2021/04/08 更新

写真a

ウチダ ハルヒト
内田 治仁
UCHIDA Haruhito
所属
医歯薬学域 教授(特任)
職名
教授(特任)
外部リンク

研究分野

  • ライフサイエンス / 内科学一般

学歴

  • 岡山大学   医学部大学院医学研究科  

    1999年4月 - 2006年3月

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    国名: 日本国

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  • 岡山大学   医学部   医学科

    1993年4月 - 1999年3月

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    国名: 日本国

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所属学協会

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論文

  • Vasohibin-2 Aggravates Development of Ascending Aortic Aneurysms But Not Abdominal Aortic Aneurysms Nor Atherosclerosis in ApoE Deficient Mice. 国際誌

    Nozomu Otaka, Haruhito A Uchida, Michihiro Okuyama, Yoshiko Hada, Yasuhiro Onishi, Yuki Kakio, Hidemi Takeuchi, Ryoko Umebayashi, Katsuyuki Tanabe, Venkateswaran Subramanian, Alan Daugherty, Yasufumi Sato, Jun Wada

    American journal of hypertension   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Vasohibin-2 (VASH2) has been isolated as a homologue of vasohibin-1 (VASH1) that promote angiogenesis counteracting with VASH1. Chronic angiotensin II (AngII) infusion promotes both ascending and abdominal aortic aneurysms (AAs) in mice. The present study aimed to investigate whether exogenous VASH2 influenced AngII-induced vascular pathology in apolipoprotein E deficient (ApoE  -/-) mice. METHODS: Male, ApoE  -/- mice (9 to 14 weeks old) were injected with Ad LacZ or Ad VASH2. After a week, saline or AngII (1,000 ng/kg/min) was infused into the mice subcutaneously via mini-osmotic pumps for 3 weeks. Consequently, all these mice were divided into 4 groups: saline + LacZ (n=5), saline + VASH2 (n=5), AngII + LacZ (n=18), and AngII + VASH2 (n=17). RESULTS: Exogenous VASH2 had no significant effect on ex vivo maximal diameters of abdominal aortas (AngII + LacZ; 1.67±0.17 mm, AngII + VASH2; 1.52±0.16 mm, n.s.) or elastin fragmentation and accumulation of inflammatory cells. Conversely, exogenous VASH2 significantly increased intima areas of aortic arches (AngII + LacZ; 16.6±0.27 mm 2, AngII + VASH2; 18.6±0.64 mm 2, p=0.006). VASH2 effect of AngII-induced ascending AAs was associated with increased cleaved caspase-3 abundance. AngII-induced atherosclerosis was not altered by VASH2. CONCLUSION: The present study demonstrated that augmented VASH2 expression had no effect of AngII-induced abdominal AAs or atherosclerosis, while increasing dilation in the ascending aorta.

    DOI: 10.1093/ajh/hpaa181

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  • Inhibition of Interleukin-6 Signaling Attenuates Aortitis, Left Ventricular Hypertrophy and Arthritis in Interleukin-1 Receptor Antagonist Deficient Mice. 査読 国際誌

    Yoshiko Hada, Haruhito A Uchida, Tomoyuki Mukai, Fumiaki Kojima, Masashi Yoshida, Hidemi Takeuchi, Yuki Kakio, Nozomu Otaka, Yoshitaka Morita, Jun Wada

    Clinical science (London, England : 1979)   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The aim of this study was to examine whether inhibition of Interleukin (IL)-6 signaling by MR16-1, an IL-6 receptor antibody, attenuates aortitis, cardiac hypertrophy, and arthritis in IL-1 receptor antagonist deficient (IL-1RA KO) mice.  Four weeks old mice were intraperitoneally administered with either MR16-1 or non-immune IgG at dosages that were adjusted over time for 5 weeks.  These mice were stratified into 4 groups: MR16-1 treatment groups, KO/MR low group (first 2.0 mg, following 0.5 mg/week, n=14) and KO/MR high group (first 4.0 mg, following 2.0 mg/week, n=19) in IL-1RA KO mice, and IgG treatment groups, KO/IgG group (first 2.0 mg, following 1.0 mg/week, n=22) in IL-1RA KO mice, and wild/IgG group (first 2.0 mg, following 1.0 mg/week, n=17) in wild mice.  Aortitis, cardiac hypertrophy and arthropathy were histologically analyzed.  Sixty-eight % of the KO/IgG group developed aortitis (53% developed severe aortitis).  In contrast, only 21% of the KO/MR high group developed mild aortitis, without severe aortitis (P<0.01, vs KO/IgG group).  Infiltration of inflammatory cells, such as neutrophils, T cells, and macrophages, was frequently observed around aortic sinus of the KO/IgG group.  Left ventricle and cardiomyocyte hypertrophy were observed in IL-1RA KO mice.  Administration of high dosage of MR16-1 significantly suppressed cardiomyocyte hypertrophy.  MR16-1 attenuated the incidence and severity of arthritis in IL-1RA KO mice in a dose-dependent manner.  In conclusion, blockade of IL-6 signaling may exert a beneficial effect to attenuate severe aortitis, left ventricle hypertrophy, and arthritis.

    DOI: 10.1042/CS20201036

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  • Low-dose rituximab induction therapy is effective in immunological high-risk renal transplantation without increasing cytomegalovirus infection. 査読 国際誌

    Kasumi Yoshinaga, Motoo Araki, Koichiro Wada, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Yasuyuki Kobayashi, Hidemi Takeuchi, Katsuyuki Tanabe, Masashi Kitagawa, Hiroshi Morinaga, Haruhito Adam Uchida, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Yasutomo Nasu

    International journal of urology : official journal of the Japanese Urological Association   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: To analyze the effect and impact of low-dose rituximab induction therapy on cytomegalovirus infection in living-donor renal transplantation. METHODS: A total of 92 recipients undergoing living-donor renal transplantation at Okayama University Hospital from May 2009 to August 2018 were evaluated retrospectively. Indications for preoperative rituximab (200 mg/body) were the following: (i) ABO major mismatch; (ii) ABO minor mismatch; (iii) donor-specific anti-human leukocyte antigen antibody-positive; and (iv) focal segmental glomerulosclerosis. We excluded four recipients who were followed <3 months, five who received >200 mg/body rituximab and seven who received prophylactic therapy for cytomegalovirus. RESULTS: There were 59 patients in the rituximab group and 17 in the non-rituximab group. Groups differed significantly in age (median age 53 vs 37 years, respectively; P = 0.04), but not in sex (male 64% vs 65%, P = 1.00), focal segmental glomerulosclerosis (3% vs 0%, P = 1.00) or percentage of cytomegalovirus-seronegative recipients of renal allografts from cytomegalovirus-seropositive donors (12% vs 18%, P = 0.68). The estimated glomerular filtration rate did not differ significantly between groups until 24 months after transplantation. Cytomegalovirus clinical symptoms (10% vs 24%, P = 0.22), including fever ≥38°C (5% vs 12%, P = 0.31) and gastrointestinal symptoms (5% vs 12%, P = 0.31), and the 5-year survival rates of death-censored graft loss (90% vs 83%, P = 0.43) did not differ significantly between groups. CONCLUSIONS: Low-dose rituximab induction therapy is effective in immunological high-risk recipients without increasing cytomegalovirus infection in the absence of valganciclovir prophylaxis.

    DOI: 10.1111/iju.14382

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  • Dysfunction of CD8 + PD-1 + T cells in type 2 diabetes caused by the impairment of metabolism-immune axis. 査読 国際誌

    Ichiro Nojima, Shingo Eikawa, Nahoko Tomonobu, Yoshiko Hada, Nobuo Kajitani, Sanae Teshigawara, Satoshi Miyamoto, Atsuhito Tone, Haruhito A Uchida, Atsuko Nakatsuka, Jun Eguchi, Kenichi Shikata, Heiichiro Udono, Jun Wada

    Scientific reports10 ( 1 ) 14928 - 14928   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The metabolic changes and dysfunction in CD8 + T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D). In C57BL/6JJcl mice fed with high fat-high sucrose chow (HFS), multifunctionality of CD8 + splenic and tumor-infiltrating lymphocytes (TILs) was impaired and associated with enhanced tumor growth, which were inhibited by metformin. In CD8 + splenic T cells from the HFS mice, glycolysis/basal respiration ratio was significantly reduced and reversed by metformin. In the patients with T2D (DM), multifunctionality of circulating CD8 + PD-1 + T cells stimulated with PMA/ionomycin as well as with HLA-A*24:02 CMV peptide was dampened, while metformin recovered multifunctionality. Both glycolysis and basal respiration were reduced in DM, and glycolysis was increased by metformin. The disturbance of the link between metabolism and immune function in CD8 + PD-1 + T cells in T2D was proved by recovery of antigen-specific and non-specific cytokine production via metformin-mediated increase in glycolytic activity.

    DOI: 10.1038/s41598-020-71946-3

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  • Tubulointerstitial Nephritis Cases With IgM-Positive Plasma Cells. 査読 国際誌

    Natsumi Matsuoka-Uchiyama, Kenji Tsuji, Kazuhiko Fukushima, Shinji Kitamura, Haruhito A Uchida, Hitoshi Sugiyama, Naoki Takahashi, Masayuki Iwano, Jun Wada

    Kidney international reports5 ( 9 ) 1576 - 1580   2020年9月

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  • The Protective Effect of Chlorogenic Acid on Vascular Senescence via the Nrf2/HO-1 Pathway. 査読 国際誌

    Yoshiko Hada, Haruhito A Uchida, Nozomu Otaka, Yasuhiro Onishi, Shugo Okamoto, Mariko Nishiwaki, Rika Takemoto, Hidemi Takeuchi, Jun Wada

    International journal of molecular sciences21 ( 12 )   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The world faces the serious problem of aging. In this study, we aimed to investigate the effect of chlorogenic acid (CGA) on vascular senescence. C57/BL6 female mice that were 14 ± 3 months old were infused with either Angiotensin II (AngII) or saline subcutaneously for two weeks. These mice were administered CGA of 20 or 40 mg/kg/day, or saline via oral gavage. AngII infusion developed vascular senescence, which was confirmed by senescence associated-β-galactosidase (SA-β-gal) staining. CGA administration attenuated vascular senescence in a dose-dependent manner, in association with the increase of Sirtuin 1 (Sirt1) and endothelial nitric oxide synthase (eNOS), and with the decrease of p-Akt, PAI-1, p53, and p21. In an in vitro study, with or without pre-treatment of CGA, Human Umbilical Vein Endothelial Cells (HUVECs) were stimulated with H2O2 for an hour, then cultured in the absence or presence of 0.5-5.0 μM CGA for the indicated time. Endothelial cell senescence was induced by H2O2, which was attenuated by CGA treatment. Pre-treatment of CGA increased Nrf2 in HUVECs. After H2O2 treatment, translocation of Nrf2 into the nucleus and the subsequent increase of Heme Oxygenase-1 (HO-1) were observed earlier in CGA-treated cells. Furthermore, the HO-1 inhibitor canceled the beneficial effect of CGA on vascular senescence in mice. In conclusion, CGA exerts a beneficial effect on vascular senescence, which is at least partly dependent on the Nuclear factor erythroid 2-factor 2 (Nrf2)/HO-1 pathway.

    DOI: 10.3390/ijms21124527

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  • Effect of Angiotensin II on Bone Erosion and Systemic Bone Loss in Mice with Tumor Necrosis Factor-Mediated Arthritis. 査読 国際誌

    Takahiko Akagi, Tomoyuki Mukai, Takafumi Mito, Kyoko Kawahara, Shoko Tsuji, Shunichi Fujita, Haruhito A Uchida, Yoshitaka Morita

    International journal of molecular sciences21 ( 11 )   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Angiotensin II (Ang II) is the main effector peptide of the renin-angiotensin system (RAS), which regulates the cardiovascular system. The RAS is reportedly also involved in bone metabolism. The upregulation of RAS components has been shown in arthritic synovial tissues, suggesting the potential involvement of Ang II in arthritis. Accordingly, in the present study, we investigated the role of Ang II in bone erosion and systemic bone loss in arthritis. Ang II was infused by osmotic pumps in tumor necrosis factor-transgenic (TNFtg) mice. Ang II infusion did not significantly affect the severity of clinical and histological inflammation, whereas bone erosion in the inflamed joints was significantly augmented. Ang II administration did not affect the bone mass of the tibia or vertebra. To suppress endogenous Ang II, Ang II type 1 receptor (AT1R)-deficient mice were crossed with TNFtg mice. Genetic deletion of AT1R did not significantly affect inflammation, bone erosion, or systemic bone loss. These results suggest that excessive systemic activation of the RAS can be a risk factor for progressive joint destruction. Our findings indicate an important implication for the pathogenesis of inflammatory bone destruction and for the clinical use of RAS inhibitors in patients with rheumatoid arthritis.

    DOI: 10.3390/ijms21114145

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  • Frailty Raises as a New Target in Patients with Chronic Hemodialysis in any Country and the Problem we Should Solve 査読

    Hidemi Takeuchi, Haruhito A Uchida, Jun Wada

    Journal of Clinical Trials10 ( 3 )   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Targeting Mitochondrial Fission as a Potential Therapeutic for Abdominal Aortic Aneurysm. 査読 国際誌

    Hannah A Cooper, Stephanie Cicalese, Kyle J Preston, Tatsuo Kawai, Keisuke Okuno, Eric T Choi, Shingo Kasahara, Haruhito A Uchida, Nozomu Otaka, Rosario Scalia, Victor Rizzo, Satoru Eguchi

    Cardiovascular research   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIMS: Angiotensin II is a potential contributor to the development of abdominal aortic aneurysm (AAA). In aortic vascular smooth muscle cells, exposure to angiotensin II induces mitochondrial fission via dynamin-related protein 1 (Drp1). However, pathophysiological relevance of mitochondrial morphology in angiotensin II-associated AAA remains unexplored. Here, we tested the hypothesis that mitochondrial fission is involved in the development of AAA. METHODS AND RESULTS: Immunohistochemistry was performed on human AAA samples and revealed enhanced expression of Drp1. In C57BL6 mice treated with angiotensin II plus β-aminopropionitrile, AAA tissue also showed an increase in Drp1 expression. A mitochondrial fission inhibitor, mdivi1, attenuated AAA size, associated aortic pathology, Drp1 protein induction and mitochondrial fission but not hypertension in these mice. Moreover, Western blot analysis showed that induction of matrix metalloproteinase-2, which precedes the development of AAA, was blocked by mdivi1. Mdivi1 also reduced the development of AAA in apolipoprotein E deficient mice infused with angiotensin II. As with mdivi1, Drp1+/- mice treated with angiotensin II plus β-aminopropionitrile showed a decrease in AAA compared to control Drp1+/+ mice. In abdominal aortic vascular smooth muscle cells, angiotensin II induced phosphorylation of Drp1 and mitochondrial fission, the latter of which was attenuated with Drp1 silencing as well as mdivi1. Angiotensin II also induced vascular cell adhesion molecule-1 expression and enhanced leukocyte adhesion and mitochondrial oxygen consumption in smooth muscle cells, which were attenuated with mdivi1. CONCLUSION: These data indicate that Drp1 and mitochondrial fission play salient roles in AAA development, which likely involves mitochondrial dysfunction and inflammatory activation of vascular smooth muscle cells. TRANSLATIONAL PERSPECTIVES: Mitochondrial fission/fusion regulation is critical to maintain mitochondrial homeostasis. A shift toward mitochondrial fission is associated with a variety of cardiovascular diseases. A GTPase, Drp1 is known to mediate mitochondrial fission and we found evidence of Drp1 dysregulation in human and mouse abdominal aortic aneurysms (AAA). The results from the present study demonstrate that pharmacological as well as genetic inhibition of mitochondrial fission via Drp1 prevents AAA formation and vascular smooth muscle aneurysmal phenotype in mouse models of the disease. These data indicate that intervening in this pathway may have therapeutic potential for treating AAA.

    DOI: 10.1093/cvr/cvaa133

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  • Associated factors of poor treatment outcomes in patients with giant cell arteritis: clinical implication of large vessel lesions. 査読 国際誌

    Takahiko Sugihara, Hitoshi Hasegawa, Haruhito A Uchida, Hajime Yoshifuji, Yoshiko Watanabe, Eisuke Amiya, Yasuhiro Maejima, Masanori Konishi, Yohko Murakawa, Noriyoshi Ogawa, Shunsuke Furuta, Yasuhiro Katsumata, Yoshinori Komagata, Taio Naniwa, Takahiro Okazaki, Yoshiya Tanaka, Tsutomu Takeuchi, Yoshikazu Nakaoka, Yoshihiro Arimura, Masayoshi Harigai, Mitsuaki Isobe

    Arthritis research & therapy22 ( 1 ) 72 - 72   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Relapses frequently occur in giant cell arteritis (GCA), and long-term glucocorticoid therapy is required. The identification of associated factors with poor treatment outcomes is important to decide the treatment algorithm of GCA. METHODS: We enrolled 139 newly diagnosed GCA patients treated with glucocorticoids between 2007 and 2014 in a retrospective, multi-center registry. Patients were diagnosed with temporal artery biopsy, 1990 American College of Rheumatology classification criteria, or large vessel lesions (LVLs) detected by imaging based on the modified classification criteria. Poor treatment outcomes (non-achievement of clinical remission by week 24 or relapse during 52 weeks) were evaluated. Clinical remission was defined as the absence of clinical signs and symptoms in cranial and large vessel areas, polymyalgia rheumatica (PMR), and elevation of C-reactive protein (CRP) levels. A patient was determined to have a relapse if he/she had either one of the signs and symptoms that newly appeared or worsened after achieving clinical remission. Re-elevation of CRP without clinical manifestations was considered as a relapse if other causes such as infection were excluded and the treatment was intensified. Associated factors with poor treatment outcomes were analyzed by using the Cox proportional hazard model. RESULTS: Cranial lesions, PMR, and LVLs were detected in 77.7%, 41.7%, and 52.5% of the enrolled patients, respectively. Treatment outcomes were evaluated in 119 newly diagnosed patients who were observed for 24 weeks or longer. The mean initial dose of prednisolone was 0.76 mg/kg/day, and 29.4% received any concomitant immunosuppressive drugs at baseline. Overall, 41 (34.5%) of the 119 patients had poor treatment outcomes; 13 did not achieve clinical remission by week 24, and 28 had a relapse after achieving clinical remission. Cumulative rates of the events of poor treatment outcomes in patients with and without LVLs were 47.5% and 17.7%, respectively. A multivariable model showed the presence of LVLs at baseline was significantly associated with poor treatment outcomes (adjusted hazard ratio [HR] 3.54, 95% CI 1.52-8.24, p = 0.003). Cranial lesions and PMR did not increase the risk of poor treatment outcomes. CONCLUSION: The initial treatment intensity in the treatment algorithm of GCA could be determined based upon the presence or absence of LVLs detected by imaging at baseline.

    DOI: 10.1186/s13075-020-02171-6

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  • JCS 2017 Guideline on Management of Vasculitis Syndrome - Digest Version. 査読

    Mitsuaki Isobe, Koichi Amano, Yoshihiro Arimura, Akihiro Ishizu, Shuichi Ito, Shinya Kaname, Shigeto Kobayashi, Yoshinori Komagata, Issei Komuro, Kimihiro Komori, Kei Takahashi, Kazuo Tanemoto, Hitoshi Hasegawa, Masayoshi Harigai, Shouichi Fujimoto, Tatsuhiko Miyazaki, Tetsuro Miyata, Hidehiro Yamada, Akitoshi Yoshida, Takashi Wada, Yoshinori Inoue, Haruhito A Uchida, Hideki Ota, Takahiro Okazaki, Mitsuho Onimaru, Tamihiro Kawakami, Reiko Kinouchi, Atsushi Kurata, Hisanori Kosuge, Ken-Ei Sada, Kunihiro Shigematsu, Eiichi Suematsu, Eijun Sueyoshi, Takahiko Sugihara, Hitoshi Sugiyama, Mitsuhiro Takeno, Naoto Tamura, Michi Tsutsumino, Hiroaki Dobashi, Yoshikazu Nakaoka, Kenji Nagasaka, Yasuhiro Maejima, Hajime Yoshifuji, Yoshiko Watanabe, Shoichi Ozaki, Takeshi Kimura, Hiroshi Shigematsu, Keiko Yamauchi-Takihara, Toyoaki Murohara, Shin-Ichi Momomura

    Circulation journal : official journal of the Japanese Circulation Society84 ( 2 ) 299 - 359   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1253/circj.CJ-19-0773

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  • Podocyte autophagy is associated with foot process effacement and proteinuria in patients with minimal change nephrotic syndrome. 査読 国際誌

    Ayu Ogawa-Akiyama, Hitoshi Sugiyama, Masashi Kitagawa, Keiko Tanaka, Yuzuki Kano, Koki Mise, Nozomu Otaka, Katsuyuki Tanabe, Hiroshi Morinaga, Masaru Kinomura, Haruhito A Uchida, Jun Wada

    PloS one15 ( 1 ) e0228337   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Autophagy is a cellular mechanism involved in the bulk degradation of proteins and turnover of organelle. Several studies have shown the significance of autophagy of the renal tubular epithelium in rodent models of tubulointerstitial disorder. However, the role of autophagy in the regulation of human glomerular diseases is largely unknown. The current study aimed to demonstrate morphological evidence of autophagy and its association with the ultrastructural changes of podocytes and clinical data in patients with idiopathic nephrotic syndrome, a disease in which patients exhibit podocyte injury. The study population included 95 patients, including patients with glomerular disease (minimal change nephrotic syndrome [MCNS], n = 41; idiopathic membranous nephropathy [IMN], n = 37) and 17 control subjects who underwent percutaneous renal biopsy. The number of autophagic vacuoles and the grade of foot process effacement (FPE) in podocytes were examined by electron microscopy (EM). The relationships among the expression of autophagic vacuoles, the grade of FPE, and the clinical data were determined. Autophagic vacuoles were mainly detected in podocytes by EM. The microtubule-associated protein 1 light chain 3 (LC3)-positive area was co-localized with the Wilms tumor 1 (WT1)-positive area on immunofluorescence microscopy, which suggested that autophagy occurred in the podocytes of patients with MCNS. The number of autophagic vacuoles in the podocytes was significantly correlated with the podocyte FPE score (r = -0.443, p = 0.004), the amount of proteinuria (r = 0.334, p = 0.033), and the level of serum albumin (r = -0.317, p = 0.043) in patients with MCNS. The FPE score was a significant determinant for autophagy after adjusting for the age in a multiple regression analysis in MCNS patients (p = 0.0456). However, such correlations were not observed in patients with IMN or in control subjects. In conclusion, the results indicated that the autophagy of podocytes is associated with FPE and severe proteinuria in patients with MCNS. The mechanisms underlying the activation of autophagy in association with FPE in podocytes should be further investigated in order to elucidate the pathophysiology of MCNS.

    DOI: 10.1371/journal.pone.0228337

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  • The Aging Population and Research into Treatments for Abdominal Aortic Aneurysms. 査読

    Ryoko Umebayashi, Haruhito Adam Uchida, Jun Wada

    Acta medica Okayama73 ( 6 ) 475 - 477   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Abdominal aortic aneurysms (AAAs) usually expand asymptomatically until the occurrence of a life-threatening event such as aortic rupture, which is closely associated with high mortality. AAA and aortic dissection are ranked among the top 10 causes of death in Japan. The major risk factors for AAA are age over 65 years, male gender, family history, and smoking. Thus, for prevention, smoking cessation is the most important lifestyle-intervention. For treatment, since AAA generally affects elderly people, less invasive treatment is preferable. However, the only established treatment for AAA is open repair and endovascular repair. This review describes potential medical treatments to slow aneurysm growth or prevent AAA rupture.

    DOI: 10.18926/AMO/57710

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  • Impaired mental health status in patients with chronic kidney disease is associated with estimated glomerular filtration rate decline. 査読 国際誌

    Yasuhiro Onishi, Haruhito A Uchida, Hidemi Takeuchi, Yuki Kakio, Hitoshi Sugiyama, Jun Wada, Noriaki Shimada, Hironobu Tokumasu, Masaki Fukushima, Kenichiro Asano

    Nephrology (Carlton, Vic.)24 ( 9 ) 926 - 932   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIM: Deteriorated health-related quality of life (HRQOL) is associated with increased risk for death in both chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients; however, the impact of HRQOL on CKD progression is not well investigated. METHODS: We aimed to evaluate the association between HRQOL and CKD progression in Japanese patients with CKD. One hundred and three outpatients who visited the department of nephrology at our hospital (mean estimated glomerular filtration rate (eGFR); 32.1 ± 11.2 mL/min per 1.73 m2 ) between April 2007 and March 2012 were enrolled in this study. The primary outcome was 30% decline of eGFR or ESRD. We assessed HRQOL of all participants at baseline, including the physical component summary (PCS), the mental component summary (MCS) and the role/social component summary (RCS), using SF-36. Based on the baseline score of PCS, MCS and RCS, we divided all subjects into two groups by median. RESULTS: We studied 66 men (64.1%) and 37 women aged 61.7 ± 10.0 years old. During approximately 2.5 years of follow-up period, 59 patients (57.3%) reached 30% eGFR decline or ESRD. Cox regression analyses demonstrated that lower MCS score was significantly associated with CKD progression (hazard ratio (HR) = 1.83, 95% CI = 1.04-3.21, P = 0.035), but that lower PCS score and RCS score were not (HR = 0.70, 95% CI = 0.39-1.25, P = 0.223; HR = 0.95, 95% CI = 0.54-1.67, P = 0.854, respectively). CONCLUSION: We found that impaired mental health was associated with CKD progression. The evaluation of the mental health should be performed in the patients with CKD.

    DOI: 10.1111/nep.13515

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  • A Patient with Type 3 Autoimmune Polyglandular Syndrome who Developed Systemic Lupus Erythematosus 8 years after the Diagnosis of Autoimmune Hepatitis. 査読

    Tomoyo Mifune-Morioka, Haruhito A Uchida, Kazuhiko Fukushima, Mayu Watanabe, Chihiro Ouchi, Koki Mise, Chieko Kawakita, Yuzuki Kano, Akifumi Onishi, Kishio Toma, Jun Eguchi, Nozomu Wada, Fusao Ikeda, Erika Sasaki, Yu Suganami, Masayuki Kishida, Hitoshi Sugiyama, Hiroyuki Okada, Jun Wada

    Acta medica Okayama73 ( 4 ) 367 - 372   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Eight years prior to her present admission, a 61-year-old Japanese woman was diagnosed with autoimmune hepatitis, slowly progressive insulin-dependent diabetes mellitus, and chronic thyroiditis; she had been treated with oral prednisolone (PSL). After she suddenly discontinued PSL, she newly developed systemic lupus erythematosus. A combination therapy of oral PSL and intravenous cyclophosphamide resulted in remission. She was finally diagnosed with autoimmune polyglandular syndrome (APS) type 3 (3A ,3B, 3D), complicated with four different autoimmune diseases. Since patients with type 3 APS may present many manifestations over a long period of time, they should be carefully monitored.

    DOI: 10.18926/AMO/56940

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  • Combination of Renal Angioplasty and Angiotensin-converting-enzyme Inhibitor Can Reduce Proteinuria in Patients with Bilateral Renal Artery Disease. 査読

    Hironobu Toda, Haruhito Uchida, Kazufumi Nakamura, Hidemi Takeuchi, Masaru Kinomura, Koji Nakagawa, Atsuyuki Watanabe, Toru Miyoshi, Nobuhiro Nishii, Hiroshi Morita, Jun Wada, Hiroshi Ito

    Internal medicine (Tokyo, Japan)58 ( 13 ) 1917 - 1922   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recent large clinical trials failed to show clear benefits of percutaneous transluminal renal angioplasty (PTRA) as compared with medical therapy on patients with renal artery stenosis. It was also reported that proteinuria is an adverse prognostic factor after PTRA, and PTRA is less effective in patients with overt proteinuria. From the renoprotective point of view, to reduce proteinuria after PTRA is an important therapeutic goal in patients with renal artery stenosis with overt proteinuria. We hereby describe two patients successfully treated by combination therapy with PTRA and administration of angiotensin-converting enzyme (ACE) inhibitor for bilateral renal artery disease with overt proteinuria.

    DOI: 10.2169/internalmedicine.2076-18

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  • Osteomalacia and Fanconi Syndrome Induced by Adefovir. 査読

    Natsumi Matsuoka, Haruhito A Uchida, Yoshikazu Hara, Hiroto Matsuda

    Internal medicine (Tokyo, Japan)58 ( 11 ) 1659 - 1659   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.2169/internalmedicine.2229-18

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  • The clinical efficacy of angiotensin II type1 receptor blockers on inflammatory markers in patients with hypertension: a multicenter randomized-controlled trial; MUSCAT-3 study. 査読 国際誌

    Ryoko Umebayashi, Haruhito A Uchida, Yuka Okuyama, Yuki Kakio, Yoshihisa Hanayama, Kenichi Shikata, Jun Wada

    Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals24 ( 3 ) 255 - 261   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Purpose: The purpose of present study was to evaluate the clinical efficacy of irbesartan on the anti-inflammatory and anti-oxidative stress effect in patients with hypertension compared to other ARBs. Further, we assessed the effect of the ARBs on kidney function and urinary albumin excretion. Methods: Eighty-five outpatients with hypertension who took an ARB except irbesartan more than 3 months were assigned into two groups, one continued the same ARB and the other switched the ARB to irbesartan for 6 months. Results: Although blood pressures were equally controlled (continue group: 148 ± 2/79 ± 2 mmHg to 131 ± 2/74 ± 2 mmHg; switch group: 152 ± 2/81 ± 2 mmHg to 132 ± 2/74 ± 2 mmHg; p < 0.001 each), the inflammatory markers (hsCRP, PTX3, MCP-1) and oxidative stress marker (MDA-LDL) did not change after 6 months in both groups. Urinary albumin excretion was significantly reduced only in the switch group without renal function deterioration (switch group 292.4 ± 857.9 mg/gCr to 250.6 ± 906.5 mg/gCr, p = 0.012). Conclusion: These results provide knowledge of the characteristics of irbesartan, suggesting appropriate choice of ARBs in the treatment for hypertension should be considered.

    DOI: 10.1080/1354750X.2018.1548033

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  • Higher Serum Testosterone Levels Associated with Favorable Prognosis in Enzalutamide- and Abiraterone-Treated Castration-Resistant Prostate Cancer. 査読 国際誌

    Shinichi Sakamoto, Maihulan Maimaiti, Minhui Xu, Shuhei Kamada, Yasutaka Yamada, Hiroki Kitoh, Hiroaki Matsumoto, Nobuyoshi Takeuchi, Kosuke Higuchi, Haruhito A Uchida, Akira Komiya, Maki Nagata, Hiroomi Nakatsu, Hideyasu Matsuyama, Koichiro Akakura, Tomohiko Ichikawa

    Journal of clinical medicine8 ( 4 )   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Testosterone plays a significant role in maintaining the tumor microenvironment. The role of the target serum testosterone (TST) level in enzalutamide- (Enza) and abiraterone (Abi)-treated castration-resistant prostate cancer (CRPC) patients was studied. In total, 107 patients treated with Enza and/or Abi at Chiba University Hospital and affiliated hospitals were studied. The relationships between progression-free survival (PFS), overall survival (OS), and clinical factors were studied by Cox proportional hazard and Kaplan-Meier models. In the Abi and Enza groups overall, TST ≥ 13 ng/dL (median) (Hazard Ratio (HR) 0.43, p = 0.0032) remained an independent prognostic factor for PFS. In the Enza group, TST ≥ 13 ng/dL (median) was found to be a significant prognostic factor (HR 0.28, p = 0.0044), while, in the Abi group, TST ≥ 12 ng/dL (median) was not significant (HR 0.40, p = 0.0891). TST showed significant correlation with PFS periods (r = 0. 32, p = 0.0067), whereas, for OS, TST ≥ 13 ng/dL (median) showed no significant difference in the Abi and Enza groups overall. According to Kaplan-Meier analysis, a longer PFS at first-line therapy showed a favorable prognosis in the Enza group (p = 0.0429), while no difference was observed in the Abi group (p = 0.6051). The TST level and PFS of first-line therapy may be considered when determining the treatment strategy for CRPC patients.

    DOI: 10.3390/jcm8040489

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  • Exogenous Vasohibin-2 Exacerbates Angiotensin II-Induced Ascending Aortic Dilation in Mice 査読

    Michihiro Okuyama, Haruhito A. Uchida, Yoshiko Hada, Yuki Kakio, Nozomu Otaka, Ryoko Umebayashi, Katsuyuki Tanabe, Yasuhiro Fujii, Shingo Kasahara, Venkateswaran Subramanian, Alan Daugherty, Yasufumi Sato, Jun Wada

    Circulation Reports1 ( 4 ) 155 - 161   2019年4月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Circulation Society  

    DOI: 10.1253/circrep.cr-19-0008

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  • The relationship between repeated measurement of casual and 24-h urinary sodium-to-potassium ratio in patients with chronic kidney disease. 査読 国際誌

    Yuka Okuyama, Haruhito A Uchida, Toshiyuki Iwahori, Hiroyoshi Segawa, Ayako Kato, Hidemi Takeuchi, Yuki Kakio, Ryoko Umebayashi, Masashi Kitagawa, Hitoshi Sugiyama, Katsuyuki Miura, Hirotsugu Ueshima, Jun Wada

    Journal of human hypertension33 ( 4 ) 286 - 297   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    This study aimed to clarify the relationship between repeated measurements of casual (spot) and 24-h urinary sodium-to-potassium (Na/K) ratios in patients with chronic kidney disease (CKD). A total of 61 inpatients with CKD, 31 in stage 1-3 (eGFR [estimated glomerular filtration rate] ≥ 30 ml/min/1.73 m2) and 30 in stage 4-5 (eGFR < 30 ml/min/1.73 m2), aged 20-85 consuming a low-sodium diet (NaCl [sodium chloride] 6 g/day) were recruited. Urinary Na, K, and Na/K ratios were measured in both casual urine samples and 2-day, 24 h urine samples, and then analyzed by correlation and Bland-Altman analyses. Mean 24-h urine Na/K ratio was higher in participants in stage 4-5 (5.1) than in participants in stage 1-3 (4.1) CKD. Casual urine Na/K ratio was strongly correlated with 2-day, 24-h urine Na/K ratio by sampling 4 casual urine specimens every morning and evening in participants in stage 1-3 (r = 0.69-0.78), but not in stage 4-5 (r = 0.12-0.19). The bias for mean Na/K ratio between 2-day, 24-h urine, and the 4 casual urine sampling ranged from -0.86 to 0.16 in participants in stage 1-3, and the quality of agreement for the mean of this casual urine sampling was similar to that of sampling 8 casual urine samples for estimating 2-day, 24-h values. Methods using repeated casual urine Na/K ratios may provide a reasonable estimation of 24-h urine Na/K ratio in normotensive and hypertensive as well as individuals with stage 1-3, but not stage 4-5 CKD.

    DOI: 10.1038/s41371-018-0127-1

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  • Urine 5MedC, a Marker of DNA Methylation, in the Progression of Chronic Kidney Disease. 査読 国際誌

    Akifumi Onishi, Hitoshi Sugiyama, Masashi Kitagawa, Toshio Yamanari, Keiko Tanaka, Ayu Ogawa-Akiyama, Yuzuki Kano, Koki Mise, Katsuyuki Tanabe, Hiroshi Morinaga, Masaru Kinomura, Haruhito A Uchida, Jun Wada

    Disease markers2019   5432453 - 5432453   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Alterations in DNA methylation may be involved in disease progression in patients with chronic kidney disease (CKD). Recent studies have suggested that 5-methyl-2'-deoxycytidine (5MedC) may be a marker of hypermethylation of DNA. Currently, there is no information available regarding the urine levels of 5MedC and its association with the progression of CKD. Method: We examined the urine levels of 5MedC in spot urine samples from 308 patients with CKD (median age: 56 years, male: 53.2%, and glomerulonephritis: 51.0%) using a competitive enzyme-linked immunosorbent assay and investigated the relationships among urine 5MedC, urine albumin, urine α1-microglobulin (α1MG), and the laboratory parameters associated with CKD. The patients were followed for three years to evaluate renal endpoints in a prospective manner. Results: The urine 5MedC level was significantly increased in the later stages of CKD compared to the early to middle stages of CKD. In multiple logistic regression models, urine 5MedC was significantly associated with the prediction of later CKD stages. Urine 5MedC (median value, 65.9 μmol/gCr) was significantly able to predict a 30% decline in the estimated GFR or a development of end-stage renal disease when combined with macroalbuminuria or an increased level of urine α1MG (median value, 5.7 mg/gCr). Conclusion: The present data demonstrate that the urine 5MedC level is associated with a reduced renal function and can serve as a novel and potent biomarker for predicting the renal outcome in CKD patients. Further studies will be necessary to elucidate the role of urine DNA methylation in the progression of CKD.

    DOI: 10.1155/2019/5432453

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  • Report of health checkup system for chronic kidney disease in general population in Okayama city: effect of health guidance intervention on chronic kidney disease outcome. 査読 国際誌

    Yuki Kakio, Haruhito A Uchida, Hidemi Takeuchi, Yuka Okuyama, Ryoko Umebayashi, Hiroyuki Watatani, Yohei Maeshima, Hitoshi Sugiyama, Jun Wada

    International journal of nephrology and renovascular disease12   143 - 152   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: From 2011, Okayama municipal government started the health checkup follow-up project to find those who were unaware of suffering chronic kidney disease and to prevent from aggravation of CKD stage. In this study, we aimed to evaluate the effect of 2 years' CKD-follow-up project regarding renal function and CKD risks. Patients and methods: Those who received a health checkup by the national health insurance in Okayama city in 2011 were recruited. The patients with lifestyle-related diseases or metabolic syndrome were excluded. Subjects who had an estimated glomerular filtration rate<50 mL/min/1.73 m2 or urinary protein positive by dipstick test were defined as compromised renal function group. They were recommended to visit a medical institution. Non-compromised renal function participants with two or more risks for CKD (hyperglycemia, higher blood pressure, dyslipidemia, hyperuricemia) were recommended to receive a health guidance (risk group). The change of renal function and CKD risks between 2011 and 2013 in each group was examined. Results: A total of 28,309 people received a health checkup in 2011. In compromised renal function group, 39.5% (96/243) of the subjects improved their CKD stages in 2013 regardless of the visit of medical institutions or the frequency of receiving health checkup. In risk group, 63.4% (260/410) of the subjects decreased their CKD risks in 2013 independent of the reception of health guidance. Conclusion: In both compromised renal function group and risk group, more than half of subjects kept their kidney function (217/243) and decreased the number of CKD risks (260/410) in 2 years' follow-up. Receiving a health checkup itself and notification of one's own health condition could exert a protective effect on kidney function.

    DOI: 10.2147/IJNRD.S198781

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  • Abdominal aortic aneurysm in aged population. 査読 国際誌

    Ryoko Umebayashi, Haruhito A Uchida, Jun Wada

    Aging10 ( 12 ) 3650 - 3651   2018年12月

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    記述言語:英語  

    DOI: 10.18632/aging.101702

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  • Diabetic nephropathy is associated with frailty in patients with chronic hemodialysis. 査読

    Yuki Kakio, Haruhito A Uchida, Hidemi Takeuchi, Yuka Okuyama, Michihiro Okuyama, Ryoko Umebayashi, Kentaro Wada, Hitoshi Sugiyama, Ken Sugimoto, Hiromi Rakugi, Shingo Kasahara, Jun Wada

    Geriatrics & gerontology international18 ( 12 ) 1597 - 1602   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIM: Since 1998, the leading cause of chronic hemodialysis in Japan has been diabetic nephropathy. Diabetes mellitus is known to be a risk factor for frailty, but it still remains unknown whether diabetic nephropathy is associated with frailty in chronic dialysis patients. The authors carried out the present study to reveal the association between frailty and diabetic nephropathy in chronic hemodialysis patients. METHODS: A total of 355 patients who were on hemodialysis were recruited. Participants were divided into two groups of either patients who suffered diabetic nephropathy with end-stage renal disease (DN group, n = 150) or not (Non-DN group, n = 205). The authors investigated the difference of the prevalence of frailty between the two groups. Furthermore, the authors examined the risk factors for frailty. RESULTS: The prevalence of frailty in the DN group was significantly higher than that in the Non-DN group (28.0% vs 16.5%, P = 0.0161). To evaluate the association between frailty and its risk factors, we compared frail patients (n = 71) and non-frail patients (n = 262). After adjusting their interrelationships by using multivariate logistic regression analysis, diabetic nephropathy was determined as a significant risk factor for frailty. CONCLUSIONS: The authors found the close association between frailty and diabetic nephropathy in chronic hemodialysis patients. Geriatr Gerontol Int 2018; 18: 1597-1602.

    DOI: 10.1111/ggi.13534

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  • Chronic kidney disease is associated with carotid atherosclerosis and symptomatic ischaemic stroke. 査読 国際誌

    Nobuo Kajitani, Haruhito A Uchida, Isao Suminoe, Yuki Kakio, Masashi Kitagawa, Hajime Sato, Jun Wada

    The Journal of international medical research46 ( 9 ) 3873 - 3883   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objective We aimed to investigate the relationships among chronic kidney disease (CKD), symptomatic ischaemic stroke, and carotid atherosclerosis. Methods We enrolled 455 patients who underwent carotid ultrasonography in our hospital, including 311 patients with symptomatic ischaemic stroke and 144 patients without symptomatic ischaemic stroke. Carotid intima-media thickness (IMT), the rate of internal carotid artery stenosis, and maximal plaque size were evaluated. Results The mean age of the patients was 68.5 ± 11.0 years and the mean estimated glomerular filtration rate (eGFR) was 68.8 ± 18.2 mL/min/1.73 m2. After adjustment for cardiovascular risk factors, the mean IMT was significantly higher in patients with CKD than in those without CKD. The IMT and eGFR were negatively correlated in patients with stroke (r = -0.169). Multiple logistic regression analyses showed that mean IMT, plaque size, and internal carotid artery stenosis were significant determinants of symptomatic ischaemic stroke after adjustment of multivariate risk factors. Furthermore, the eGFR was a negative determinant of symptomatic ischaemic stroke after adjusting for classical risk factors (odds ratio [95% confidence interval] = 0.868 [0.769-0.979]). Conclusion CKD might be associated with the carotid atherosclerosis and symptomatic ischaemic stroke.

    DOI: 10.1177/0300060518781619

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  • Peripheral artery disease is associated with frailty in chronic hemodialysis patients. 査読 国際誌

    Michihiro Okuyama, Hidemi Takeuchi, Haruhito A Uchida, Yuki Kakio, Yuka Okuyama, Ryoko Umebayashi, Kentaro Wada, Hitoshi Sugiyama, Ken Sugimoto, Hiromi Rakugi, Shingo Kasahara, Jun Wada

    Vascular26 ( 4 ) 425 - 431   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objectives The clinical condition of frailty is a common problem in the elderly population. However, the relationship between peripheral artery disease and frailty in hemodialysis patients remains unknown. The aim of this study was to identify the relationships between peripheral artery disease and frailty in Japanese chronic hemodialysis patients. Methods A total of 362 chronic hemodialysis patients who regularly visited six institutions were enrolled. To evaluate frailty, the modified Fried's frailty phenotype adjusted for Japanese were used. Peripheral artery disease was defined as ankle-brachial index <0.9. Results Of 362 patients, 62 patients (17.1%) were categorized as peripheral artery disease group and 300 patients (82.9%) as Non-peripheral artery disease group. The prevalence of frailty in the peripheral artery disease group was significantly higher than in the Non-peripheral artery disease group (34% vs. 18%, P = 0.0103). Non-shunt side grip strength was significantly stronger in the Non-peripheral artery disease group (23.6 kg vs. 17.0 kg, P < 0.0001). Thigh circumferences were also significantly larger in the Non-peripheral artery disease group (41.7 cm vs. 39.7 cm, P = 0.0054). A multivariate logistic regression analysis demonstrated that the factors independently associated with peripheral artery disease were as follows: frailty (odds ratio = 2.06, 95% confidence interval 1.09-3.89) and myocardial infarction (odds ratio = 3.74, 95% confidence interval 2.05-6.83). Conclusions It is concluded that peripheral artery disease is closely associated with frailty in hemodialysis patients.

    DOI: 10.1177/1708538118756690

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  • Identification of Novel Urinary Biomarkers for Predicting Renal Prognosis in Patients With Type 2 Diabetes by Glycan Profiling in a Multicenter Prospective Cohort Study: U-CARE Study 1. 査読 国際誌

    Koki Mise, Mariko Imamura, Satoshi Yamaguchi, Sanae Teshigawara, Atsuhito Tone, Haruhito A Uchida, Jun Eguchi, Atsuko Nakatsuka, Daisuke Ogawa, Michihiro Yoshida, Masao Yamada, Kenichi Shikata, Jun Wada

    Diabetes care41 ( 8 ) 1765 - 1775   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Because quantifying glycans with complex structures is technically challenging, little is known about the association of glycosylation profiles with the renal prognosis in diabetic kidney disease (DKD). RESEARCH DESIGN AND METHODS: In 675 patients with type 2 diabetes, we assessed the baseline urinary glycan signals binding to 45 lectins with different specificities. The end point was a decrease of estimated glomerular filtration rate (eGFR) by ≥30% from baseline or dialysis for end-stage renal disease. RESULTS: During a median follow-up of 4.0 years, 63 patients reached the end point. Cox proportional hazards analysis revealed that urinary levels of glycans binding to six lectins were significantly associated with the outcome after adjustment for known indicators of DKD, although these urinary glycans, except that for DBA, were highly correlated with baseline albuminuria and eGFR. Hazard ratios for these lectins were (+1 SD for the glycan index) as follows: SNA (recognizing glycan Siaα2-6Gal/GalNAc), 1.42 (95% CI 1.14-1.76); RCA120 (Galβ4GlcNAc), 1.28 (1.01-1.64); DBA (GalNAcα3GalNAc), 0.80 (0.64-0.997); ABA (Galβ3GalNAc), 1.29 (1.02-1.64); Jacalin (Galβ3GalNAc), 1.30 (1.02-1.67); and ACA (Galβ3GalNAc), 1.32 (1.04-1.67). Adding these glycan indexes to a model containing known indicators of progression improved prediction of the outcome (net reclassification improvement increased by 0.51 [0.22-0.80], relative integrated discrimination improvement increased by 0.18 [0.01-0.35], and the Akaike information criterion decreased from 296 to 287). CONCLUSIONS: The urinary glycan profile identified in this study may be useful for predicting renal prognosis in patients with type 2 diabetes. Additional investigation of glycosylation changes and urinary glycan excretion in DKD is needed.

    DOI: 10.2337/dc18-0030

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  • IgA Nephropathy Complicated with X-linked Thrombocytopenia. 査読

    Yuki Kakio, Haruhito Adam Uchida, Masashi Kitagawa, Yuka Arata, Ayako Kato, Akiko Inoue-Torii, Norikazu Hinamoto, Ayu Ogawa-Akiyama, Hitoshi Sugiyama, Jun Wada

    Acta medica Okayama72 ( 3 ) 301 - 307   2018年6月

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    記述言語:英語  

    Renal involvement is occasionally observed in Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). It has been reported that galactose-deficient IgA is a closely linked to IgA nephropathy (IgAN), suggesting that patients with XLT/WAS associated with reduced galactosylation on serum IgA are susceptible to IgAN. It is necessary to pay more attention to patients with IgAN due to the potential complication with XLT/WAS. We here present a patient of XLT complicated with mild IgAN who underwent tonsillectomy combined with steroid pulse therapy to achieve complete clinical remission.

    DOI: 10.18926/AMO/56077

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  • Cilostazol Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysms but Not Atherosclerosis in Apolipoprotein E-Deficient Mice. 査読 国際誌

    Ryoko Umebayashi, Haruhito A Uchida, Yuki Kakio, Venkateswaran Subramanian, Alan Daugherty, Jun Wada

    Arteriosclerosis, thrombosis, and vascular biology38 ( 4 ) 903 - 912   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Abdominal aortic aneurysm (AAA) is a permanent dilation of the abdominal aorta associated with rupture, which frequently results in fatal consequences. AAA tissue is commonly characterized by localized structural deterioration accompanied with inflammation and profound accumulation of leukocytes, although the specific function of these cells is unknown. Cilostazol, a phosphodiesterase III inhibitor, is commonly used for patients with peripheral vascular disease or stroke because of its anti-platelet aggregation effect and anti-inflammatory effect, which is vasoprotective effect. In this study, we evaluated the effects of cilostazol on angiotensin II-induced AAA formation. APPROACH AND RESULTS: Male apolipoprotein E-deficient mice were fed either normal diet or a diet containing cilostazol (0.1% wt/wt). After 1 week of diet consumption, mice were infused with angiotensin II (1000 ng/kg per minute) for 4 weeks. Angiotensin II infusion increased maximal diameters of abdominal aortas, whereas cilostazol administration significantly attenuated dilatation of abdominal aortas, thereby, reducing AAA incidence. Cilostazol also reduced macrophage accumulation, matrix metalloproteinases activation, and inflammatory gene expression in the aortic media. In cultured vascular endothelial cells, cilostazol reduced expression of inflammatory cytokines and adhesive molecules through activation of the cAMP-PKA (protein kinase A) pathway. CONCLUSIONS: Cilostazol attenuated angiotensin II-induced AAA formation by its anti-inflammatory effect through phosphodiesterase III inhibition in the aortic wall. Cilostazol may be a promising new therapeutic option for AAAs.

    DOI: 10.1161/ATVBAHA.117.309707

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  • The Prevalence of Frailty and its Associated Factors in Japanese Hemodialysis Patients. 査読 国際誌

    Hidemi Takeuchi, Haruhito A Uchida, Yuki Kakio, Yuka Okuyama, Michihiro Okuyama, Ryoko Umebayashi, Kentaro Wada, Hitoshi Sugiyama, Ken Sugimoto, Hiromi Rakugi, Jun Wada

    Aging and disease9 ( 2 ) 192 - 207   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The population undergoing dialysis is aging worldwide, particularly in Japan. The clinical condition of frailty is the most problematic expression in the elderly population. Potential pathophysiological factors of frailty present in patients with CKD and are accentuated in patients with ESRD. The aim of this study was to identify the prevalence and predictors of frailty in Japanese HD patients. This study was a multicenter, cross-sectional and observational investigation conducted at 6 institutions. To evaluate frailty, the modified Fried's frailty phenotype adjusted for Japanese as the self-reported questionnaire was used. Of the 542 patients visiting each institution, 388 were enrolled in this study. In total, 26.0% of participants were categorized as not-frailty, 52.6% as pre-frailty and 21.4% as frailty. The prevalence of frailty increased steadily with age and was more prevalent in females than in males and the subjects with frailty received polypharmacy. A multivariate logistic regression analysis revealed that the factors independently associated with frailty were the following: female gender (odds ratio [OR] = 3.661, 95% confidence interval [CI] 1.398-9.588), age (OR = 1.065, 95% CI 1.014-1.119), age ≥ 75 years old (OR = 4.892, 95% CI 1.715-13.955), body mass index (BMI) < 18.5 (OR = 0.110, 95% CI 0.0293-0.416), number of medications being taken (OR = 1.351, 95% CI 1.163-1.570), diabetes mellitus (DM) (OR = 2.765, 95% CI 1.081-7.071) and MNA-SF ≤ 11 (OR = 7.405, 95% CI 2.732-20.072). Frailty was associated with the accumulation of risk factors. The prevalence of frailty in Japanese patients with HD was relatively lower than that previously reported in Western developed countries; however, it was extremely high compared to the general population regardless of age. Our findings suggest that frailty might be associated with an increase in the prevalence of adverse health outcomes in patients with HD.

    DOI: 10.14336/AD.2017.0429

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  • Impact of nocturnal blood pressure variability on renal arterioles. 査読 国際誌

    Haruhito A Uchida, Masashi Kitagawa, Jun Wada

    Hypertension research : official journal of the Japanese Society of Hypertension41 ( 1 ) 6 - 7   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/hr.2017.88

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  • Serum cystatin C is an independent biomarker associated with the renal resistive index in patients with chronic kidney disease. 査読 国際誌

    Ayu Ogawa-Akiyama, Hitoshi Sugiyama, Masashi Kitagawa, Keiko Tanaka, Akifumi Onishi, Toshio Yamanari, Hiroshi Morinaga, Haruhito Adam Uchida, Kazufumi Nakamura, Hiroshi Ito, Jun Wada

    PloS one13 ( 3 ) e0193695   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cystatin C is a cysteine protease inhibitor that is produced by nearly all human cells. The serum level of cystatin C is a stronger predictor of the renal outcome and the risk of cardiovascular events than the creatinine level. The resistive index (RI) on renal Doppler ultrasonography is a good indicator of vascular resistance as well as the renal outcomes in patients with chronic kidney disease (CKD). However, it is unclear whether serum cystatin C is associated with signs of vascular dysfunction, such as the renal RI. We measured the serum cystatin C levels in 101 CKD patients and investigated the relationships between cystatin C and markers of vascular dysfunction, including the renal RI, ankle-brachial pulse wave velocity (baPWV), intima-media thickness (IMT), and cardiac function. The renal RI was significantly correlated with the serum cystatin C level (p < 0.0001, r = 0.6920). The serum cystatin C level was found to be a significant determinant of the renal RI (p < 0.0001), but not the baPWV, in a multivariate regression analysis. The multivariate odds ratio of the serum cystatin C level for a renal RI of more than 0.66 was statistically significant (2.92, p = 0.0106). The area under the receiver-operating characteristic curve comparing the sensitivity and specificity of cystatin C for predicting an RI of more than 0.66 was 0.882 (cutoff value: 2.04 mg/L). In conclusion, the serum cystatin C level is an independent biomarker associated with the renal RI in patients with CKD.

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  • Poor glycemic control attributable to insulin antibody in a fulminant type 1 diabetes patient under hemodialysis: successful treatment with double filtration plasmapheresis and prednisolone 査読

    Kentaro Wada, Haruhito A. Uchida, Yuko Wada

    Renal Replacement Therapy3 ( 1 )   2017年4月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    DOI: 10.1186/s41100-017-0096-9

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  • Practical efficacy of olmesartan versus azilsartan in patients with hypertension: a multicenter randomized-controlled trial (MUSCAT-4 study). 査読 国際誌

    Yuki Kakio, Haruhito A Uchida, Ryoko Umebayashi, Hidemi Takeuchi, Yuka Okuyama, Yoshihisa Hanayama, Jun Wada

    Blood pressure monitoring22 ( 2 ) 59 - 67   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Olmesartan and azilsartan, angiotensin II receptor blockers (ARBs), are expected to decrease blood pressure more than the other ARBs. We conducted randomized-controlled trials to compare the practical efficacy of olmesartan with azilsartan. METHODS: Eighty-four patients treated with the conventional ARBs for more than 3 months were assigned randomly to receive either 20 mg of olmesartan (olmesartan medoxomil, OL group) or 20 mg of azilsartan (azilsartan, not azilsartan medoxomil, AZ group) once daily for 16 weeks. The practical efficacy on blood pressure was compared between the OL and AZ groups. RESULTS: Office blood pressure of both groups decreased significantly (OL group: 152/86-141/79 mmHg, P<0.05, AZ group: 149/83-135/75 mmHg; P<0.05). Diastolic home blood pressure in the AZ group decreased significantly (79±9-74±7 mmHg; P<0.05), but not in the OL group (79±11-75±10 mmHg; P=0.068). However, there were no significant differences between the groups. The dosage of olmesartan and azilsartan increased significantly and slightly for 16 weeks (OL group: 20.3-23.1 mg; P<0.05, AZ group: 20.5-23.2 mg; P<0.05), without a significant difference between groups. Furthermore, there were no significant differences in renal function, lipid profiles, brain natriuretic peptide, soluble fms-like tyrosine kinase-1, and urinary L-type fatty acid-binding protein between the two groups. CONCLUSION: Both olmesartan and azilsartan equally reduced blood pressures. Both olmesartan and azilsartan showed a renoprotective effect and were well tolerated without any major adverse events.

    DOI: 10.1097/MBP.0000000000000229

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  • Effectiveness case of Jidabokuippo (traditional Japanese Kampo medicine) on pain, venous thrombosis, and subcutaneous hematoma after percutaneous femoral catheterization in a hemodialysis patient 査読

    Kentaro Wada, Haruhito A. Uchida, Yuko Wada

    Renal Replacement Therapy3 ( 1 )   2017年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    DOI: 10.1186/s41100-016-0086-3

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  • Arterial Stiffness is an Independent Risk Factor for Anemia After Percutaneous Native Kidney Biopsy. 査読 国際誌

    Keiko Tanaka, Masashi Kitagawa, Akifumi Onishi, Toshio Yamanari, Ayu Ogawa-Akiyama, Koki Mise, Tatsuyuki Inoue, Hiroshi Morinaga, Haruhito A Uchida, Hitoshi Sugiyama, Jun Wada

    Kidney & blood pressure research42 ( 2 ) 284 - 293   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND/AIMS: Bleeding is the most common complication after renal biopsy. Although numerous predictors of bleeding have been reported, it remains unclear whether arterial stiffness affects bleeding complications. METHOD: We performed an observational study of the renal biopsies performed in our division over an approximately 6-year period (May 2010 to May 2016). The clinical and laboratory factors were analyzed to reveal the risk factors associated with bleeding, with a focus on anemia (defined as a ≥10% decrease in hemoglobin [Hb] after biopsy). The brachial-ankle pulse wave velocity (baPWV) was measured to evaluate arterial stiffness. RESULTS: This study included 462 patients (male, n=244; female, n=218). Anemia (defined above) was observed in 54 patients (11.7%). The risk of anemia was higher in women, older patients, and patients with lower serum albumin, lower eGFR and lower diastolic blood pressure after biopsy. We then performed a further analysis of 187 patients whose baPWV data were available. Multivariate analysis revealed that a higher baPWV was an independent risk factor for anemia. ROC analysis for predicting anemia found that a baPWV value of 1839 cm/s had the best performance (AUC 0.689). CONCLUSION: An increased baPWV may be a more valuable predictor of bleeding than any of the other reported risk factors.

    DOI: 10.1159/000477453

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  • The possible involvement of intestine-derived IgA1: a case of IgA nephropathy associated with Crohn's disease. 査読 国際誌

    Tomohiro Terasaka, Haruhito A Uchida, Ryoko Umebayashi, Keiko Tsukamoto, Keiko Tanaka, Masashi Kitagawa, Hitoshi Sugiyama, Hiroaki Tanioka, Jun Wada

    BMC nephrology17 ( 1 ) 122 - 122   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: A link between IgA nephropathy and Crohn's disease has recently been reported. Other researchers hypothesize that intestine-derived IgA complexes deposit in glomerular mesangial cells, eliciting IgA nephropathy. Intestinal mucosal plasma cells mainly secrete IgA2. Nevertheless, IgA1 deposition is strongly implicated as being the primary cause of IgA nephropathy. CASE PRESENTATION: A 46-year-old Japanese man developed IgA nephropathy 29 years ago, following tonsillectomy. As a result, a normal urinalysis was obtained. The patient previously suffered Crohn's disease followed by urinary occult blood and proteinuria six years ago. Exacerbation of IgA nephropathy was highly suspected. Therefore a renal biopsy was performed. A diagnosis of exacerbation of IgA nephropathy with mesangial cell proliferation and fibrotic cellular crescent was based upon the pathological findings. The patient exhibited a positive clinical course and eventually achieved a remission with immunosuppressive therapy including prednisolone treatment. Immunostaining for the detection of IgA subtypes was performed on both of his kidney and excised ileum. The results revealed IgA1 and IgA2 deposition by submucosal cells in intestine. Furthermore, IgA1 deposition of mesangial areas in the patient's kidney, indicated an association of IgA1 with the exacerbation of IgA nephropathy. CONCLUSION: This case represents the possibility that the intestine-derived IgA1 can be the origin of galactose-deficient IgA which is known to cause IgA nephropathy exacerbation.

    DOI: 10.1186/s12882-016-0344-1

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  • The Possible Association of the Incidence of ESRD in the Patient with Diabetic Nephropathy with Salt Intake in the World 査読

    Haruhito A. Uchida, Jun Wada, Hirofumi Makino

    BMJ open e-letter   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Leukocyte Calpain Deficiency Reduces Angiotensin II-Induced Inflammation and Atherosclerosis But Not Abdominal Aortic Aneurysms in Mice. 査読 国際誌

    Deborah A Howatt, Anju Balakrishnan, Jessica J Moorleghen, Latha Muniappan, Debra L Rateri, Haruhito A Uchida, Jiro Takano, Takaomi C Saido, Athar H Chishti, Laurent Baud, Venkateswaran Subramanian

    Arteriosclerosis, thrombosis, and vascular biology36 ( 5 ) 835 - 45   2016年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Angiotensin II (AngII) infusion profoundly increases activity of calpains, calcium-dependent neutral cysteine proteases, in mice. Pharmacological inhibition of calpains attenuates AngII-induced aortic medial macrophage accumulation, atherosclerosis, and abdominal aortic aneurysm in mice. However, the precise functional contribution of leukocyte-derived calpains in AngII-induced vascular pathologies has not been determined. The purpose of this study was to determine whether calpains expressed in bone marrow (BM)-derived cells contribute to AngII-induced atherosclerosis and aortic aneurysms in hypercholesterolemic mice. APPROACH AND RESULTS: To study whether leukocyte calpains contributed to AngII-induced aortic pathologies, irradiated male low-density lipoprotein receptor(-/-) mice were repopulated with BM-derived cells that were either wild-type or overexpressed calpastatin, the endogenous inhibitor of calpains. Mice were fed a fat-enriched diet and infused with AngII (1000 ng/kg per minute) for 4 weeks. Overexpression of calpastatin in BM-derived cells significantly attenuated AngII-induced atherosclerotic lesion formation in aortic arches, but had no effect on aneurysm formation. Using either BM-derived cells from calpain-1-deficient mice or mice with leukocyte-specific calpain-2 deficiency generated using cre-loxP recombination technology, further studies demonstrated that independent deficiency of either calpain-1 or -2 in leukocytes modestly attenuated AngII-induced atherosclerosis. Calpastatin overexpression significantly attenuated AngII-induced inflammatory responses in macrophages and spleen. Furthermore, calpain inhibition suppressed migration and adhesion of macrophages to endothelial cells in vitro. Calpain inhibition also significantly decreased hypercholesterolemia-induced atherosclerosis in the absence of AngII. CONCLUSIONS: The present study demonstrates a pivotal role for BM-derived calpains in mediating AngII-induced atherosclerosis by influencing macrophage function.

    DOI: 10.1161/ATVBAHA.116.307285

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  • Acute idiopathic blue fingers: a young man with Achenbach's syndrome. 査読 国際誌

    Hidemi Takeuchi, Haruhito Adam Uchida, Yuka Okuyama, Jun Wada

    BMJ case reports2016   10.1136/bcr-2016-214491   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We report a case of a 20-year-old man presenting with acute painful blue fingers. All physical findings, including an Allen test, were normal, and systematic symptoms frequently seen in collagen diseases were absent. Although we performed a wide variety of investigations including medical imaging, no specific abnormal findings were observed. Skin biopsy pathology was an important reference. The patient's symptoms gradually improved and were completely resolved without specific treatment. Based on the clinical presentation and course, we gave a diagnosis of Achenbach's syndrome, developed in a young male. Achenbach's syndrome is rare, but still may be encountered in clinical practice. The symptoms can be startling to the patient, eliciting fear of something terrible when, in fact, the syndrome is relatively benign and has a good prognosis. Recognising this disease quickly after presentation helps to eliminate the anxiety of the patient, as well as reducing excessively invasive investigations. We present a case report to enlighten Achenbach's syndrome.

    DOI: 10.1136/bcr-2016-214491

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  • Chronic Kidney Disease Is Positively and Diabetes Mellitus Is Negatively Associated with Abdominal Aortic Aneurysm. 査読 国際誌

    Hidemi Takeuchi, Michihiro Okuyama, Haruhito A Uchida, Yuki Kakio, Ryoko Umebayashi, Yuka Okuyama, Yasuhiro Fujii, Susumu Ozawa, Masashi Yoshida, Yu Oshima, Shunji Sano, Jun Wada

    PloS one11 ( 10 ) e0164015   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AND AIMS: Chronic kidney disease (CKD) and diabetes mellitus (DM) are considered as risk factors for cardiovascular diseases. The purpose of this study was to clarify the relationship of CKD and DM with the presence of abdominal aortic aneurysm (AAA). METHODS: We enrolled 261 patients with AAA (AAA+) and age-and-sex matched 261 patients without AAA (AAA-) at two hospitals between 2008 and 2014, and examined the association between the risk factors and the presence of AAA. Furthermore, in order to investigate the prevalence of AAA in each group, we enrolled 1126 patients with CKD and 400 patients with DM. RESULTS: The presence of CKD in patients with AAA+ was significantly higher than that in patients with AAA- (AAA+; 65%, AAA-; 52%, P = 0.004). The presence of DM in patients with AAA+ was significantly lower than that in patients with AAA- (AAA+; 17%, AAA-; 35%, P < 0.001). A multivariate logistic regression analysis demonstrated that hypertension, ischemic heart disease and CKD were independent determinants, whereas, DM was a negatively independent determinant, for the presence of AAA. The prevalence of AAA in patients with CKD 65 years old and above was 5.1%, whereas, that in patients with DM 65 years old and above was only 0.6%. CONCLUSION: CKD is a positively associated with the presence of AAA. In contrast, DM is a negatively associated with the presence of AAA in Japanese population.

    DOI: 10.1371/journal.pone.0164015

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  • Successful treatment by mycophenolate mofetil in a patient with focal segmental glomerulosclerosis associated with posterior reversible encephalopathy syndrome. 査読

    Masafumi Tenta, Haruhito Adam Uchida, Tomokazu Nunoue, Ryoko Umebayashi, Yuka Okuyama, Masashi Kitagawa, Yohei Maeshima, Hitoshi Sugiyama, Jun Wada

    CEN case reports4 ( 2 ) 190 - 195   2015年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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.

    DOI: 10.1007/s13730-014-0165-7

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  • Retrograde Renal Ablation via the Renal Vein as a New Treatment Option for Renovascular Hypertension. 査読 国際誌

    Hiroyasu Fujiwara, Hideo Gobara, Takao Hiraki, Toshihiro Iguchi, Haruhito Adam Uchida, Susumu Kanazawa

    Journal of vascular and interventional radiology : JVIR26 ( 6 ) 807 - 8   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jvir.2015.01.030

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  • Autoimmune pancreatitis and minimal change nephrotic syndrome: an unusual association? 査読 国際誌

    Yuka Okuyama, Haruhito Adam Uchida, Masafumi Tenta, Tomokazu Nunoue, Ryoko Umebayashi, Hiroshi Morinaga, Shinji Kitamura, Yohei Maeshima, Hitoshi Sugiyama, Jun Wada

    Nephrology (Carlton, Vic.)20 ( 3 ) 225 - 6   2015年3月

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    記述言語:英語  

    DOI: 10.1111/nep.12370

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  • Effects of lanthanum carbonate versus calcium carbonate on vascular stiffness and bone mineral metabolism in hemodialysis patients with type 2 diabetes mellitus: a randomized controlled trial. 査読 国際誌

    Kentaro Wada, Yuko Wada, Haruhito Adam Uchida, Shuichi Tsuruoka

    International journal of nephrology and renovascular disease8   111 - 8   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Vascular calcification contributes to cardiovascular disease in hemodialysis (HD) patients with diabetes. The randomized controlled trial reported here compared the effects of lanthanum carbonate (LC) and calcium carbonate (CC) on vascular stiffness assessed using brachial-ankle pulse wave velocity (ba-PWV), intima-media thickness (IMT), bone mineral density (BMD), and serum markers of chronic kidney disease - mineral and bone disorder in such patients. METHODS: Ba-PWV, IMT, BMD, and the biomarkers osteocalcin (OC) and bone alkaline phosphatase (BAP) were examined in 43 type 2 diabetes HD patients treated with LC (n=21) or CC (n=22) for 2 years. RESULTS: Forty-one patients completed the study (19, LC; 22, CC). The mean ba-PWV significantly increased only in the CC group (median: 2,280.5 to 2,402.5 cm/s, P<0.05), after 24-month treatment; it remained unchanged in the LC group (median: 1,830.5 to 2,018.3 cm/s). However, the difference between the groups did not reach statistical significance. Changes in IMT and BMD were not different between the two groups. Changes in serum phosphorus, corrected calcium, and intact parathyroid hormone levels were similar between the groups. The incidence of fracture was 0% (0/19) in the LC group, and 13.6% (3/22) in the CC group (P=0.2478). The OC/BAP ratio increased significantly in the LC group (median: 0.83 to 2.47), compared with in the CC group (median: 0.77 to 1.40) (P=0.036). CONCLUSION: From this study, in Japanese type 2 diabetes HD patients, we conclude that 2-year treatment with LC might have slowed the progression of ba-PWV; however, it did not cause a difference in ba-PWV, IMT, BMD, or fracture, compared with CC. Further, LC increased the OC/BAP ratio to a greater extent than CC.

    DOI: 10.2147/IJNRD.S90791

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  • Acute Effect of Aliskiren on Smoking-Induced Endothelial Dysfunction in Smoker 査読

    Haruhito A. Uchida, Hatsuzo Uchida, Jun Wada

    Journal of Cardiovascular Medicine and Cardiology   038 - 041   2014年10月

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    担当区分:筆頭著者   掲載種別:研究論文(学術雑誌)   出版者・発行元:Peertechz Publications Private Limited  

    DOI: 10.17352/2455-2976.000010

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  • Large vessel vasculitis with myelodysplastic syndrome. 査読

    Takayuki Katsuyama, Haruhito Adam Uchida, Kishio Toma, Yoshinobu Maeda, Daisho Hirota, Ryoko Umebayashi, Ken-Ei Sada, Hirofumi Makino

    Internal medicine (Tokyo, Japan)53 ( 1 ) 63 - 6   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A 71-year-old woman presented with a high-grade fever, neck pain, anemia and thrombocytopenia. After performing further examinations, we concluded that she had simultaneously developed large vessel vasculitis and myelodysplastic syndrome (MDS). Although glucocorticoid administration improved her clinical symptoms, the MDS transformed into acute myeloid leukemia and she died one year after receiving the diagnosis. The occurrence of immune-mediated disorders in patients with MDS is a well-known phenomenon; however, large vessel vasculitis is a rare complication of MDS. Our case suggests that the association between systemic vasculitis and MDS may result in poor outcomes.

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  • The effects of telmisartan treatment on the abdominal fat depot in patients with metabolic syndrome and essential hypertension: Abdominal fat Depot Intervention Program of Okayama (ADIPO). 査読 国際誌

    Kazutoshi Murakami, Jun Wada, Daisuke Ogawa, Chikage Sato Horiguchi, Tomoko Miyoshi, Motofumi Sasaki, Haruhito A Uchida, Yoshio Nakamura, Hirofumi Makino

    Diabetes & vascular disease research10 ( 1 ) 93 - 6   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Telmisartan partially activates the peroxisome proliferator-activated receptor γ (PPARγ), which may ameliorate the accumulation of visceral adipose tissues and sensitise insulin action. Nineteen patients with essential hypertension and metabolic syndrome were randomly assigned to receive 40 mg of telmisartan (TELMI group) once daily or 80 mg of valsartan (VAL group) once daily for 24 weeks. The visceral fat area (VFA) measured by computed tomography (CT) was significantly reduced from 150.4±15.5 to 127.7±16.7 cm(2) in the TELMI group (p=0.049). Although VFA was also reduced in the VAL group from 169.8±14.8 to 155.3±14.8 cm(2), the change was not significant (p=0.173). There were no significant changes in body weight, body mass index (BMI), waist circumference, subdermal fat area (SFA), fasting plasma glucose, and homeostasis model assessment of insulin resistance (HOMA-IR) in comparison to the baseline and follow-up data in both groups. In conclusion, telmisartan may have a benefit in the reduction of visceral adipose tissues in comparison to valsartan.

    DOI: 10.1177/1479164112444640

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  • A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. 査読 国際誌

    Masashi Kitagawa, Hitoshi Sugiyama, Hiroshi Morinaga, Tatsuyuki Inoue, Keiichi Takiue, Ayu Ogawa, Toshio Yamanari, Yoko Kikumoto, Haruhito Adam Uchida, Shinji Kitamura, Yohei Maeshima, Kazufumi Nakamura, Hiroshi Ito, Hirofumi Makino

    PloS one8 ( 2 ) e56695   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Klotho was originally identified in a mutant mouse strain unable to express the gene that consequently showed shortened life spans. In humans, low serum Klotho levels are related to the prevalence of cardiovascular diseases in community-dwelling adults. However, it is unclear whether the serum Klotho levels are associated with signs of vascular dysfunction such as arterial stiffness, a major determinant of prognosis, in human subjects with chronic kidney disease (CKD). METHODS: We determined the levels of serum soluble Klotho in 114 patients with CKD using ELISA and investigated the relationship between the level of Klotho and markers of CKD-mineral and bone disorder (CKD-MBD) and various types of vascular dysfunction, including flow-mediated dilatation, a marker of endothelial dysfunction, ankle-brachial pulse wave velocity (baPWV), a marker of arterial stiffness, intima-media thickness (IMT), a marker of atherosclerosis, and the aortic calcification index (ACI), a marker of vascular calcification. RESULTS: The serum Klotho level significantly correlated with the 1,25-dihydroxyvitamin D level and inversely correlated with the parathyroid hormone level and the fractional excretion of phosphate. There were significant decreases in serum Klotho in patients with arterial stiffness defined as baPWV≥1400 cm/sec, atherosclerosis defined as maximum IMT≥1.1 mm and vascular calcification scores of ACI>0%. The serum Klotho level was a significant determinant of arterial stiffness, but not endothelial dysfunction, atherosclerosis or vascular calcification, in the multivariate analysis in either metabolic model, the CKD model or the CKD-MBD model. The adjusted odds ratio of serum Klotho for the baPWV was 0.60 (p = 0.0075). CONCLUSIONS: Decreases in the serum soluble Klotho levels are independently associated with signs of vascular dysfunction such as arterial stiffness in patients with CKD. Further research exploring whether therapeutic approaches to maintain or elevate the Klotho level could improve arterial stiffness in CKD patients is warranted.

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  • Calpain-2 compensation promotes angiotensin II-induced ascending and abdominal aortic aneurysms in calpain-1 deficient mice. 査読 国際誌

    Venkateswaran Subramanian, Jessica J Moorleghen, Anju Balakrishnan, Deborah A Howatt, Athar H Chishti, Haruhito A Uchida

    PloS one8 ( 8 ) e72214   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AND OBJECTIVE: Recently, we demonstrated that angiotensin II (AngII)-infusion profoundly increased both aortic protein and activity of calpains, calcium-activated cysteine proteases, in mice. In addition, pharmacological inhibition of calpain attenuated AngII-induced abdominal aortic aneurysm (AA) in mice. Recent studies have shown that AngII infusion into mice leads to aneurysmal formation localized to the ascending aorta. However, the precise functional contribution of calpain isoforms (-1 or -2) in AngII-induced abdominal AA formation is not known. Similarly, a functional role of calpain in AngII-induced ascending AA remains to be defined. Using BDA-410, an inhibitor of calpains, and calpain-1 genetic deficient mice, we examined the relative contribution of calpain isoforms in AngII-induced ascending and abdominal AA development. METHODOLOGY/RESULTS: To investigate the relative contribution of calpain-1 and -2 in development of AngII-induced AAs, male LDLr -/- mice that were either calpain-1 +/+ or -/- were fed a saturated fat-enriched diet and infused with AngII (1,000 ng/kg/min) for 4 weeks. Calpain-1 deficiency had no significant effect on body weight or blood pressure during AngII infusion. Moreover, calpain-1 deficiency showed no discernible effects on AngII-induced ascending and abdominal AAs. Interestingly, AngII infusion induced increased expression of calpain-2 protein, thus compensating for total calpain activity in aortas of calpain-1 deficient mice. Oral administration of BDA-410, a calpain inhibitor, along with AngII-infusion significantly attenuated AngII-induced ascending and abdominal AA formation in both calpain-1 +/+ and -/- mice as compared to vehicle administered mice. Furthermore, BDA-410 administration attenuated AngII-induced aortic medial hypertrophy and macrophage accumulation. Western blot and immunostaining analyses revealed BDA-410 administration attenuated AngII-induced C-terminal fragmentation of filamin A, an actin binding cytoskeletal protein in aorta. CONCLUSION: Calpain-2 compensates for loss of calpain-1, and both calpain isoforms are involved in AngII-induced aortic aneurysm formation in mice.

    DOI: 10.1371/journal.pone.0072214

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  • Case of emphysematous cholecystitis in a patient with type 2 diabetes mellitus associated with schizophrenia. 査読

    Ayu Ogawa, Kenichi Shikata, Haruhito Adam Uchida, Susumu Shinoura, Naosuke Yokomichi, Daisuke Ogawa, Chicage Sato-Horiguchi, Takahito Yagi, Jun Wada, Hirofumi Makino

    Journal of diabetes investigation3 ( 6 ) 534 - 5   2012年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Emphysematous cholecystitis is a rare, but life-threatening, form of acute cholecystitis caused by gas-forming organisms in the gallbladder. A 73-year-old male patient with type 2 diabetes mellitus complicated with neuropathy associated with schizophrenia was admitted to Okayama University Hospital, Okayama, Japan, because of a high fever and general malaise. On the fourth hospital day, despite normal liver function tests and little abdominal pain, his abdominal computed tomography showed huge gas formation in the gallbladder lumen along with a dilated gallbladder with a thickened wall, consistent with emphysematous cholecystitis. The patient underwent an emergency open cholecystectomy. Few abdominal symptoms appeared because of the hyposensitivity to pain caused by not only diabetic neuropathy, but also antipsychotic agents the patient was taking for schizophrenia. Emphysematous cholecystitis should be taken into consideration for the differential diagnosis of high fever in diabetic patients with schizophrenia, irrespective of the level of liver function tests and clinical symptoms.

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  • Activation of liver X receptor inhibits osteopontin and ameliorates diabetic nephropathy. 査読 国際誌

    Hiromi Tachibana, Daisuke Ogawa, Yuichi Matsushita, Dennis Bruemmer, Jun Wada, Sanae Teshigawara, Jun Eguchi, Chikage Sato-Horiguchi, Haruhito Adam Uchida, Kenichi Shikata, Hirofumi Makino

    Journal of the American Society of Nephrology : JASN23 ( 11 ) 1835 - 46   2012年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Osteopontin is a proinflammatory cytokine and monocyte chemoattractant implicated in the pathogenesis of diabetic nephropathy. Synthetic agonists for liver X receptors (LXRs) suppress the expression of proinflammatory genes, including osteopontin, but whether LXR activation modulates diabetic nephropathy is unknown. We administered the LXR agonist T0901317 to mice with streptozotocin-induced diabetes and evaluated its effects on diabetic nephropathy. The LXR agonist decreased urinary albumin excretion without altering blood glucose levels and substantially attenuated macrophage infiltration, mesangial matrix accumulation, and interstitial fibrosis. LXR activation suppressed the gene expression of inflammatory mediators, including osteopontin, in the kidney cortex. In vitro, LXR activation suppressed osteopontin expression in proximal tubular epithelial cells by inhibiting AP-1-dependent transcriptional activation of the osteopontin promoter. Taken together, these results suggest that inhibition of renal osteopontin by LXR agonists may have therapeutic potential for diabetic nephropathy.

    DOI: 10.1681/ASN.2012010022

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  • A case of focal segmental glomerulosclerosis in an adult patient with hypogammaglobulinemia superimposed on membranoproliferative glomerulonephritis in childhood. 査読 国際誌

    Kenji Tsuji, Haruhito Adam Uchida, Tetsuichirou Ono, Tatsuyuki Inoue, Katsuji Shinagawa, Shinji Kitamura, Yohei Maeshima, Hitoshi Sugiyama, Hirofumi Makino

    BMC nephrology13   46 - 46   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Common variable immunodeficiency (CVID) is a disorder characterized by hypogammaglobulinemia without a known predisposing cause. CASE PRESENTATION: We report a 36-year-old man who had suffered membranoproliferative glomerulonephritis (MPGN) in his childhood, later diagnosed with CVID at 35 years of age. He presented at our hospital with signs of proteinuria. A renal biopsy revealed he suffered from focal segmental glomerulosclerosis (FSGS), possibly due to obesity and hypertension, not CVID - associated MPGN. CONCLUSION: This is the first case report of FSGS in a CVID patient. In this case, we have to pay attention not only to the treatment of obesity and hypertension for FSGS but also to the recurrence of immune-complex glomerulonephritis such as MPGN, in case of the restoration of hypogammaglobulinemia.

    DOI: 10.1186/1471-2369-13-46

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  • Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophage: anti-inflammatory effect of cholecystokinin. 査読 国際誌

    Satoshi Miyamoto, Kenichi Shikata, Kyoko Miyasaka, Shinichi Okada, Motofumi Sasaki, Ryo Kodera, Daisho Hirota, Nobuo Kajitani, Tetsuharu Takatsuka, Hitomi Usui Kataoka, Shingo Nishishita, Chikage Sato, Akihiro Funakoshi, Hisakazu Nishimori, Haruhito Adam Uchida, Daisuke Ogawa, Hirofumi Makino

    Diabetes61 ( 4 ) 897 - 907   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Inflammatory process is involved in the pathogenesis of diabetic nephropathy. In this article, we show that cholecystokinin (CCK) is expressed in the kidney and exerts renoprotective effects through its anti-inflammatory actions. DNA microarray showed that CCK was upregulated in the kidney of diabetic wild-type (WT) mice but not in diabetic intracellular adhesion molecule-1 knockout mice. We induced diabetes in CCK-1 receptor (CCK-1R) and CCK-2R double-knockout (CCK-1R(-/-),-2R(-/-)) mice, and furthermore, we performed a bone marrow transplantation study using CCK-1R(-/-) mice to determine the role of CCK-1R on macrophages in the diabetic kidney. Diabetic CCK-1R(-/-),-2R(-/-) mice revealed enhanced albuminuria and inflammation in the kidney compared with diabetic WT mice. In addition, diabetic WT mice with CCK-1R(-/-) bone marrow-derived cells developed more albuminuria than diabetic CCK-1R(-/-) mice with WT bone marrow-derived cells. Administration of sulfated cholecystokinin octapeptide (CCK-8S) ameliorated albuminuria, podocyte loss, expression of proinflammatory genes, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, CCK-8S inhibited both expression of tumor necrosis factor-α and chemotaxis in cultured THP-1 cells. These results suggest that CCK suppresses the activation of macrophage and expression of proinflammatory genes in diabetic kidney. Our findings may provide a novel strategy of therapy for the early stage of diabetic nephropathy.

    DOI: 10.2337/db11-0402

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  • Calpain inhibition attenuates angiotensin II-induced abdominal aortic aneurysms and atherosclerosis in low-density lipoprotein receptor-deficient mice. 査読 国際誌

    Venkateswaran Subramanian, Haruhito A Uchida, Talha Ijaz, Jessica J Moorleghen, Deborah A Howatt, Anju Balakrishnan

    Journal of cardiovascular pharmacology59 ( 1 ) 66 - 76   2012年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Chronic infusion of angiotensin II (AngII) augments atherosclerosis and abdominal aortic aneurysm (AAA) formation in hypercholesterolemic mice. AngII-induced AAAs are associated with medial macrophage accumulation and matrix metalloproteinase (MMP) activation. Inhibition of calpain, a calcium-activated neutral cysteine protease, by overexpression of its endogenous inhibitor, calpastatin, attenuates AngII-induced leukocyte infiltration, perivascular inflammation, and MMP activation in mice. The purpose of this study was to define whether pharmacological inhibition of calpain influences AngII-induced AAAs in hypercholesterolemic mice. Male low-density lipoprotein receptor-/- mice were fed a fat-enriched diet and administered with either vehicle or a calpain-specific inhibitor, BDA-410 (30 mg/kg per day) for 5 weeks. After 1 week of feeding, mice were infused with AngII (1000 ng/kg per minute) for 4 weeks. AngII-infusion profoundly increased aortic calpain protein and activity. BDA-410 administration had no effect on plasma cholesterol concentrations or AngII-increased systolic blood pressure. Calpain inhibition significantly attenuated AngII-induced AAA formation and atherosclerosis development. BDA-410 administration attenuated activation of MMP12, proinflammatory cytokines (IL-6, monocyte chemoattractant protein-1), and macrophage infiltration into the aorta. BDA-410 administration significantly attenuated thioglycolate-elicited macrophage accumulation in the peritoneal cavity. We conclude that calpain inhibition using BDA-410 attenuated AngII-induced AAA formation and atherosclerosis development in low-density lipoprotein receptor-/- mice.

    DOI: 10.1097/FJC.0b013e318235d5ea

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  • Losartan/hydrochlorothiazide combination therapy surpasses high-dose angiotensin receptor blocker in the reduction of morning home blood pressure in patients with morning hypertension. 査読

    Yoshihisa Hanayama, Haruhito Adam Uchida, Yoshio Nakamura, Hirofumi Makino

    Acta medica Okayama66 ( 6 ) 449 - 59   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Angiotensin receptor blockers (ARBs) are the first-line antihypertensive agents. In clinical practice, it is often difficult to achieve the recommended blood pressure level by ARBs in their ordinal dosages alone. This study examined the practical efficacy of a combination therapy of ARB with thiazide diuretics for lowering morning home blood pressure (MHBP) in comparison to high-dose ARB therapy in patients with morning hypertension administered an ordinal dosage of ARB. This study was performed in a prospective, randomized, open-labeled and blind-endpoint fashion. Patients were considered to have morning hypertension when their self-measured systolic MHBPs were 135mmHg or higher, irrespective of their diastolic MHBP and office blood pressures (OBPs). Forty-eight outpatients with morning hypertension receiving the ordinal dosage of ARB were given either losartan/hydrochlorothiazide (n = 26) or high-dose ARB (n = 22) in place of their previously prescribed ARB. No change in any medication was permitted during this period. Decreases of both systolic and diastolic MHBP after 3 months of treatment were significantly greater in the losartan/hydrochlorothiazide group than in the high-dose ARB group (p < 0.05, respectively). The ratio of adverse events was somewhat high (23.1% in the losartan/hydrochlorothiazide group, 9.1% in the high-dose ARB group, respectively). However, there were no significant differences in any particular adverse event between groups. This study suggested losartan/hydrochlorothiazide might be superior to high-dose ARB for reducing morning home blood pressure.

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  • Urokinase-type plasminogen activator deficiency in bone marrow-derived cells augments rupture of angiotensin II-induced abdominal aortic aneurysms. 査読 国際誌

    Haruhito A Uchida, Aruna Poduri, Venkateswaran Subramanian, Lisa A Cassis, Alan Daugherty

    Arteriosclerosis, thrombosis, and vascular biology31 ( 12 ) 2845 - 52   2011年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Abdominal aortic aneurysms (AAAs) are associated with fragmentation of extracellular matrix during development of aortic dilation and rupture. Therefore, it is important to identify specific protease systems involved in extracellular matrix degradation during AAA formation. The present study determined the contribution of the urokinase system to AAA formation and rupture. METHODS AND RESULTS: Angiotensin II (Ang II)-induced AAAs were associated with increased aortic abundance of both urokinase-type plasminogen activator receptor (uPAR) and urokinase-type plasminogen activator (uPA) proteins. However, this increased presence was unrelated to AAA formation because deficiencies of either uPAR or uPA had no effect on either the incidence or size of Ang II-induced AAAs in both normolipidemic mice and low-density lipoprotein receptor-/- mice fed a saturated fat-enriched diet. Although uPA deficiency did not affect development of AAAs, there was an effect of increasing mortality rate from AAA rupture in hypercholesterolemic mice. Bone marrow transplantation demonstrated that enhanced aneurysmal rupture was attributable to deficiency of uPA in leukocytes. uPA deficiency led to an increased propensity for impaired resolution of the thrombotic material within the aneurysmal tissue. Neither uPAR nor uPA deficiency had any effect on Ang II-induced atherosclerosis in low-density lipoprotein receptor-/- mice. CONCLUSIONS: The uPA-uPAR axis has no effect on the formation of Ang II-induced AAAs, but uPA deficiency promotes aneurysmal rupture.

    DOI: 10.1161/ATVBAHA.111.234997

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  • Development of angiotensin II-induced abdominal aortic aneurysms is independent of catalase in mice. 査読 国際誌

    Haruhito A Uchida, Hitoshi Sugiyama, Keiichi Takiue, Yoko Kikumoto, Tatsuyuki Inoue, Hirofumi Makino

    Journal of cardiovascular pharmacology58 ( 6 ) 633 - 8   2011年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Chronic infusion of angiotensin II (AngII) into mice augments the development of abdominal aortic aneurysms (AAAs). Catalase is an important antioxidant enzyme in cellular peroxisome, and it physiologically maintains tissue and cellular redox homeostasis and thus plays a central role in defense against oxidative stress. The purpose of this study was to define whether deficiency of catalase influences AngII-induced AAAs. Male acatalasemic (C3H/AnLCsCs) mice and wild-type (C3H/AnLCsCs) mice (8-12 weeks old, N = 24 and 25, respectively) were fed a normal chow for 5 weeks. After 1 week of acclimtion, mice were infused subcutaneously with AngII (1000 ng·kg·min) by osmotic minipumps for 4 weeks. AngII increased systolic blood pressure equivalently in both groups. Acatalasemia had no effect on serum cholesterol concentrations. The body weight of acatalasemic mice was slightly greater than that of wild-type mice (P = 0.008). Although aortic catalase activity in acatalasemic mice was significantly low (P < 0.001), acatalasemia had no significant effect on the incidence of AngII-induced AAA formation (acatalasemia, 23%; wild, 21%), ex vivo measurement of maximal diameter of abdominal aorta (acatalasemia, 1.22 ± 0.29 mm; wild, 1.21 ± 0.17 mm), or aortic deposition of lipid peroxidation products such as 4-hydroxy-2-nonenal. The development of AngII-induced AAAs is independent of catalase.

    DOI: 10.1097/FJC.0b013e3182317196

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  • Serum high-sensitivity cardiac troponin T is a significant biomarker of left-ventricular diastolic dysfunction in subjects with non-diabetic chronic kidney disease. 査読 国際誌

    Masashi Kitagawa, Hitoshi Sugiyama, Hiroshi Morinaga, Tatsuyuki Inoue, Keiichi Takiue, Yoko Kikumoto, Haruhito Adam Uchida, Shinji Kitamura, Yohei Maeshima, Norihisa Toh, Kazufumi Nakamura, Hiroshi Ito, Hirofumi Makino

    Nephron extra1 ( 1 ) 166 - 77   2011年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Chronic kidney disease (CKD) is associated with left-ventricular (LV) diastolic dysfunction (LVDD) which progresses to diastolic heart failure. However, biomarkers predicting LVDD in patients with CKD are largely unknown. METHODS: In 93 patients with non-diabetic CKD, the relationships among echocardiography, high-sensitivity cardiac troponin T (hs-cTnT), B-type natriuretic peptide (BNP), and renal function were evaluated. LV mass index, peak early diastolic mitral filling velocity (E), peak early diastolic mitral annular velocity (E'), and E/E' were recorded. RESULTS: The E' values were significantly decreased and E/E', BNP, and hs-cTnT increased with increasing CKD stage. The CKD patients with LVDD with E' <5 cm/s had a significantly higher hs-cTnT level as well as a significantly higher BNP level compared to those with E' ≥5 cm/s. The area under the receiver-operating characteristic curve for hs-cTnT and BNP to detect E' <5 cm/s was 0.880 (p = 0.0101) and 0.741 (p = 0.0570), respectively. In multivariate analysis, hs-cTnT and albuminuria were significantly associated with E', and estimated glomerular filtration rate with the hs-cTnT level, after adjusting for age, cause of CKD, and other parameters. CONCLUSIONS: These data suggest that hs-cTnT may be a useful biomarker of LVDD in non- diabetic CKD patients.

    DOI: 10.1159/000333801

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  • Insufficient control of morning home blood pressure in Japanese patients with hypertension associated with diabetes mellitus. 査読

    Haruhito A Uchida, Yoshio Nakamura, Hisanao Norii, Masanobu Kaihara, Yoshihisa Hanayama, Ken-Ei Sada, Jun Wada, Kenichi Shikata, Hirofumi Makino

    Journal of diabetes investigation1 ( 6 ) 266 - 72   2010年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    UNLABELLED: Aims/Introduction:  The combination of hypertension with diabetes mellitus (DM) has been recognized as a critical risk factor for cardiovascular disease (CVD). We investigated the blood pressure levels in hypertensive patients with DM (HDM patients) compared with those without DM (HnDM patients). Furthermore, we examined the effect of risk factors, including chronic kidney disease (CKD) and stroke, on the management of both office blood pressure (OBP) and morning home blood pressure (MHBP). MATERIALS AND METHODS:   OBP and MHBP were evaluated in 1230 essential hypertensive patients in 30 institutions. Among them, 366 (30%) were complicated with DM. RESULTS:   The ratio of masked hypertensives whose systolic OBP was <140 mmHg and systolic MHBP was more than 135 mmHg in HDM patients was significantly higher than that in HnDM patients (P < 0.02). HDM patients had significantly lower systolic and diastolic OBP and diastolic MHBP than HnDM patients (P < 0.05, respectively). However, systolic MHBP in HDM patients tended to be higher compared with HnDM patients (P = 0.0623). A stratified analysis showed that HDM patients with CKD or stroke had significantly higher systolic MHBP than others (P < 0.05, respectively). The adjusted odds ratio for morning hypertension defined by a systolic MHBP more than 135 mmHg was significantly higher in the HDM patients with CKD (1.98) compared with HnDM patients without CKD (reference). CONCLUSIONS:   Diabetes, CKD and stroke are risk factors for MHBP. More intensive treatment is needed to achieve the thera-peutic goal for systolic MHBP in HDM patients, especially those who are complicated with CKD or stroke. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00056.x, 2010).

    DOI: 10.1111/j.2040-1124.2010.00056.x

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  • Total lymphocyte deficiency attenuates AngII-induced atherosclerosis in males but not abdominal aortic aneurysms in apoE deficient mice. 査読 国際誌

    Haruhito A Uchida, Fjoralba Kristo, Debra L Rateri, Hong Lu, Richard Charnigo, Lisa A Cassis, Alan Daugherty

    Atherosclerosis211 ( 2 ) 399 - 403   2010年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: T and B lymphocytes are associated with atherosclerosis and aneurysms. Angiotensin II (AngII) infusion into hypercholesterolemic mice results in augmentation of atherosclerosis and abdominal aortic aneurysm (AAA) formation. In this study, we determined whether total lymphocyte deficiency reduced AngII-induced vascular diseases. METHODS AND RESULTS: ApoE deficient (apoE -/-) mice were cross-bred with recombination activating gene-1 (Rag-1) deficient mice that lack mature T and B lymphocytes. Heterozygous littermates (Rag-1 +/-) have normal lymphocytic function and served as controls. Male and female apoE -/- mice that were either Rag-1 +/- or -/- were fed a normal laboratory diet and infused with either saline or AngII (1000ng/kg/min) subcutaneously via osmotic mini pump for 28 days. Total lymphocyte deficiency had no significant effect on body weight and systolic blood pressure prior to and during AngII infusion. However, it was associated with decreased serum cholesterol concentrations. AngII infusion increased atherosclerotic lesion area in Rag-1 +/- mice compared to saline (P=0.017 in males and P=0.004 in females). This effect was significantly blunted in Rag-1 -/- male (P=0.044), but not female mice. AngII-infusion promoted increased width of the abdominal aorta, with a greater effect in males. Despite the reduction in atherosclerosis in males, Rag-1 deficiency had no significant effect on AngII-induced aortic dilation in either gender. CONCLUSION: T and B lymphocyte deficiency attenuates AngII-induced atherosclerosis in males but not AAA formation in apoE -/- mice.

    DOI: 10.1016/j.atherosclerosis.2010.02.034

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  • Olmesartan and temocapril prevented the development of hyperglycemia and the deterioration of pancreatic islet morphology in Otsuka-Long-Evans-Tokushima Fatty rats. 査読

    Masanobu Kaihara, Yoshio Nakamura, Taro Sugimoto, Haruhito A Uchida, Hisanao Norii, Hisanao Norii, Yoshihisa Hanayama, Hirofumi Makino

    Acta medica Okayama63 ( 1 ) 35 - 42   2009年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We investigated the impact of olmesartan and temocapril on pancreatic islet beta-cells during the development of diabetes mellitus using Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats. Four-week-old male OLETF rats were fed standard chow (untreated:n5), or chow containing either 0.005% olmesartan(n5) or 0.01% temocapril (n5) until being sacrificed at 35 weeks of age. Pancreas sections were double-stained with anti-insulin and anti-glucagon antibodies. The percent areas of beta-cells, alpha-cells and non-alpha-non-beta-cells were compared among groups. In untreated OLETF rats, the fasting plasma glucose (FPG) level was elevated at the 18th week and remained elevated until the 35th week. On the other hand, no significant elevation in FPG levels was observed in olmesartan- or temocapril-treated rats. Pancreatic islets from olmesartan-treated rats were significantly smaller in size as compared with those from untreated OLETF rats. Furthermore, the average area occupied by beta-cells as a fraction of the total area of an individual islet was significantly higher in olmesartan- or temocapril-treated rats than that in untreated OLETF rats. Olmesartan and temocapril both prevented the development of hyperglycemia, possibly through the prevention of islet beta-cell loss in spontaneously diabetic OLETF rats.

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  • The MUSCAT study: a Multicenter PROBE Study Comparing the Effects of Angiotensin II Type-1 Receptor Blockers on Self-Monitored Home Blood Pressure in Patients with Morning Hypertension: study design and background characteristics. 査読 国際誌

    Haruhito Uchida, Yoshio Nakamura, Masanobu Kaihara, Hisanao Norii, Yoshihisa Hanayama, Hirofumi Makino

    Hypertension research : official journal of the Japanese Society of Hypertension31 ( 1 ) 51 - 8   2008年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Elevated morning home blood pressure (MHBP) has been reported to have a close relationship to cerebro-cardiovascular events and hypertensive target organ damages, and hence is regarded as a predictor of cardiovascular events. However, there is no evidence that lowering of MHBP can improve morbidity, mortality or target organ damage. In recent guidelines, angiotensin II type-1 receptor blockers (ARBs) are recommended as the first-choice drugs for antihypertensive therapy. Pharmacological characteristics differ among ARBs, and some are suggested to have greater efficacy in lowering MHBP than others. In preparation for the MUSCAT study, we surveyed both self-monitored MHBP and office blood pressure (OBP) in 1,234 patients with essential hypertension. Among them, 367 patients had diabetes mellitus (DM) and 229 suffered from chronic kidney disease (CKD). More than 64% (n=790) of patients had morning hypertension. In MUSCAT, we will investigate the different effects of four ARBs (losartan, candesartan, valsartan, and telmisartan) in patients with morning hypertension, with a focus on the drugs' MHBP-lowering efficiency. Secondly, we will evaluate the different actions of the four ARBs on cardiovascular surrogate markers, such as the brachial-ankle pulse wave velocity, high-sensitive C-reactive protein level, and urinary albumin excretion/creatinine ratio. Patients will be randomized into four arms, and given one of the four "sartans" once daily for 12 months. MHBPs and surrogate markers will be examined at baseline and after 1 year of follow-up. In the stratified analysis, we will determine the significance of MHBP reduction on cardiovascular risk management.

    DOI: 10.1291/hypres.31.51

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  • Enhanced TGF-beta/Smad signaling in the early stage of diabetic nephropathy is independent of the AT1a receptor. 査読

    Yuko Okazaki, Yasushi Yamasaki, Haruhito A Uchida, Kazunori Okamoto, Minoru Satoh, Keisuke Maruyama, Yohei Maeshima, Hitoshi Sugiyama, Takeshi Sugaya, Naoki Kashihara, Hirofumi Makino

    Clinical and experimental nephrology11 ( 1 ) 77 - 87   2007年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Angiotensin II (AII) and transforming growth factor-beta (TGF-beta) are closely involved in the pathogenesis of diabetic nephropathy (DN). AII is known to induce TGF-beta production in resident renal cells, including glomerular mesangial cells and tubular epithelial cells. TGF-beta receptor types I and II (TGF-betaRI, II) are up-regulated in the diabetic kidney. The aim of this study was to clarify the role of AII in the regulation of the TGF-beta system in the early stage of DN using AII type1a receptor-deficient(AT1a(-/-)) mice. METHODS: We investigated the expression of TGF-beta1, TGF-betaRI, II, and Smad signaling in AT1a(-/-) mice with streptozotocin (STZ)-induced DN. Mice were killed 10 and 20 days after the induction of hyperglycemia. The expression of TGF-beta receptors was analyzed by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR). TGF-beta-specific Smad signaling was analyzed by electrophoretic mobility shift assay and Western blotting. RESULTS: The expression of both TGF-betaRI and RII was up-regulated in the glomerular tufts and vasculature in diabetic AT1a(+/+) mice kidney by immunohistochemistry. RT-PCR revealed that mRNAs for TGF-betaRI and RII were also up-regulated. Smad2 and 4 protein levels were reduced in the renal cortex after the induction of diabetes, with an increase of Smad 3/4 complex in the nucleus. The expression of TGF-beta receptors increased in both diabetic AT1a(-/-) and AT1a(+/+) mice. Smad signaling in AT1a(-/-) mice was also enhanced. CONCLUSIONS: Our results suggest that the complete blockade of the AT1a-mediated pathway has a minimal effect on the enhanced TGF-beta/Smad signaling in the early stage of DN, at least in the AT1a(-/-) model.

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  • Steroid pulse therapy impaired endothelial function while increasing plasma high molecule adiponectin concentration in patients with IgA nephropathy. 査読 国際誌

    Haruhito Adam Uchida, Yoshio Nakamura, Masanobu Kaihara, Hisanao Norii, Yoshihisa Hanayama, Hitoshi Sugiyama, Yohei Maeshima, Yasushi Yamasaki, Hirofumi Makino

    Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association21 ( 12 ) 3475 - 80   2006年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Decreased plasma adiponectin is associated with impaired endothelial function and, thereby, increased risk for cardiovascular events. Glucocorticoid (GC) affects vascular endothelial cells either favourably or harmfully depending upon the dosages and duration. We examined the effect of GC pulse therapy on vascular endothelial function. METHODS: Fourteen young patients with IgA nephropathy were evaluated for flow-mediated vasodilation (FMD), plasma levels of adiponectin both in high molecular weight (HMW adiponectin) form and in single molecular form (total adiponectin), hepatocyte growth factor (HGF), asymmetric dimethylarginine (ADMA), and high-sensitive C-reactive protein, before and after a course of GC pulse therapy. RESULTS: GC pulse therapy significantly decreased FMD (from 7.2 +/- 2.6 to 5.7 +/- 2.5%, P < 0.01). Meanwhile, plasma adiponectin levels were significantly augmented (total adiponectin: from 10.2 +/- 4.0 to 12.1 +/- 6.3 microg/ml, P < 0.05; HMW: from 6.5 +/- 3.2 to 7.7 +/- 3.3 microg/ml, P < 0.05). In parallel, elevated concentrations of serum HGF (from 0.28 +/- 0.12 to 0.63 +/- 0.38 ng/ml, P < 0.01) and plasma ADMA (from 0.45 +/- 0.07 to 0.53 +/- 0.04 nmol/ml, P < 0.05) were observed. CONCLUSIONS: GC pulse therapy impaired endothelial function while increasing plasma adiponectin levels, which may in turn restore the endothelial function in patients with IgA nephropathy.

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  • An elderly patient with severe acute renal failure due to sodium bromate intoxication. 査読

    Haruhito A Uchida, Hitoshi Sugiyama, Sadahide Kanehisa, Kazushi Harada, Kenta Fujiwara, Tetsuya Ono, Michio Yamakido, Hirofumi Makino

    Internal medicine (Tokyo, Japan)45 ( 3 ) 151 - 4   2006年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Accidental or deliberate ingestion of bromate solution has been reported in pediatric as well as adult cases; however there have been no reports of such intoxication in the elderly. We report a 78-year-old woman who suffered severe acute renal failure due to the accidental ingestion of sodium bromate solution. The patient was successfully treated with hemodialysis therapy and renal function recovered without hearing loss. This case suggests that emergency therapeutic measures, including hemodialysis, should be taken as soon as possible, and the rapid removal of bromate is essential to prevent severe intoxication and its sequelae. To the best of our knowledge this is the first report of an elderly patient that demonstrates the clinical benefit of hemodialysis therapy for bromate intoxication.

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  • Practical efficacy of telmisartan for decreasing morning home blood pressure and pulse wave velocity in patients with mild-to-moderate hypertension. 査読 国際誌

    Haruhito Uchida, Yoshio Nakamura, Masanobu Kaihara, Taro Sugimoto, Hisanori Norii, Motofumi Sasaki, Hajime Sato, Hirofumi Makino

    Hypertension research : official journal of the Japanese Society of Hypertension27 ( 8 ) 545 - 50   2004年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The current guideline-recommended blood pressure values are difficult to maintain in general practice, partly due to the lack of ideal anti-hypertensive agents. Since morning hypertension has a high correlation with cardiovascular events, expectations that telmisartan, a long-acting angiotensin-II type-1 receptor blocker (ARB), can improve cardiovascular mortality are high. In this study, the efficiency of telmisartan in reducing morning hypertension and pulse wave velocity (PWV) as a practical surrogate endpoint was investigated. Seventeen unsupervised and 7 untreated hypertensive patients were prescribed telmisartan 40 mg/day for 3 months. Medication already prescribed upon enrollment in this study was continued, with the exception of ARBs (all of which turned out to be losartan 50 mg/day), which were discontinued and replaced with telmisartan. Morning home blood pressure (MHBP), office blood pressure (OBP), and brachial-ankle PWV (baPWV) were investigated in a prospective fashion. A stratified analysis was performed regarding previous use (group L) or non-use (group N) of losartan. Over a 3-month period, telmisartan was found to significantly reduce both OBP (from 153+/-13/85+/-9 to 141+/-17/80+/-7 mmHg (p <0.01)) and MHBP (from 153+/-23/93+/-11 to 137+/-22/82+/-10 mmHg (p <0.001)). Surprisingly, 7 patients (70%) from group L achieved an OBP of less than 140/90 mmHg by simply changing their medication to telmisartan. Furthermore, baPWV fell significantly from 1,892+/-334 cm/s to 1,672+/-324 cm/s (p <0.01), which was greater than the change in baPWV estimated by OBP reduction. Here it must be mentioned that there were no significant differences between group L and group N in the courses of blood pressures and baPWV. In conclusion, telmisartan 40 mg/day was found to be effective for reducing MHBP and arterial wall stiffness in patients with mild-to-moderate hypertension, and thus may also be effective for improving cerebrocardiovascular mortality.

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  • Pelvic lymphocyst infection associated with maternally inherited diabetes mellitus. 査読 国際誌

    Daisuke Ogawa, Kenichi Shikata, Mitsuhiro Matsuda, Jun Wada, Haruhito Uchida, Maki Asada, Hirofumi Makino

    Diabetes research and clinical practice61 ( 2 ) 137 - 41   2003年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A 45-year-old woman with 20-year history of diabetes mellitus was admitted to our hospital because of high fever and abdominal pain. Radical hysterectomy and bilateral pelvic lymphadenectomy had been performed 4 months before admission for invasive cervical cancer. On admission, elastic hard tumors were palpable in the lower abdomen. Laboratory examination showed positive C-reactive protein (CRP), anemia and renal dysfunction. Computed tomography (CT) revealed several lymphocysts in the pelvis. She was diagnosed with infection of pelvic lymphocysts. Since her mother also had diabetes associated with deafness, we examined mitochondrial DNA in leukocytes and detected an A to G transition at the nucleotide position of 3243 (A3243G mutation). She was diagnosed as maternally inherited diabetes mellitus and deafness (MIDD). Puncture of the cysts followed by administration of antibiotics resulted in marked improvement of symptoms and laboratory findings. This is a rare case of pelvic lymphocyst infection in a patient with a mitochondrial disorder. Although the exact mechanism of infection is not clear, MIDD may represent an unusual risk factor for infection, and further investigation is necessary to assess the influence of mitochondrial dysfunction on the immune system. Pelvic lymphocyst infection should be considered in the differential diagnosis of abdominal pain and fever in patients with MIDD after abdominal surgery.

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