Hitoshi Sugiyama

Okayama University, Okayama, Okayama, Japan

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Publications (126)402.13 Total impact

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    ABSTRACT: Introduction: The Japan Renal Biopsy Registry (J-RBR) was started in 2007 by the Committee for the Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to clarify drug-induced kidney disease (DIKD) of renal biopsied cases in Japan. Subjects and methods: We analyzed the data of 26,535 cases that were registered in the J-RBR from 2007 to 2015. Results: Based on clinical and pathological diagnoses, 328 cases (176 males and 152 females) of renal biopsy-proven DIKD were registered in the J-RBR from 2007 to 2015 (1.24 % of all cases). The frequency of DIKD increased with age. The number of cases peaked in the 6th-8th decade in all pathological categories, except for the number of chronic tubulointerstitial lesions (CTIL), which peaked in the 4th-5th decade. Overall, the frequency of DIKD was 3 times higher in the 7th decade than in the 2nd decade (1.86 vs. 0.62 %). The main clinical diagnoses were DIKD in 150 cases (45.7 %), nephrotic syndrome in 66 cases (20.1 %), chronic nephritic syndrome in 55 cases (16.8 %), and rapidly progressive glomerulonephritis in 30 cases (9.1 %). DIKD was registered as a secondary diagnosis in 136 cases (41.5 %). The pathological findings of these cases were glomerular lesions in 105 cases (32.0 %), acute tubulointerstitial lesions (ATIL) in 87 cases (26.5 %), CTIL in 72 cases (22.0 %), and sclerotic glomerular lesions and/or nephrosclerosis in 18 cases (5.5 %). ATIL and CTIL were mainly found in cases in which DIKD was diagnosed on the basis of the patient's clinical findings. In addition, nephrotic syndrome-related membranous nephropathy (MN) was the major cause of renal damage in 59.4 % of the cases involving glomerular injuries. According to the CGA risk classification, high-risk (red zone) cases accounted for 56.1 % of all cases of DIKD and 75.9, 64.9, and 33.3 % of the cases involving ATIL, CTIL, and glomerular injuries, respectively. The causative drugs were identified in 102 cases, including bucillamine in 38 cases of MN, gemcitabine in 3 cases of thrombotic microangiopathy, and other anticancer drugs in 14 cases (anti-vascular endothelial growth factor drugs in 3 cases and propyl thiouracil in 3 cases of anti-neutrophil cytoplasmic antibody-related nephritis). Conclusion: Our analysis of the J-RBR revealed that DIKD mainly affects elderly people in Japan. ATIL or CTIL were found in approximately half of the biopsied cases of DIKD, and one-third involved glomerular lesions, mainly MN or clinical nephrotic syndrome.
    No preview · Article · Nov 2015 · Clinical and Experimental Nephrology
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    ABSTRACT: Background: The clinical presentation of Henoch-Schönlein purpura nephritis (HSPN) has not been thoroughly investigated among patients of different ages. We therefore compared the features of HSPN and IgA nephropathy (IgAN) based on data from the Japan Renal Biopsy Registry (J-RBR). Methods: This cross-sectional study analyzed data from patients who were registered in the J-RBR between 2007 and 2012. Clinico-pathological findings at diagnosis were compared among children (aged ≤18 years), adult (aged 19-64 years) and elderly (aged ≥65 years) patients with HSPN (n = 513) and IgAN (n = 5679). Results: The age at diagnosis considerably differed between HSPN and IgAN; HSPN peaked at 1-19 and at 60-69 years, whereas IgAN peaked at 30-39 years. The clinical features were significantly more severe for HSPN than IgAN, especially proteinuria (children, 1.28 vs. 0.57; adult, 1.95 vs. 1.05; elderly patients, 2.71 vs. 1.64 g/day), and low albumin levels (children, 3.72 vs. 4.13; adults, 3.62 vs. 3.99; elderly patients, 3.07 vs. 3.57 g/dL). The rate (%) of histologically classified endocapillary proliferative or crescentic glomerulonephritis was higher in patients with HSPN than with IgAN. Multiple regression analysis revealed that low albumin level and high BP were independent factors associated with decreased estimated glomerular filtration rates in adult and elderly patients with HSPN. Conclusions: Age at HSPN diagnosis was bimodally distributed, and the clinical features of HSPN were more severe than those of IgAN across all age groups.
    No preview · Article · Oct 2015 · Clinical and Experimental Nephrology
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    ABSTRACT: We report the case of a 46-year-old hypertensive Japanese female with renal insufficiency related to unilateral renal hypoplasia. The patient was found to have developed paraganglioma in the retroperitoneal space over a 5-year period. Catecholamine-producing tumors are not usually recognized as conditions associated with renal hypoplasia. Our long-term observation of the patient eventually led us to the diagnosis of paraganglioma. In hypertensive patients with chronic kidney disease, not only the renin-angiotensin-aldosterone system but also catecholamine activity may be involved, particularly in the patients whose cases are complicated with unilateral renal hypoplasia.
    No preview · Article · Apr 2015 · Acta medica Okayama

  • No preview · Article · Mar 2015 · Nephrology
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    ABSTRACT: Acute kidney injury (AKI) is frequently observed in critically ill patients in the intensive care unit (ICU) and is associated with increased mortality. Prostanoids regulate numerous biological functions, including hemodynamics and renal tubular transport. We herein investigated the ability of urinary prostanoid metabolites to predict the onset of AKI in critically ill adult patients. The current study was conducted as a prospective observational study. Urine of patients admitted to the ICU at Okayama University Hospital was collected and the urinary levels of prostaglandin E2 (PGE2), PGI2 metabolite (2,3-dinor-6-OXO-PGF1α), thromboxane A2 (TXA2) metabolite (11-dehydro-TXB2) were determined. Of the 93 patients, 24 developed AKI (AKIN criteria). Surgical intervention (93, 75 %) was the leading cause of ICU admission. Overall, the ratio of the level of serum Cr on Day 1 after ICU admission to that observed at baseline positively correlated with the urinary 2,3-dinor-6-OXO-PGF1α/Cr (r = 0.57, p < 0.0001) and 11-dehydro-TXB2/Cr (r = 0.47, p < 0.0001) ratios. In 16 cases of de novo AKI, the urinary 2,3-dinor-6-OXO-PGF1α/Cr and 11-dehydro-TXB2/Cr values were significantly elevated compared with that observed in the non-AKI group, whereas the urinary PGE2/Cr values were not. The urinary 2,3-dinor-6-OXO-PGF1α/Cr ratio exhibited the best diagnostic and predictive performance among the prostanoid metabolites according to the receiver operating characteristic (ROC) analysis [ROC-area under the curve (AUC): 0.75]. Taken together, these results demonstrate that the urinary 2,3-dinor-6-OXO-PGF1α/Cr and 11-dehydro-TXB2/Cr ratios are associated with the subsequent onset of AKI and poor outcomes in adult heterogeneous ICU patients.
    No preview · Article · Feb 2015 · Clinical and Experimental Nephrology
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    ABSTRACT: Diabetic nephropathy is the most common pathological disorder predisposing patients to end-stage renal disease. Considering the increasing prevalence of type 2 diabetes mellitus worldwide, novel therapeutic approaches are urgently needed. ONO-1301 is a novel sustained-release prostacyclin analog that inhibits thromboxane A2 synthase. Here we examined the therapeutic effects of the intermittent administration of slow-release ONO-1301 (SR-ONO) on diabetic nephropathy in obese type 2 diabetes mice, as well as its direct effects on mesangial cells. The subcutaneous injection of SR-ONO (3mg/kg) every 3 wks did not affect the obesity or hyperglycemia in the db/db obese mice used as a model of type 2 diabetes, but it significantly ameliorated their albuminuria, glomerular hypertrophy, glomerular accumulation of type IV collagen, and monocyte/macrophage infiltration, and also the increase of TGF-β1, α-smooth muscle actin (α-SMA) and MCP-1 compared to vehicle treatment. In cultured mouse mesangial cells, ONO-1301 concentration-dependently suppressed the increases in TGF-β, type IV collagen, α-SMA, MCP-1 and fibronectin induced by high ambient glucose, at least partly through prostacyclin (PGI2) receptor-mediated signaling. Taken together, these results suggest the potential therapeutic efficacy of the intermittent administration of SR-ONO against type 2 diabetic nephropathy, possibly through protective effects on mesangial cells.
    Full-text · Article · Feb 2015 · Acta medica Okayama
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    ABSTRACT: Pulmonary involvement is one of the hallmark lesions of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) as well as rapidly progressive glomerulonephritis (RPGN). However, the pulmonary involvement of AAV patients seems to differ between Europe and Japan, as does the ANCA serotype. This retrospective and prospective multicenter cohort study collected the clinical data of the features and outcomes of 1772 RPGN patients treated from 1989 to 2007 in Japan. Based on this nationwide RPGN survey, we analyzed the cases of 1147 AAV patients. We found that 52.3% of the AAV patients had pulmonary involvements: 15.4% of the AAV patients had alveolar hemorrhage (AH), 26.2% had interstitial lung disease (ILD), 2.8% had bronchial asthma, 2.4% had pulmonary granuloma and 12.8% had a chest X-ray abnormality without AH, ILD or pulmonary granuloma. Patient survival was significantly different among the following six groups: the 5-year survival rate was 41.5% in the patients with AH, 50.2% in those with ILD, 67.9% in those with bronchial asthma, 62.5% in those with pulmonary granuloma, 55.8% in those with chest X-ray abnormality and 73.3% in those without pulmonary involvement. AH was one of the predictors of 1- and 5-year mortality for patient survival in AAV, and ILD was added as one of the predictors of 5-year mortality. In these AAV patients, not only AH but also ILD was frequently observed. AH was associated with the prognosis, but ILD was associated with the long-term prognosis of AAV. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
    No preview · Article · Jan 2015 · Nephrology Dialysis Transplantation

  • No preview · Article · Jan 2015 · Journal of Diabetes Mellitus
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    ABSTRACT: It has been reported that cyclosporine A (CsA) treatment may be associated with posterior reversible encephalopathy syndrome. We report a 16-year-old man who exhibited nephrotic syndrome and posterior reversible encephalopathy syndrome. Intensive antihypertensive therapy restored him to consciousness. Renal biopsy revealed that he suffered from focal segmental glomerulosclerosis. Although he was treated with prednisolone and low-density lipoprotein apheresis therapy, his proteinuria remained at high level. Then, mycophenolate mofetil (MMF) with less influence on vessel endothelium compared with CsA and tacrolimus was administered. Soon after, he reached remission of nephrotic syndrome without recurrence of posterior reversible encephalopathy syndrome. This is the first case that a young patient of focal segmental glomerulosclerosis with posterior reversible encephalopathy syndrome achieved a complete remission by MMF treatment without recurrence of posterior reversible encephalopathy syndrome. MMF may be effective for young patients of focal segmental glomerulosclerosis especially with clinical condition of vascular endothelial damage such as posterior reversible encephalopathy syndrome.
    No preview · Article · Dec 2014
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    ABSTRACT: Vasohibin-1 (VASH1) is a unique endogenous inhibitor of angiogenesis that is induced in endothelial cells by pro-angiogenic factors. We previously reported renoprotective effect of adenoviral delivery of VASH1 in diabetic nephropathy model, and herein investigated the potential protective role of endogenous VASH1 by using VASH1-deficient mice. Streptozotocin-induced type 1 diabetic VASH1 heterozygous knockout mice (VASH1+/-) or wild-type diabetic mice were sacrificed 16 weeks after inducing diabetes. In the diabetic VASH1+/- mice, albuminuria were significantly exacerbated compared with the diabetic wild-type littermates, in association with the dysregulated distribution of glomerular slit diaphragm related proteins, nephrin and ZO-1, glomerular basement membrane thickning and reduction of slit diaphragm density. Glomerular monocyte/macrophage infiltration and glomerular nuclear translocation of phosphorylated NF-κB p65 were significantly exacerbated in the diabetic VASH1+/- mice compared with the diabetic wild-type littermates, accompanied by the augmentation of VEGF-A, M1 macrophage-derived MCP-1 and phosphorylation of IκBα, and the decrease of angiopoietin-1/2 ratio and M2 macrophage-derived Arginase-1. The glomerular CD31+ endothelial area was also increased in the diabetic VASH1+/- mice compared with the diabetic-wild type littermates. Furthermore, the renal and glomerular hypertrophy, glomerular accumulation of mesangial matrix and type IV collagen and activation of renal TGF-β1/Smad3 signaling, a key mediator of renal fibrosis, were exacerbated in the diabetic VASH1+/- mice compared with the diabetic wild-type littermates. In conditionally immortalized mouse podocytes cultured under high glucose condition, transfection of VASH1 small interfering RNA (siRNA) resulted in the reduction of nephrin, angiopoietin-1 and ZO-1, and the augmentation of VEGF-A compared with control siRNA. These results suggest that endogenous VASH1 may regulate the development of diabetic renal alterations, partly via direct effects on podocytes, and thus, a strategy to recover VASH1 might potentially lead to the development of a novel therapeutic approach for diabetic nephropathy.
    Full-text · Article · Sep 2014 · PLoS ONE
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    ABSTRACT: Background and objectives There are very little data available regarding nephrotic syndrome (NS) in elderly (aged ≥65 years) Japanese. The aim of this study was to examine the causes and outcomes of NS in elderly patients who underwent renal biopsies between 2007 and 2010. Design, setting, participants, and measurements From July 2007 to June 2010, all of the elderly (aged ≥65 years) Japanese primary NS patients who underwent native renal biopsies and were registered in the Japan renal biopsy registry (J-RBR; 438 patients including 226 males and 212 females) were identified. From this cohort, 61 patients [28 males and 33 females including 29, 19, 6, 4, and 3 patients with membranous nephropathy (MN), minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN), and other conditions, respectively] were registered from the representative multi-centers over all districts of Japan, and analyzed retrospectively. The treatment outcome was assessed using proteinuria-based criteria; i.e., complete remission (CR) was defined as urinary protein level of
    Preview · Article · Sep 2014 · Clinical and Experimental Nephrology
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    ABSTRACT: Experimental studies have demonstrated the involvement of angiogenesis-related factors in the progression of chronic kidney disease (CKD). There have so far been no reports investigating the distribution and clinical roles of Vasohibin-1 (VASH-1), a negative feedback regulator of angiogenesis, in CKD. We recruited 54 Japanese CKD patients and 6 patients who had normal renal tissues excised due to localized renal cell carcinoma. We evaluated the correlations between the renal expression level of VASH-1 and the clinical/histological parameters. VASH-1 was observed in renal endothelial/mesangial cells, crescentic lesions and interstitial inflammatory cells. Significant positive correlations were observed between 1) crescent formation and the number of VASH-1+ cells in the glomerulus (r=0.48, p=0.001) or cortex (r=0.64, p<0.0001), 2) interstitial cell infiltration and the number of VASH-1+ cells in the cortex (r=0.34, p=0.02), 3) the glomerular VEGFR-2+ area and the number of VASH-1+ cells in the glomerulus (r=0.44, p=0.01) or medulla (r=0.63, p=0.01). These results suggest that the renal levels of VASH-1 may be affected by local inflammation, crescentic lesions and VEGFR-2.
    Full-text · Article · Aug 2014 · Acta medica Okayama
  • Hiroshi Sato · Hitoshi Sugiyama · Hitoshi Yokoyama

    No preview · Article · Jun 2014 · Nippon Jinzo Gakkai shi
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    ABSTRACT: Background: This study aimed to describe the influences of larger physical constitutions including obesity on the amount of urine protein excretion (AUPE) in primary glomerulonephritis. The distinct effects on the AUPE in various types of glomerulonephritis were evaluated. Methods: Using the database of the Japan Renal Biopsy Registry (J-RBR) from 2007 to 2010, 4060 cases with primary glomerulonephritis including MCNS, FSGS, MN, MPGN, IgAN, and non-IgA were reviewed. The AUPEs were compared between high and low Body Mass Index (BMI) groups, and larger and smaller body surface area (BSA) groups using the indexes of BMI 25.0 kg/m(2) and BSA 1.73 m(2) in all cases and in each histological group. Multivariable analysis was performed to evaluate the predominant contributors to the AUPE. Results: The larger physical constitution groups (BMI ≥25.0 kg/m(2) or BSA ≥1.73 m(2)) had significantly higher AUPEs in all cases with primary glomerulonephritis. When compared in each histological group, the mean AUPEs were significantly higher in the larger physical constitution groups, excluding the FSGS and non-IgA groups. Multiple regression analysis revealed that the significant contributors to the AUPE were BMI and BSA in MCNS and MN, whereas BMI and BSA were not significant and mean blood pressure and serum creatinine were significant in FSGS and non-IgA. Conclusion: Larger physical constitutions including obesity had a significant impact on the increase in the AUPE in primary glomerulonephritis, especially in MCNS and MN. However, FSGS and non-IgA were distinct for having blood pressure and renal dysfunction as possibly the major causes of proteinuria.
    No preview · Article · Jun 2014 · Clinical and Experimental Nephrology
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    ABSTRACT: Vasohibin-1 (VASH-1) is a negative feedback regulator of angiogenesis, and a small vasohibin-binding protein (SVBP) serves as its secretory chaperone and contributes to its antiangiogenic effects. In the present study, we aimed to define the clinical significance of VASH-1 and SVBP in patients with chronic kidney disease (CKD). We recruited 67 Japanese hospitalized patients with renal disorders with (n = 45) or without (n = 22) renal biopsy samples and 10 Japanese healthy controls. We evaluated the correlations between the plasma and urinary levels of VASH-1/VASH-1-SVBP complex/SVBP and the clinicopathological parameters. The plasma levels of VASH-1 were inversely correlated with age and systolic and diastolic blood pressure and positively correlated with crescent formation. Increased plasma and urinary levels of VASH-1 and VASH-1-SVBP complex were significantly correlated with worse renal outcomes. These results demonstrate an association between elevated urinary and plasma levels of VASH-1 and progressive decline of the renal function, thus suggesting a potential role for VASH-1 in predicting a worse renal prognosis in patients with renal disease, including CKD.
    Full-text · Article · Jun 2014 · PLoS ONE
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    ABSTRACT: Tubulointerstitial injuries are known to predict the deterioration of renal function in chronic kidney disease (CKD). We recently reported the protective role of Vasohibin-1(VASH-1), a negative feedback regulator of angiogenesis, in diabetic nephropathy, but its impact on tubulointerstitial injuries remains to be elucidated. In the present study, we evaluated the role of endogenous VASH-1 in regulating the tubulointerstitial alterations induced by unilateral ureteral obstruction (UUO), and assessed its role on fibrogenesis and the activation of Smad3 signaling in renal fibroblasts. UUO was induced in female Vasohibin-1 heterozygous knockout mice (VASH-1+/−) or wild-type (WT) (VASH-1+/+) littermates. Mice were sacrificed on Day 7 after left ureter ligation, and the kidney tissue was obtained. Interstitial fibrosis, the accumulation of type I and type III collagen and monocytes/macrophages infiltration in the obstructed kidneys (OBK) were significantly exacerbated in VASH-1+/− mice compared with WT mice (Day 7). The increases in the renal levels of TGF-β1, pSmad3, NF-κB pp65, CCL2 mRNA, and the number of interstitial fibroblast-specific protein-1 (FSP-1)+ fibroblasts in the OBK were significantly aggravated in VASH-1+/− mice. In addition, treatment with VASH-1 siRNA enhanced the TGF-β1-induced phosphorylation of Smad3, the transcriptional activation of the Smad3 pathway and the production of type I/type III collagen in fibroblasts, in vitro. Taken together, our findings demonstrate a protective role for endogenous VASH-1 on tubulointerstitial alterations via its regulation of inflammation and fibrosis and also show the direct anti-fibrotic effects of VASH-1 on renal fibroblasts through its modulation of TGF-β1 signaling.
    Full-text · Article · Jun 2014
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    ABSTRACT: A 64-year-old man suffering polyarthralgia and bone pain was referred to our hospital. Renal dysfunction, hypophosphatemia and increased levels of bone alkaline phosphatase were found. The patient's serum creatinine level had gradually increased after the initiation of adefovir dipivoxil administration for hepatitis B. In agreement with multifocal uptakes of bone scintigraphy, iliac bone biopsy revealed an abnormal increase in osteoid tissues. Reducing the dose of adefovir and initiating the administration of eldecalcitol were effective for reducing proteinuria and glucosuria, and for ameliorating bone pain with an increase in serum phosphate level. This case first showed a clinical course of hypophosphatemic osteomalacia caused by secondary Fanconi's syndrome for 8 years after adefovir administration. Early diagnosis is important for the reversibility of bone damage and for a better renal prognosis.
    No preview · Article · Feb 2014 · Acta medica Okayama
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    ABSTRACT: Disturbed mineral metabolism in patients with chronic kidney disease (CKD), known as CKD-mineral and bone disorder (CKD-MBD), is associated with bone disease as well as a high risk of cardiovascular disease (CVD) and reduced patient survival due to the development of vascular calcification. Hyperphosphatemia is a risk factor for vascular calcification, CVD, and mortality. The fibroblast growth factor-23 (FGF-23)-Klotho system plays a key role in the regulation of mineral metabolism. Klotho was originally identified as an aging-suppressor gene and is predominantly expressed in the distal renal tubules. Klotho exists in two forms: membrane Klotho functions as an obligate coreceptor for FGF-23 in the kidneys and parathyroid gland, while secreted Klotho functions as a humoral factor with antiaging, renoprotective, and cardiovascular protective properties. The urinary and circulating Klotho levels have been found to be decreased in patients with acute kidney injury and CKD, and experimental studies have shown that Klotho has beneficial effects on the vascular system. Furthermore, Klotho exerts pleiotropic effects on the endothelium, including anti-inflammatory, antithrombotic, and vasodilatory effects, and increases the availability of nitric oxide, and Klotho deficiency is associated with the vascular calcification observed in CKD patients. Therefore, soluble Klotho has the potential to serve as a biomarker for diagnosing early CKD and predicting the progression of both CKD and CVD. The renoprotective and cardiovascular protective functions of Klotho have also led researchers to hope that this protein may be used as a therapeutic agent for improving the kidney function and CVD.
    No preview · Chapter · Jan 2014
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    ABSTRACT: Long-term peritoneal dialysis (PD) causes chronic peritoneal damage. Peritoneal mesothelial cells (PMCs) play an important role for peritoneal function. We investigated the possibility of cell therapy using the PMCs to prevent peritoneal damage in PD patients. We harvested human PMCs from the peritoneal dialysis effluent of PD patients. The PMCs were separated based on morphological characteristics into epithelial-like (Epi) cells and fibroblast-like (Fib) cells by the limiting dilution method. We transplanted these cells into nude mice whose parietal and visceral peritoneum were scratched by mechanical scraping. The transplanted cells were detected at the parietal and visceral peritoneum. Compared with the positive control, the Epi cell therapy group showed very few adhesions and exhibited no thickening of the parietal and visceral peritoneum. However, the group with Fib cell therapy could not inhibit peritoneal adhesion and thickening. In addition, HGF was expressed by the grafted Epi cells but not Fib cells. Fib cells expressed VEGF stronger than Epi cells. These two types of cells from same patient showed different character and effect for cell therapy. These findings suggest that the PMCs from the PD patient showed different character, such as Epi cells and Fib cells, and the selection of PMCs is important for cell therapy on the point of not only the direct cellular interactions but also cytokine secretion from the grafted cells. Furthermore, the differences in the morphological cell characteristics may influence their role in peritoneal regeneration.
    No preview · Article · Sep 2013 · Tissue Engineering Part A
  • Hitoshi Sugiyama · Hiroshi Sato · Yoshihiko Ueda · Hitoshi Yokoyama

    No preview · Article · May 2013 · Nihon Naika Gakkai Zasshi