.4% men) without diabetes or hypertension in 2004. After multiple adjustments, higher baseline blood glucose level is an independent risk for hypertension (OR: 1.176; 95% CI 1.086-1.275), as well as aging, women, higher BMI, drinking habits, and higher serum uric acid. After stratifying by sex, higher baseline blood glucose level is an independent risk for hypertension both in women (OR: 1.295; 95% CI 1.135-1.478) and men (OR: 1.108; 95% CI 1.001-1.227). When we conducted the same analysis using glycated hemoglobin instead of blood glucose, glycated hemoglobin was not a risk for hypertension. CONCLUSION: Higher fasting blood glucose is an independent risk for developing hypertension. Further studies are needed to determine if treatment for elevated blood glucose can prevent developing hypertension.

RATIONALE & OBJECTIVE: Epidemiologic and clinical studies have suggested that urate-lowering therapy may slow the progression of chronic kidney disease (CKD). However, definitive evidence is lacking. STUDY DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING & PARTICIPANTS: 467 patients with stage 3 CKD and asymptomatic hyperuricemia at 55 medical institutions in Japan. INTERVENTION: Participants were randomly assigned in a 1:1 ratio to receive febuxostat or placebo for 108 weeks. OUTCOMES: The primary end point was the slope (in mL/min/1.73m2 per year) of estimated glomerular filtration rate (eGFR). Secondary end points included changes in eGFRs and serum uric acid levels at 24, 48, 72, and 108 weeks of follow-up and the event of doubling of serum creatinine level or initiation of dialysis therapy. RESULTS: Of 443 patients who were randomly assigned, 219 and 222 assigned to febuxostat and placebo, respectively, were included in the analysis. There was no significant difference in mean eGFR slope between the febuxostat (0.23±5.26mL/min/1.73m2 per year) and placebo (-0.47±4.48mL/min/1.73m2 per year) groups (difference, 0.70; 95% CI, -0.21 to 1.62; P=0.1). Subgroup analysis demonstrated a significant benefit from febuxostat in patients without proteinuria (P=0.005) and for whom serum creatinine concentration was lower than the median (P=0.009). The incidence of gouty arthritis was significantly lower (P=0.007) in the febuxostat group (0.91%) than in the placebo group (5.86%). Adverse events specific to febuxostat were not observed. LIMITATIONS: GFR was estimated rather than measured, and patients with stages 4 and 5 CKD were excluded. CONCLUSIONS: Compared to placebo, febuxostat did not mitigate the decline in kidney function among patients with stage 3 CKD and asymptomatic hyperuricemia. FUNDING: Funded by Teijin Pharma Limited. TRIAL REGISTRATION: Registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry with study number UMIN000008343.

BACKGROUND: Fructose intake, mainly as table sugar or high fructose corn syrup, has increased in recent decades and is associated with increased risk for kidney stones. We hypothesized that fructose intake alters serum and urinary components involved in stone formation. METHODS: We analyzed a previously published randomized controlled study that included 33 healthy male adults (40-65 years of age) who ingested 200 g of fructose (supplied in a 2-L volume of 10% fructose in water) daily for 2 weeks. Participants were evaluated at the Unit of Nephrology of the Mateo Orfila Hospital in Menorca. Changes in serum levels of magnesium, calcium, uric acid, phosphorus, vitamin D, and intact PTH levels were evaluated. Urine magnesium, calcium, uric acid, phosphorus, citrate, oxalate, sodium, potassium, as well as urinary pH, were measured. RESULTS: Ingestion of fructose was associated with an increased serum level of uric acid (p < 0.001), a decrease in serum ionized calcium (p = 0.003) with a mild increase in PTH (p < 0.05) and a drop in urinary pH (p = 0.02), an increase in urine oxalate (p = 0.016) and decrease in urinary magnesium (p = 0.003). CONCLUSIONS: Fructose appears to increase urinary stone formation in part via effects on urate metabolism and urinary pH, and also via effects on oxalate. Fructose may be a contributing factor for the development of kidney stones in subjects with metabolic syndrome and those suffering from heat stress. TRIAL REGISTRATION: ClinicalTrials.gov NCT00639756 March 20, 2008.

β-Adrenergic receptor blockers (β-blockers) are well-known useful and cost-effective drugs for managing hypertensive patients with coronary heart disease, stroke, and heart failure. However, it is often difficult to use β-blockers for patients with asthma or chronic obstructive pulmonary disease (COPD). Moreover, most β-blockers negatively influence glucose or lipid metabolism. Nebivolol is a third-generation lipophilic β-1 receptor-selective blocker with nitric oxide-mediated vasodilatory effects, metabolically neutral and usually well tolerated by patients with asthma or COPD. Nebivolol has significant effects of reduction in central blood pressure and improvements in endothelial dysfunction and arterial stiffness. To summarize the merits and demerits of nebivolol in different clinical situations, we conducted a review using the word 'nebivolol' on Pubmed and Embase, limiting the search to hypertension, clinical trials, and meta-analyses. This review summarizes the clinical studies on nebivolol itself and on the combination of nebivolol with other antihypertensive drugs, such as hydrochlorothiazide, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and amlodipine. Most studies showed the safety and well-tolerated profile of nebivolol and the combination of nebivolol with other antihypertensive drugs, which suggests that new fixed combinations of nebivolol with other antihypertensive drugs would be useful for patients who are unable to tolerate traditional β-blockers.

BACKGROUND: Although intravenous immunoglobulin (IVIG) therapy is the standard therapy for Kawasaki disease (KD) to prevent coronary aneurysms including dilatations, it is unclear whether early IVIG therapy is more efficient in the acute stage of KD. METHODS: We conducted a cohort study using data from the 22nd nationwide survey of KD in Japan from January 2011 to December 2012. We excluded patients with recurrent KD and whose first admission day was later than seven days from the onset of symptoms. Finally, 20,933 patients with echocardiography assessment and IVIG therapy were divided into three groups according to the start of the IVIG therapy: 1) early: ≤4 days, 2) conventional: 5-7 days, and 3) late: 8-10 days. Then we investigated whether the early IVIG therapy prevented coronary dilatation or aneurysm after multiple adjustments for age, sex, total amount of IVIG, use of steroids, infliximab, other immunosuppressive agents, and plasma exchange. RESULTS: After multiple adjustments, conventional therapy had similar risks for coronary dilatation or aneurysm compared with early therapy (odds ratio [OR]:0.95; 95% confidence interval [CI], 0.78-1.16), whereas late therapy had a higher risk (OR:1.66; 95% CI, 1.03-2.68). Other risk factors for coronary dilatation or aneurysm were young male, older age, use of steroids, infliximab, other immunosuppressive agents, and a larger amount of total IVIG. CONCLUSIONS: Early IVIG therapy for KD did not reduce the risk for coronary dilatation or aneurysm compared with conventional therapy. It is recommended to start IVIG therapy within 7 days from the onset of symptoms.

Osteopontin (OPN) is a pro-and anti-inflammatory molecule that simultaneously attenuates oxidative stress. Both inflammation and oxidative stress play a role in the pathogenesis of glomerulonephritis and in the progression of kidney injury. Importantly, OPN is highly induced in nephritic kidneys. To characterize further the role of OPN in kidney injury we used OPN-/- mice in antiglomerular basement membrane reactive serum-induced immune (NTS) nephritis, an inflammatory and progressive model of kidney disease. Normal wild-type (WT) and OPN-/- mice did not show histological differences. However, nephritic kidneys from OPN-/- mice showed severe damage compared with WT mice. Glomerular proliferation, necrotizing lesions, crescent formation, and tubulointerstitial injury were significantly higher in OPN-/- mice. Macrophage infiltration was increased in the glomeruli and interstitium in OPN-/- mice, with higher expression of IL-6, CCL2, and chemokine CXCL1. In addition, collagen (Col) I, Col III, and Col IV deposition were increased in kidneys from OPN-/- mice. Elevated expression of the reactive oxygen species-generating enzyme Nox4 and blunted expression of Nrf2, a molecule that inhibits reactive oxygen species and inflammatory pathways, was observed in nephritic kidneys from OPN-/- mice. Notably, CD11b diphteria toxin receptor mice with NTS nephritis selectively depleted of macrophages and reconstituted with OPN-/- macrophages showed less kidney injury compared with mice receiving WT macrophages. These findings suggest that in global OPN-/- mice there is increased inflammation and redox imbalance that mediate kidney damage. However, absence of macrophage OPN is protective, indicating that macrophage OPN plays a role in the induction and progression of kidney injury in NTS nephritis.

It is classically thought that it is the amount of salt that is critical for driving acute blood pressure responses. However, recent studies suggest that blood pressure responses, at least acutely, may relate to changes in serum osmolality. Here, we test the hypothesis that acute blood pressure responses to salt can be altered by concomitant water loading. Ten healthy patients free of any disease and medication underwent 4 interventions each a week apart in which they took 300 mL of lentil soup with no salt (visit 1), lentil soup with 3 g salt (visit 2), or lentil soup with 3 g salt and 500 mL water (visit 3) or 750 mL water (visit 4). At each visit, hourly blood measurements and blood pressure measurements (baseline, 1st, 2nd, 3rd, and 4th hour) were performed and plasma osmolarity, sodium and copeptin levels were measured. Patients receiving the 3 g salt showed a 6 mOsm/L change in osmolality with a 2.5 mmol/L change in plasma sodium and 10 mm Hg rise in systolic blood pressure at 2 hours. When the same patients drank salty soup with water, the changes in plasma osmolarity, plasma sodium, and blood pressure were prevented. The ability to raise blood pressure acutely with salt appears dependent on changes in plasma osmolality rather than the amount of salt. Our findings suggest that concurrent intake of water must be considered when evaluating the role of salt in blood pressure.

日本の65歳以上の人口は3,500万人を超え、総人口の27.7%と4人に1人以上を占めており、90歳以上の人口も200万人を超えている。日本の高齢者人口の割合は世界で最も高く、高齢者に対する医療の重要性が増している。高齢者では、併存疾患が多くなりやすく、特に循環器疾患を有する割合が多い。特に、高血圧、心不全、冠動脈疾患、閉塞性動脈硬化症、心房細動などの不整脈、大動脈弁狭窄症などの弁膜症を有する患者は年々増加している。本稿では、高齢者の循環器疾患に焦点を当て、最近の研究、最新のガイドラインを参考にしつつ、健診・診療における注意点などを解説する。(著者抄録)

An epidemic of chronic kidney disease (CKD) has been observed in Central America among workers in the sugarcane fields. One hypothesis is that the CKD may be caused by recurrent heat stress and dehydration, and potentially by hyperuricemia. Accordingly, we developed a murine model of kidney injury associated with recurrent heat stress. In the current experiment, we tested whether treatment with allopurinol (a xanthine oxidase inhibitor that reduces serum urate) provides renal protection against recurrent heat stress and dehydration. Eight-week-old male C57BL/6 mice were subjected to recurrent heat stress (39.5°C for 30 min, 7 times daily, for 5 wk) with or without allopurinol treatment and were compared with control animals with or without allopurinol treatment. Mice were allowed ad libitum access to normal laboratory chow (Harlan Teklad). Kidney histology, liver histology, and renal function were examined. Heat stress conferred both kidney and liver injury. Kidneys showed loss of proximal tubules, infiltration of monocyte/macrophages, and interstitial collagen deposition, while livers of heat-stressed mice displayed an increase in macrophages, collagen deposition, and myofibroblasts. Allopurinol provided significant protection and improved renal function in the heat-stressed mice. The renal protection was associated with reduction in intrarenal uric acid concentration and heat shock protein 70 expression. Heat stress-induced renal and liver injury can be protected with allopurinol treatment. We recommend a clinical trial of allopurinol for individuals developing renal injury in rural areas of Central America where the epidemic of chronic kidney disease is occurring.

The prevalence of fatty liver disease (FLD) is increasing. To clarify risk factors for developing FLD, we analyzed a database from healthy Japanese adults who had annual medical check-ups in 2004 and reexamined in 2009. We used the fatty liver index (FLI) to classify participants as FLD (FLI ≥60), borderline FLD (30≤ FLI <60), and normal liver (FLI <30). Subjects with hepatitis B or C virus infection and subjects with FLD at the baseline were excluded. The cumulative incidence of FLD from normal liver and from borderline FLD over five years were 0.65% (52/8,025) and 12.9% (244/1,888), respectively. After multiple adjustments, higher serum uric acid (SUA) (OR:1.92; 95% CI:1.40-2.63) and increased SUA change (OR:3.734; 95% CI:2.57-5.42) became risk factors for developing FLD from normal liver, as well as younger age and higher body mass index. The risk factors for developing FLD from borderline FLD were similar. Not only higher baseline SUA but also increased SUA change became independent risks for developing FLD.

Obesity is a risk factor for hypertension, diabetes mellitus (DM), dyslipidemia, and hyperuricemia. Here, we evaluated whether the same body mass index (BMI) for the U.S. population conferred similar metabolic risk in Japan. This was a cross-sectional analysis involving 90,047 Japanese adults (18⁻85 years) from St. Luke's International Hospital, Tokyo, Japan and 14,734 adults from National Health and Nutrition Examination Survey (NHANES) collected in the U.S. We compared the prevalence of hypertension, DM, dyslipidemia, and hyperuricemia according to BMI in Japan and the U.S. The prevalence of hypertension, DM, and dyslipidemia were significantly higher in the U.S. than Japan, whereas the prevalence of hyperuricemia did not differ between countries. Higher BMI was an independent risk factor for hypertension, DM, dyslipidemia, and hyperuricemia both in Japan and in the U.S. after adjusting for age, sex, smoking and drinking habits, chronic kidney disease, and other cardiovascular risk factors. The BMI cut-off above which the prevalence of these cardio-metabolic risk factors increased was significantly higher in the U.S. than in Japan (27 vs. 23 kg/m² for hypertension, 29 vs. 23 kg/m² for DM, 26 vs. 22 kg/m² for dyslipidemia, and 27 vs. 23 kg/m² for hyperuricemia). Higher BMI is associated with an increased prevalence of hypertension, DM, dyslipidemia, and hyperuricemia both in Japan and U.S. The BMI cut-off above which the prevalence of cardio-metabolic risk factors increases is significantly lower in Japan than the U.S., suggesting that the same definition of overweight/obesity may not be similarly applicable in both countries.

背景・目的:生活習慣病患者は血管内皮機能が低下し、一酸化窒素(NO)合成が減少しており、動脈硬化の一因と考えられている。フェノフィブラートはPPARαアゴニスト作用・URAT1阻害作用があり、高尿酸血症合併脂質異常症患者には使用が推奨されている。今回、フェノフィブラート投与によるNO、血流依存性血管拡張反応(FMD)への効果、その変動に対する関連因子を明らかにするために本研究を行った。方法:外来通院中のフェノフィブラートが投与された脂質異常症患者35例を対象に、後ろ向きに同薬投与前後での尿酸代謝ならびに脂質代謝の変化を検討した。さらに、FMDならびに尿中NOが測定された9例に関して、フェノフィブラート投与前後での尿中NO、FMD、血液・尿生化学検査、血圧、脈拍などの変化を検討した。結果:フェノフィブラートを投与した35例で、血清尿酸値の低下、尿酸・クレアチニンクリアランス比の上昇、中性脂肪、LDL-C、non-HDL-Cの減少、HDL-Cの上昇を認めた。前後で観察し得た9例に関して、フェノフィブラート投与により収縮期・拡張期血圧の低下とFMDの改善傾向を認めた。また、尿中NOの上昇とFMD、尿中NOと尿酸排泄の間には正の相関傾向を認めた。結論:フェノフィブラートは尿酸代謝ならびに脂質代謝を改善するのみならず、尿酸排泄亢進を伴ったNO合成を介してFMDの改善に寄与する可能性がある。(著者抄録)

BACKGROUND: Increasing evidence suggests heat stress induced chronic kidney disease (CKD) may be mediated by endogenous fructose generation and may be exacerbated by rehydration by fructose-containing solutions. We have recently reported a model of CKD induced by heat stress. Here we test the hypothesis that rehydration with fructose may induce worse kidney injury than rehydration with equal amounts of water, and we also test if this fructose-induced injury is associated with activation of inflammasomes in the kidney. METHODS: Mice were recurrently exposed to heat (39.5 C0 for 30 min/h, 5 times daily for 5 wks) with rehydration consisting of 6 ml each night of water (Heat, n = 7) or fructose (Heat+F, 10%, n = 7), and were compared to control mice on water (Control, n = 7) or fructose (Fructose, n = 7). Various markers of renal injury were assessed. RESULTS: Compared to control animals, there was a progressive worsening of renal injury (inflammation and fibrosis) with fructose alone, heat stress alone, and heat stress with fructose rehydration (P < 0.01 by ANOVA). The combination of heat stress with rehydration with fructose was associated with increased intrarenal expression of the inflammasome markers, NLRP3 and IL-18, compared to heat stress alone. In addition, heat stress with or without fructose was associated with increased expression of caspase - 3 and monocyte chemoattractant protein-1 levels. Fructose administration was also associated with an increase in serum copeptin levels (a biomarker of vasopressin) and elevated copeptin was also observed in mice undergoing heat stress alone. CONCLUSIONS: These studies suggest that heat stress may activate intrarenal inflammasomes leading to inflammation and renal injury, and provide evidence that rehydration with fructose may accelerate the renal injury and inflammatory response.

BACKGROUND: High serum uric acid (SUA) is associated with the dyslipidemia, but whether hyperuricemia predicts an increase in serum low-density lipoprotein (LDL) cholesterol is unknown. This study is to evaluate whether an elevated SUA predicts the development of high LDL cholesterol as well as hypertriglyceridemia. METHODS: This is a retrospective 5-year cohort study of 6476 healthy Japanese adults (age, 45.7 ± 10.1 years; 2.243 men) who underwent health examinations at 2004 and were reevaluated in 2009 at St. Luke's International Hospital, Tokyo, Japan. Subjects were included if at their baseline examination they did not have hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, or if they were on medication for hyperuricemia and/or gout. The analysis was adjusted for age, body mass index (BMI), smoking and drinking habits, baseline estimated glomerular filtration rate (eGFR), baseline SUA and SUA change over the 5 years. RESULTS: High baseline SUA was an independent risk for developing high LDL cholesterol both in men (OR: 1.159 per 1 mg/dL increase, 95% CI:1.009-1.331) and women (OR: 1.215, 95% CI:1.061-1.390). Other risk factors included a higher baseline LDL cholesterol, higher BMI, and higher baseline eGFR (the latter two in women only). Increased SUA over 5 years were also independent risks for developing high LDL cholesterol and hypertriglyceridemia, but not for low high-density lipoprotein (HDL) cholesterol. CONCLUSIONS: This is the first study to report that an elevated SUA increases the risk for developing high LDL cholesterol, as well as hypertriglyceridemia. This may shed light into the role of SUA in cardiovascular disease.

BACKGROUND: Serum uric acid (SUA) and oxidized LDL (oxLDL) may be associated with arterial aging. The aim of our study was to evaluate the relationship between SUA, oxLDL and arterial stiffness in subjects with normal renal function and in patients with mild or moderate renal impairment. METHODS: From the database of the 2012 Brisighella Heart Study, we compared age-matched adult, non-smoker subjects without cardiovascular disease and with normal renal function (n = 205), subjects with stage II chronic kidney disease (CKD) (n = 118) and subjects with stage III CKD (n = 94). All subjects underwent a determination of the LDL oxidative susceptibility, oxLDL levels, SUA and Pulse Wave Velocity (PWV). RESULTS: By univariate analysis, PWV correlated with a large number of clinical, haemodynamic and metabolic parameters, including estimated glomerular filtration rate (eGFR) in subjects with normal renal function and in those with stage II or III CKD. Stepwise multiple regression analyses showed that in the presence of normal renal function or stage II CKD, the main predictors of PWV were age, systolic blood pressure (SBP), ox-LDL, apolipoprotein B and SUA (p < 0.05), while in the presence of stage III CKD only age, SBP and apolipoprotein B remained significant (p < 0.05). CONCLUSION: Both ox-LDL and SUA independently predicts PWV only in subjects with normal or mildly reduced renal function, but not in the subjects with more compromised eGFR. This study confirms the complex relationship of SUA with cardiovascular and metabolic disease in the patient with established renal disease.

Increasing evidence suggests a role for excessive intake of fructose in the Western diet as a contributor to the current epidemics of metabolic syndrome and obesity. Hereditary fructose intolerance (HFI) is a difficult and potentially lethal orphan disease associated with impaired fructose metabolism. In HFI, the deficiency of aldolase B results in the accumulation of intracellular phosphorylated fructose, leading to phosphate sequestration and depletion, increased adenosine triphosphate (ATP) turnover, and a plethora of conditions that lead to clinical manifestations such as fatty liver, hyperuricemia, Fanconi syndrome, and severe hypoglycemia. Unfortunately, there is currently no treatment for HFI, and avoiding sugar and fructose has become challenging in our society. In this report, through use of genetically modified mice and pharmacological inhibitors, we demonstrate that the absence or inhibition of ketohexokinase (Khk), an enzyme upstream of aldolase B, is sufficient to prevent hypoglycemia and liver and intestinal injury associated with HFI. Herein we provide evidence for the first time to our knowledge of a potential therapeutic approach for HFI. Mechanistically, our studies suggest that it is the inhibition of the Khk C isoform, not the A isoform, that protects animals from HFI.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome; its rising prevalence parallels the rise in obesity and diabetes. Historically thought to result from overnutrition and a sedentary lifestyle, recent evidence suggests that diets high in sugar (from sucrose and/or high-fructose corn syrup [HFCS]) not only increase the risk of NAFLD, but also non-alcoholic steatohepatitis (NASH). Herein, we review the experimental and clinical evidence that fructose precipitates fat accumulation in the liver, due to both increased lipogenesis and impaired fat oxidation. Recent evidence suggests that the predisposition to fatty liver is linked to the metabolism of fructose by fructokinase C, which results in ATP consumption, nucleotide turnover and uric acid generation that mediate fat accumulation. Alterations to gut permeability, the microbiome, and associated endotoxemia contribute to the risk of NAFLD and NASH. Early clinical studies suggest that reducing sugary beverages and total fructose intake, especially from added sugars, may have a significant benefit on reducing hepatic fat accumulation. We suggest larger, more definitive trials to determine if lowering sugar/HFCS intake, and/or blocking uric acid generation, may help reduce NAFLD and its downstream complications of cirrhosis and chronic liver disease.

BACKGROUND: Fontan-associated liver disease (FALD) is an important late complication involving liver dysfunction, such as liver cirrhosis (LC) and hepatocellular carcinoma (HCC), in patients undergoing the Fontan procedure. However, the prevalence, clinical manifestation, and methods of diagnosis of FALD are still not well established.Methods and Results:This study comprised 2 nationwide surveys in Japan. First, the prevalence of LC and/or HCC in patients undergoing the Fontan procedure was determined. Second, clinical manifestations in patients with LC and/or HCC were analyzed, along with data from blood tests, echocardiography, and right heart catheterization. In the 1st survey, of the 2,700 patients who underwent the Fontan procedure, 31 were diagnosed with LC and/or HCC (1.15%), and 5 died due to liver diseases (mortality: 0.19%). In the 2nd survey, data were collected from 17 patients (12 with LC, 2 with HCC, and 3 with LC+HCC. Of these 17 patients, 5 died (mortality: 29.4%). The mean age at diagnosis of LC and HCC was 23 and 31 years, respectively. Computed tomography followed by ultrasound was most frequently used for diagnosis. Blood tests revealed low platelet counts, increased hemoglobin, aspartate aminotransferase, γ-guanosine triphosphate, and total bilirubin levels, and an elevated international normalized ratio of prothrombin time. CONCLUSIONS: LC and/or HCC in patients undergoing the Fontan procedure were not rare late complications and were associated with high mortality rates.

BACKGROUND: Ischemia/reperfusion (I/R) injury triggers cardiac dysfunctions via creating reactive oxygen species (ROS). Because xanthine oxidase (XO) is one of the major enzymes that generate ROS, inhibition of XO is expected to suppress ROS-induced I/R injury. However, it remains unclear whether XO inhibition really yields cardioprotection during I/R. The protective effects of the XO inhibitors, topiroxostat and allopurinol, on cardiac I/R injury were evaluated.Methods and Results:Using isolated rat hearts, ventricular functions, occurrence of arrhythmias, XO activities and thiobarbituric acid reactive substances (TBARS) productions and myocardial levels of adenine nucleotides before and after I/R, and cardiomyocyte death markers during reperfusion, were evaluated. Topiroxostat prevented left ventricular dysfunctions and facilitated recovery from arrhythmias during I/R. Allopurinol and the antioxidant, N-acetylcysteine (NAC), exhibited similar effects at higher concentrations. Topiroxostat inhibited myocardial XO activities and TBARS productions after I/R. I/R decreased myocardial levels of ATP, ADP and AMP, but increased that of xanthine. While topiroxostat, allopurinol or NAC did not change myocardial levels of ATP, ADP or AMP after I/R, all of the agents decreased the level of xanthine. They also decreased releases of CPK and LDH during reperfusion. CONCLUSIONS: Topiroxostat showed protective effects against I/R injury with higher potency than allopurinol or NAC. It dramatically inhibited XO activity and TBARS production, suggesting suppression of ROS generation.

Dietary guidelines for obesity typically focus on three food groups (carbohydrates, fat, and protein) and caloric restriction. Intake of noncaloric nutrients, such as salt, are rarely discussed. However, recently high salt intake has been reported to predict the development of obesity and insulin resistance. The mechanism for this effect is unknown. Here we show that high intake of salt activates the aldose reductase-fructokinase pathway in the liver and hypothalamus, leading to endogenous fructose production with the development of leptin resistance and hyperphagia that cause obesity, insulin resistance, and fatty liver. A high-salt diet was also found to predict the development of diabetes and nonalcoholic fatty liver disease in a healthy population. These studies provide insights into the pathogenesis of obesity and diabetes and raise the potential for reduction in salt intake as an additional interventional approach for reducing the risk for developing obesity and metabolic syndrome.

<p>Background: Irbesartan has been reported to inhibit renal uric acid reabsorption and thereby decrease serum uric acid (Sur) levels. However, its effect on uric acid metabolism in hypertensive patients has not been reported. Methods and Results: We conducted a retrospective observational study that included 40 hypertensive patients to clarify the effects of irbesartan (mean dose 87.5 mg) on blood pressure (BP) and uric acid metabolism [Sur, urinary uric acid (Uur), serum creatinine (Scr), urinary creatinine (Ucr), uric acid clearance (Cur), creatinine clearance (Ccr), urinary uric acid to urinary creatinine ratio (Uur/Ucr), and uric acid clearance to creatinine clearance ratio (Cur/Ccr) ] at baseline and after 3 months of treatment. We allocated patients into two groups, patients with Uur/Ucr <0.5 (low Uur/Ucr group) or those with Uur/Ucr ≥0.5 (normal/high Uur/Ucr group), into other two groups, patients with Cur/Ccr <5.5% (low Cur/Ccr group) or those with Cur/Ccr ≥5.5% (normal/ high Cur/Ccr group). The hypoexcretion group contained low Uur/Ucr group and low Cur/Ccr group, and the normal/ hyperexcretion group contained normal/high Uur/Ucr group and normal/ high Cur/Ccr group. Further, we allocated patients into another two groups, patients with Sur ≥7 mg/dl (hyperuricemic group) or those with Sur <7 mg/dl (normouricemic group). Irbesartan significantly decreased systolic BP without affecting heart rate, and decreased Sur without altering Uur/Ucr or Cur/Ccr. In the hypoexcretion group, irbesartan decreased Sur while increasing Uur/Ucr and Cur/Ccr. In contrast, in the normal/hyperexcretion and hyperuricemic groups, irbesartan decreased Sur without changing Uur/Ucr or Cur/Ccr. In a normouricemic group, patients showed no changes in Sur after treatment with irbesartan. Conclusions: Irbesartan improved the secretion of uric acid, and reduced Sur in the hypoexcretion group, but did not influence uric acid excretion in the normal/hyperexcretion group. In hyperuricemic patients, irbesartan did not affect uric acid excretion but may have influenced uric acid production.</p>

The patients with anorexia nervosa (AN) are known to be associated with high mortality, but the actual causes of death are still undefined. We tested the hypothesis that AN patients had cardiac disorders, including left ventricular (LV) dysfunction and LV atrophy. This study is a cross-sectional study at St. Luke's International Hospital, Tokyo. We analyzed 13 female inpatients with AN. We assessed cardiac function and heart volume in AN by echocardiography, LV ejection fraction (LVEF), LV mass, and LV mass index (LVMI). We assessed the correlations between body mass index (BMI) and heart volume (LV mass and LVMI). The mean age and BMI were 34.8 ± 11.2 years and 15.5 ± 3.1 kg/m2, respectively. There was no patient with mitral valve prolapse, but 3 patients had trivial to small amount of pericardial effusion. The mean LVEF was 67.7 ± 6.5%, and 12 out of 13 patients had normal LVEF. Their LV mass (89.0 ± 27.3 g) and LVMI (66.3 ± 16.4 g/m2) were small. BMI positively correlated with LVMI (r = 0.58, p = 0.040), as well as LV mass (r = 0.74, p = 0.004). Lower BMI reflects lower LVMI, as well as smaller LV mass. These issues suggest that heart volume is initially decreased in severe AN conditions. Low LVMI could be a good marker of severity of AN.

Prehypertension frequently progresses to hypertension, a condition associated with high morbidity and mortality from cardiovascular diseases and stroke. However, the risk factors for developing hypertension from prehypertension remain poorly understood. We conducted a retrospective cohort study using the data from 3584 prehypertensive Japanese adults (52.1±11.0 years, 2081 men) found to be prehypertensive in 2004 and reexamined in 2009. We calculated the cumulative incidences of hypertension over 5 years, examined risk factors, and calculated odds ratios (ORs) for developing hypertension after adjustments for age, sex, body mass index, smoking and drinking habits, baseline systolic and diastolic blood pressure, pulse rate, diabetes mellitus, dyslipidemia, chronic kidney disease, and serum uric acid levels. The additional analysis evaluated whether serum uric acid (hyperuricemia) constituted an independent risk factor for developing hypertension. The cumulative incidence of hypertension from prehypertension over 5 years was 25.3%. There were no significant differences between women and men (24.4% versus 26.0%; P=0.28). The cumulative incidence of hypertension in subjects with hyperuricemia (n=726) was significantly higher than those without hyperuricemia (n=2858; 30.7% versus 24.0%; P<0.001). After multivariable adjustments, the risk factors for developing hypertension from prehypertension were age (OR, 1.023; P<0.001), female sex (OR, 1.595; P<0.001), higher body mass index (OR, 1.051; P<0.001), higher baseline systolic (OR, 1.072; P<0.001) and diastolic blood pressure (OR, 1.085; P<0.001), and higher serum uric acid (OR, 1.149; P<0.001). Increased serum uric acid is a strong risk marker for developing hypertension from prehypertension. Further studies are needed to determine whether treatment of hyperuricemia in prehypertensive subjects could impede the onset of hypertension.

Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD). One of the most important pathophysiological mechanisms for CVD in patients with CKD is the widespread and possibly accelerated formation of atherosclerotic plaques due to hyperlipidemia, uremic toxins, inflammation, oxidative stress, and endothelial dysfunction. Recent studies showed that the level of oxidized low-density lipoprotein cholesterol increases, and that high--density lipoprotein cholesterol dysfunction occurs as kidney function declines and inflammation becomes more prevalent. In this review, we aimed to discuss the effect of kidney dysfunction, oxidative stress, and inflammation on lipid -profile.

【背景】口腔内環境が全身の健康状態へ影響を及ぼすことが注目されている。心血管疾患の発症が歯磨きの頻度と負の関連を示すとの報告があるが、生活習慣を考慮した上で、歯磨きと心血管疾患のリスクとの関係性を検討された報告は少ない。【目的】歯磨き習慣と心血管疾患のリスク因子:高血圧、糖尿病、脂質異常症、高尿酸血症、心房細動との関連を検討する。【方法】横断研究と後向きコホート研究。1)横断研究:2004年1月から2010年6月の間に、聖路加国際病院予防医療センターを健康診断のため受診した90,143人(男性49.1%、46.3±12.0歳)の内、30歳以上85歳未満の85,866人のデータを解析対象とした。歯磨き習慣を3群(毎食後歯を磨く、1日1回は磨く、1日1回も磨かない)に分け、3群間で高血圧、糖尿病、脂質異常症、高尿酸血症、心房細動の有病率について検討を行った。多変量解析では、年齢、性別、Body Mass Index、飲酒習慣、喫煙の有無、運動習慣(歩行時間)、睡眠時間、慢性腎臓病の有無を共変数としてロジスティック回帰分析を行った。2)コホート研究:2004年に上記医療機関を受診した31,233人の内、2009年にも再受診し両期間でデータ利用可能な13,201人を抽出し、30歳以上85歳未満の13,070人を解析対象とした。高血圧、糖尿病、脂質異常症、高尿酸血症、心房細動の5年間の累積罹患を歯磨き頻度の3群で比較した。さらに、毎食後歯を磨く群と、毎食後は歯を磨かない群の2群に分け、糖尿病、脂質異常症の新規発症頻度を、性別ごとに、年齢、肥満、糖尿病、脂質異常症、高血圧、高尿酸血症を共変数としたロジスティック回帰分析を行った。【結果】1)横断研究:歯磨き頻度が少ない程、高血圧(毎食後歯を磨く:13.3%、1日1回は磨く:17.9%、磨かない:31.0%)糖尿病(3.1%、5.3%、17.4%)、脂質異常症(29.0%、42.1%、60.3%)、高尿酸血症(8.6%、17.5%、27.2%)、慢性腎臓病(3.8%、3.1%、8.3%)、心房細動の有病率が高かった(p<0.001)。多変量解析の結果、毎食後菌を磨く群と比較したオッズ比は、1日1回は磨く群、及び1日1回も磨かない群において、糖尿病は1.17倍(p=0.001)、2.03倍(p=0.002)、脂質異常症は1.18倍(p<0.001)、1.50倍(p=0.023)であった。2)コホート研究:2004年から2009年の糖尿病、脂質異常症、高血圧症、高尿酸血症、心房細動の累積罹患(率)はそれぞれ318人(2.5%)、1.454人(18.3%)、1,108人(10.6%)、489人(4.4%)、53%(10.4%)であった。多変量解析の結果、毎食後に歯磨きをしない群で、毎食後に歯磨きをする群と比較し、男性の糖尿病が1.43倍(p=0.028)、女性の脂質異常症が1.18倍(p=0.045)のオッズ比が認められた。【結論】歯磨きの頻度が少ない程、心血管疾患を増加させる原因として、男性で糖尿病、女性で脂質異常症の関与が大きいことが示された。循環器病の予防に、歯磨き習慣が1つの指標として有効である可能性が示唆された。(著者抄録)

OBJECTIVE: Whether obesity without metabolic syndrome (i.e., "metabolically healthy" obesity) confers similar or less metabolic risk remains controversial. METHODS: A retrospective 5-year cohort study of 9,721 Japanese subjects (48.5 ± 10.5 years, 4,160 men) was conducted in 2004 and reevaluated 5 years later. Subjects were excluded if they were hypertensive or diabetic or were receiving medications for dyslipidemia and/or gout or hyperuricemia in 2004. Study subjects were categorized according to baseline BMI  ≥ 25 kg/m2 (overweight/obesity) and < 25 kg/m2 (lean/normal weight) and also whether they had metabolic syndrome. The cumulative incidence of hypertension and diabetes over 5 years between groups was assessed. A second analysis evaluated whether baseline hyperuricemia provided additional risk. RESULTS: Subjects with overweight/obesity but without metabolic syndrome carried increased cumulative incidence of hypertension (14.6% vs. 7.2%, P < 0.001) and diabetes (2.6% vs. 1.1%, P = 0.004) over 5 years compared to lean/normal subjects without metabolic syndrome. Overweight/obesity conferred an increased risk for diabetes even in individuals with normal fasting blood glucose. Hyperuricemia became an independent risk factor for developing hypertension over 5 years in lean/normal subjects without metabolic syndrome. A 1 mg/dL increase in serum uric acid carried increased risk for hypertension (19%) and diabetes (27%). CONCLUSIONS: Metabolically healthy obesity and hyperuricemia confer increased risk for hypertension and diabetes.

Metabolic syndrome and diabetes are main health problems of modern life in the twenty-first century. Alarming ratios of global prevalence lead to conduct more and more researches about etiological factors and pathogenesis. Disease mechanism is elementary for advancing more efficient and practicable treatment methods. Concurrent increase in both fructose consumption with Western diet and metabolic syndrome has revealed fructose hypothesis that suggests fructose as one of etiological factor of metabolic syndrome (insulin resistance, central obesity, hypertension, etc.). Recent studies have increasingly lightened the unknowns about role of fructose on pathogenesis. This review discusses fructose hypothesis by exploring current studies and their results in wide perspective. Potential mechanisms covering low-grade inflammation or de novo lipogenesis, etc., in the development of insulin resistance and obesity are explained. Clinical trials have revealed connection of fructose-induced hyperuricemia with insulin resistance and chronic inflammatory state leading to hepatosteatosis or obesity. Further, novel hypothesizes suggesting role of fructose-induced modifications in epigenetics, gut microbiota and oxidative stress on disease pathogenesis are reviewed based on recent clinical trials. More innovative theories including fructose-induced malignancy; decreased satiety feeling, and unfavorable bone health are argued covering fructose-induced neurotransmitter changes in central nervous system, more aggressive malignancy phenotype and impaired calcium absorption.

BACKGROUND: We previously reported the association between toothbrushing practices and diabetes mellitus (DM) and dyslipidemia (DL) in a cross-sectional study. This study was conducted to clarify whether low frequency of toothbrushing practices is an independent risk factor for DM and DL using a follow-up design. METHODS: This study was a 5-year retrospective cohort study at St. Luke's International Hospital, Tokyo, Japan. We analyzed study subjects between 30 and 85 years old in 2004, who underwent annual medical examination both in 2004 and 2009. We compared the cumulative incidences of developing DM, DL, hypertension (HT), and hyperuricemia (HUA) between 2004 and 2009 among 3 groups: toothbrushing practices 'after every meal,' 'at least once a day,' and 'less than once a day'. Furthermore, we analyzed odds ratios (ORs) of risk for developing DM and DL by sex after making adjustments for age, obesity, DM, DL, HT, and HUA between two groups: 'after every meal' and 'not after every meal.' RESULTS: The number of study subjects was 13,070. Of 13,070 study subjects, 575 had DM, 5118 had DL, 2599 had HT, and 1908 had HUA in 2004. We excluded the subjects with each disease in 2004. The cumulative incidences (rates) of DM, DL, HT, and HUA between 2004 and 2009 were 318 (2.5%), 1454 (18.3%), 1108 (10.6%), and 489 (4.4%), respectively. Toothbrushing practices 'not after every meal' was a significant risk factor for developing DM in male [OR: 1.43; 95% confidence interval (CI), 1.040-1.970] and developing DL in female (OR: 1.18; 95% CI, 1.004-1.383) compared with toothbrushing practices 'after every meal.' CONCLUSION: Toothbrushing practices 'after every meal' prevented developing DM in males and DL in females significantly. Toothbrushing practices may be beneficial to reduce developing risk factors for cardiovascular disease.

わが国では高齢化が急速に進んでおり、心房細動の患者数も増加している。心房細動の危険因子としては、加齢のほかに、男性・高血圧・糖尿病・慢性閉塞性肺疾患などが知られているが、近年の多くの研究で高尿酸血症も心房細動に関与することが報告されている。心房細動の予防については、残念ながら確立したものはなく、今後の大きな研究課題である。本稿では、心房細動の危険因子としての尿酸に注目し、これまでの臨床疫学研究、尿酸の炎症を含めた基礎研究を紹介しつつ、今後の展望について述べる。(著者抄録)

BACKGROUNDS: The relationship between serum uric acid (SUA) and atrial fibrillation (AF) remains unclear because many parameters and diseases influence AF. This study was conducted to clarify the role of hyperuricemia as an independent competing risk factor for AF in an apparently healthy general population. METHODS: We retrospectively analyzed the medical records of 90,143 Japanese subjects who underwent annual regular health check-up in St. Luke's International Hospital, Tokyo, between January 2004 and June 2010. Of those subjects, 291 (0.32%) were identified as having AF by 12 leads electrocardiography. First, we analyzed 90,117 subjects to clarify the independent competing risk factors for AF and obtained odds ratios (ORs) by logistic regression analysis. Second, we excluded 40,825 subjects with hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, and current medication for hyperuricemia and/or gout, and we analyzed 49,292 subjects. RESULTS: First, AF groups were significantly higher SUA level (OR: 1.35; 95% confidence interval (CI), 1.22-1.50) than non-AF group. OR of hyperuricemia (>7.0mg/dL of SUA) for AF was 2.75 (95% CI, 2.10-3.60). Second, after multiple adjustments, higher SUA level (OR: 1.53; 95% CI, 1.21-1.92) was a significantly independent competing risk factor for AF, as well as older age, male sex, higher body mass index, lower FEV1/FVC, and higher hemoglobin. OR of hyperuricemia for AF was 3.19 (95% CI, 1.81-5.62). CONCLUSIONS: Hyperuricemia is an independent competing risk factor for AF. Further prospective intervention studies are needed to prove whether lowering SUA level might be important for preventing AF or not.

AIM: We previously proposed the concept of caregiver daily impression (CDI) as a practical tool for emergency triage. We herein assessed how CDI varies by sex, education and career length by determining CDI scores as quantitative outcome measures. METHODS: We carried out a cross-sectional study using a self-reported questionnaire among caregivers in 20 long-term care facilities in Hyogo, Japan. A total of 10 CDI variables measured participants' previous experience of emergency transfers using a scale from 0-10. The resulting total was defined as the CDI score. We hypothetically considered that higher scores indicated greater caregiver focus. The CDI scores were compared by sex, education and career length using analysis of covariance. RESULTS: A total of 601 personal caregivers were evaluated (mean age 36.7 years; 36% men). The mean career length was 6.9 years, with the following groupings: 1-4 years (38%), 5-9 years (37%) and >10 years (24%). After adjustment for sex and education, the CDI scores for the variable, "poor eye contact," significantly differed between caregivers with ≥10 and <5 years of experience (scores of 5.0 ± 3.1 and 4.0 ± 2.7, respectively). The CDI scores for variables related to eyes tended to increase with experience, whereas other CDI scores decreased. Male caregivers focused on residents' eyes significantly more than did female caregivers. CONCLUSIONS: We found that the CDI variable, "poor eye contact," is influenced by career length. Caregivers with more experience attach more importance to their impression of residents' eyes than do those with less experience. Sex-related differences in CDI might also exist. Geriatr Gerontol Int 2016; 17: 410-415.

Recurrent heat stress and dehydration have recently been shown experimentally to cause chronic kidney disease (CKD). One potential mediator may be vasopressin, acting via the type 2 vasopressin receptor (V2 receptor). We tested the hypothesis that desmopressin accelerates CKD in mice subjected to heat stress and recurrent dehydration. Recurrent exposure to heat with limited water availability was performed in male mice over a 5-wk period, with one group receiving desmopressin two times daily and the other group receiving vehicle. Two additional control groups were not exposed to heat or dehydration and received vehicle or desmopressin. The effects of the treatment on renal injury were assessed. Heat stress and recurrent dehydration induced functional changes (albuminuria, elevated urinary neutrophil gelatinase-associated protein), glomerular changes (mesangiolysis, matrix expansion), and tubulointerstitial changes (fibrosis, inflammation). Desmopressin also induced albuminuria, glomerular changes, and tubulointerstitial fibrosis in normal animals and also exacerbated injury in mice with heat stress nephropathy. Both heat stress and/or desmopressin were also associated with activation of the polyol pathway in the renal cortex, likely due to increased interstitial osmolarity. Our studies document both glomerular and tubulointerstitial injury and inflammation in heat stress nephropathy and may be clinically relevant to the pathogenesis of Mesoamerican nephropathy. Our data also suggest that vasopressin may play a role in the pathogenesis of the renal injury of heat stress nephropathy, likely via a V2 receptor-dependent pathway.

Fructose stimulates vasopressin in humans and can be generated endogenously by activation of the polyol pathway with hyperosmolarity. We hypothesized that fructose metabolism in the hypothalamus might partly control vasopressin responses after acute dehydration. Wild-type and fructokinase-knockout mice were deprived of water for 24 h. The supraoptic nucleus was evaluated for vasopressin and markers of the aldose reductase-fructokinase pathway. The posterior pituitary vasopressin and serum copeptin levels were examined. Hypothalamic explants were evaluated for vasopressin secretion in response to exogenous fructose. Water restriction increased serum and urine osmolality and serum copeptin in both groups of mice, although the increase in copeptin in wild-type mice was larger than that in fructokinase-knockout mice. Water-restricted, wild-type mice showed an increase in vasopressin and aldose reductase mRNA, sorbitol, fructose and uric acid in the supraoptic nucleus. In contrast, fructokinase-knockout mice showed no change in vasopressin or aldose reductase mRNA, and no changes in sorbitol or uric acid, although fructose levels increased. With water restriction, vasopressin in the pituitary of wild-type mice was significantly less than that of fructokinase-knockout mice, indicating that fructokinase-driven vasopressin secretion overrode synthesis. Fructose increased vasopressin release in hypothalamic explants that was not observed in fructokinase-knockout mice. In situ hybridization documented fructokinase mRNA in the supraoptic nucleus, paraventricular nucleus and suprachiasmatic nucleus. Acute dehydration activates the aldose reductase-fructokinase pathway in the hypothalamus and partly drives the vasopressin response. Exogenous fructose increases vasopressin release in hypothalamic explants dependent on fructokinase. Nevertheless, circulating vasopressin is maintained and urinary concentrating is not impaired. NEW & NOTEWORTHY: This study increases our understanding of the mechanisms leading to vasopressin release under conditions of water restriction (acute dehydration). Specifically, these studies suggest that the aldose reductase-fructokinase pathways may be involved in vasopressin synthesis in the hypothalamus and secretion by the pituitary in response to acute dehydration. Nevertheless, mice undergoing water restriction remain capable of maintaining sufficient vasopressin (copeptin) levels to allow normal urinary concentration. Further studies of the aldose reductase-fructokinase system in vasopressin regulation appear indicated.

BACKGROUND: Epidemics of chronic kidney disease (CKD) not due to diabetes mellitus (DM) or hypertension have been observed among individuals working in hot environments in several areas of the world. Experimental models have documented that recurrent heat stress and water restriction can lead to CKD, and the mechanism may be mediated by hyperosmolarity that activates pathways (vasopressin, aldose reductase-fructokinase) that induce renal injury. Here we tested the hypothesis that elevated serum sodium, which reflects serum osmolality, may be an independent risk factor for the development of CKD. METHODS: This study was a large-scale, single-center, retrospective 5-year cohort study at Center for Preventive Medicine, St. Luke's International Hospital, Tokyo, Japan, between 2004 and 2009. We analyzed 13,201 subjects who underwent annual medical examination of which 12,041 subjects (age 35 to 85) without DM and/or CKD were enrolled. This analysis evaluated age, sex, body mass index, abdominal circumference, hypertension, dyslipidemia, hyperuricemia, fasting glucose, BUN, serum sodium, potassium, chloride and calculated serum osmolarity. RESULTS: Elevated serum sodium was an independent risk factor for development of CKD (OR: 1.03, 95% CI, 1.00-1.07) after adjusted regression analysis with an 18 percent increased risk for every 5 mmol/L change in serum sodium. Calculated serum osmolarity was also an independent risk factor for CKD (OR: 1.04; 95% CI, 1.03-1.05) as was BUN (OR: 1.08; 95% CI, 1.06-1.10) (independent of serum creatinine). CONCLUSIONS: Elevated serum sodium and calculated serum osmolarity are independent risk factors for developing CKD. This finding supports the role of limiting salt intake and preventing dehydration to reduce risk of CKD.

BACKGROUND: While elevated serum uric acid level (SUA) is a recognized risk factor for chronic kidney disease, it remains unclear whether change in SUA is independently associated with change in estimated glomerular filtration rate (eGFR) over time. Accordingly, we examined the longitudinal associations between change in SUA and change in eGFR over 5 years in a general Japanese population. METHODS: This was a large, single-center, retrospective 5-year cohort study at St. Luke's International Hospital, Tokyo, Japan, between 2004 and 2009. We included 13,070 subjects (30-85 years) in our analyses whose data were available between 2004 and 2009. Of those, we excluded 492 subjects with eGFR <60 mL/min/1.73 m2 at baseline. In addition to examining the entire cohort (n = 12,578), we stratified our analyses by baseline eGFR groups: 60-90, 90-120, and ≥120 mL/min/1.73 m2. Linear and logistic regressions models were applied to examine the relationships between baseline and change in SUA, change in eGFR, and rapid eGFR decline (defined as the highest quartile of change in eGFR), adjusted for age, gender, body mass index, abdominal circumference, hypertension, dyslipidemia, and diabetes mellitus. RESULTS: After multivariable adjustments including baseline eGFR, 1 mg/dL increase in baseline SUA was associated with greater odds of developing rapid eGFR decline (OR 1.27, 95% CI 1.17-1.38), and 1 mg/dL increase in SUA over 5 years was associated with 3.77-fold greater odds of rapid eGFR decline (OR 3.77, 95% CI 3.35-4.26). CONCLUSIONS: Elevated baseline SUA and increasing SUA over time were independent risk factors for rapid eGFR decline over 5 years.

BACKGROUNDS: Hypouricemia was reported as a risk factor for exercise-induced acute renal injury (EIAKI) and urinary stones. However, the prevalence of kidney diseases among hypouricemic subjects has not been evaluated. This study was conducted to clarify the prevalence of hypouricemia and the association of hypouricemia with kidney diseases by using a large-scale Japanese population data. METHODS: This study is a retrospective cross-sectional study at the Center for Preventive Medicine, St. Luke's International Hospital, Tokyo, Japan, and Sanin Rousai Hospital, Yonago, Japan. We analyzed the medical records of 90,143 Japanese subjects at the center in St. Luke's International Hospital, Tokyo, and 4,837 subjects in Sanin Rousai Hospital, Yonago, who underwent annual regular health check-up between January 2004 and June 2010. We defined hypouricemia as serum uric acid level of ≤2.0 mg/dL. We checked the medical history of all the study subjects and compared the rates of complications including urinary stones and kidney diseases among those with or without hypouricemia. RESULTS: The prevalence of hypouricemia was 0.19% in St. Luke's International Hospital, Tokyo, and 0.58% in Sanin Rousai Hospital, Yonago. The prevalence of hypouricemia in women was larger than that in men both in Tokyo (0.31% vs 0.068%, p<0.001) and in Yonago (1.237% vs 0.318%, p<0.001). Among 172 hypouricemic subjects (30 men), the rates of previous urinary stones and kidney diseases (including nephritis/nephrosis) were 1.2% (3.3% men, 0.7% women) and 2.3% (10% men, 0.7% women), respectively. Hypouricemic men had a 9-fold higher rate of previously having kidney diseases compared to non-hypouricemic men (p<0.001). However, the rates of other diseases including urinary stones were not significantly different between the two groups. CONCLUSIONS: Hypouricemia was associated with a history of kidney disease especially in men.

Proepicardium (PE) cells generate cardiac fibroblasts, smooth muscle cells (SMCs) and endothelial cells that form coronary arteries. T-box18 (Tbx18) is a well-known marker of PE cells and epicardium. We examined whether Tbx18-positive cells differentiated from murine embryonic stem (ES) cells serve as PE progenitors to give rise to vascular SMCs and fibroblasts. To collect Tbx18-positive cells, we established Tbx18-EGFP knock-in mouse ES cells using the CRISPR/Cas9 system. We harvested the Tbx18-EGFP-positive cells on day 8, 10 and 14 after the initiation of differentiation; Tbx18 mRNA was enriched on day 8 to 14 and Snai2 mRNA was enriched on day 8 and 10, indicating successful collection of Tbx18-positive cells. Tbx18-EGFP-positive cells expressed the PE marker WT1 on day 8 and 10. They also expressed the SMC marker Acta2 and fibroblast markers Thy1 and Fsp1 on day 8 to 14, but did not express the endothelial cell marker PECAM or the cardiac cell marker CD166 or Myh7. In conclusion, Tbx18-positive cells represent a part of PE cells in the initial phase of differentiation and subsequently include SMCs as well as fibroblasts. These results indicate that Tbx18-positive cells serve as a PE progenitor to supply a variety of cells that contribute to the formation of coronary arteries.

Background: Hypertension is a common complication in patients with gout and/or hyperuricemia. Besides, hyperuricemia is a risk factor of gout as well as ischemic heart disease in hypertensive patients. Moreover, the risk of gout is modified by antihypertensive drugs. However, it remains unclear how antihypertensive agents affect uric acid metabolism. Purpose: In the present study, we investigated the uric acid metabolism in treated hypertensive patients to find out whether any of them would influence serum levels of uric acid. Patients and methods: 751 hypertensive patients (313 men and 438 women) under antihypertensive treatment were selected. Blood pressure (BP), serum uric acid (SUA) and serum creatinine (Scr) were measured and evaluated statistically. Results: In patients treated with diuretics, beta-blockers and/or alpha-1 blockers SUA levels were significantly higher than in patients who were not taking these drugs. Besides, the estimated glomerular filtration rate (eGFR) in patients treated with diuretics, beta-blockers and/or alpha-1 blockers was negatively correlated with SUA level. There were gender differences in the effects of beta-blockers and alpha-1 blockers. Multiple regression analysis indicated that both diuretics and beta-blockers significantly contributed to hyperuricemia in patients with medication for hypertension. Conclusion: Diuretics, beta-blockers and alpha-1 blockers reduced glomerular filtration rate and raised SUA levels. Calcium channel blockers, ACE inhibitors and angiotensin receptor blockers, including losartan, did not increase SUA levels.

Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (<5%) fructose content. At the end of 2 yr, wild-type mice showed elevations in systolic blood pressure, mild albuminuria, and glomerular changes with mesangial matrix expansion, variable mesangiolysis, and segmental thrombi. The renal injury was amplified by provision of high-salt diet for 3 wk, as noted by the presence of glomerular hypertrophy, mesangial matrix expansion, and alpha smooth muscle actin expression, and with segmental thrombi. Fructokinase knockout mice were protected from renal injury both at baseline and after high salt intake (3 wk) compared with wild-type mice. This was associated with higher levels of active (phosphorylated serine 1177) endothelial nitric oxide synthase in their kidneys. These studies suggest that aging-associated renal disease might be due to activation of specific metabolic pathways that could theoretically be targeted therapeutically, and raise the hypothesis that aging-associated renal injury may represent a disease process as opposed to normal age-related degeneration.