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1.  Dietary Patterns and Clinical Outcomes in Hemodialysis Patients in Japan: A Cohort Study 
PLoS ONE  2015;10(1):e0116677.
Background & Objectives
Little is known about actual dietary patterns and their associations with clinical outcomes in hemodialysis patients. We identified dietary patterns in hemodialysis patients in Japan and examined associations between dietary patterns and clinical outcomes.
Design, setting, participants, measurements
We used data from 3,080 general-population participants in the Hisayama study (year 2007), and data from 1,355 hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study (JDOPPS: years 2005–2007). Food intake was measured using a brief self-administered diet-history questionnaire (BDHQ). To identify food groups with the Hisayama population data, we used principal components analysis with Promax rotation. We adjusted the resulting food groups for total daily energy intake, and then we used those adjusted food-group scores to identify dietary patterns in the JDOPPS patients by cluster analysis (Ward’s method). We then used Cox regression to examine the association between dietary patterns and a composite of adverse clinical outcomes: hospitalization due to cardiovascular disease or death due to any cause.
We identified three food groups: meat, fish, and vegetables. Using those groups we then identified three dietary patterns: well-balanced, unbalanced, and other. After adjusting for potential confounders, we found an association between an unbalanced diet and important clinical events (hazard ratio 1.90, 95% C.I. 1.19–3.04).
Hemodialysis patients whose diet was unbalanced were more likely to have adverse clinical outcomes. Thus hemodialysis patients might benefit not only from portion control, but also from a diet that is well-balanced diet with regard to the food groups identified here as meat, fish, and vegetables.
PMCID: PMC4301814  PMID: 25607947
2.  Association between Combined Lifestyle Factors and Non-Restorative Sleep in Japan: A Cross-Sectional Study Based on a Japanese Health Database 
PLoS ONE  2014;9(9):e108718.
Although lifestyle factors such as cigarette smoking, excessive drinking, obesity, low or no exercise, and unhealthy dietary habits have each been associated with inadequate sleep, little is known about their combined effect. The aim of this study was to quantify the overall impact of lifestyle-related factors on non-restorative sleep in the general Japanese population.
Methods and Findings
A cross-sectional study of 243,767 participants (men, 39.8%) was performed using the Specific Health Check and Guidance System in Japan. A healthy lifestyle score was calculated by adding up the number of low-risk lifestyle factors for each participant. Low risk was defined as (1) not smoking, (2) body mass index<25 kg/m2, (3) moderate or less alcohol consumption, (4) regular exercise, and (5) better eating patterns. Logistic regression analysis was used to examine the relationship between the score and the prevalence of non-restorative sleep, which was determined from questionnaire responses. Among 97,062 men (mean age, 63.9 years) and 146,705 women (mean age, 63.7 years), 18,678 (19.2%) and 38,539 (26.3%) reported non-restorative sleep, respectively. The prevalence of non-restorative sleep decreased with age for both sexes. Compared to participants with a healthy lifestyle score of 5 (most healthy), those with a score of 0 (least healthy) had a higher prevalence of non-restorative sleep (odds ratio, 1.59 [95% confidence interval, 1.29–1.97] for men and 2.88 [1.74–4.76] for women), independently of hypertension, hypercholesterolemia, diabetes, and chronic kidney disease. The main limitation of the study was the cross-sectional design, which limited causal inferences for the identified associations.
A combination of several unhealthy lifestyle factors was associated with non-restorative sleep among the general Japanese population. Further studies are needed to establish whether general lifestyle modification improves restorative sleep.
PMCID: PMC4182544  PMID: 25268956
3.  Diabetes Influences Peritoneal Morphology in Uremic Patients at the Initiation of Peritoneal Dialysis 
♦ Background: The peritoneum begins to undergo morphologic changes before the start of peritoneal dialysis (PD), particularly in diabetic patients. The present study was conducted to investigate the effects of diabetes on the peritoneum.
♦ Methods: This study involved 17 patients who began receiving PD and had diabetes as an underlying disease (DM group), and 30 patients without diabetes who served as a control group (nonDM group). At the start of PD, the parietal peritoneum was sampled to assess submesothelial connective tissue thickness, number of capillaries and postcapillary venules, and indications of vasculopathy (grades 0 - 3).
♦ Results: Submesothelial connective tissue thickness was significantly greater in the DM group than in the nonDM group (p < 0.01). The number of capillaries was significantly greater in the DM group (p < 0.01). Based on multivariate linear regression analysis, diabetes was identified as a significant independent variable of both submesothelial connective tissue thickness and number of capillaries (p < 0.01).
♦ Conclusions: In diabetic patients, morphologic changes of the peritoneum are marked at the start of PD.
PMCID: PMC3598107  PMID: 22942267
Morphologic change; diabetes; vascular density
4.  Budget impact analysis of chronic kidney disease mass screening test in Japan 
Our recently published cost-effectiveness study on chronic kidney disease mass screening test in Japan evaluated the use of dipstick test, serum creatinine (Cr) assay or both in specific health checkup (SHC). Mandating the use of serum Cr assay additionally, or the continuation of current policy mandating dipstick test only was found cost-effective. This study aims to examine the affordability of previously suggested reforms.
Budget impact analysis was conducted assuming the economic model would be good for 15 years and applying a population projection. Costs expended by social insurers without discounting were counted as budgets.
Annual budget impacts of mass screening compared with do-nothing scenario were calculated as ¥79–¥−1,067 million for dipstick test only, ¥2,505–¥9,235 million for serum Cr assay only and ¥2,517–¥9,251 million for the use of both during a 15-year period. Annual budget impacts associated with the reforms were calculated as ¥975–¥4,129 million for mandating serum Cr assay in addition to the currently used mandatory dipstick test, and ¥963–¥4,113 million for mandating serum Cr assay only and abandoning dipstick test.
Estimated values associated with the reform from ¥963–¥4,129 million per year over 15 years are considerable amounts of money under limited resources. The most impressive finding of this study is the decreasing additional expenditures in dipstick test only scenario. This suggests that current policy which mandates dipstick test only would contain medical care expenditure.
PMCID: PMC4271136  PMID: 24515308
CKD; Budget impact; Dipstick test; Mass screening; Proteinuria; Serum creatinine assay
5.  Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules 
Hypertension  2009;54(4):868-876.
Xanthine oxidoreductase (XOR) is an enzyme responsible for purine degradation, reactive oxygen species (ROS) production and adipogenesis. XOR gene disrupted (XOR−/−) mice demonstrate renal failure and early death within several months. The aim of this study was to elucidate the mechanism of renal damage in XOR−/− mice and to determine the physiological role of XOR in the kidney. Histological analysis revealed that renal tubular damage in XOR−/− mice was accompanied by deposition of crystals and lipid rich substances. Triglyceride content in renal homogenates was significantly increased in XOR−/− mice. The level of lipogenesis-related gene expression was comparable in XOR+/+ and XOR−/− mice, while the expression of adipogenesis-related gene expression was significantly elevated in XOR−/− mice. Urinary excretions of xanthine and hypoxanthine were markedly elevated in XOR−/− mice. Immunohistochemical analysis, Western blotting and real time RT-PCR revealed that various markers of fibrosis, inflammation, ischemia and oxidative stress were increased in XOR−/− mice. Finally, we demonstrate that primary renal epithelial cells from XOR−/− mice are more readily transformed to myofibroblasts, which is a marker of increased epithelial mesenchymal transition. These results suggest that XOR gene disruption induced the depletion of uric acid and the accumulation of triglyceride rich substances, xanthine and hypoxanthine in the renal tubules. We believe these changes contribute to a complex cellular milieu characterized by inflammation, tissue hypoxia and ROS production ultimately resulting in renal failure through increased renal interstitial fibrosis.
PMCID: PMC3773720  PMID: 19667249
xanthine oxidoreductase; lipid; uric acid; xanthine; renal interstitial fibrosis; epithelial mesenchymal transition; oxidative stress
6.  Slowly Progressive and Painless Thoracic Aortic Dissection Presenting with a Persistent Fever in an Elderly Patient: The Usefulness of Combined Measurement of Biochemical Parameters 
Case Reports in Medicine  2013;2013:498129.
Aortic dissection is a fatal medical condition that requires urgent diagnosis and appropriate intervention. Because acute aortic dissection often manifests as sudden onset excruciating chest pain, physicians can easily reach a proper diagnosis. However, some patients with aortic dissection present with varied clinical manifestations without exhibiting typical chest pain, leading to a delayed diagnosis and possible fatality. We herein present the case of an elderly subject with a fever of unknown origin who was ultimately diagnosed with aortic dissection. In the present case, a negative procalcitonin test, increased D-dimer and serum creatinine phosphokinase-BB levels, and reelevation of the CPR level led us to the correct diagnosis.
PMCID: PMC3703400  PMID: 23843799
7.  Association of High Pulse Pressure With Proteinuria in Subjects With Diabetes, Prediabetes, or Normal Glucose Tolerance in a Large Japanese General Population Sample 
Diabetes Care  2012;35(6):1310-1315.
To examine whether there is a difference in the association between high pulse pressure and proteinuria, independent of other blood pressure (BP) indices, such as systolic or diastolic BP, among subjects with diabetes, prediabetes, or normal glucose tolerance.
Using a nationwide health checkup database of 228,778 Japanese aged ≥20 years (mean 63.2 years; 39.3% men; none had pre-existing cardiovascular disease), we examined the association between high pulse pressure, defined as the highest quintile of pulse pressure (≥63 mmHg, n = 40,511), and proteinuria (≥1+ on dipstick, n = 12,090) separately in subjects with diabetes (n = 27,913), prediabetes (n = 100,214), and normal glucose tolerance (n = 100,651).
The prevalence of proteinuria was different among subjects with diabetes, prediabetes, and normal glucose tolerance (11.3 vs. 5.0 vs. 3.9%, respectively; P < 0.001). In subjects with diabetes, but not those with prediabetes or normal glucose tolerance, high pulse pressure was associated with proteinuria independently of significant covariates, including systolic BP (odds ratio 1.15 [95% CI 1.04–1.28]) or diastolic or mean BP (all P < 0.01). In patients with diabetes, a +1 SD increase of pulse pressure (+13 mmHg) was associated with proteinuria, even after adjustment for systolic BP (1.07 [1.00–1.13]) or diastolic or mean BP (all P < 0.05).
Among the Japanese general population, there was a significant difference in the association between high pulse pressure and proteinuria among subjects with diabetes, prediabetes, and normal glucose tolerance. Only in diabetes was high pulse pressure associated with proteinuria independent of systolic, diastolic, or mean BP levels.
PMCID: PMC3357237  PMID: 22474041
8.  Radial Basis Function-Sparse Partial Least Squares for Application to Brain Imaging Data 
Magnetic resonance imaging (MRI) data is an invaluable tool in brain morphology research. Here, we propose a novel statistical method for investigating the relationship between clinical characteristics and brain morphology based on three-dimensional MRI data via radial basis function-sparse partial least squares (RBF-sPLS). Our data consisted of MRI image intensities for multimillion voxels in a 3D array along with 73 clinical variables. This dataset represents a suitable application of RBF-sPLS because of a potential correlation among voxels as well as among clinical characteristics. Additionally, this method can simultaneously select both effective brain regions and clinical characteristics based on sparse modeling. This is in contrast to existing methods, which consider prespecified brain regions because of the computational difficulties involved in processing high-dimensional data. RBF-sPLS employs dimensionality reduction in order to overcome this obstacle. We have applied RBF-sPLS to a real dataset composed of 102 chronic kidney disease patients, while a comparison study used a simulated dataset. RBF-sPLS identified two brain regions of interest from our patient data: the temporal lobe and the occipital lobe, which are associated with aging and anemia, respectively. Our simulation study suggested that such brain regions are extracted with excellent accuracy using our method.
PMCID: PMC3666301  PMID: 23762188
9.  A Case of Cell-Free and Concentrated Ascites Reinfusion Therapy Effective for Refractory Ascites in Spontaneous Bacterial Peritonitis in a Renal Transplant Patient 
A 58-year-old Japanese male with chronic hepatitis C underwent kidney transplantation from an unrelated donor in October 1998. In December 2004, the patient was admitted for spontaneous bacterial peritonitis (SBP). Abdominal paracentesis and albumin transfusion were performed, but control of ascites was poor. A randomized, controlled study of patients with SBP showed that patients receiving cefotaxime with a high-volume albumin transfusion (50–75 g/50 kg) were significantly less likely to have irreversible renal failure and had lower mortality. Japan, however, relies on imports for 70% of its albumin formulations, which complicates high-volume albumin transfusion. Consequently, albumin transfusion is often limited to single treatments in the range of only 25 g (25%, 100 ml). A single cell-free and concentrated ascites reinfusion therapy (CART) treatment can reinfuse approximately 60 g of albumin, corresponding to a high-volume albumin transfusion capable of reducing the associated risk of infection or allergic reaction. Though this case was an SBP patient, after the ascites were found to be negative for endotoxins, CART was performed, and control of ascites was achieved without observation of fever, hypotension, or other adverse effects. CART provides greater supplementation of albumin than albumin transfusion and can be an effective modality of treatment for hypoalbuminemia in SBP patients if ascites are negative for endotoxins.
PMCID: PMC3499181  PMID: 23289021
Acute renal failure; Cell-free and concentrated ascites reinfusion therapy; Refractory ascites; Renal transplantation; Spontaneous bacterial peritonitis
10.  Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome in a Chronic Hemodialysis Patient 
Case Reports in Medicine  2012;2012:371795.
A 75-year-old male who was undergoing chronic hemodialysis developed abrupt-onset pitting edema and pain in the dorsum of both hands and feet. Biochemical analysis disclosed increased C-reactive protein, and negative rheumatoid factor and antinuclear antibody. Radiological examination showed no bony erosion. Computed tomography and gallium scintigraphy revealed no active infection or neoplasms. The clinical diagnosis was remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. The pitting edema and inflammatory response quickly subsided after low-dose prednisolone therapy. This case demonstrates that RS3PE syndrome could be a differential diagnosis in elderly patients undergoing dialysis who develop pitting edema and joint pain.
PMCID: PMC3295845  PMID: 22431931
11.  Cost-effectiveness of chronic kidney disease mass screening test in Japan 
Chronic kidney disease (CKD) is a significant public health problem. Strategy for its early detection is still controversial. This study aims to assess the cost-effectiveness of population strategy, i.e. mass screening, and Japan’s health checkup reform.
Cost-effectiveness analysis was carried out to compare test modalities in the context of reforming Japan’s mandatory annual health checkup for adults. A decision tree and Markov model with societal perspective were constructed to compare dipstick test to check proteinuria only, serum creatinine (Cr) assay only, or both.
Incremental cost-effectiveness ratios (ICERs) of mass screening compared with do-nothing were calculated as ¥1,139,399/QALY (US $12,660/QALY) for dipstick test only, ¥8,122,492/QALY (US $90,250/QALY) for serum Cr assay only and ¥8,235,431/QALY (US $91,505/QALY) for both. ICERs associated with the reform were calculated as ¥9,325,663/QALY (US $103,618/QALY) for mandating serum Cr assay in addition to the currently used mandatory dipstick test, and ¥9,001,414/QALY (US $100,016/QALY) for mandating serum Cr assay and applying dipstick test at discretion.
Taking a threshold to judge cost-effectiveness according to World Health Organization’s recommendation, i.e. three times gross domestic product per capita of ¥11.5 million/QALY (US $128 thousand/QALY), a policy that mandates serum Cr assay is cost-effective. The choice of continuing the current policy which mandates dipstick test only is also cost-effective. Our results suggest that a population strategy for CKD detection such as mass screening using dipstick test and/or serum Cr assay can be justified as an efficient use of health care resources in a population with high prevalence of the disease such as in Japan and Asian countries.
PMCID: PMC3328680  PMID: 22167460
Chronic kidney disease; Cost-effectiveness; Dipstick test; Mass screening; Proteinuria; Serum creatinine
12.  Osteoclast-like multi-nucleated giant cells in uraemic tumoral calcinosis 
NDT Plus  2009;2(2):155-157.
A 46-year-old woman under 6-year haemodialysis was admitted for uncontrollable hip pain. An X-ray film revealed calcified mass around the ‘left femur head’, which was diagnosed as calcium deposition by percutaneous biopsy. Calcinotic tissues were removed surgically, and the resected specimen revealed tumoral calcinosis caused by low bone turnover. A complete resolution of calcinotic lesions around the ‘left knee’ occurred 6 months after treatment modification. Immunohistochemistry showed recruitment of multi-nucleated giant cells positive for CD68, tartrate resistant acidic phosphatase and calcitonin receptor, indicative of osteoclast-like features. We propose the involvement of osteoclast-like cells in active resorption of tumoral calcinosis.
PMCID: PMC2655761  PMID: 19461864
calcitonin receptor; multi-nucleated giant cell; osteoclast; tumoral calcinosis
13.  Intravenous calcitriol therapy in an early stage prevents parathyroid gland growth 
Nephrology Dialysis Transplantation  2008;23(11):3662-3669.
Background. Both the phenotypic alterations of parathyroid (PT) cells, e.g. down-regulation of the calcium-sensing receptor, and the increase of the PT cell number in nodular hyperplasia are the main causes of refractory secondary hyperparathyroidism. It is of great importance to prevent PT growth in an early stage.
Methods. To examine a more effective method of calcitriol therapy for the prevention of PT hyperplasia, we randomized haemodialysis patients with mild hyperparathyroidism to receive either daily orally administered calcitriol (n = 33) or intravenous calcitriol (n = 27) over a 12-month study period. Calcitriol was modulated so as to keep the serum intact PTH level between 100 and 150 pg/ml.
Results. Both groups showed similar reductions of the serum PTH level and similar increases in serum calcium. In both groups, there were no significant changes in the serum phosphate level. Long-term daily oral calcitriol therapy failed to prevent the increase of both maximum PT volume and total volume, as assessed by ultrasonography; however, intravenous calcitriol therapy successfully suppressed this progression. In the daily, oral group, both the bone-specific alkaline phosphatase (BAP) and the N-telopeptide cross-linked of type I collagen (NTX) significantly decreased, which was probably due to the PTH suppression. However, these bone metabolism markers remained stable in the intravenous group. The total dosage of calcitriol during the study was comparable in both groups.
Conclusions. These data indicate that intravenous calcitriol therapy in an early stage of secondary hyperparathyroidism is necessary to prevent PT growth and to keep a good condition of bone metabolism.
PMCID: PMC2568009  PMID: 18515308
calcium; calcitriol; growth; parathyroid; phosphate

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