Magnesium inhibits peritoneal calcification as a late-stage characteristic of encapsulating peritoneal sclerosis.

Peritoneal calcification is a prominent feature of the later stage of encapsulating peritoneal sclerosis (EPS) in patients undergoing long-term peritoneal dialysis (PD). However, the pathogenesis and preventive strategy for peritoneal calcification remain unclear. Peritoneum samples from EPS patients were examined histologically. Peritoneal calcification was induced in mice by feeding with an adenine-containing diet combined with intraperitoneal administration of lipopolysaccharide and a calcifying solution containing high calcium and phosphate. Excised mouse peritoneum, human mesothelial cells (MeT5A), and mouse embryonic fibroblasts (MEFs) were cultured in calcifying medium. Immunohistochemistry confirmed the appearance of osteoblastic differentiation-marker-positive cells in the visceral peritoneum from EPS patients. Intraperitoneal administration of magnesium suppressed peritoneal fibrosis and calcification in mice. Calcifying medium increased the calcification of cultured mouse peritoneum, which was prevented by magnesium. Calcification of the extracellular matrix was accelerated in Met5A cells and MEFs treated with calcification medium. Calcifying medium also upregulated osteoblastic differentiation markers in MeT5A cells and induced apoptosis in MEFs. Conversely, magnesium supplementation mitigated extracellular matrix calcification and phenotypic transdifferentiation and apoptosis caused by calcifying conditions in cultured MeT5A cells and MEFs. Phosphate loading contributes to the progression of EPS through peritoneal calcification and fibrosis, which can be prevented by magnesium supplementation.

Idiopathic myointimal hyperplasia of mesenteric veins depicted by barium enema examination, and conventional and magnifying colonoscopy.

A 71-year-old man was admitted to our institution complaining of abdominal pain and constipation. Barium enema examination revealed narrowing, cobble stoning, and longitudinal ulcerations in the sigmoid colon and upper rectum. Conventional colonoscopy, magnifying narrow-band imaging endoscopy, and magnifying chromoendoscopy revealed edematous mucosa, longitudinal ulcerations with luminal narrowing, and multiple pseudopolyps. The histologic examination of the biopsy specimens showed thick-walled (arterialized) capillaries and subendothelial fibrin deposits in the mucosa and submucosa. Based on a preoperative diagnosis of idiopathic myointimal hyperplasia of mesenteric veins (IMHMV), he underwent a laparoscopic resection of the sigmoid colon and upper rectum. The histologic examination of the resected specimens showed marked proliferation of venous walls with marked myointimal thickening and luminal occlusion from the submucosa to the mesentery throughout the entire resected tissue section. The final diagnosis was IMHMV.

Prevalence, treatment status, and predictors of anemia and erythropoietin hyporesponsiveness in Japanese patients with non-dialysis-dependent chronic kidney disease: a cross-sectional study.

BACKGROUND: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) has been highlighted as a potential risk factor for cardiovascular disease in patients with chronic kidney disease (CKD). METHODS: We assessed cross-sectionally the prevalence, associated factors, and treatment status of anemia and ESA hyporesponsiveness in 4460 non-dialysis-dependent CKD patients enrolled in a multicenter cohort in Japan. Anemia was defined as a hemoglobin (Hb) level of less than 11 g/dL or receiving ESA therapy. ESA hyporesponsiveness was defined by the erythropoietin-resistance index (ERI), which was the erythropoietin dose per week divided by body weight and Hb level (U/kg/week/g/dl). RESULTS: Of the 4460 patients, 1050 (23.5%) had anemia. ESAs were administered to 626 patients, reaching a percentage of 57.5% of patients with stage G5 CKD. However, the ESA treatment rate was only 49.0% in patients with a hemoglobin level of < 11 g/dL. The proportion of patients receiving iron supplementation was lower than that of patients receiving ESAs regardless of CKD stage or hemoglobin level, and a significant proportion of patients did not receive iron supplementation, even those with iron deficiency. The ERI increased with CKD stage progression, and the multiple regression analysis showed that age, female sex, body mass index, cholesterol, glomerular filtration rate, and intact parathyroid hormone level were independent contributors. CONCLUSIONS: Our findings demonstrate that many Japanese patients with non-dialysis-dependent CKD receiving ESAs fail to maintain adequate hemoglobin levels. These results suggest the need for interventions for ESA hyporesponsiveness factors in addition to iron supplementation.

Protective Roles of Xenotropic and Polytropic Retrovirus Receptor 1 (XPR1) in Uremic Vascular Calcification.

Cellular phosphate transporters play critical roles in the pathogenesis of vascular calcification (VC) in chronic kidney disease (CKD). However, the mechanistic link between VC and xenotropic and polytropic receptor 1 (XPR1), a newly identified phosphate exporter, remains unknown. We developed a new mouse model with rapidly progressive uremic VC in C57BL/6 mice and examined the roles of XPR1. The combination of surgical heminephrectomy and 8 weeks of feeding a customized warfarin and adenine-based diet induced extensive aortic VC in almost all mice. The XPR1 mRNA level in the aorta of CKD mice was significantly lower than those in control mice as early as week 2, when there was no apparent VC, which progressively declined thereafter. Dietary phosphate restriction increased XPR1 mRNA expression in the aorta but reduced aortic VC in CKD mice. In cultured vascular smooth muscle cells (VSMCs), a calcifying medium supplemented with high phosphate and calcium did not affect XPR1 mRNA expression. The XPR1 mRNA expression in cultured VCMCs was also unaffected by administration of indoxyl sulfate or calcitriol deficiency but was decreased by 1-34 parathyroid hormone or fibroblast growth factor 23 supplementation. Furthermore, XPR1 deletion in the cultured VSMCs exacerbated calcification of the extracellular matrix as well as the osteogenic phenotypic switch under the condition of calcifying medium. Our data suggest that XPR1 plays protective roles in the pathogenesis of VC and its decrease in the aorta may contribute to the progression of VC in CKD.

Relationship of coffee consumption with a decline in kidney function among patients with type 2 diabetes: The Fukuoka Diabetes Registry.

AIMS/INTRODUCTION: The evidence regarding the effects of coffee consumption on incident chronic kidney disease is inconclusive, and no studies have investigated the relationship in patients with diabetes. We aimed to prospectively investigate the relationship between coffee consumption and the decline in estimated glomerular function rate (eGFR) in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 3,805 patients (2,112 men, 1,693 women) with type 2 diabetes (mean age 64.2 years) and eGFR ≥60 mL/min/1.73 m2 were followed (completion of follow up, 97.6%; median 5.3 years). Coffee consumption was assessed at baseline. The end-point was a decline in eGFR to <60 mL/min/1.73 m2 during the follow-up period. RESULTS: During follow up, 840 participants experienced a decline in eGFR to <60 mL/min/1.73 m2 . Higher coffee consumption reduced the risk of decline in eGFR. Compared with no coffee consumption, the multivariate-adjusted hazard ratios (95% confidence intervals) were 0.77 (0.63-0.93) for less than one cup per day, 0.77 (0.62-0.95) for one cup per day and 0.75 (0.62-0.91) for two or more cups per day (P for trend 0.01). This trend was unaffected by further adjustment for baseline eGFR and albuminuria. The mean eGFR change per year was -2.16 mL/min/1.73 m2 with no coffee consumption, -1.89 mL/min/1.73 m2 with less than one cup per day, -1.80 mL/min/1.73 m2 with one cup per day and -1.78 mL/min/1.73 m2 with two or more cups per day (P for trend 0.03). CONCLUSIONS: Coffee consumption is significantly associated with a lower risk of decline in eGFR in patients with type 2 diabetes.

Role of barium enema examination for the diagnosis of submucosal invasion depth in T1 colorectal cancers.

BACKGROUND: The indication for endoscopic resection for submucosally invasive colorectal cancer (T1-CRC) depends on the preoperative diagnosis of invasion depth. The aim of this investigation was to evaluate the association between barium enema examination (BE) profile views and depth of submucosal (SM) invasion in CRCs. METHODS: We reviewed the radiographic and endoscopic findings of 145 T1-CRCs diagnosed from 2008 to 2019. We measured the widths of horizontal and vertical rigidity under a BE profile view corresponding to CRC and compared the values with SM invasion depth. Horizontal rigidity was defined as the horizontal length and vertical rigidity as the vertical width of the barium defect corresponding to each target lesion. The most appropriate cut-off values for predicting SM invasion ≥1.8 mm were calculated by receiver operating characteristic curve analysis. RESULTS: Values of horizontal rigidity (r = 0.626, P < 0.05) and vertical rigidity (r = 0.482, P < 0.05) correlated significantly with SM invasion depth. The most appropriate cut-off values for the prediction of SM invasion depth ≥ 1.8 mm were 4.5 mm for horizontal rigidity, with an accuracy of 80.7%; and 0.7 mm for vertical rigidity, with an accuracy of 77.9%. The prevalence of lympho-vascular invasion was significantly different when those cut-off values were applied (43.2% vs. 17.5% for horizontal rigidity, P < 0.005). CONCLUSIONS: In T1-CRC, values of horizontal and vertical rigidities under a BE profile view were correlated with SM invasion depth. While the accuracy of the rigidities for the prediction of SM invasion depth ≥ 1.8 mm was not high, horizontal rigidity may be predictive of lympho-vascular invasion, thus aiding in therapeutic decision-making.

Additive effects of green tea and coffee on all-cause mortality in patients with type 2 diabetes mellitus: the Fukuoka Diabetes Registry.

INTRODUCTION: The impact of consuming green tea or coffee on mortality in patients with diabetes is controversial. We prospectively investigated the impact of each beverage and their combination on mortality among Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In all, 4923 patients (2790 men, 2133 women) with type 2 diabetes (mean age, 66 years) were followed prospectively (median, 5.3 years; follow-up rate, 99.5%). We evaluated the amount of green tea and coffee consumed using self-administered questionnaires. RESULTS: During the follow-up period, 309 participants died. The consumption of green tea, coffee, and a combination of the beverages was associated with reduced all-cause mortality. Multivariable-adjusted hazard ratios (95% CIs) for green tea were as follows: none 1.0 (referent); 0.85 (0.60-1.22) for ≤1 cup/day; 0.73 (0.51-1.03) for 2-3 cups/day; 0.60 (0.42-0.85) for ≥4 cups/day; and P for trend, 0.002. For coffee, they were: none 1.0 (referent); 0.88 (0.66-1.18) for <1 cup/day; 0.81 (0.58-1.13) for 1 cup/day; 0.59 (0.42-0.82) for ≥2 cups/day; P for trend, 0.002. With the combination they were 1.0 (referent) for no consumption of green tea and coffee; 0.49 (0.24-0.99) for 2-3 cups/day of green tea with ≥2 cups/day of coffee; 0.42 (0.20-0.88) for ≥4 cups/day of green tea with 1 cup/day of coffee; and 0.37 (0.18-0.77) for ≥4 cups/day of green tea with ≥2 cups/day of coffee. CONCLUSIONS: Higher consumption of green tea and coffee was associated with reduced all-cause mortality: their combined effect appeared to be additive in patients with type 2 diabetes.

Association of aortic valve calcification with carotid artery lesions and peripheral artery disease in patients with chronic kidney disease: a cross-sectional study.

BACKGROUND: Patients with chronic kidney disease (CKD) reportedly have a high prevalence of aortic valve calcification (AVC). In population-based studies, AVC is considered a manifestation of systemic atherosclerosis. The association of AVC with atherosclerotic lesions has not been fully investigated in predialysis patients. The present study was performed to determine whether carotid artery lesions and peripheral artery disease (PAD) are associated with AVC in patients with CKD not on dialysis. METHODS: In total, 749 patients were included in this cross-sectional study. AVC was evaluated using echocardiography. Carotid artery lesions including carotid artery plaque (CAP) and PAD were simultaneously examined in each patient. A logistic regression analysis was applied to determine the factors associated with AVC. RESULTS: AVC, CAP, and PAD were found in 201, 583, and 123 patients, respectively. In the multivariable analyses adjusted for covariates including the estimated glomerular filtration rate and makers of mineral metabolism (serum calcium, serum phosphorus, parathyroid hormone, 1,25-dihydroxyvitamin D, and fibroblast growth factor 23), AVC was significantly associated with the presence of CAP [odds ratio (OR), 3.37; 95% confidence interval (CI), 1.43-7.95], the presence of PAD (OR, 1.76; 95% CI, 1.10-2.81), the CAP score (per 1.0-point increase) (OR, 1.06; 95% CI, 1.02-1.11), and the ankle-brachial blood pressure index (per 0.1-point increase) (OR, 0.83; 95% CI, 0.72-0.95). CONCLUSIONS: AVC was associated with atherosclerotic lesions independent of kidney function and mineral metabolism. We consider that this association between AVC and atherosclerosis might reflect the burden of shared atherosclerotic risk factors.

Impact of body mass index on real-world outcomes of rivaroxaban treatment in Japanese patients with non-valvular atrial fibrillation.

This sub-analysis of the XAPASS, a prospective, single-arm, observational study, aimed to evaluate relationships between body mass index (BMI) and safety (major bleeding and all-cause mortality) and effectiveness [stroke/non-central nervous system (non-CNS) systemic embolism (SE)/myocardial infarction (MI)] outcomes in Japanese patients with non-valvular atrial fibrillation (NVAF) receiving rivaroxaban. Patients were categorized according to BMI (kg/m2) as underweight (< 18.5), normal weight (18.5 to < 25), overweight (25 to < 30), or obese (≥ 30). In total, 9578 patients with NVAF completed the 1-year follow-up and were evaluated; of these, 7618 patients had baseline BMI data. Overall, 542 (5.7%), 4410 (46.0%), 2167 (22.6%), and 499 (5.2%) patients were underweight, normal weight, overweight, and obese, respectively. Multivariable Cox regression analysis demonstrated that none of the BMI categories were independent predictors of major bleeding whereas being underweight was independently associated with increased all-cause mortality [hazard ratio (HR) 3.56, 95% confidence interval (CI) 2.40-5.26, p < 0.001]. The incidence of stroke/non-CNS SE/MI was higher in patients who were underweight than in those of normal weight (HR 2.11, 95% CI 1.20-3.70, p = 0.009). However, in multivariable analyses, being underweight was not identified as an independent predictor of stroke/non-CNS SE/MI (HR 1.64, 95% CI 0.90-2.99, p = 0.104). In conclusion, the high incidence of thromboembolic events and all-cause mortality in patients who were underweight highlights that thorough evaluation of disease status and comorbidities may be required in this population.

Real-world outcomes of rivaroxaban treatment in elderly Japanese patients with nonvalvular atrial fibrillation.

Direct oral anticoagulants (DOACs), such as rivaroxaban, reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). However, it is still unclear whether the stroke reduction benefit outweighs the bleeding risk in elderly Japanese patients with NVAF. The Xarelto Post-Authorization Safety and Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) was a real-world, prospective observational, post-marketing surveillance study on the safety and effectiveness of rivaroxaban in Japanese clinical practice. This sub-analysis evaluated the clinical outcomes of elderly patients aged ≥ 75 years. At the 1-year follow-up, there were 4,685 (48.91%) and 4,893 (51.09%) patients aged ≥ 75 and < 75 years, respectively. Safety and effectiveness outcomes were compared between patients aged ≥ 75 years and those aged < 75 years, and among 3 elderly sub-populations (age ranges: 75-79, 80-84, and ≥ 85 years). Patients aged ≥ 75 years had higher rates of major bleeding [2.22 vs. 1.35 events per 100 patient-years, hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.17-2.28] and composite of stroke (ischemic or hemorrhagic)/non-central nervous system (non-CNS) systemic embolism (SE)/myocardial infarction (MI) (2.41 vs. 1.21 events per 100 patient-years, HR 1.97, 95% CI 1.40-2.77) compared to patients aged < 75 years. Intracranial hemorrhage rates were < 1 event per 100 patient-years in both groups (0.85 vs. 0.59 events per 100 patient-years, HR 1.43, 95% CI 0.85-2.40). Kaplan-Meier curves of major bleeding and stroke/non-CNS SE/MI showed that no significant differences of cumulative event rates were identified among the 3 elderly sub-populations. Stepwise Cox regression analyses revealed that creatinine clearance (CrCl) (<50 mL/min), hepatic impairment, and hypertension were specific predictors for major bleeding and no specific predictors were found for stroke/non-CNS SE/MI in patients aged ≥ 75 years. In conclusion, safety and effectiveness event rates were higher in patients aged ≥ 75 years compared with those aged < 75 years, yet, no distinct differences were observed among the 3 elderly sub-populations.

Short-term and long-term outcomes of indigo naturalis treatment for inflammatory bowel disease.

BACKGROUND AND AIM: Indigo naturalis (IN) is a traditional Chinese herbal medicine reported to be effective in inducing remission in ulcerative colitis (UC). We conducted a retrospective observational study to investigate the efficacy and safety of IN for induction and maintenance therapy in patients with inflammatory bowel disease. METHODS: Data were collected from the electric medical records of patients with inflammatory bowel disease who had started IN treatment between March 2015 and April 2017 at Kyushu University Hospital. Clinical response and remission rates were assessed based on the clinical activity index determined by Rachmilewitz index or Crohn's disease (CD) activity index. Cumulative IN continuation rates were estimated using the Kaplan-Meier method. Overall adverse events (AEs) during follow-up were also analyzed. RESULTS: Seventeen UC patients and eight CD patients were enrolled. Clinical response and remission rates at week 8 were 94.1% and 88.2% in UC patients and 37.5% and 25.0% in CD patients, respectively. Clinical remission rates, as assessed through non-responders imputation analyses at weeks 52 and 104, were 76.4% and 70.4% in UC patients and 25.0% and 25.0% in CD patients, respectively. Ten patients (40%) experienced AEs during follow-up. Three patients (12%) experienced severe AEs, including acute colitis requiring hospitalization in two patients and acute colitis with intussusception requiring surgery in one patient. CONCLUSIONS: Indigo naturalis showed favorable therapeutic efficacy in UC, whereas its therapeutic efficacy in CD appeared to be modest. The risk of severe AEs should be recognized for IN treatment.

Real-World Outcomes of Rivaroxaban Treatment in Patients with Both Nonvalvular Atrial Fibrillation and a History of Ischemic Stroke/Transient Ischemic Attack.

INTRODUCTION: Prior stroke is a risk factor for stroke and bleeding during anticoagulation in patients with atrial fibrillation (AF). Although rivaroxaban is widely prescribed to reduce their risk of stroke in patients with nonvalvular AF (NVAF), the real-world evidence on rivaroxaban treatment is limited. We aimed to examine the outcomes of rivaroxaban treatment in NVAF patients with prior ischemic stroke/transient ischemic attack (TIA) by using the data of the Xarelto Post-Authorization Safety and Effectiveness Study in Japanese -Patients with AF, a prospective, single-arm, observational study. METHODS: The clinical outcomes of 9,578 patients who completed the 1-year follow-up were evaluated. Safety and effectiveness outcomes were compared between patients with and without prior ischemic stroke/TIA. RESULTS: Among the patients, 2,153 (22.5%) had prior ischemic stroke/TIA. They were significantly older and had lower body weight, lower creatinine clearance, higher CHADS2, CHA2DS2-VASc, and modified HAS-BLED scores as compared to those without prior ischemic stroke/TIA. Any bleeding (9.1 vs. 7.2 events per 100 patient-years), major bleeding (2.3 vs. 1.6 events per 100 patient-years), and stroke/non-central nervous system systemic embolism/myocardial infarction (3.4 vs. 1.3 events per 100 patient-years) were more frequent in patients with prior ischemic stroke/TIA. Stepwise regression analysis suggested that body weight of ≤50 kg and diabetes mellitus were predictive of major bleeding in patients with prior ischemic stroke/TIA. CONCLUSIONS: Safety and effectiveness event rates were higher in patients with prior ischemic stroke/TIA than those without. This might be explained by differences in several risk profiles including age, body weight, renal function, and risk scores such as CHADS2 between the groups. Clinicaltrials.gov: NCT01582737.

Development of Quality Indicators of Stroke Centers and Feasibility of Their Measurement Using a Nationwide Insurance Claims Database in Japan　­ J-ASPECT Study ­

BACKGROUND: We aimed to develop quality indicators (QIs) related to primary and comprehensive stroke care and examine the feasibility of their measurement using the existing Diagnosis Procedure Combination (DPC) database. METHODS AND RESULTS: We conducted a systematic review of domestic and international studies using the modified Delphi method. Feasibility of measuring the QI adherence rates was examined using a DPC-based nationwide stroke database (396,350 patients admitted during 2013-2015 to 558 hospitals participating in the J-ASPECT study). Associations between adherence rates of these QIs and hospital characteristics were analyzed using hierarchical logistic regression analysis. We developed 17 and 12 measures as QIs for primary and comprehensive stroke care, respectively. We found that measurement of the adherence rates of the developed QIs using the existing DPC database was feasible for the 6 QIs (primary stroke care: early and discharge antithrombotic drugs, mean 54.6% and 58.7%; discharge anticoagulation for atrial fibrillation, 64.4%; discharge antihypertensive agents, 51.7%; comprehensive stroke care: fasudil hydrochloride or ozagrel sodium for vasospasm prevention, 86.9%; death complications of diagnostic neuroangiography, 0.4%). We found wide inter-hospital variation in QI adherence rates based on hospital characteristics. CONCLUSIONS: We developed QIs for primary and comprehensive stroke care. The DPC database may allow efficient data collection at low cost and decreased burden to evaluate the developed QIs.

Real-world outcomes of rivaroxaban treatment in patients with nonvalvular atrial fibrillation and worsening renal function.

BACKGROUND: Rivaroxaban is a direct oral anticoagulant administered to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). The Xarelto Post-Authorization Safety and Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) was a prospective, observational, post-marketing surveillance study that examined the safety and effectiveness of rivaroxaban in routine clinical practice. This sub-analysis of the XAPASS investigated the outcomes of patients with worsening renal function (WRF). METHODS: The XAPASS included 11,308 patients with NVAF who began treatment with rivaroxaban. Of 9578 patients who completed 1-year follow-up, the 7509 patients, for whom the change in creatinine clearance could be assessed, were included in the present analysis. Patients with WRF were those with a decrease in creatinine clearance of ≥20% from enrollment to any time point; patients with stable renal function (SRF) were those without such a decrease. Outcomes in patients with WRF versus SRF were compared at 1 year. RESULTS: We identified 1229 patients with WRF and 6280 patients with SRF. Patients with WRF were older and had higher mean CHADS2 and modified HAS-BLED scores compared to patients with SRF. The incidence rates of any bleeding (hazard ratio: 1.12; 95% confidence interval: 0.88-1.41), major bleeding (1.20; 0.75-1.90), and the composite endpoint stroke/systemic embolism/myocardial infarction (1.06; 0.65-1.71) were similar between the two groups. CONCLUSIONS: No association between WRF and occurrence of any bleeding, major bleeding, and stroke/systemic embolism/myocardial infarction was observed in patients with AF on rivaroxaban treatment during 1-year follow-up in real-world clinical practice. Clinicaltrials.gov: NCT01582737.

Hemodialysis treatment time versus erythropoietin dose requirement: Reduction in 2,000 units per week by extension of hemodialysis for 1 hour
.

INTRODUCTION: High-dose erythropoietin (EPO) administration to hemodialysis (HD) patients with EPO hyporesponsiveness, due to iron deficiency, hyperparathyroidism, malnutrition, inflammation, and inadequate HD, results in increased risk of mortality and cardiovascular events. We investigated the relationship of the EPO dose requirement with 4-, 5-, and 6-hour HD treatment times. MATERIALS AND METHODS: This cross-sectional study enrolled 300 HD patients, including those on 4-hour HD (n = 78), 5-hour HD (n = 106), and 6-hour HD (n = 116). We studied the following parameters: weekly EPO dose, hemoglobin (Hb), serum ferritin, Kt/V, membrane surface area, quantity of blood flow, quantity of dialysate flow, age, HD vintage, serum albumin, C-reactive protein (CRP), intact parathyroid hormone (iPTH), and ß2-microglobulin. These parameters were analyzed with JMP9TM statistical software. FINDINGS: The EPO requirement (units per week) of the 6-hour HD group (4,035 ± 269) was significantly lower than that of the 5-hour HD group (6,628 ± 630), which was significantly lower than that of the 4-hour HD group (8,567 ± 684). The Hb level, mean corpuscular volume, quantity of blood flow, quantity of dialysate flow, age, gender, ratio of diabetic patients, body mass index, dry weight, CRP, iPTH, use of antiplatelet agents and anticoagulants were not significantly different among the three groups. Multiple regression analysis with the weekly EPO requirement as the dependent variable showed HD treatment time (p < 0.0001) and CRP level (p < 0.001) as the significant independent variables. DISCUSSION: The EPO dose can be reduced by ~ 2,000 U/week by extending the HD treatment time for 1 hour; annual cost savings were calculated to be USD 570 per patient.

Serum Ethylamine Levels as an Indicator of l-Theanine Consumption and the Risk of Type 2 Diabetes in a General Japanese Population: The Hisayama Study.

OBJECTIVE: This study investigated the association between serum ethylamine levels as an indicator of l-theanine consumption and the development of type 2 diabetes in a Japanese community. RESEARCH DESIGN AND METHODS: A total of 2,253 community-dwelling Japanese individuals aged 40-79 years without diabetes were monitored for 7 years. Serum ethylamine levels were divided into quartiles: ≤0.86, 0.87-2.10, 2.11-5.28, and ≥5.29 ng/mL. Kinetic analysis of serum ethylamine concentrations was performed after ingestion of l-theanine-rich green tea products containing 8 mg of l-theanine by 12 healthy volunteers. RESULTS: During follow-up, 282 subjects developed type 2 diabetes. The age- and sex-adjusted cumulative incidence of type 2 diabetes decreased significantly with elevating levels of serum ethylamine (P for trend = 0.04). This association remained unchanged after adjusting for potential confounding factors. The multivariable-adjusted hazard ratio (HR) for type 2 diabetes was significantly lower in the fourth quartile of serum ethylamine than in the first quartile (HR 0.69, 95% CI 0.49-0.98). This trend of decrease in diabetic risk across serum ethylamine levels was more prominent in middle-aged subjects and in subjects with prediabetes, obesity, or insulin resistance. Kinetic analysis estimated that the minimum concentration at the steady state was >5.90 ng/mL in the case of twice-daily ingestion with an interval of 12 h. CONCLUSIONS: Higher serum ethylamine was significantly associated with lower risk of the development of type 2 diabetes in a general Japanese population. The measurement of serum ethylamine concentration would be a useful biomarker for the objective estimation of l-theanine consumption.

Clinical risk factors of stroke and major bleeding in patients with non-valvular atrial fibrillation under rivaroxaban: the EXPAND Study sub-analysis.

For Japanese patients with non-valvular atrial fibrillation (NVAF), the risk of stroke and major bleeding events was assessed by using the CHADS2, CHA2DS2-VASc, and HAS-BLED scores. The risk factors for embolism and major bleeding under DOAC may be different from current reports. We analyzed the data set of the EXPAND Study to determine the risk factors for events among Japanese NVAF patients in the era of direct oral anticoagulant. Using the data of EXPAND Study, the validity for predictability of the CHADS2, CHA2DS2-VASc, and HAS-BLED scores was identified using the receiver operating characteristic curve analysis. Multivariate analysis was performed with the Cox proportional hazard model to determine the independent risk factors for stroke/systemic embolism and major bleeding among NVAF patients receiving rivaroxaban. Explanatory variables were selected based on the univariate analysis. A total of 7141 patients (mean age 71.6 ± 9.4 years, women 32.3%, and rivaroxaban 15 mg per day 56.5%) were included. Incidence rates of stroke/systemic embolism and major bleeding were 1.0%/year and 1.2%/year, respectively. The multivariate analysis revealed that only history of stroke was associated with stroke/systemic embolism (hazard ratio 3.4, 95% confidence interval 2.5-4.7, p < 0.0001). By contrast, age (1.7, 1.1-2.6, p = 0.0263), creatinine clearance (CrCl) 30-49 mL/min (1.6, 1.2-2.2, p = 0.0011), liver dysfunction (1.7, 1.1-2.8, p = 0.0320), history/disposition of bleeding (1.8, 1.0-3.0, p = 0.0348), and concomitant use of antiplatelet agents (1.6, 1.2-2.3, p = 0.0030) were associated with major bleeding. This sub-analysis showed that some components of the HAS-BLED score were independently associated with major bleeding in Japanese NVAF patients receiving anticoagulation therapy by rivaroxaban. Additionally, CrCl value of 30-49 mL/min was an independent predictor of major bleeding in patients receiving rivaroxaban.

Design and baseline characteristics of the Xarelto Post-Authorization Safety & Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS).

Background: The phase III Japanese Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (J-ROCKET AF) showed that the rivaroxaban group had a lower event rate of intracranial bleeding than the warfarin group and that rivaroxaban was noninferior to warfarin for the principal safety outcome. However, safety and effectiveness data from unselected patients with AF in everyday clinical practice in Japan are lacking. Methods: The Xarelto Post-Authorization Safety & Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) is a real-world, prospective, single-arm, observational study mandated by the Japanese authority as postmarketing surveillance. XAPASS involves patients with nonvalvular AF prescribed rivaroxaban. The principal safety outcome is a composite of major and nonmajor bleeding events, and the primary effectiveness outcome is the incidence of ischemic stroke, hemorrhagic stroke, noncentral nervous system systemic embolism, and myocardial infarction. Results: In total, 11 308 patients were enrolled from April 2012 to June 2014. Their age was 73.1 ± 9.9 years, and their CHADS 2 score was 2.2 ± 1.3. Female patients, patients aged ≥75 years, patients with a body weight of ≤50 kg, and patients with a creatinine clearance of <50 mL/min constituted 38.1%, 48.7%, 19.5%, and 23.9% of all patients, respectively. Almost half (53.2%) of patients were prescribed other anticoagulants before starting rivaroxaban. Conclusions: Data from this study will supplement those from the J-ROCKET AF and provide practical information for the optimal use of rivaroxaban for stroke prevention in Japanese patients with AF (Clinicaltrials.gov: NCT01582737).

The EXPAND study: Efficacy and safety of rivaroxaban in Japanese patients with non-valvular atrial fibrillation.

AIMS: The EXPAND study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients ≥20 years of age (mean, 71.6 ±â€¯9.4 years) who were being or about to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for an average of 897.1 (±206.8) days with a high follow-up rate (99.65%). The mean CHADS2 score at baseline was 2.1 (1.3) (0-1, 37%; 2, 29%; ≥3, 34%). The total incidence rate of symptomatic stroke and SE (primary efficacy endpoint) was 1.0%/year, and 0.5%, 0.9%, and 1.7%/year for those with CHADS2 scores of 0-1, 2, and ≥3, respectively. Cumulative incidence rates for major bleeding (primary safety endpoint) and non-major bleeding (secondary safety endpoint) were 1.2%/year and 4.9%/year, respectively. Differences were noted between new and current users only for major bleeding event rate (1.7% vs. 1.1%/year, P = 0.0024). Comparisons with previous studies suggested that rivaroxaban is effective and safe for low-risk patients (0-1 CHADS2), as shown for warfarin in the XANTUS international prospective post-marketing study. CONCLUSIONS: The EXPAND study demonstrated that low dosages of rivaroxaban for Japanese NVAF patients in real-world clinical practice, including those with CHADS2 scores 0-1, resulted in low rates of stroke and SE, and major and non-major bleeding.

Study Design and Baseline Characteristics of the EXPAND Study: Evaluation of Effectiveness and Safety of Xa Inhibitor, Rivaroxaban for the Prevention of Stroke and Systemic Embolism in a Nationwide Cohort of Japanese Patients Diagnosed as Non-Valvular Atrial Fibrillation.

The use of rivaroxaban, a factor Xa inhibitor, has been increasing for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) in Japan. We conducted the nationwide multicenter study, termed as the EXPAND Study, to address its effectiveness and safety in the real-world practice of patients with non-valvular AF in Japan. The EXPAND Study is a prospective, non-interventional, observational cohort study to evaluate the effectiveness and safety of rivaroxaban in non-valvular AF patients in a real-world clinical practice. A total of 7,178 patients with non-valvular AF were enrolled in 684 medical institutes between November 20, 2012 and June 30, 2014. As for the baseline demographic and clinical characteristics of 7,164 patients, the proportion of female patients was 32.2%, and those of patients with creatinine clearance < 50 mL/min and non-paroxysmal (persistent or permanent) AF were 21.8% and 55.1%, respectively. The proportions of patients complicated with hypertension, congestive heart failure, diabetes mellitus, and a history of ischemic stroke were 70.9%, 25.9%, 24.3%, and 20.2%, respectively. The proportions of patients with a CHADS2 score ≤ 1 and a CHA2DS2-VASc score ≤ 1 were 37.3% and 13.6%, respectively. They were followed up until March 31, 2016 for a mean follow-up period of approximately 2.5 years. The findings of the EXPAND Study will help to establish an appropriate treatment with rivaroxaban for Japanese patients with non-valvular AF.