Papers - UCHIDA Haruhito

Performance of the modified 2022 ACR/EULAR giant cell arteritis classification criteria without age restriction for discriminating from Takayasu arteritis

Takahiko Sugihara, Masayoshi Harigai, Haruhito A. Uchida, Hajime Yoshifuji, Yasuhiro Maejima, Jun Ishizaki, Yoshiko Watanabe, Hiroaki Dobashi, Yoshinori Komagata, Naoto Tamura, Yoshikazu Nakaoka, Yoshiya Tanaka, Tsutomu Takeuchi, Taio Naniwa, Hiroko Nagafuchi, Takahiro Okazaki, Tetsuya Horita, Tatsuya Atsumi, Yoshihiro Arimura, Mitsuaki Isobe, Kazuo Tanemoto, Noriyoshi Ogawa, Yohko Murakawa, Shunsuke Furuta, Hitoshi Hasegawa, Yasuhiro Katsumata, Eisuke Amiya, Hiroshi Akazawa, Issei Komuro, Koichi Amano, Atsushi Kawakami, Shigeto Kobayashi, Takashi Wada, Eri Muso, Atsushi Komatsuda, Satoshi Ito, Noriyuki Homma, Taichi Hayashi, Shinichi Takeda, Takashi Wada

Arthritis Research & Therapy   27 ( 1 )   2025.1

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Objective

To evaluate the ability to discriminate giant cell arteritis (GCA) from Takayasu arteritis (TAK) according to the modified 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) GCA classification criteria.

Methods

Patients enrolled in the Japanese nationwide retrospective registry were evaluated using the criteria with partial modification; wall thickening of descending thoracic-abdominal aorta were mainly diagnosed by contrast-enhanced computed tomography (CT) or magnetic resonance imaging instead of evaluating with positron emission tomography (PET)-CT. The discriminability of the criteria was evaluated using C-statistic (> 0.7: good ability).

Results

Newly diagnosed patients with GCA (n = 139) and TAK (n = 129) were assessed, and 23.3% of TAK were aged 50 years or older at onset. The sensitivity of the modified 2022 ACR/EULAR GCA classification criteria with a score ≥ 6 was 82.0%, 68.5%, and 32.1% in all GCA, GCA with large-vessel involvement, and GCA without cranial arteritis, respectively. The specificity of the modified criteria was 96.1% for the 129 TAK as controls. Five patients with late-onset TAK met the modified criteria, and four had cranial signs and symptoms, two had bilateral axillary artery involvement, and four had descending thoracic-abdominal aorta involvement. The discriminability of the criteria was good (C-statistic: 0.986, 95% confidence interval [CI]: 0.976–0.996) and remained good after excluding age (C-statistic: 0.927, 95% CI: 0.894–0.961). The discriminability of a set of large-vessel lesions (bilateral axillary artery and descending thoracic-abdominal aorta) and inflammatory markers was markedly decreased with poor C-statistic value (C-statistic: 0.598, 95% CI: 0.530–0.667). Discriminability was improved after adding polymyalgia rheumatica (PMR) (C-statistic: 0.757, 95% CI: 0.700–0.813) or age (C-statistic: 0.913, 95%CI: 0.874–0.951) to the set of large-vessel lesions. In GCA patients with a score ≤ 5, 52% had bilateral subclavian and/or axillary artery involvement.

Conclusion

The modified 2022 ACR/EULAR GCA classification criteria well performed in classifying GCA and TAK without PET-CT in routine clinical practice. A set of items included in the modified GCA classification criteria had good discriminative ability for GCA and TAK, even when age was excluded. However, age restriction or PMR was required to distinguish GCA without cranial lesions from TAK.

DOI： 10.1186/s13075-025-03486-y

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Other Link： https://link.springer.com/article/10.1186/s13075-025-03486-y/fulltext.html

The Change in Public Perception and Knowledge Acquisition Methods of Chronic Kidney Disease Among General Population in Okayama Prefecture, Japan. International journal

Ryoko Umebayashi, Natsumi Matsuoka-Uchiyama, Hitoshi Sugiyama, Kenichi Shikata, Naoki Kashihara, Hirofumi Makino, Jun Wada, Haruhito A Uchida

Diseases (Basel, Switzerland)   12 ( 11 )   2024.10

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CKD public education plays a very important role in effective chronic kidney disease (CKD) countermeasure. We have been conducting CKD public education programs in Okayama Prefecture since 2007. Here, we aimed to examine the actual status of CKD perceptance and changes in CKD perceptance due to these education programs. The study was conducted on individuals who underwent health checkups at 12 medical institutions across five medical regions in Okayama Prefecture between 1 October and 30 November in 2015, 2019, and 2023. The results showed that overall CKD perceptance has improved over time (perceptance of "CKD" 4% to 7%, "chronic kidney disease" 27% to 34%, 2015 vs. 2023). "Chronic kidney disease" was more commonly recognized than "CKD", and the elderly were more aware of the disease than younger people. The CKD perceptance improved across all age groups. However, the rate of CKD perceptance is still low, especially among young people. Previously, newspapers were the second most common resource of information about CKD after television. However, the Internet has recently replaced newspapers as the second most common source of information, especially among younger people. Understanding of the exact diagnosis of CKD also remains insufficient. It is necessary to continue more effective CKD public education programs through more intelligible terminology and information sources that match the demographics of target population.

DOI： 10.3390/diseases12110268

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Clinical Characteristics and Treatment Outcomes of Patients With Newly Diagnosed Takayasu Arteritis in Japan During the First 2 Years of Treatment ― A Nationwide Retrospective Cohort Study ―

Haruhito A. Uchida, Yoshikazu Nakaoka, Takahiko Sugihara, Hajime Yoshifuji, Yasuhiro Maejima, Yoshiko Watanabe, Hiroko Nagafuchi, Takahiro Okazaki, Yoshinori Komagata, Yoshiya Tanaka, Eisuke Amiya, Tatsuya Atsumi, Kazuo Tanemoto, Tsutomu Takeuchi, Taio Naniwa, Atsushi Komatsuda, Hiroaki Dobashi, Koichi Amano, Noriyoshi Ogawa, Yohko Murakawa, Hitoshi Hasegawa, Taichi Hayashi, Yoshihiro Arimura, Mitsuaki Isobe, Masayoshi Harigai

Circulation Journal   2024.9

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Publishing type：Research paper (scientific journal)   Publisher：Japanese Circulation Society  

DOI： 10.1253/circj.cj-24-0178

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A case of renal hypouricemia due to T217M mutation in SLC22A12 incidentally associated with IgA nephropathy. International journal

Yoshimasa Sakurabu, Haruhito A Uchida, Toshihisa Tahara, Tomohiko Asakawa, Haruka Yamasaki, Katsuyoshi Katayama, Shugo Okamoto, Yasuhiro Onishi, Natsumi Matsuoka-Uchiyama, Keiko Tanaka, Hidemi Takeuchi, Kenji Tsuji, Ryoko Umebayashi, Yuki Ohashi, Kimiyoshi Ichida, Jun Wada

Clinical case reports   12 ( 9 )   e9368   2024.9

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A T217M heterozygous mutation in the SLC22A12 gene caused renal hypouricemia; this patient with IgA nephropathy had no findings other than IgA nephropathy on renal biopsy. Hypouricemia was susceptible to oxidative stress, but IgA nephropathy in the patient with hypouricemia could be treated with steroid pulse therapy without adverse events.

DOI： 10.1002/ccr3.9368

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A case of membranous nephropathy complicated by Cronkhite-Canada syndrome successfully treated with mizoribine.

Hiroyuki Nakanoh, Kenji Tsuji, Shiho Morimoto, Kazuhiko Fukushima, Masaya Iwamuro, Haruhito A Uchida, Jun Wada

CEN case reports   2024.7

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Cronkhite-Canada syndrome (CCS) is a non-hereditary disorder characterized by non-neoplastic hamartomatous gastrointestinal polyposis, hair loss, nail atrophy, hyperpigmentation, and diarrhea. While the relationship between CCS and nephritis remains unclear, seven cases of nephritis complicated by CCS have been reported to date, all of which were membranous nephropathy (MN). A 57-year-old man presented with taste disturbance, hair loss, nail plate atrophy, skin pigmentation, and frequent diarrhea. Endoscopic findings showed multiple polyposis of the stomach and large intestine. Given the above, he was diagnosed with CCS. The symptoms gradually improved with prednisolone treatment, although urinary protein and hypoproteinemia appeared during the tapering of prednisolone. He was diagnosed with MN using a renal biopsy, and immunofluorescence microscopy with IgG subclass staining showed predominantly diffuse granular capillary wall staining of IgG4. The cause of secondary MN was not found, including malignant tumors. Nephrotic-range proteinuria persisted despite treatment with prednisolone and cyclosporine. Additional treatment with mizoribine resulted in incomplete remission type 1 of nephrotic syndrome, suggesting that mizoribine may be a treatment option for patients with CCS with steroid-resistant MN. Considering a high prevalence of hypoproteinemia due to chronic diarrhea and protein-losing enteropathy in patients with CCS, proteinuria might be overlooked; thus, follow-up urinalysis would be recommended in patients with CCS.

DOI： 10.1007/s13730-024-00908-9

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岡山市CKDネットワーク(OCKD-NET)2の登録2年後のデータ解析

田中 景子, 内田 治仁, 大西 康博, 岡本 修吾, 竹内 英実, 辻 憲二, 田邊 克幸, 森永 裕士, 太田 康介, 丸山 啓輔, 大城 義之, 森岡 茂, 瀧上 慶一, 蒲生 直幸, 杉山 斉, 和田 淳

日本腎臓学会誌   66 ( 4 )   677 - 677   2024.6

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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医学生教育における腎生検シミュレーターを用いた腎生検実習の意義

辻 憲二, 大西 康博, 岡本 修吾, 田中 景子, 竹内 英実, 田邊 克幸, 森永 裕士, 内田 治仁, 和田 淳

日本腎臓学会誌   66 ( 4 )   597 - 597   2024.6

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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岡山県における地域別の透析導入患者数の推移に関する検討

梅林 亮子, 内山 奈津実, 岡本 修吾, 田中 景子, 内田 治仁, 杉山 斉, 和田 淳

日本腎臓学会誌   66 ( 4 )   661 - 661   2024.6

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Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3). International journal

Asami Ueno, Yasuhiro Onishi, Koki Mise, Satoshi Yamaguchi, Ayaka Kanno, Ichiro Nojima, Chigusa Higuchi, Haruhito A Uchida, Kenichi Shikata, Satoshi Miyamoto, Atsuko Nakatsuka, Jun Eguchi, Kazuyuki Hida, Akihiro Katayama, Mayu Watanabe, Tatsuaki Nakato, Atsuhito Tone, Sanae Teshigawara, Takashi Matsuoka, Shinji Kamei, Kazutoshi Murakami, Ikki Shimizu, Katsuhito Miyashita, Shinichiro Ando, Tomokazu Nunoue, Jun Wada

BMJ open diabetes research & care   12 ( 3 )   2024.5

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INTRODUCTION: ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing vasodilatation by acting on the Mas receptor. In diabetic kidney disease (DKD), it is still unclear whether plasma or urine ACE2 levels predict renal outcomes or not. RESEARCH DESIGN AND METHODS: Among 777 participants with diabetes enrolled in the Urinary biomarker for Continuous And Rapid progression of diabetic nEphropathy study, the 296 patients followed up for 9 years were investigated. Plasma and urinary ACE2 levels were measured by the ELISA. The primary end point was a composite of a decrease of estimated glomerular filtration rate (eGFR) by at least 30% from baseline or initiation of hemodialysis or peritoneal dialysis. The secondary end points were a 30% increase or a 30% decrease in albumin-to-creatinine ratio from baseline to 1 year. RESULTS: The cumulative incidence of the renal composite outcome was significantly higher in group 1 with lowest tertile of plasma ACE2 (p=0.040). Group 2 with middle and highest tertile was associated with better renal outcomes in the crude Cox regression model adjusted by age and sex (HR 0.56, 95% CI 0.31 to 0.99, p=0.047). Plasma ACE2 levels demonstrated a significant association with 30% decrease in ACR (OR 1.46, 95% CI 1.044 to 2.035, p=0.027) after adjusting for age, sex, systolic blood pressure, hemoglobin A1c, and eGFR. CONCLUSIONS: Higher baseline plasma ACE2 levels in DKD were protective for development and progression of albuminuria and associated with fewer renal end points, suggesting plasma ACE2 may be used as a prognosis marker of DKD. TRIAL REGISTRATION NUMBER: UMIN000011525.

DOI： 10.1136/bmjdrc-2024-004237

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Successful treatment for life threatening recurrent non-traumatic rectus sheath hematoma in a case with microscopic polyangiitis with rapidly progressive glomerulonephritis.

Hiroyuki Nakanoh, Hidemi Takeuchi, Morimoto Shiho, Yuya Terajima, Shugo Okamoto, Yasuhiro Onishi, Keiko Tanaka, Takayuki Katsuyama, Kenji Tsuji, Yoshinori Matsumoto, Katsuyuki Tanabe, Hiroshi Morinaga, Mayu Uka, Koji Tomita, Haruhito A Uchida, Takao Hiraki, Jun Wada

Internal medicine (Tokyo, Japan)   2024.4

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A 68-year-old woman was admitted to our hospital because of a rapid progression of renal dysfunction with positive myeloperoxidase antineutrophil cytoplasmic antibody and was diagnosed with rapidly progressive glomerulonephritis associated with microscopic polyangiitis (MPA). Severe right rectus sheath hematoma (RSH) bleeding from the inferior epigastric artery developed after starting hemodialysis, which required 4 transarterial embolizations due to recurrent bleeding. After additional treatment with methylprednisolone pulse therapy and rituximab, no rebleeding occurred. Although the giant hematoma reached the pelvis, it shrank spontaneously without any intervention. Nontraumatic RSH should therefore be considered when treating patients with multiple risk factors.

DOI： 10.2169/internalmedicine.3239-23

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A Case of Pseudoxanthoma Elasticum with juvenile-onset hypertension.

Katsuyoshi Katayama, Haruhito A Uchida, Aya Takehara, Jun Wada

Internal medicine (Tokyo, Japan)   2024.4

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DOI： 10.2169/internalmedicine.3050-23

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The real-world clinical decisions of physicians in the management of Takayasu arteritis and giant cell arteritis in Japan: A cross-sectional web-questionnaire survey

Yoshiyuki Abe, Takao Fujii, Yoshia Miyawaki, Takahiko Sugihara, Haruhito A Uchida, Yasuhiro Maejima, Yoshiko Watanabe, Takuya Hashimoto, Takako Miyamae, Yoshikazu Nakaoka, Masayoshi Harigai, Naoto Tamura

Modern Rheumatology   2024.4

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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Objectives: To access the real-world clinical management of physicians who treat Takayasu arteritis (TAK) and giant cell arteritis (GCA) after the publication of the Japanese Circulation Society (JCS) 2017 Guidelines for the Management of Vasculitis Syndrome.

Methods: This descriptive, cross-sectional study utilized self-administered electronic questionnaires, which were answered in February 2022 by physicians treating TAK or GCA and registered with Macromill Inc.

Results: The 329 survey respondents comprised 110 cardiologists, 110 rheumatologists, 34 cardiovascular surgeons, 24 surgeons, 35 internal medicine physicians, 13 nephrologists, and 7 pediatricians. The 2017 JCS Guidelines were the most commonly referenced information source for resolving clinical questions, accessed by 70% of respondents. Ophthalmoscopy was performed in only 50% of patients with TAK, and in 70% for GCA. The median percentages of patients who underwent 18F-fluorodeoxyglucose-positron emission tomography/computed tomography for TAK and GCA patients were 23% and 20% at diagnosis, respectively, and 10% each at follow-up within 12 months. Tocilizumab was the most frequently used medication in combination with glucocorticoids for both TAK and GCA, especially in remission induction therapy for relapsed patients.

Conclusions: The majority of physician treating TAK and GCA referred to the 2017 JCS guidelines. This report clarified the current clinical practice for large vessel vasculitis in Japan, providing information for the next revision of the guidelines.

DOI： 10.1093/mr/roae034

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Late-onset renal variant Fabry disease with R112H mutation and mild increase in plasma globotriaosylsphingosine: a case report. International journal

Keiko Tanaka, Hitoshi Sugiyama, Hiroshi Morinaga, Akifumi Onishi, Katsuyuki Tanabe, Haruhito A Uchida, Hiroki Maruyama, Jun Wada

Frontiers in medicine   11   1383309 - 1383309   2024

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Fabry disease (FD) is an X-linked disorder resulting in a deficiency of α-galactosidase A (GLA) activity. The R112H mutation of GLA is relatively common in Japanese FD patients, characterized by a late-onset phenotype, almost normal to mild lyso-Gb3 elevation, and mild clinical symptoms, despite low GLA activity. This is due to the structural features of the R112H GLA protein. We herein report the case of a 42-year-old male patient with late-onset FD with a R112H mutation. The patient exhibited only renal involvement with no other organ damage and was successfully treated with galactosidase beta and subsequent migalastat for approximately 10 years. Especially, migalastat was clinically effective in normalizing plasma lyso-Gb3 levels and inhibiting the progression of renal damage associated with FD. Therefore, the use of migalastat in the FD patients with R112H mutation is highly recommended based on this case report.

DOI： 10.3389/fmed.2024.1383309

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Organ Damage and Quality of Life in Takayasu Arteritis - Evidence From a National Registry Analysis.

Hajime Yoshifuji, Yoshikazu Nakaoka, Haruhito A Uchida, Takahiko Sugihara, Yoshiko Watanabe, Sohei Funakoshi, Mitsuaki Isobe, Masayoshi Harigai

Circulation journal : official journal of the Japanese Circulation Society   2023.12

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BACKGROUND: Takayasu arteritis, affecting primarily young women, damages large arteries and organs. We examined the impact of disease duration and sex on organ damage and quality of life using Japan's Intractable Disease Registry.Methods and Results: After refining data, 2,013 of 2,795 patients were included in the study. Longer disease duration was related to a lower prevalence of disease activity symptoms, a higher prevalence of organ damage, and a higher proportion of patients requiring nursing care. Compared with men, women tended to have an earlier onset age, exhibiting longer disease duration. A higher proportion of women had aortic regurgitation and required nursing care. The proportion of female patients in employment was lower than that of the general female population, whereas no difference was observed between male patients and the general male population. Logistic regression analysis revealed that age at surveillance, brain ischemia, visual impairment/loss, and ischemic heart disease were significant factors associated with high nursing care needs (Level ≥2, with daily activity limitations). CONCLUSIONS: Early diagnosis and effective treatment, particularly to prevent brain ischemia, visual impairment, and ischemic heart disease, may improve the quality of life of patients with Takayasu arteritis, especially women.

DOI： 10.1253/circj.CJ-23-0656

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Kidney Veno-Muscular Characteristics and Kidney Disease Progression: A Native Kidney-Biopsy Study. International journal

Kenji Tsuji, Hiroyuki Nakanoh, Kensaku Takahashi, Takafumi Morita, Yizhen Sang, Kazuhiko Fukushima, Natsumi Matsuoka-Uchiyama, Yasuhiro Onishi, Haruhito A Uchida, Shinji Kitamura, Jun Wada

Kidney medicine   5 ( 12 )   100733 - 100733   2023.12

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RATIONALE & OBJECTIVE: Assessment of kidney biopsies provides crucial information for diagnosis and disease activity, as well as prognostic value. Kidney-biopsy specimens occasionally contain veno-muscular complex (VMC), which consists of muscle tissues around the kidney venous system in the corticomedullary region. However, the role of VMC and the clinical significance of VMC variants are poorly understood. In the present study, we investigated kidney prognostic values of VMC variants. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Among 808 patients who underwent a kidney biopsy from 2011 to 2019, 246 patients whose kidney biopsy specimens contained VMC were enrolled. PREDICTORS: VMC variants; inflammatory-VMC (an infiltration of ≥80 inflammatory cells/mm2-VMC area) and VMC hypertrophy (hyper-VMC, a VMC average width ≥850 μm), and the interstitial fibrosis/tubular atrophy (IFTA) score. OUTCOMES: A decline in estimated glomerular filtration rate (eGFR) ≥40% from the baseline or commencement of kidney replacement therapy. ANALYTICAL APPROACH: Cox proportional hazards model. RESULTS: Among 246 patients with data on VMC, mean baseline eGFR was 56.0±25.6 ml/min per 1.73 m2; 80 had high inflammatory-VMC, and 62 had VMC hypertrophy. There were 51 kidney events over median follow-up of 2.5 years. We analyzed 2 VMC variants. Multivariable logistic regression analysis revealed that eGFR negatively correlated with the presence of both inflammatory-VMC and hyper-VMC. A Cox proportional hazards analysis revealed that inflammatory-VMC (but not hyper-VMC) was independently associated with the primary outcome after adjustments for known risk factors of progression, including proteinuria, eGFR, and the interstitial fibrosis/tubular atrophy (IFTA) score (hazard ratio, 1.97; 95% confidence interval, 1.00-3.91). LIMITATIONS: Single-center study and small sample size. CONCLUSIONS: Assessment of inflammatory-VMC provides additional kidney prognostic information to known indicators of kidney disease progression in patients who undergo kidney biopsy. PLAIN-LANGUAGE SUMMARY: Assessment of kidney biopsies provides crucial information for diagnosis, disease activity, and prognostic value. Kidney-biopsy specimens occasionally contain veno-muscular complex (VMC), which consists of muscle tissues around the kidney venous system. Currently, the role of VMC in kidney health and diseases and the clinical significance of VMC variants are poorly understood. In the present study, we have shown that an infiltration of ≥80 inflammatory cells/mm2-VMC area (inflammatory-VMC) is independently associated with kidney disease progression after adjustments for known risk factors of progression. Therefore, assessment of inflammatory-VMC provides additional kidney prognostic information to known indicators of kidney disease progression in patients who undergo kidney biopsy.

DOI： 10.1016/j.xkme.2023.100733

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Neutrophil Elastase Inhibition by Sivelestat (ONO-5046) Attenuates AngII-induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice. International journal

Yoshiko Hada, Haruhito A Uchida, Shugo Okamoto, Nozomu Otaka, Katsuyoshi Katayama, Venkateswaran Subramanian, Alan Daugherty, Jun Wada

American journal of hypertension   2023.11

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BACKGROUND: Abdominal aortic aneurysm (AAA) is an arterial disease characterized by dilatation of the aortic wall. It has been suggested that neutrophil counts and neutrophil elastase activity are associated with AAA. We investigated whether a neutrophil elastase (NE) inhibitor, sivelestat (Siv), had a protective effect against angiotensin II (AngII)-induced AAAs. METHODS: Male apolipoprotein E-deficient mice were assigned into 3 groups: Vehicle+saline, AngII+saline, and AngII+Siv. All mice were administered intraperitoneally with either Siv or vehicle twice daily after AngII infusion. RESULTS: In the 4-week AngII infusion study, plasma NE concentration (p=0.041) and its activity (p=0.011) were elevated by AngII. These increases were attenuated by Siv (concentration:p=0.010, activity:p=0.027). Further, plasma elastase activity was closely correlated with aortic width (R=0.6976, p<0.001). In the 1-week AngII infusion study, plasma and tissue elastase activity increased by AngII (plasma:p=0.034, tissue:p<0.001), but were reduced by Siv (plasma:p=0.014, tissue:p=0.024). AngII increased aortic width (p=0.011) but was attenuated by co-administration of Siv (p=0.022). Moreover, Siv decreased the incidence of AAAs (p=0.009). Elastin fragmentation induced by AngII was reduced by Siv. Many inflammatory cells that were either CD68 or Gr-1 positive were observed in the AngII+saline group, whereas few inflammatory cells were accumulated in the AngII+Siv group. MMP-2 and MMP-9 were enhanced by AngII, but were reduced by Siv. In vitro, MMP-2 activity was induced by human NE (medium:p<0.001, cells:p=0.001), which was attenuated by co-incubation of Siv in medium (p<0.001) and protein of human aortic smooth muscle cells (p=0.001). CONCLUSION: Siv attenuated AngII-induced AAA through the inhibition of NE.

DOI： 10.1093/ajh/hpad107

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ヘパリン起因性血小板減少症患者に対する内シャント造設術の経験

藤井 泰宏, 廣田 真規, 加藤 源太郎, 竹内 英実, 黒子 洋介, 川畑 拓也, 小谷 恭弘, 小林 純子, 内田 治仁, 小松 弘明, 井上 善紀, 枝木 大治, 鈴木 浩之, 岸 良匡, 成宮 悠仁, 森岡 慧, 三浦 望, 杭ノ瀬 慶彦, 武田 直人, 笠原 真悟

脈管学   63 ( Suppl. )   S178 - S178   2023.10

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Language：Japanese   Publisher：(一社)日本脈管学会  

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ヘパリン起因性血小板減少症患者に対する内シャント造設術の経験

藤井 泰宏, 廣田 真規, 加藤 源太郎, 竹内 英実, 黒子 洋介, 川畑 拓也, 小谷 恭弘, 小林 純子, 内田 治仁, 小松 弘明, 井上 善紀, 枝木 大治, 鈴木 浩之, 岸 良匡, 成宮 悠仁, 森岡 慧, 三浦 望, 杭ノ瀬 慶彦, 武田 直人, 笠原 真悟

脈管学   63 ( Suppl. )   S178 - S178   2023.10

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神経障害(2) 糖尿病神経障害におけるミエリン傷害

片山 勝喜, 内田 治仁, 檜山 武史, 徐 珊珊, 栢野 功政, 松本 真実, 浦久保 秀俊, 大野 伸彦, 宮本 聡, 四方 賢一, 和田 淳

糖尿病合併症   37 ( Suppl.1 )   149 - 149   2023.9

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Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

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検尿異常の精査中に発見したIgA腎症に腎性低尿酸血症が合併した1例

櫻武 敬真, 内田 治仁, 田原 稔久, 山崎 遥香, 大西 康博, 田中 景子, 竹内 英実, 辻 憲二, 梅林 亮子, 和田 淳

日本腎臓学会誌   65 ( 6-W )   810 - 810   2023.9

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Cronkhite-Canada症候群に膜性腎症を合併した1例

中納 弘幸, 森本 志帆, 辻 憲二, 田邊 克幸, 内田 治仁, 和田 淳

日本腎臓学会誌   65 ( 6-W )   767 - 767   2023.9

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Behcet病の経過中にIgA腎症を合併し,ステロイド療法とコルヒチン併用により蛋白尿の大幅な改善を認めた一例

浅川 知彦, 内田 治仁, 片山 祐, 田中 景子, 竹内 英実, 辻 憲二, 梅林 亮子, 田邊 克幸, 森永 裕士, 和田 淳

日本腎臓学会誌   65 ( 6-W )   755 - 755   2023.9

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Elderly Brothers With Fabry Disease Exhibiting Cardiac and Renal Manifestations

Keiko Tanaka, Hitoshi Sugiyama, Hiroshi Morinaga, Akifumi Onishi, Yuzuki Kano, Hidemi Takeuchi, Kenji Tsuji, Motoki Kubo, Katsuyuki Tanabe, Haruhito A. Uchida, Kazufumi Nakamura, Jun Wada

Annals of Internal Medicine: Clinical Cases   2 ( 5 )   2023.5

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DOI： 10.7326/aimcc.2022.1003

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岡山市CKDネットワーク(OCKD-NET)2の登録時データ解析 OCKD-NET1との比較

田中 景子, 内田 治仁, 大西 康博, 岡本 修吾, 竹内 英実, 辻 憲二, 田邊 克幸, 森永 裕士, 太田 康介, 丸山 啓輔, 大城 義之, 森岡 茂, 瀧上 慶一, 蒲生 直幸, 杉山 斉, 和田 淳

日本腎臓学会誌   65 ( 3 )   268 - 268   2023.5

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岡山市CKDネットワーク(OCKD-NET)におけるCKD病診連携12年後の追跡調査

大西 康博, 内田 治仁, 田中 景子, 岡本 修吾, 竹内 英実, 辻 憲二, 田邊 克幸, 森永 裕士, 喜多村 真治, 前島 洋平, 太田 康介, 丸山 啓輔, 大城 義之, 森岡 茂, 瀧上 慶一, 蒲生 直幸, 杉山 斉, 和田 淳

日本腎臓学会誌   65 ( 3 )   240 - 240   2023.5

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医学生に対する腎セミナー開催についての検討

辻 憲二, 岡本 修吾, 大西 康博, 田中 景子, 竹内 英実, 田邊 克幸, 森永 裕士, 内田 治仁, 喜多村 真治, 和田 淳

日本腎臓学会誌   65 ( 3 )   326 - 326   2023.5

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岡山市CKDネットワーク(OCKD-NET)2の登録時データ解析 OCKD-NET1との比較

田中 景子, 内田 治仁, 大西 康博, 岡本 修吾, 竹内 英実, 辻 憲二, 田邊 克幸, 森永 裕士, 太田 康介, 丸山 啓輔, 大城 義之, 森岡 茂, 瀧上 慶一, 蒲生 直幸, 杉山 斉, 和田 淳

日本腎臓学会誌   65 ( 3 )   268 - 268   2023.5

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岡山市CKDネットワーク(OCKD-NET)におけるCKD病診連携12年後の追跡調査

大西 康博, 内田 治仁, 田中 景子, 岡本 修吾, 竹内 英実, 辻 憲二, 田邊 克幸, 森永 裕士, 喜多村 真治, 前島 洋平, 太田 康介, 丸山 啓輔, 大城 義之, 森岡 茂, 瀧上 慶一, 蒲生 直幸, 杉山 斉, 和田 淳

日本腎臓学会誌   65 ( 3 )   240 - 240   2023.5

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医学生に対する腎セミナー開催についての検討

辻 憲二, 岡本 修吾, 大西 康博, 田中 景子, 竹内 英実, 田邊 克幸, 森永 裕士, 内田 治仁, 喜多村 真治, 和田 淳

日本腎臓学会誌   65 ( 3 )   326 - 326   2023.5

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The Effect of Medical Cooperation in the CKD Patients: 10-Year Multicenter Cohort Study. International journal

Yasuhiro Onishi, Haruhito A Uchida, Yohei Maeshima, Yuka Okuyama, Nozomu Otaka, Haruyo Ujike, Keiko Tanaka, Hidemi Takeuchi, Kenji Tsuji, Masashi Kitagawa, Katsuyuki Tanabe, Hiroshi Morinaga, Masaru Kinomura, Shinji Kitamura, Hitoshi Sugiyama, Kosuke Ota, Keisuke Maruyama, Makoto Hiramatsu, Yoshiyuki Oshiro, Shigeru Morioka, Keiichi Takiue, Kazuyoshi Omori, Masaki Fukushima, Naoyuki Gamou, Hiroshi Hirata, Ryosuke Sato, Hirofumi Makino, Jun Wada

Journal of personalized medicine   13 ( 4 )   2023.3

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INTRODUCTION: While chronic kidney disease (CKD) is one of the most important contributors to mortality from non-communicable diseases, the number of nephrologists is limited worldwide. Medical cooperation is a system of cooperation between primary care physicians and nephrological institutions, consisting of nephrologists and multidisciplinary care teams. Although it has been reported that multidisciplinary care teams contribute to the prevention of worsening renal functions and cardiovascular events, there are few studies on the effect of a medical cooperation system. METHODS: We aimed to evaluate the effect of medical cooperation on all-cause mortality and renal prognosis in patients with CKD. One hundred and sixty-eight patients who visited the one hundred and sixty-three clinics and seven general hospitals of Okayama city were recruited between December 2009 and September 2016, and one hundred twenty-three patients were classified into a medical cooperation group. The outcome was defined as the incidence of all-cause mortality, or renal composite outcome (end-stage renal disease or 50% eGFR decline). We evaluated the effects on renal composite outcome and pre-ESRD mortality while incorporating the competing risk for the alternate outcome into a Fine-Gray subdistribution hazard model. RESULTS: The medical cooperation group had more patients with glomerulonephritis (35.0% vs. 2.2%) and less nephrosclerosis (35.0% vs. 64.5%) than the primary care group. Throughout the follow-up period of 5.59 ± 2.78 years, 23 participants (13.7%) died, 41 participants (24.4%) reached 50% decline in eGFR, and 37 participants (22.0%) developed end-stage renal disease (ESRD). All-cause mortality was significantly reduced by medical cooperation (sHR 0.297, 95% CI 0.105-0.835, p = 0.021). However, there was a significant association between medical cooperation and CKD progression (sHR 3.069, 95% CI 1.225-7.687, p = 0.017). CONCLUSION: We evaluated mortality and ESRD using a CKD cohort with a long-term observation period and concluded that medical cooperation might be expected to influence the quality of medical care in the patients with CKD.

DOI： 10.3390/jpm13040582

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Serum sCD40L and IL-31 in Association with Early Phase of IgA Nephropathy. International journal

Keiko Tanaka, Hitoshi Sugiyama, Hiroshi Morinaga, Masashi Kitagawa, Yuzuki Kano, Yasuhiro Onishi, Koki Mise, Katsuyuki Tanabe, Haruhito A Uchida, Jun Wada

Journal of clinical medicine   12 ( 5 )   2023.3

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BACKGROUND: IgA nephropathy (IgAN) is a major cause of chronic glomerulonephritis worldwide. T cell dysregulation has been reported to contribute to the pathogenesis of IgAN. Methods We measured a broad range of Th1, Th2 and Th17 cytokines in the serum of IgAN patients. We searched for significant cytokines, which were associated with clinical parameters and histological scores in IgAN patients. RESULTS: Among 15 cytokines, the levels of soluble CD40L (sCD40L) and IL-31 were higher in IgAN patients and were significantly associated with a higher estimated glomerular filtration rate (eGFR), a lower urinary protein to creatinine ratio (UPCR), and milder tubulointerstitial lesions (i.e., the early phase of IgAN). Multivariate analysis revealed that serum sCD40L was an independent determinant of a lower UPCR after adjustment for age, eGFR, and mean blood pressure (MBP). CD40, a receptor of sCD40L, has been reported to be upregulated on mesangial cells in IgAN. The sCD40L/CD40 interaction may directly induce inflammation in mesangial areas and may therefore be involved in the development of IgAN. CONCLUSIONS: The present study demonstrated the significance of serum sCD40L and IL-31 in the early phase of IgAN. Serum sCD40L may be a marker of the beginning of inflammation in IgAN.

DOI： 10.3390/jcm12052023

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Association between Urinary Creatinine Excretion and Hypothyroidism in Patients with Chronic Kidney Disease. International journal

Natsumi Matsuoka-Uchiyama, Kenji Tsuji, Kensaku Takahashi, Kazuhiko Fukushima, Hidemi Takeuchi, Shinji Kitamura, Kenichi Inagaki, Haruhito A Uchida, Jun Wada

Diagnostics (Basel, Switzerland)   13 ( 4 )   2023.2

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While hypothyroidism increases serum creatinine (Cr) levels, it is uncertain whether the elevation is mediated via a decline in the glomerular filtration rate (GFR) or the reflection of enhanced Cr production from the muscles or both. In the present study, we explored an association between urinary Cr excretion rate (CER) and hypothyroidism. A total of 553 patients with chronic kidney disease were enrolled in a cross-sectional study. Multiple linear regression analysis was performed to explore the association between hypothyroidism and urinary CER. The mean urinary CER was 1.01 ± 0.38 g/day and 121 patients (22%) had hypothyroidism. The multiple linear regression analysis revealed explanatory variables with urinary CER, including age, sex, body mass index, 24 h Cr clearance (24hrCcr), and albumin while hypothyroidism was not considered an independent explanatory variable. In addition, scatter plot analysis with regression fit line representing the association between estimated GFR calculated using s-Cr (eGFRcre) and 24hrCcr revealed that eGFRcre and 24hrCcr had strong correlations with each other in hypothyroid patients as well as euthyroid patients. Collectively, hypothyroidism was not considered an independent explanatory variable for urinary CER in the present study and eGFRcre is a useful marker to evaluate kidney function regardless of the presence of hypothyroidism.

DOI： 10.3390/diagnostics13040669

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Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study. International journal

Haruhito A Uchida, Hirofumi Nakajima, Masami Hashimoto, Akihiko Nakamura, Tomokazu Nunoue, Kazuharu Murakami, Takeshi Hosoya, Kiichi Komoto, Takashi Taguchi, Takaaki Akasaka, Kazuhito Shiosakai, Kotaro Sugimoto, Jun Wada

Advances in therapy   39 ( 11 )   5158 - 5175   2022.11

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INTRODUCTION: Clinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment. METHODS: In this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety. RESULTS: In total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (- 11.6/- 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (- 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was - 4.8 mL/min/1.73 m2. CONCLUSION: Esaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction. CLINICAL TRIAL REGISTRATION: jRCTs06119002.

DOI： 10.1007/s12325-022-02294-z

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The Beneficial Effect of Personalized Lifestyle Intervention in Chronic Kidney Disease Follow-Up Project for National Health Insurance Specific Health Checkup: A Five-Year Community-Based Cohort Study. International journal

Hidemi Takeuchi, Haruhito A Uchida, Katsuyoshi Katayama, Natsumi Matsuoka-Uchiyama, Shugo Okamoto, Yasuhiro Onishi, Yuka Okuyama, Ryoko Umebayashi, Kodai Miyaji, Akiko Kai, Izumi Matsumoto, Keiko Taniguchi, Fukiko Yamashita, Tsutomu Emi, Hitoshi Sugiyama, Jun Wada

Medicina (Kaunas, Lithuania)   58 ( 11 )   2022.10

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Background and Objectives: Mimasaka city is a relatively small city with a population of 28,381, and an aging rate (≥65 years old) of 38.9%, where only one nephrology clinic is available. Since 2013, the city has conducted its own unique lifestyle intervention for the participants of the National Health Insurance specific medical health checkup, aiming to prevent the progression of chronic kidney disease (CKD) severity. Materials and Methods: The persons in National Health Insurance specific medical health checkup (40-74 years old) conducted in Mimasaka city in 2013, with eGFR less than 50 mL/min/1.73 m² or 50-90 mL/min/1.73 m² with urine dipstick protein 1+ or more, were registered for the CKD follow-up project, as high-risk subjects for advanced renal dysfunction. Municipal workers directly visited the subjects' homes to provide individual health guidance and encourage medical consultation. We aimed to examine the effect of home-visit intervention on the changes of renal function and related factors until 2017. Results: The number of the high-risk subjects who continuously received the health checkup until 2017 was 63, and only 23 (36.5%) visited a medical institution in the first year. The eGFR decreased by only 0.4 mL/min/1.73 m²/year, and the subjects with urinary protein 1+ or higher decreased significantly from 20 (31.7%) to 9 (14.3%) (p = 0.034) in the high-risk subjects. The changes in eGFR and urinary protein was almost in the same fashion regardless of their medical institution visits. Next, we examined the effects of various factors on ΔeGFR, the changes of eGFR from 2013 to 2017, by multivariate linear regression analysis. The effects of medical institution visit were not significant, and the degree of urinary protein (coefficient B: 4.503, β: 0.705, p &lt; 0.001), age (coefficient B: 4.753, β: 0.341, p = 0.004), and smoking (coefficient B: 5.878, β: 0.295, p = 0.031) had independent significant effects, indicating that they were the factors exacerbating the decrease in eGFR from the baseline. Conclusions: The personalized lifestyle intervention by home-visit in CKD follow-up project showed the possibility of beneficial effects on the deterioration of renal function. This may be an efficient method to change behavior in a small community with limited medical resources.

DOI： 10.3390/medicina58111529

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Association between the patterns of large-vessel lesions and treatment outcomes in patients with large-vessel giant cell arteritis. International journal

Takahiko Sugihara, Haruhito A Uchida, Hajime Yoshifuji, Yasuhiro Maejima, Taio Naniwa, Yasuhiro Katsumata, Takahiro Okazaki, Jun Ishizaki, Yohko Murakawa, Noriyoshi Ogawa, Hiroaki Dobashi, Tetsuya Horita, Yoshiya Tanaka, Shunsuke Furuta, Tsutomu Takeuchi, Yoshinori Komagata, Yoshikazu Nakaoka, Masayoshi Harigai

Modern rheumatology   2022.10

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OBJECTIVE: We aimed to identify associations between patterns of large-vessel lesions of large-vessel giant cell arteritis (LV-GCA) and treatment outcomes. METHODS: We extracted data on 68 newly-diagnosed patients with LV-GCA from a retrospective, multi-centric, nationwide registry of GCA patients treated with glucocorticoids between 2007 and 2014. Patients with aortic lesions were identified based on findings from contrast-enhanced computed tomography (CT), magnetic resonance imaging, or positron emission tomography-CT (group 2, n=49). Patients without aortic lesions were subdivided into LV-GCA with or without subclavian lesions defined as group 1 (n=9) or group 3 (n=10), respectively. Primary outcome evaluation was failure to achieve clinical remission by week 24 and/or relapse within 104 weeks. RESULTS: The mean age and proportion of patients with cranial lesions and polymyalgia rheumatica in group 2 was numerically lower than in the other two groups. Large-vessel lesions in group 3 included carotid, pulmonary, renal, hepatic or mesenteric lesions. The cumulative rate of poor treatment outcomes over two years was 11.1%, 55.3%, and 88.0% in groups 1, 2, and 3, respectively (by Kaplan-Meier analysis). The mean time to poor outcome was significantly different between the groups. CONCLUSIONS: Classification by subclavian and aortic lesions may be useful to determine treatment strategy.

DOI： 10.1093/mr/roac122

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異なる経過をたどった腎動脈狭窄を伴う高安動脈炎の2症例

武本 梨佳, 内田 治仁, 戸田 洋伸, 岡本 修吾, 竹内 英実, 梅林 亮子, 大塚 文男, 伊藤 浩, 和田 淳

脈管学   62 ( Suppl. )   S195 - S195   2022.10

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ベーチェット病により腎動脈狭窄症をきたした1例

内田 治仁, 戸田 洋伸, 武本 梨佳, 岡本 修吾, 竹内 英実, 梅林 亮子, 和田 淳

脈管学   62 ( Suppl. )   S182 - S183   2022.10

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当院における腎移植後コロナウイルス感染症の臨床経過

吉永 香澄, 関戸 崇了, 丸山 雄樹, 山野井 友昭, 西村 慎吾, 竹内 英実, 田邉 克幸, 森永 裕士, 内田 治仁, 和田 淳, 枝村 康平, 小林 知子, 小林 泰之, 荒木 元朗

移植   57 ( 総会臨時 )   262 - 262   2022.10

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00083&link_issn=&doc_id=20221028010244&doc_link_id=%2Fcl8isoke%2F2022%2Fs057s1%2F007%2F0262-0262%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcl8isoke%2F2022%2Fs057s1%2F007%2F0262-0262%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

異なる経過をたどった腎動脈狭窄を伴う高安動脈炎の2症例

武本 梨佳, 内田 治仁, 戸田 洋伸, 岡本 修吾, 竹内 英実, 梅林 亮子, 大塚 文男, 伊藤 浩, 和田 淳

脈管学   62 ( Suppl. )   S195 - S195   2022.10

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The association between hypothyroidism and proteinuria in patients with chronic kidney disease: a cross-sectional study. International journal

Natsumi Matsuoka-Uchiyama, Kenji Tsuji, Yizhen Sang, Kensaku Takahashi, Kazuhiko Fukushima, Hidemi Takeuchi, Kenichi Inagaki, Haruhito A Uchida, Shinji Kitamura, Hitoshi Sugiyama, Jun Wada

Scientific reports   12 ( 1 )   14999 - 14999   2022.9

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Hypothyroidism is known to be correlated with kidney function and nephrotic range proteinuria. However, it is uncertain whether non-nephrotic proteinuria is associated with hypothyroidism. This study aimed to evaluate the association of proteinuria and hypothyroidism in chronic kidney disease (CKD) patients. We conducted a cross-sectional study composed of 421 CKD patients in a single hospital with measurements of 24-h urine protein excretion (UP) and thyroid function tests. Spearman correlation analysis revealed that 24-h Cr clearance (24hrCcr) was positively (r = 0.273, p < 0.001) and UP was negatively (r = - 0.207, p < 0.001) correlated with free triiodothyronine. Frequency distribution analysis stratified by CKD stage and UP for hypothyroidism revealed that the prevalence of hypothyroidism was higher among participants with higher CKD stage and nephrotic range proteinuria. Multivariate logistic regression analysis revealed that 24hrCcr and UP were significantly correlated with hypothyroidism (24hrCcr/10 mL/min decrease: odds ratio [OR], 1.29; 95% confidence interval [CI], 1.18-1.41; UP/1 g increase: OR, 1.10; 95% CI, 1.03-1.17). In addition, nephrotic range proteinuria, but not moderate UP (UP: 1.5-3.49 g/day), was significantly correlated with hypothyroidism compared to UP < 0.5 g/day. In summary, decreased kidney function and nephrotic range proteinuria, not non-nephrotic proteinuria, are independently associated with the hypothyroidism.

DOI： 10.1038/s41598-022-19226-0

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Simulation for ultrasound-guided renal biopsy using boiled egg. International journal

Kenji Tsuji, Shinji Kitamura, Haruhito A Uchida, Jun Wada

Nephrology (Carlton, Vic.)   27 ( 9 )   753 - 757   2022.9

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Real-time ultrasound-guided renal biopsy is generally applied to diagnose multiple kidney diseases. A practical simulation model is desired since it is an invasive technique with higher risks of complications such as bleeding. We developed a simple simulation tool for ultrasound-guided renal biopsy using boiled eggs. Boiled chicken eggs were embedded in the agar, and a biopsy simulation was performed using a real-time ultrasound-guided technique as the renal biopsy simulator by trainees and biopsy-proficient nephrologists, and the feedback from the participants was obtained. The ultrasonographic evaluation revealed a clear contrast between egg yolk and white, which clearly mimicked the kidney cortex and medulla region. In addition, we observed the needle entering the egg white under needle penetration, and we obtained the biopsy core consisting of egg white. As for the simulations, all the participants succeeded in obtaining the appropriate samples. A total of 92% of the trainees agreed that the simulation could reduce their fears of performing renal biopsies in patients. In addition, all the trainees and biopsy-proficient nephrologists recommend using the simulator for trainees before conducting renal biopsies on patients. The total cost of the simulator was low (<USD 1/simulator). Collectively, our simulation tool using boiled eggs may be a good candidate for practical simulation models of renal biopsy.

DOI： 10.1111/nep.14079

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Establishing clinical remission criteria and the framework of a treat-to-target algorithm for Takayasu arteritis: Results of a Delphi exercise carried out by an expert panel of the Japan Research Committee of the Ministry of Health, Labour and Welfare for intractable vasculitis. International journal

Takahiko Sugihara, Yoshikazu Nakaoka, Haruhito A Uchida, Hajime Yoshifuji, Yasuhiro Maejima, Yoshiko Watanabe, Eisuke Amiya, Kazuo Tanemoto, Tetsuro Miyata, Natsuka Umezawa, Yusuke Manabe, Jun Ishizaki, Tsuyoshi Shirai, Hiroko Nagafuchi, Hitoshi Hasegawa, Takako Miyamae, Hiroaki Niiro, Shuichi Ito, Tomonori Ishii, Mitsuaki Isobe, Masayoshi Harigai

Modern rheumatology   32 ( 5 )   930 - 937   2022.8

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OBJECTIVE: To develop a proposal for remission criteria and a framework for a treat-to-target (T2T) algorithm for Takayasu arteritis (TAK). METHODS: A study group of the large-vessel vasculitis group of the Japanese Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) consists of 10 rheumatologists, 5 cardiologists, 1 nephrologist, 1 vascular surgeon, 1 cardiac surgeon, and 2 pediatric rheumatologists. A Delphi survey of remission criteria items was circulated among the study group over 4 reiterations. To develop the T2T algorithm, the study group conducted four face-to-face meetings and two rounds of Delphi together with 3 patients. RESULTS: Initial literature review resulted in a list of 117 candidate items for remission criteria, of which 56 items with a mean score of ≥4 (0-5) were extracted including disease activity domains and treatment/comorbidity domains. The study group provided six overarching principles for the T2T algorithm, two recommendations on treatment goals, five on evaluation of disease activity and imaging findings including PET-CT, and two on treatment intensification. CONCLUSIONS: We developed a T2T algorithm and proposals for standardized remission criteria by means of a Delphi exercise. These will guide future evaluation of different TAK treatment regimens.

DOI： 10.1093/mr/roab081

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Edaravone Attenuated Angiotensin II-Induced Atherosclerosis and Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice. International journal

Haruhito A Uchida, Tetsuharu Takatsuka, Yoshiko Hada, Ryoko Umebayashi, Hidemi Takeuchi, Kenichi Shikata, Venkateswaran Subramanian, Alan Daugherty, Jun Wada

Biomolecules   12 ( 8 )   2022.8

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BACKGROUND: The aim of the study was to define whether edaravone, a free-radical scavenger, influenced angiotensin II (AngII)-induced atherosclerosis and abdominal aortic aneurysms (AAAs) formation. METHODS: Male apolipoprotein E-deficient mice (8-12 weeks old) were fed with a normal diet for 5 weeks. Either edaravone (10 mg/kg/day) or vehicle was injected intraperitoneally for 5 weeks. After 1 week of injections, mice were infused subcutaneously with either AngII (1000 ng/kg/min, n = 16-17 per group) or saline (n = 5 per group) by osmotic minipumps for 4 weeks. RESULTS: AngII increased systolic blood pressure equivalently in mice administered with either edaravone or saline. Edaravone had no effect on plasma total cholesterol concentrations and body weights. AngII infusion significantly increased ex vivo maximal diameters of abdominal aortas and en face atherosclerosis but was significantly attenuated by edaravone administration. Edaravone also reduced the incidence of AngII-induced AAAs. In addition, edaravone diminished AngII-induced aortic MMP-2 activation. Quantitative RT-PCR revealed that edaravone ameliorated mRNA abundance of aortic MCP-1 and IL-1β. Immunostaining demonstrated that edaravone attenuated oxidative stress and macrophage accumulation in the aorta. Furthermore, edaravone administration suppressed thioglycolate-induced mice peritoneal macrophages (MPMs) accumulation and mRNA abundance of MCP-1 in MPMs in male apolipoprotein E-deficient mice. In vitro, edaravone reduced LPS-induced mRNA abundance of MCP-1 in MPMs. CONCLUSIONS: Edaravone attenuated AngII-induced AAAs and atherosclerosis in male apolipoprotein E-deficient mice via anti-oxidative action and anti-inflammatory effect.

DOI： 10.3390/biom12081117

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Cilostazol Attenuates AngII-Induced Cardiac Fibrosis in apoE Deficient Mice. International journal

Yoshiko Hada, Haruhito A Uchida, Ryoko Umebayashi, Masashi Yoshida, Jun Wada

International journal of molecular sciences   23 ( 16 )   2022.8

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Cardiac fibrosis is characterized by the net accumulation of extracellular matrix in the myocardium and is an integral component of most pathological cardiac conditions. Cilostazol, a selective inhibitor of phosphodiesterase type III with anti-platelet, anti-mitogenic, and vasodilating properties, is widely used to treat the ischemic symptoms of peripheral vascular disease. Here, we investigated whether cilostazol has a protective effect against Angiotensin II (AngII)-induced cardiac fibrosis. Male apolipoprotein E-deficient mice were fed either a normal diet or a diet containing cilostazol (0.1% wt/wt). After 1 week of diet consumption, the mice were infused with saline or AngII (1000 ng kg-1 min-1) for 28 days. AngII infusion increased heart/body weight ratio (p &lt; 0.05), perivascular fibrosis (p &lt; 0.05), and interstitial cardiac fibrosis (p &lt; 0.0001), but were significantly attenuated by cilostazol treatment (p &lt; 0.05, respectively). Cilostazol also reduced AngII-induced increases in fibrotic and inflammatory gene expression (p &lt; 0.05, respectively). Furthermore, cilostazol attenuated both protein and mRNA abundance of osteopontin induced by AngII in vivo. In cultured human cardiac myocytes, cilostazol reduced mRNA expression of AngII-induced osteopontin in dose-dependent manner. This reduction was mimicked by forskolin treatment but was cancelled by co-treatment of H-89. Cilostazol attenuates AngII-induced cardiac fibrosis in mice through activation of the cAMP-PKA pathway.

DOI： 10.3390/ijms23169065

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IL-17A promotes vascular calcification in an ex vivo murine aorta culture. International journal

Sumie Hiramatsu-Asano, Tomoyuki Mukai, Takahiko Akagi, Haruhito A Uchida, Shunichi Fujita, Kazuhisa Nakano, Yoshitaka Morita

Biochemical and biophysical research communications   604   83 - 87   2022.5

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BACKGROUND: Vascular calcification is characterized by mineral deposition in the vasculature, which is triggered by chronic systemic inflammation, including psoriasis. Psoriasis is an IL-17A-mediated inflammatory skin disease that is associated with exacerbated vascular calcification and high cardiovascular mortality. Although previous studies have shown that IL-17A induces vascular dysfunction in murine psoriasis models, it has not been clarified whether IL-17A induces vascular calcification. In this study, we investigated the potential vascular calcification-inducing effect of IL-17A in an ex vivo culture system. METHODS: Thoracic and abdominal aortas from mice were cultured in a medium supplemented with inorganic phosphate and were treated with inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-17A). Vascular calcification was determined using micro-computed tomography (CT) and histological analyses. RESULTS: IL-1β, TNF-α, and IL-6 did not significantly promote vascular calcification, whereas IL-17A significantly accelerated vascular calcification of the aorta, as indicated by the increased mineralized volume based on micro-CT analysis. Micro-CT and histological analyses also revealed that the promoting effect of IL-17A on vascular calcification was concentration dependent. CONCLUSIONS: IL-17A significantly promoted vascular calcification in ex vivo cultured aortas, which suggests that this mechanism is involved in the increased risk of cardiovascular events in IL-17A-mediated inflammatory diseases.

DOI： 10.1016/j.bbrc.2022.03.051

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岡山市CKDネットワーク(OCKD-NET)におけるCKD病診連携11年後の追跡調査

大西 康博, 内田 治仁, 竹内 英実, 田中 景子, 辻 憲二, 田邊 克幸, 森永 裕士, 木野村 賢, 喜多村 真治, 前島 洋平, 杉山 斉, 太田 康介, 丸山 啓輔, 大城 義之, 森岡 茂, 瀧上 慶一, 蒲生 直幸, 和田 淳

日本腎臓学会誌   64 ( 3 )   234 - 234   2022.5

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ゆで卵を用いた模擬腎生検 コロンブスの卵

辻 憲二, 田中 景子, 竹内 英実, 田邊 克幸, 森永 裕士, 木野村 賢, 内田 治仁, 喜多村 真治, 杉山 斉, 和田 淳

日本腎臓学会誌   64 ( 3 )   297 - 297   2022.5

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加齢による筋萎縮に対するクロロゲン酸の保護効果

内田 治仁, 秦 昌紫子, 岡本 修吾, 片山 勝喜, 竹内 英実, 和田 淳

日本老年医学会雑誌   59 ( Suppl. )   151 - 151   2022.5

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ゆで卵を用いた模擬腎生検 コロンブスの卵

辻 憲二, 田中 景子, 竹内 英実, 田邊 克幸, 森永 裕士, 木野村 賢, 内田 治仁, 喜多村 真治, 杉山 斉, 和田 淳

日本腎臓学会誌   64 ( 3 )   297 - 297   2022.5

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岡山市CKDネットワーク(OCKD-NET)におけるCKD病診連携11年後の追跡調査

大西 康博, 内田 治仁, 竹内 英実, 田中 景子, 辻 憲二, 田邊 克幸, 森永 裕士, 木野村 賢, 喜多村 真治, 前島 洋平, 杉山 斉, 太田 康介, 丸山 啓輔, 大城 義之, 森岡 茂, 瀧上 慶一, 蒲生 直幸, 和田 淳

日本腎臓学会誌   64 ( 3 )   234 - 234   2022.5

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Silica-associated systemic lupus erythematosus with lupus nephritis and lupus pneumonitis: A case report and a systematic review of the literature. International journal

Kazuhiko Fukushima, Haruhito A Uchida, Yasuko Fuchimoto, Tomoyo Mifune, Mayu Watanabe, Kenji Tsuji, Katsuyuki Tanabe, Masaru Kinomura, Shinji Kitamura, Yosuke Miyamoto, Sae Wada, Taisaku Koyanagi, Hitoshi Sugiyama, Takumi Kishimoto, Jun Wada

Medicine   101 ( 7 )   e28872   2022.2

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INTRODUCTION: Several epidemiological studies have shown that silica exposure triggers the onset of systemic lupus erythematosus (SLE); however, the clinical characteristics of silica-associated SLE have not been well studied. PATIENT CONCERNS: A 67-year-old man with silicosis visited a primary hospital because of a fever and cough. His respiratory condition worsened, regardless of antibiotic medication, and he was referred to our hospital. DIAGNOSIS: The patient showed leukopenia, lymphopenia, serum creatinine elevation with proteinuria and hematuria, decreased serum C3 level, and was positive for anti-double stranded DNA antibody, anti-nuclear antibody, and direct Coombs test. He was diagnosed with SLE. Renal biopsy was performed, and the patient was diagnosed with lupus nephritis (class IV-G(A/C) + V defined by the International Society of Nephrology/Renal Pathology Society classification). Computed tomography revealed acute interstitial pneumonitis, bronchoalveolar lavage fluid showed elevation of the lymphocyte fraction, and he was diagnosed with lupus pneumonitis. INTERVENTIONS: Prednisolone (50 mg/day) with intravenous cyclophosphamide (500 mg/body) were initiated. OUTCOMES: The patient showed a favorable response to these therapies. He was discharged from our hospital and received outpatient care with prednisolone slowly tapered off. He had cytomegalovirus and herpes zoster virus infections during treatment, which healed with antiviral therapy. REVIEW: We searched for the literature on sSLE, and selected 11 case reports and 2 population-based studies. The prevalence of SLE manifestations in sSLE patients were comparative to that of general SLE, particularly that of elderly-onset SLE. Our renal biopsy report and previous reports indicate that lupus nephritis of sSLE patients show as various histological patterns as those of general SLE patients. Among the twenty sSLE patients reported in the case articles, three patients developed lupus pneumonitis and two of them died of it. Moreover, two patients died of bacterial pneumonia, one developed aspergillus abscesses, one got pulmonary tuberculosis, and one developed lung cancer. CONCLUSION: Close attention is needed, particularly for respiratory system events and infectious diseases, when treating patients with silica-associated SLE using immunosuppressive therapies.

DOI： 10.1097/MD.0000000000028872

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Circulating GPIHBP1 levels and microvascular complications in patients with type 2 diabetes: A cross-sectional study. International journal

Naoko Kurooka, Jun Eguchi, Kazutoshi Murakami, Shinji Kamei, Toru Kikutsuji, Sakiko Sasaki, Akiho Seki, Satoshi Yamaguchi, Ichiro Nojima, Mayu Watanabe, Chigusa Higuchi, Akihiro Katayama, Haruhito A Uchida, Atsuko Nakatsuka, Kenichi Shikata, Jun Wada

Journal of clinical lipidology   16 ( 2 )   237 - 245   2022.1

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BACKGROUND: Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) plays a crucial role in lipolytic processing. Previous studies have shown that GPIHBP1 mutations cause severe hypertriglyceridemia and that serum GPIHBP1 levels are marginally higher in patients with coronary heart disease; however, the role of GPIHBP1 in type 2 diabetes mellitus (T2DM) remains unknown. OBJECTIVE: We investigated the association between circulating GPIHBP1 levels and the prevalence of microvascular complications in T2DM. METHODS: A total of 237 subjects with T2DM and 235 non-diabetic control subjects were enrolled in this study. Their serum GPIHBP1 levels were evaluated using ELISA assays. RESULTS: Circulating GPIHBP1 levels were higher in patients with T2DM (952.7 pg/mL [761.3-1234.6], p < 0.0001) than in non-diabetic subjects (700.6 [570.8-829.6]), but did not differ in T2DM patients with or without hypertriglyceridemia. Serum GPIHBP1 levels were significantly higher in patients with T2DM with diabetic retinopathy (DR), diabetic nephropathy (DN), and microvascular complications than in those without these complications. Multivariable logistic regression and receiver operating characteristic (ROC) curve analyses revealed that the presence of microvascular complications, but not macrovascular complications, was independently associated with serum GPIHBP1 levels, which could predict the presence of diabetic microvascular complications. CONCLUSIONS: Elevated GPIHBP1 levels are associated with microvascular complications in T2DM and may help to predict their progression.

DOI： 10.1016/j.jacl.2022.01.006

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Prevalence of Chronic Kidney Disease and Variation of Its Risk Factors by the Regions in Okayama Prefecture. International journal

Ryoko Umebayashi, Haruhito Adam Uchida, Natsumi Matsuoka-Uchiyama, Hitoshi Sugiyama, Jun Wada

Journal of personalized medicine   12 ( 1 )   2022.1

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OBJECTIVE: The prevention of chronic kidney disease (CKD) progression is an important issue from health and financial perspectives. We conducted a single-year cross-sectional study to clarify the prevalence of CKD and its risk factors along with variations in these factors among five medical regions in Okayama Prefecture, Japan. METHODS AND RESULTS: Data concerning the renal function and proteinuria as well as other CKD risk factors were obtained from the database of the Japanese National Health Insurance. The proportion of CKD patients at an increased risk of progression to end-stage renal disease (ESRD), classified as orange and red on the CKD heatmap, ranged from 6-9% and did not vary significantly by the regions. However, the causes of the increased severity differed between regions where renal dysfunction was predominant and regions where there were many patients with proteinuria. CKD risk factors, such as diabetes mellitus, hypertension, hyper low-density lipoprotein-cholesterolemia, obesity, smoking and lack of exercise, also differed among these regions, suggesting that different regions need tailored interventions that suit the characteristics of the region, such as an increased health checkup ratio, dietary guidance and promotion of exercise opportunities. CONCLUSIONS: Approximately 6-9% of people are at an increased risk of developing ESRD (orange or red on a CKD heatmap) among the population with National Health Insurance in Okayama Prefecture. The underlying health problems that cause CKD may differ among the regions. Thus, it is necessary to consider intervention methods for preventing CKD progression that are tailored to each region's health problems.

DOI： 10.3390/jpm12010097

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The Association of Postprandial Triglyceride Variability with Renal Dysfunction and Microalbuminuria in Patients with Type 2 Diabetic Mellitus: A Retrospective and Observational Study. International journal

Natsumi Matsuoka-Uchiyama, Haruhito A Uchida, Shugo Okamoto, Yasuhiro Onishi, Katsuyoshi Katayama, Mariko Tsuchida-Nishiwaki, Hidemi Takeuchi, Rika Takemoto, Yoshiko Hada, Ryoko Umebayashi, Naoko Kurooka, Kenji Tsuji, Jun Eguchi, Hirofumi Nakajima, Kenichi Shikata, Jun Wada

Journal of diabetes research   2022   3157841 - 3157841   2022

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OBJECTIVE: We examined whether or not day-to-day variations in lipid profiles, especially triglyceride (TG) variability, were associated with the exacerbation of diabetic kidney disease. METHODS: We conducted a retrospective and observational study. First, 527 patients with type 2 diabetes mellitus (DM) who had had their estimated glomerular filtration rate (eGFR) checked every 6 months since 2012 for over 5 years were registered. Variability in postprandial TG was determined using the standard deviation (SD), SD adjusted (Adj-SD) for the number of measurements, and maximum minus minimum difference (MMD) during the first three years of follow-up. The endpoint was a ≥40% decline from baseline in the eGFR, initiation of dialysis or death. Next, 181 patients who had no micro- or macroalbuminuria in February 2013 were selected from among the 527 patients for an analysis. The endpoint was the incidence of microalbuminuria, initiation of dialysis, or death. RESULTS: Among the 527 participants, 110 reached a ≥40% decline from baseline in the eGFR or death. The renal survival was lower in the higher-SD, higher-Adj-SD, and higher-MMD groups than in the lower-SD, lower-Adj-SD, and lower-MMD groups, respectively (log-rank test p = 0.0073, 0.0059, and 0.0195, respectively). A lower SD, lower Adj-SD, and lower MMD were significantly associated with the renal survival in the adjusted model (hazard ratio, 1.62, 1.66, 1.59; 95% confidence intervals, 1.05-2.53, 1.08-2.58, 1.04-2.47, respectively). Next, among 181 participants, 108 developed microalbuminuria or death. The nonincidence of microalbuminuria was lower in the higher-SD, higher-Adj-SD, and higher-MMD groups than in the lower-SD, lower-Adj-SD, and lower-MMD groups, respectively (log-rank test p = 0.0241, 0.0352, and 0.0474, respectively). CONCLUSIONS: Postprandial TG variability is a novel risk factor for eGFR decline and the incidence of microalbuminuria in patients with type 2 DM.

DOI： 10.1155/2022/3157841

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Development of Urinary Diagnostic Biomarker for IgA Nephropathy by Lectin Microarray. International journal

Yasuhiro Onishi, Koki Mise, Chieko Kawakita, Haruhito A Uchida, Hitoshi Sugiyama, Ryosuke Sugawara, Satoshi Yamaguchi, Michihiro Yoshida, Toshiharu Mitsuhashi, Masao Yamada, Jun Hirabayashi, Jun Wada

American journal of nephrology   53 ( 1 )   10 - 20   2022

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INTRODUCTION: The pathogenic roles of aberrantly glycosylated IgA1 have been reported. However, it is unexplored whether the profiling of urinary glycans contributes to the diagnosis of IgAN. METHODS: We conducted a retrospective study enrolling 493 patients who underwent renal biopsy at Okayama University Hospital between December 2010 and September 2017. We performed lectin microarray in urine samples and investigated whether c-statistics of the reference standard diagnosis model employing hematuria, proteinuria, and serum IgA were improved by adding the urinary glycan intensity. RESULTS: Among 45 lectins, 3 lectins showed a significant improvement of the models: Amaranthus caudatus lectin (ACA) with the difference of c-statistics 0.038 (95% CI: 0.019-0.058, p < 0.001), Agaricus bisporus lectin (ABA) 0.035 (95% CI: 0.015-0.055, p < 0.001), and Maackia amurensis lectin (MAH) 0.035 (95% CI: 0.015-0.054, p < 0.001). In 3 lectins, each signal plus reference standard showed good reclassification (category-free NRI and relative IDI) and good model fitting associated with the improvement of AIC and BIC. Stratified by eGFR, the discriminatory ability of ACA plus reference standard was maintained, suggesting the robust renal function-independent diagnostic performance of ACA. By decision curve analysis, there was a 3.45% net benefit by adding urinary glycan intensity of ACA to the reference standard at the predefined threshold probability of 40%. CONCLUSIONS: The reduction of Gal(β1-3)GalNAc (T-antigen), Sia(α2-3)Gal(β1-3)GalNAc (Sialyl T), and Sia(α2-3)Gal(β1-3)Sia(α2-6)GalNAc (disialyl-T) was suggested by binding specificities of 3 lectins. C1GALT1 and COSMC were responsible for the biosynthesis of these glycans, and they were known to be downregulated in IgAN. The urinary glycan analysis by ACA is a useful and robust noninvasive strategy for the diagnosis of IgAN.

DOI： 10.1159/000520998

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Masked CKD in hyperthyroidism and reversible CKD status in hypothyroidism. International journal

Natsumi Uchiyama-Matsuoka, Kenji Tsuji, Haruhito A Uchida, Shinji Kitamura, Yoshihiko Itoh, Yuki Nishiyama, Eisaku Morimoto, Satoshi Fujisawa, Tomohiro Terasaka, Takayuki Hara, Kanako Ogura-Ochi, Kenichi Inagaki, Jun Wada

Frontiers in endocrinology   13   1048863 - 1048863   2022

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INTRODUCTION: While it is well known that thyroid function may affect kidney function, the transition of the chronic kidney disease (CKD) status before and after treatment for thyroid disorders, as well as the factors affecting this change, remains to be explored. In the present study, we focused on the change in kidney function and their affecting factors during the treatment for both hyperthyroidism and hypothyroidism. METHODS: Eighty-eight patients with hyperthyroidism and fifty-two patients with hypothyroidism were enrolled in a retrospective and longitudinal case series to analyze the changes in kidney function and their affecting factors after treatment for thyroid disorders. RESULTS: Along with the improvement of thyroid function after treatment, there was a significant decrease in estimated glomerular filtration rate (eGFR) in hyperthyroidism (an average ΔeGFR of -41.1 mL/min/1.73 m2) and an increase in eGFR in hypothyroidism (an average ΔeGFR of 7.1 mL/min/1.73 m2). The multiple linear regression analysis revealed that sex, eGFR, free thyroxine (FT4) and free triiodothyronine (FT3) could be considered independent explanatory variables for ΔeGFR in hyperthyroidism, while age, eGFR, and FT3 were detected as independent explanatory variables in hypothyroidism. In addition, the stratification by kidney function at two points, pre- and post-treatment for thyroid disorders, revealed that 4.5% of the participants with hyperthyroidism were pre-defined as non-CKD and post-defined as CKD, indicating the presence of "masked" CKD in hyperthyroidism. On the other hand, 13.5% of the participants with hypothyroidism presented pre-defined CKD and post-defined non-CKD, indicating the presence of "reversible" CKD status in hypothyroidism. CONCLUSIONS: We uncovered the population of masked CKD in hyperthyroidism and reversible CKD status in hypothyroidism, thereby re-emphasizing the importance of a follow-up to examine kidney function after treatment for hyperthyroidism and the routine evaluation of thyroid function in CKD patients as well as the appropriate hormone therapy if the patient has hypothyroidism.

DOI： 10.3389/fendo.2022.1048863

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クロロゲン酸の血管老化に対する保護効果

内田 治仁, 秦 昌紫子, 大高 望, 竹内 英実, 和田 淳

日本老年医学会雑誌   58 ( 4 )   656 - 656   2021.10

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当院における75歳以上の患者での24時間自由行動下血圧の検討

大高 望, 内田 治仁, 岡本 修吾, 大西 康博, 竹内 英実, 和田 淳

日本老年医学会雑誌   58 ( 4 )   659 - 659   2021.10

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超高齢者(oldest-old)における腎代替療法選択を行った2例

大西 康博, 内田 治仁, 大高 望, 竹内 英実, 森永 裕士, 杉山 斉, 吉田 賢司, 和田 淳

日本老年医学会雑誌   58 ( 4 )   657 - 657   2021.10

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PADは維持透析患者におけるフレイルを促進し予後不良とさせる

竹内 英実, 内田 治仁, 大高 望, 和田 淳

日本老年医学会雑誌   58 ( 4 )   656 - 656   2021.10

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2型糖尿病患者における血中GPIHBP1濃度の臨床的意義

黒岡 直子, 江口 潤, 内田 治仁, 村上 和敏, 亀井 信二, 菊辻 徹, 佐々木 佐起子, 関 明穂, 和田 淳

日本動脈硬化学会総会プログラム・抄録集   53回   228 - 228   2021.10

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尿中クレアチニン(Cr)排泄量低下が健康関連QOLに与える影響についての検討

大西 康博, 内田 治仁, 杉山 斉, 浅野 健一郎, 徳増 裕宣, 和田 淳

日本老年医学会雑誌   58 ( 4 )   657 - 657   2021.10

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Total vascular resistance, augmentation index, and augmentation pressure increase in patients with peripheral artery disease. International journal

Rika Takemoto, Haruhito A Uchida, Hironobu Toda, Ken Okada, Fumio Otsuka, Hiroshi Ito, Jun Wada

Medicine   100 ( 32 )   e26931   2021.8

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ABSTRACT: Peripheral arterial disease (PAD) is one of major vascular diseases which frequently coexists with coronary arterial disease and cerebrovascular disease. The patients with PAD have a poor prognosis when it progresses. A new blood pressure testing device enables to simultaneously measure brachial blood pressure (BP), central BP, and several vascular parameters, with easy and non-invasive, in a short time. Here, we aimed to evaluate these arterial stiffness parameters in patients with PAD.In this study, 243 consecutive patients who were suspected of having PAD and referred to our hospital from September 2016 to June 2019, were registered. Several parameters, such as brachial BP, central BP, aortic pulse wave velocity (aPWV), total vascular resistance (TVR), augmentation index (AI) and augmentation pressure (AP), were determined by Mobil-O-Graph. Ankle-brachial pressure index (ABI) was used to define PAD (ABI ≤ 0.9 as PAD). The relationship between PAD and central BP, aPWV, TVR, AI, or AP were investigated.One hundred sixty-two patients (67%) were categorized as the PAD group and 81 patients (33%) as the non-PAD group. In the PAD group, the systolic brachial BP and central systolic BP were significantly higher than those in the non-PAD group (138 ± 24 mmHg vs 131 ± 19 mmHg, P < .05, 125 ± 22 mmHg vs 119 ± 18 mmHg, P < .05, respectively). TVR, AI, and AP were significantly higher in the PAD group (1785 ± 379 dyn s/cm5 vs 1661 ± 317 dyn s/cm5, P < .05, 26.2 ± 13.0% vs 22.2 ± 13.3%, P < .05, 13.5 ± 9.4 mmHg vs 10.7 ± 7.2 mmHg, P < .05, respectively). No significant differences in diastolic BP, central diastolic BP, and aPWV were found between the groups. Multivariate logistic regression analysis revealed that PAD was significantly associated with TVR, AI, and AP (P < .05, respectively).TVR/AP/AI were significantly higher in the PAD group than in the non-PAD group.

DOI： 10.1097/MD.0000000000026931

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Association of blood pressure and renal outcome in patients with chronic kidney disease; a post hoc analysis of FROM-J study. International journal

Mariko Tsuchida-Nishiwaki, Haruhito A Uchida, Hidemi Takeuchi, Noriyuki Nishiwaki, Yohei Maeshima, Chie Saito, Hitoshi Sugiyama, Jun Wada, Ichiei Narita, Tsuyoshi Watanabe, Seiichi Matsuo, Hirofumi Makino, Akira Hishida, Kunihiro Yamagata

Scientific reports   11 ( 1 )   14990 - 14990   2021.7

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It is well-known that hypertension exacerbates chronic kidney disease (CKD) progression, however, the optimal target blood pressure (BP) level in patients with CKD remains unclear. This study aimed to assess the optimal BP level for preventing CKD progression. The risk of renal outcome among different BP categories at baseline as well as 1 year after, were evaluated using individual CKD patient data aged between 40 and 74 years from FROM-J [Frontier of Renal Outcome Modifications in Japan] study. The renal outcome was defined as ≥ 40% reduction in estimated glomerular filtration rate to < 60 mL/min/1.73 m2, or a diagnosis of end stage renal disease. Regarding baseline BP, the group of systolic BP (SBP) 120-129 mmHg had the lowest risk of the renal outcome, which increased more than 60% in SBP ≥ 130 mmHg group. A significant increase in the renal outcome was found only in the group of diastolic BP ≥ 90 mmHg. The group of BP < 130/80 mmHg had a benefit for lowering the risk regardless of the presence of proteinuria, and it significantly reduced the risk in patients with proteinuria. Achieving SBP level < 130 mmHg after one year resulted in a 42% risk reduction in patients with SBP level ≥ 130 mmHg at baseline. Targeting SBP level < 130 mmHg would be associated with the preferable renal outcome.Clinical Trial Registration-URL: https://www.umin.ac.jp/ctr/ . Unique identifier: UMIN000001159 (16/05/2008).

DOI： 10.1038/s41598-021-94467-z

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透析患者におけるCVDとフレイルの関係

竹内 英実, 内田 治仁, 大高 望, 奥山 由加, 梅林 亮子, 杉山 斉, 和田 淳

日本腎臓学会誌   63 ( 4 )   431 - 431   2021.6

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慢性腎臓病における貧血管理 Kakusyo 3C Studyからの検討

奥山 由加, 内田 治仁, 大高 望, 竹内 英実, 辻 憲二, 田邊 克幸, 木野村 賢, 吉田 賢司, 前島 洋平, 杉山 斉, 伊藤 浩, 和田 淳

日本腎臓学会誌   63 ( 4 )   474 - 474   2021.6

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中四国地域におけるCKDおよびCVDの関連に関するコホート研究 Kakusyo 3C Studyのイベント解析

大高 望, 内田 治仁, 竹内 英実, 辻 憲二, 田邊 克幸, 木野村 賢, 吉田 賢司, 前島 洋平, 杉山 斉, 伊藤 浩, 和田 淳

日本腎臓学会誌   63 ( 4 )   464 - 464   2021.6

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岡山市CKDネットワーク(OCKD-NET)におけるCKD病診連携10年後の追跡調査

大西 康博, 内田 治仁, 大高 望, 竹内 英実, 辻 憲二, 田邊 克幸, 森永 裕士, 木野村 賢, 喜多村 真治, 前島 洋平, 杉山 斉, 太田 康介, 丸山 啓輔, 大城 義之, 森岡 茂, 瀧上 慶一, 蒲生 直幸, 和田 淳

日本腎臓学会誌   63 ( 4 )   513 - 513   2021.6

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甲状腺機能低下症とCKDの関連性におけるCr代謝の影響についての検討

内山 奈津実, 辻 憲二, 喜多村 真治, 稲垣 兼一, 内田 治仁, 杉山 斉, 和田 淳

日本腎臓学会誌   63 ( 4 )   463 - 463   2021.6

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両側乳頭浮腫を伴う肥厚性硬膜炎を発症した維持血液透析患者の一例

内山 奈津実, 木野村 賢, 高橋 謙作, 谷村 智史, 森岡 朋代, 加納 弓月, 川北 智英子, 田邊 克幸, 内田 治仁, 杉山 斉, 難波 清人, 和田 淳

中国腎不全研究会誌   29   27 - 28   2021.6

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岡山市CKDネットワーク(OCKD-NET)におけるCKD病診連携10年後の追跡調査

大西 康博, 内田 治仁, 大高 望, 竹内 英実, 辻 憲二, 田邊 克幸, 森永 裕士, 木野村 賢, 喜多村 真治, 前島 洋平, 杉山 斉, 太田 康介, 丸山 啓輔, 大城 義之, 森岡 茂, 瀧上 慶一, 蒲生 直幸, 和田 淳

日本腎臓学会誌   63 ( 4 )   513 - 513   2021.6

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甲状腺機能低下症とCKDの関連性におけるCr代謝の影響についての検討

内山 奈津実, 辻 憲二, 喜多村 真治, 稲垣 兼一, 内田 治仁, 杉山 斉, 和田 淳

日本腎臓学会誌   63 ( 4 )   463 - 463   2021.6

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中四国地域におけるCKDおよびCVDの関連に関するコホート研究 Kakusyo 3C Studyのイベント解析

大高 望, 内田 治仁, 竹内 英実, 辻 憲二, 田邊 克幸, 木野村 賢, 吉田 賢司, 前島 洋平, 杉山 斉, 伊藤 浩, 和田 淳

日本腎臓学会誌   63 ( 4 )   464 - 464   2021.6

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慢性腎臓病における貧血管理 Kakusyo 3C Studyからの検討

奥山 由加, 内田 治仁, 大高 望, 竹内 英実, 辻 憲二, 田邊 克幸, 木野村 賢, 吉田 賢司, 前島 洋平, 杉山 斉, 伊藤 浩, 和田 淳

日本腎臓学会誌   63 ( 4 )   474 - 474   2021.6

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Novel Urinary Glycan Biomarkers Predict Cardiovascular Events in Patients With Type 2 Diabetes: A Multicenter Prospective Study With 5-Year Follow Up (U-CARE Study 2) International journal

Koki Mise, Mariko Imamura, Satoshi Yamaguchi, Mayu Watanabe, Chigusa Higuchi, Akihiro Katayama, Satoshi Miyamoto, Haruhito A. Uchida, Atsuko Nakatsuka, Jun Eguchi, Kazuyuki Hida, Tatsuaki Nakato, Atsuhito Tone, Sanae Teshigawara, Takashi Matsuoka, Shinji Kamei, Kazutoshi Murakami, Ikki Shimizu, Katsuhiro Miyashita, Shinichiro Ando, Tomokazu Nunoue, Michihiro Yoshida, Masao Yamada, Kenichi Shikata, Jun Wada

Frontiers in Cardiovascular Medicine   8   668059 - 668059   2021.5

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<bold>Background:</bold> Although various biomarkers predict cardiovascular event (CVE) in patients with diabetes, the relationship of urinary glycan profile with CVE in patients with diabetes remains unclear.

<bold>Methods:</bold> Among 680 patients with type 2 diabetes, we examined the baseline urinary glycan signals binding to 45 lectins with different specificities. Primary outcome was defined as CVE including cardiovascular disease, stroke, and peripheral arterial disease.

<bold>Results:</bold> During approximately a 5-year follow-up period, 62 patients reached the endpoint. Cox proportional hazards analysis revealed that urinary glycan signals binding to two lectins were significantly associated with the outcome after adjustment for known indicators of CVE and for false discovery rate, as well as increased model fitness. Hazard ratios for these lectins (+1 SD for the glycan index) were UDA (recognizing glycan: mixture of Man5 to Man9): 1.78 (95% CI: 1.24–2.55, <italic>P</italic> = 0.002) and Calsepa [High-Man (Man2–6)]: 1.56 (1.19–2.04, <italic>P</italic> = 0.001). Common glycan binding to these lectins was high-mannose type of <italic>N</italic>-glycans. Moreover, adding glycan index for UDA to a model including known confounders improved the outcome prediction [Difference of Harrel's C-index: 0.028 (95% CI: 0.001–0.055, <italic>P</italic> = 0.044), net reclassification improvement at 5-year risk increased by 0.368 (0.045–0.692, <italic>P</italic> = 0.026), and the Akaike information criterion and Bayesian information criterion decreased from 725.7 to 716.5, and 761.8 to 757.2, respectively].

<bold>Conclusion:</bold> The urinary excretion of high-mannose glycan may be a valuable biomarker for improving prediction of CVE in patients with type 2 diabetes, and provides the rationale to explore the mechanism underlying abnormal <italic>N</italic>-glycosylation occurring in patients with diabetes at higher risk of CVE.

<bold>Trial Registration:</bold> This study was registered with the University Hospital Medical Information Network on June 26, 2012 (Clinical trial number: UMIN000011525, URL: <ext-link>https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000013482</ext-link>).

DOI： 10.3389/fcvm.2021.668059

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Vasohibin-2 Aggravates Development of Ascending Aortic Aneurysms but not Abdominal Aortic Aneurysms nor Atherosclerosis in ApoE-Deficient Mice. International journal

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   34 ( 5 )   467 - 475   2021.5

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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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Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice. International journal

Latha Muniappan, Michihiro Okuyama, Aida Javidan, Devi Thiagarajan, Weihua Jiang, Jessica J Moorleghen, Lihua Yang, Anju Balakrishnan, Deborah A Howatt, Haruhito A Uchida, Takaomi C Saido, Venkateswaran Subramanian

Arteriosclerosis, thrombosis, and vascular biology   41 ( 5 )   1694 - 1709   2021.5

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[Figure: see text].

DOI： 10.1161/ATVBAHA.120.315546

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妊娠中に加温式リサキュレーション法を施行した家族性高コレステロール血症(ホモ接合体)の1例

奥山 由加, 内田 治仁, 高橋 謙作, 藤原 千尋, 竹内 英実, 田邊 克幸, 木野村 賢, 和田 淳

日本透析医学会雑誌   54 ( Suppl.1 )   360 - 360   2021.5

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Fisetin Attenuates Lipopolysaccharide-Induced Inflammatory Responses in Macrophage. International journal

Yoshiko Hada, Haruhito A Uchida, Jun Wada

BioMed research international   2021   5570885 - 5570885   2021

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Several studies have reported the efficacy and safety of polyphenols in human health; however, the verification of their efficacy remains insufficient. The aim of this study was to examine whether fisetin, one of flavonoids prevalently present in fruits and vegetables, could suppress lipopolysaccharide- (LPS-) induced inflammatory responses in macrophages. LPS increased proinflammatory mRNA abundance (MCP 1, IL-1β, and iNOS) but were suppressed by fisetin. The increment of nitric oxide by LPS, an oxidative stress factor, was attenuated by fisetin. In addition, LPS-enhanced phosphorylation of mitogen-activated protein kinase (ERK and JNK) was reduced. Finally, fisetin attenuated the expression or activity of uPA, uPAR, MMP-2, and MMP-9, which are known as associated factors of macrophage recruitment or infiltration. In conclusion, fisetin is a promising therapeutic agent for macrophage-related inflammation diseases, like sepsis and atherosclerosis.

DOI： 10.1155/2021/5570885

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Inhibition of Interleukin-6 Signaling Attenuates Aortitis, Left Ventricular Hypertrophy and Arthritis in Interleukin-1 Receptor Antagonist Deficient Mice. Reviewed International journal

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)   134 ( 20 )   2771 - 2787   2020.10

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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. Reviewed International journal

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   27 ( 12 )   1136 - 1142   2020.10

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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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PAD合併により著明に増悪したフレイルな透析患者の予後

竹内 英実, 内田 治仁, 大高 望, 梅林 亮子, 杉山 斉, 和田 淳

日本透析医学会雑誌   53 ( Suppl.1 )   736 - 736   2020.10

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内シャント再設置術の成績・術式・リスク因子の検討

藤井 泰宏, 大澤 晋, 内田 治仁, 竹内 英実, 大高 望, 笠原 真悟

脈管学   60 ( Suppl. )   S161 - S161   2020.10

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腎不全療法選択説明が緊急透析導入と療法選択に与える影響

森永 裕士, 笠原 由美子, 井本 紀子, 角川 紫野, 矢田 光子, 大高 望, 辻 憲二, 北川 正史, 田邊 克幸, 木野村 賢, 喜多村 真治, 内田 治仁, 杉山 斉, 和田 淳

日本透析医学会雑誌   53 ( Suppl.1 )   496 - 496   2020.10

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末梢動脈疾患が動脈スティフネスパラメータに与える影響の検討

武本 梨佳, 内田 治仁, 戸田 洋伸, 大塚 文男, 伊藤 浩, 和田 淳

脈管学   60 ( Suppl. )   S172 - S172   2020.10

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Dysfunction of CD8 + PD-1 + T cells in type 2 diabetes caused by the impairment of metabolism-immune axis. Reviewed International journal

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 reports   10 ( 1 )   14928 - 14928   2020.9

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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. Reviewed International journal

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

Kidney international reports   5 ( 9 )   1576 - 1580   2020.9

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DOI： 10.1016/j.ekir.2020.06.010

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2型糖尿病に対するメトホルミンの抗腫瘍効果

野島 一郎, 榮川 伸吾, 梶谷 展生, 勅使川原 早苗, 宮本 聡, 利根 淳仁, 内田 治仁, 中司 敦子, 江口 潤, 四方 賢一, 鵜殿 平一郎, 和田 淳

糖尿病   63 ( Suppl.1 )   S - 111   2020.8

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中四国地域におけるCKDおよびCVDの関連に関するコホート研究Kakusyo 3C Study:登録3年後のCKD管理状況

西脇 麻里子, 内田 治仁, 大高 望, 辻 憲二, 北川 正史, 田邊 克幸, 木野村 賢, 吉田 賢司, 前島 洋平, 杉山 斉, 伊藤 浩, 和田 淳

日本腎臓学会誌   62 ( 4 )   378 - 378   2020.7

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慢性腎臓病における貧血管理〜Kakusyo 3C Studyからの検討

内山 奈津実, 内田 治仁, 西脇 麻里子, 大高 望, 辻 憲二, 北川 正史, 田邊 克幸, 木野村 賢, 吉田 賢司, 前島 洋平, 杉山 斉, 伊藤 浩, 和田 淳

日本腎臓学会誌   62 ( 4 )   378 - 378   2020.7

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岡山市CKDネットワーク(OCKD-NET)におけるCKD病診連携9年後の追跡調査

大西 康博, 内田 治仁, 大高 望, 辻 憲二, 田邊 克幸, 森永 裕士, 木野村 賢, 喜多村 真治, 前島 洋平, 杉山 斉, 太田 康介, 丸山 啓輔, 大城 義之, 森岡 茂, 大森 一慶, 瀧上 慶一, 蒲生 直幸, 和田 淳

日本腎臓学会誌   62 ( 4 )   307 - 307   2020.7

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The Protective Effect of Chlorogenic Acid on Vascular Senescence via the Nrf2/HO-1 Pathway. Reviewed International journal

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

International journal of molecular sciences   21 ( 12 )   2020.6

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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. Reviewed International journal

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

International journal of molecular sciences   21 ( 11 )   2020.6

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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 Reviewed

Hidemi Takeuchi, Haruhito A Uchida, Jun Wada

Journal of Clinical Trials   10 ( 3 )   2020.6

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Targeting Mitochondrial Fission as a Potential Therapeutic for Abdominal Aortic Aneurysm. Reviewed International journal

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   117 ( 3 )   971 - 982   2020.5

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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. Reviewed International journal

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 & therapy   22 ( 1 )   72 - 72   2020.4

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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. Reviewed

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 Society   84 ( 2 )   299 - 359   2020.1

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DOI： 10.1253/circj.CJ-19-0773

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Polypharmacy and frailty in chronic kidney disease

Hidemi Takeuchi, Haruhito Adam Uchida, Jun Wada

Recent Advances of Sarcopenia and Frailty in CKD   223 - 237   2020.1

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The prognoses of various diseases have improved because of progress in the field of medicine and clinical practice guidelines developed in countries around the world. However, polypharmacy and frailty have become a global public health concern because of the increase in longevity. Although polypharmacy and frailty are associated with a broad range of negative outcomes, they occur concurrently in patients with chronic kidney disease (CKD) at a higher rate. Elderly patients with CKD usually require multiple medications to prevent CKD progression and complications, and their conditions are generally complicated. In this article, we outline polypharmacy and frailty, which frequently occur in patients with CKD and introduce notes and approaches to overcome these issues.

DOI： 10.1007/978-981-15-2365-6_14

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Podocyte autophagy is associated with foot process effacement and proteinuria in patients with minimal change nephrotic syndrome. Reviewed International journal

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 one   15 ( 1 )   e0228337   2020

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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. Reviewed

Ryoko Umebayashi, Haruhito Adam Uchida, Jun Wada

Acta medica Okayama   73 ( 6 )   475 - 477   2019.12

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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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18歳時に経皮的腎動脈形成術を行い10年以上経過して血圧上昇をきたした高安動脈炎の1例

内田 治仁, 戸田 洋伸, 藤本 竜一, 大塚 寛昭, 花山 宜久, 武本 梨佳, 大西 康博, 高杉 佳奈子, 梅林 亮子, 吉田 賢司, 和田 淳

脈管学   59 ( Suppl. )   S226 - S226   2019.10

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PAD患者におけるTotal Vascular ResistanceおよびAugmentation Pressureに関する検討

内田 治仁, 武本 梨佳, 松岡 奈津美, 大西 康博, 岡本 修吾, 西脇 麻里子, 秦 昌紫子, 大高 望, 戸田 洋伸, 北川 正史, 和田 淳

日本高血圧学会総会プログラム・抄録集   42回   348 - 348   2019.10

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フェブキソスタットによる尿酸低下が血管機能に与える影響の検討

松岡 奈津実, 内田 治仁, 前島 洋平, 雛元 紀和, 浅野 健一郎, 大西 康博, 岡本 修吾, 西脇 麻里子, 秦 昌紫子, 武本 梨佳, 大高 望, 北川 正史, 和田 淳

日本高血圧学会総会プログラム・抄録集   42回   368 - 368   2019.10

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Impaired mental health status in patients with chronic kidney disease is associated with estimated glomerular filtration rate decline. Reviewed International journal

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   2019.9

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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. Reviewed

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 Okayama   73 ( 4 )   367 - 372   2019.8

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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. Reviewed

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   2019.7

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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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血管内皮細胞における細胞老化に対するクロロゲン酸の及ぼす影響の検討

秦 昌紫子, 内田 治仁, 大高 望, 大西 康博, 和田 淳

日本動脈硬化学会総会プログラム・抄録集   51回   1 - 5   2019.7

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Osteomalacia and Fanconi Syndrome Induced by Adefovir. Reviewed

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

Internal medicine (Tokyo, Japan)   58 ( 11 )   1659 - 1659   2019.6

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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. Reviewed International journal

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

Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals   24 ( 3 )   255 - 261   2019.5

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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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当院で腹膜透析を導入した多発性嚢胞腎患者に関する検討

大西 康博, 田邊 克幸, 大高 望, 大西 章史, 北川 正史, 森永 裕士, 木野村 賢, 内田 治仁, 杉山 斉, 和田 淳

日本透析医学会雑誌   52 ( Suppl.1 )   549 - 549   2019.5

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岡山市CKDネットワーク(OCKD-NET)におけるCKD病診連携8年後の追跡調査

大西 康博, 内田 治仁, 大高 望, 田邊 克幸, 森永 裕士, 木野村 賢, 前島 洋平, 杉山 斉, 太田 康介, 丸山 啓輔, 平松 信, 大城 義之, 森岡 茂, 福島 正樹, 和田 淳

日本腎臓学会誌   61 ( 3 )   388 - 388   2019.5

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Higher Serum Testosterone Levels Associated with Favorable Prognosis in Enzalutamide- and Abiraterone-Treated Castration-Resistant Prostate Cancer. Reviewed International journal

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 medicine   8 ( 4 )   2019.4

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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. Reviewed

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 reports   1 ( 4 )   155 - 161   2019.4

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Background: Chronic angiotensin II (AngII) infusion promotes ascending aortic dilation in C57BL/6J mice. Meanwhile, vasohibin-2 (VASH2) is an angiogenesis promoter in neovascularization under various pathologic conditions. The aim of this study was to investigate whether exogenous VASH2 influences chronic AngII-induced ascending aortic dilation. Methods and Results: Eight-ten-week-old male C57BL/6J mice were injected with adenovirus (Ad) expressing either VASH2 or LacZ. One week after the injection, mice were infused with either AngII or saline s.c. for 3 weeks. Mice were divided into 4 groups: AngII+VASH2, AngII+LacZ, saline+VASH2, and saline+LacZ. Overexpression of VASH2 significantly increased AngII-induced intimal areas as well as the external diameter of the ascending aorta. In addition, VASH2 overexpression promoted ascending aortic medial elastin fragmentation in AngII-infused mice, which was associated with increased matrix metalloproteinase activity and medial smooth muscle cell (SMC) apoptosis. On western blot analysis, accumulation of apoptotic signaling proteins, p21 and p53 was increased in the AngII+VASH2 group. Furthermore, transfection of human aortic SMC with Ad VASH2 increased p21 and p53 protein abundance upon AngII stimulation. Positive TUNEL staining was also detected in the same group of the human aortic SMC. Conclusions: Exogenous VASH2 exacerbates AngII-induced ascending aortic dilation in vivo, which is associated with increased medial apoptosis and elastin fragmentation.

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. Reviewed International journal

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 hypertension   33 ( 4 )   286 - 297   2019.4

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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. Reviewed International journal

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 markers   2019   5432453 - 5432453   2019

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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. Reviewed International journal

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 disease   12   143 - 152   2019

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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. Reviewed International journal

Ryoko Umebayashi, Haruhito A Uchida, Jun Wada

Aging   10 ( 12 )   3650 - 3651   2018.12

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DOI： 10.18632/aging.101702

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Diabetic nephropathy is associated with frailty in patients with chronic hemodialysis. Reviewed

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 international   18 ( 12 )   1597 - 1602   2018.12

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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. Reviewed International journal

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

The Journal of international medical research   46 ( 9 )   3873 - 3883   2018.9

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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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末梢動脈疾患が中心血圧、aPWV、AIに与える影響の検討

武本 梨佳, 内田 治仁, 垣尾 勇樹, 大高 望, 大西 康博, 秦 昌紫子, 北川 正史, 戸田 洋伸, 吉田 賢司, 大塚 文男, 杉山 斉, 伊藤 浩, 和田 淳

日本高血圧学会総会プログラム・抄録集   41回   PM01 - 03   2018.9

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Coral reef aorta一連の病変と考えられた移植腎動脈狭窄に対する血管内治療の1例 Reviewed

戸田 洋伸, 大塚 寛昭, 江尻 健太郎, 内田 治仁, 杜 徳尚, 中川 晃志, 渡邊 敦之, 三好 亨, 西井 伸洋, 中村 一文, 森田 宏, 伊藤 浩

脈管学   58 ( Suppl. )   S206 - S206   2018.9

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両大血管右室起始症患者の腎内血行動態を超音波ドプラ法で評価した1例

大高 望, 杜 徳尚, 武本 梨佳, 渡辺 修久, 木野村 賢, 大西 康博, 垣尾 勇樹, 戸田 洋伸, 内田 治仁, 伊藤 浩, 和田 淳

脈管学   58 ( Suppl. )   S209 - S210   2018.9

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Peripheral artery disease is associated with frailty in chronic hemodialysis patients. Reviewed International journal

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

Vascular   26 ( 4 )   425 - 431   2018.8

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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. Reviewed International journal

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 care   41 ( 8 )   1765 - 1775   2018.8

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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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4年半後に再発した腎血管性高血圧の1例

大高 望, 内田 治仁, 武本 梨佳, 大西 康博, 垣尾 勇樹, 奥山 由加, 梅林 亮子, 谷村 智史, 杉山 斉, 和田 淳

日本腎臓学会誌   60 ( 6 )   771 - 771   2018.8

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生体肝移植後に発症したAAアミロイドーシスの1例

大西 康博, 北川 正史, 御舩 朋代, 福島 和彦, 渡邉 真由, 木野村 賢, 内田 治仁, 杉山 斉, 高木 章乃夫, 八木 孝仁, 和田 淳

日本腎臓学会誌   60 ( 6 )   757 - 757   2018.8

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IgA Nephropathy Complicated with X-linked Thrombocytopenia. Reviewed

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 Okayama   72 ( 3 )   301 - 307   2018.6

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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. Reviewed International journal

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

Arteriosclerosis, thrombosis, and vascular biology   38 ( 4 )   903 - 912   2018.4

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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. Reviewed International journal

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 disease   9 ( 2 )   192 - 207   2018.4

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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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岡山市CKDネットワーク(OCKD-NET)におけるCKD病診連携7年後の追跡調査

大西 康博, 内田 治仁, 大高 望, 奥山 由加, 田邊 克幸, 森永 裕士, 木野村 賢, 前島 洋平, 杉山 斉, 太田 康介, 平松 信, 大城 義之, 森岡 茂, 福島 正樹, 和田 淳

日本腎臓学会誌   60 ( 3 )   399 - 399   2018.4

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動脈硬化ではなく細動脈硝子化は糸球体全節性硬化と独立して尿細管間質病変と関連する

北川 正史, 杉山 斉, 加納 弓月, 山成 俊夫, 田中 景子, 大西 章史, 内田 治仁, 和田 淳

日本腎臓学会誌   60 ( 3 )   370 - 370   2018.4

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Impact of nocturnal blood pressure variability on renal arterioles. Reviewed International journal

Haruhito A Uchida, Masashi Kitagawa, Jun Wada

Hypertension research : official journal of the Japanese Society of Hypertension   41 ( 1 )   6 - 7   2018.1

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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. Reviewed International journal

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 one   13 ( 3 )   e0193695   2018

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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.

DOI： 10.1371/journal.pone.0193695

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閉塞性動脈硬化症診断におけるトレッドミル負荷ABIの有用性

武本 梨佳, 戸田 洋伸, 越智 真金, 大塚 寛昭, 江尻 健太郎, 内田 治仁, 岡田 健, 大塚 文男, 和田 淳, 伊藤 浩

脈管学   57 ( Suppl. )   S260 - S260   2017.10

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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 Reviewed

Kentaro Wada, Haruhito A. Uchida, Yuko Wada

Renal Replacement Therapy   3 ( 1 )   2017.4

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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). Reviewed International journal

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

Blood pressure monitoring   22 ( 2 )   59 - 67   2017.4

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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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baPWVによる動脈硬化評価は腎生検後の貧血進行の予測因子となる

田中 景子, 北川 正史, 大西 章史, 山成 俊夫, 秋山 愛由, 三瀬 広記, 森永 裕士, 内田 治仁, 杉山 斉, 和田 淳

日本腎臓学会誌   59 ( 3 )   345 - 345   2017.4

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腎内細動脈硝子化、動脈硬化病変は全身の動脈硬化指標の異なる因子が規定する

北川 正史, 杉山 斉, 大西 章史, 山成 俊夫, 田中 景子, 三瀬 広記, 森永 裕士, 内田 治仁, 和田 淳

日本腎臓学会誌   59 ( 3 )   309 - 309   2017.4

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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 Reviewed

Kentaro Wada, Haruhito A. Uchida, Yuko Wada

Renal Replacement Therapy   3 ( 1 )   2017.1

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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. Reviewed International journal

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 research   42 ( 2 )   284 - 293   2017

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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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Vasohibin-2は大動脈瘤モデルマウスにおいて胸部大動脈瘤を増悪させる

奥山 倫弘, 内田 治仁, 梅林 亮子, 垣尾 勇樹, 田邊 克幸, 藤井 泰宏, 大澤 晋, 佐藤 靖史, 佐野 俊二, 和田 淳

脈管学   56 ( Suppl. )   S153 - S153   2016.10

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The possible involvement of intestine-derived IgA1: a case of IgA nephropathy associated with Crohn's disease. Reviewed International journal

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

BMC nephrology   17 ( 1 )   122 - 122   2016.9

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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 Reviewed

Haruhito A. Uchida, Jun Wada, Hirofumi Makino

BMJ open e-letter   2016.8

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Leukocyte Calpain Deficiency Reduces Angiotensin II-Induced Inflammation and Atherosclerosis But Not Abdominal Aortic Aneurysms in Mice. Reviewed International journal

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 biology   36 ( 5 )   835 - 45   2016.5

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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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腎機能障害を合併した治療抵抗性高血圧症の一例

遠藤 豊宏, 内田 治仁, 谷村 智史, 三瀬 広記, 井上 達之, 竹内 英実, 垣尾 勇樹, 梅林 亮子, 杉山 斉, 和田 淳

日本高血圧学会臨床高血圧フォーラムプログラム・抄録集   5回   181 - 181   2016.5

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Acute idiopathic blue fingers: a young man with Achenbach's syndrome. Reviewed International journal

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

BMJ case reports   2016   10.1136/bcr-2016-214491   2016.4

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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. Reviewed International journal

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 one   11 ( 10 )   e0164015   2016

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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. Reviewed

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

CEN case reports   4 ( 2 )   190 - 195   2015.11

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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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有痛性手指チアノーゼを来した若年男性の1例

竹内 英実, 内田 治仁, 奥山 由加, 垣尾 勇樹, 梅林 亮子, 武本 梨佳, 戸田 洋伸, 藤井 泰宏, 大澤 晋, 村上 和敏, 大塚 文男, 和田 淳

脈管学   55 ( Suppl. )   S246 - S247   2015.10

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下大静脈フィルター閉塞が誘因となった症候性下肢動静脈瘻の2症例 Reviewed

大澤 晋, 藤井 泰宏, 藤原 寛康, 増田 善逸, 黒子 洋介, 戸田 洋伸, 内田 治仁, 村上 和敏, 江尻 健太郎, 高樽 由美, 料治 三恵, 逢坂 大樹, 竹内 英実, 武本 梨佳, 本田 雅子, 三宅 麻希, 佐野 俊二

脈管学   55 ( Suppl. )   S212 - S212   2015.10

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日本人の体格を考慮した、タバコ窩内シャント設置術適応の検討

藤井 泰宏, 大澤 晋, 黒子 洋介, 増田 善逸, 佐野 俊二, 内田 治仁, 竹内 英実, 戸田 洋伸, 逢坂 大樹, 武本 梨佳

脈管学   55 ( Suppl. )   S179 - S179   2015.10

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Retrograde Renal Ablation via the Renal Vein as a New Treatment Option for Renovascular Hypertension. Reviewed International journal

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

Journal of vascular and interventional radiology : JVIR   26 ( 6 )   807 - 8   2015.6

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DOI： 10.1016/j.jvir.2015.01.030

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血中FGF21は腎機能、蛋白尿と独立した腎予後を予測するバイオマーカーである

北川 正史, 杉山 斉, 森永 裕士, 秋山 愛由, 山成 俊夫, 大西 章史, 田中 景子, 菊本 陽子, 井上 達之, 内田 治仁, 和田 淳

日本腎臓学会誌   57 ( 3 )   465 - 465   2015.4

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Autoimmune pancreatitis and minimal change nephrotic syndrome: an unusual association? Reviewed International journal

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   2015.3

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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. Reviewed International journal

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

International journal of nephrology and renovascular disease   8   111 - 8   2015

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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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当科で施行した生体腎移植レシピエント、ドナーのQOL評価

有吉 勇一, 荒木 元朗, 宗石 理沙, 吉岡 貴史, 和田 耕一郎, 小林 泰之, 佐々木 克己, 江原 伸, 渡辺 豊彦, 那須 保友, 公文 裕巳, 有森 千聖, 北川 正史, 田邊 克幸, 森永 裕士, 菊本 陽子, 内田 治仁, 喜多村 真治, 前島 洋平, 杉山 斉, 槇野 博史

移植   49 ( 4-5 )   377 - 377   2014.11

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

Haruhito A. Uchida, Hatsuzo Uchida, Jun Wada

Journal of Cardiovascular Medicine and Cardiology   038 - 041   2014.10

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Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Peertechz Publications Private Limited  

DOI： 10.17352/2455-2976.000010

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潰瘍性大腸炎に合併した腎血管性高血圧の1例

田中 景子, 内田 治仁, 平松 澄恵, 天田 雅文, 井上 章子, 奥山 由加, 梅林 亮子, 郷原 英夫, 大澤 晋, 平岡 佐規子, 寺坂 律子, 杉山 斉, 和田 淳

脈管学   54 ( 10 )   167 - 172   2014.10

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腎血管性高血圧はさまざまな疾患を原因とする。今回我々は、潰瘍性大腸炎に腎血管性高血圧を合併した症例を経験した。症例は40歳男性。造影CTと血管造影で右腎動脈の閉塞と側副血行路の発達を認めた。さらに左腎区域動脈と肝動脈の狭小化、両側内腸骨動脈の閉塞と腹部大動脈の一部壁不整がみられた。FDG-PETで大動脈炎症候群は否定的であった。皮疹や結腸粘膜の生検で血管炎の所見は得られず、診断に苦慮した症例であった。(著者抄録)

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インターフェロン(IFN)が著効した生体肝移植後HCV陽性の膜性増殖性糸球体腎炎(MPGN)の1例

田中 景子, 内田 治仁, 井上 章子, 雛元 紀和, 北川 正史, 高木 章乃夫, 杉山 斉, 和田 淳

日本腎臓学会誌   56 ( 6 )   702 - 702   2014.8

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Large vessel vasculitis with myelodysplastic syndrome. Reviewed

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

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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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MPO-ANCA関連腎炎と膜性腎症を合併した3症例の検討

益田 加奈, 内田 治仁, 細谷 武史, 林 啓悟, 辻 憲二, 小川 愛由, 氏家 はる代, 梅林 亮子, 喜多村 真治, 前島 洋平, 杉山 斉, 槇野 博史

日本腎臓学会誌   55 ( 6 )   1179 - 1179   2013.8

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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). Reviewed International journal

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

Diabetes & vascular disease research   10 ( 1 )   93 - 6   2013.1

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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. Reviewed International journal

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 one   8 ( 2 )   e56695   2013

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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.

DOI： 10.1371/journal.pone.0056695

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Calpain-2 compensation promotes angiotensin II-induced ascending and abdominal aortic aneurysms in calpain-1 deficient mice. Reviewed International journal

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

PloS one   8 ( 8 )   e72214   2013

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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. Reviewed

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 investigation   3 ( 6 )   534 - 5   2012.12

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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.

DOI： 10.1111/j.2040-1124.2012.00232.x

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Activation of liver X receptor inhibits osteopontin and ameliorates diabetic nephropathy. Reviewed International journal

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 : JASN   23 ( 11 )   1835 - 46   2012.11

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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. Reviewed International journal

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

BMC nephrology   13   46 - 46   2012.6

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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. Reviewed International journal

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

Diabetes   61 ( 4 )   897 - 907   2012.4

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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. Reviewed International journal

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

Journal of cardiovascular pharmacology   59 ( 1 )   66 - 76   2012.1

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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. Reviewed

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

Acta medica Okayama   66 ( 6 )   449 - 59   2012

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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. Reviewed International journal

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

Arteriosclerosis, thrombosis, and vascular biology   31 ( 12 )   2845 - 52   2011.12

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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. Reviewed International journal

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

Journal of cardiovascular pharmacology   58 ( 6 )   633 - 8   2011.12

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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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膜性増殖性糸球体腎炎と低γグロブリン血症の経過中に巣状糸球体硬化症を併発した1例

辻 憲二, 内田 治仁, 小野 哲一郎, 喜多村 真治, 前島 洋平, 杉山 斉, 槇野 博史

日本腎臓学会誌   53 ( 6 )   822 - 822   2011.8

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気腫性胆嚢炎を発症した統合失調症合併糖尿病の一例

内田 治仁, 四方 賢一, 小川 愛由, 篠浦 歩, 横道 直佑, 八木 孝仁, 小川 大輔, 佐藤 千景, 和田 淳, 梶谷 展生, 槇野 博史

糖尿病   54 ( 4 )   316 - 316   2011.4

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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. Reviewed International journal

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 extra   1 ( 1 )   166 - 77   2011.1

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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. Reviewed

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

Journal of diabetes investigation   1 ( 6 )   266 - 72   2010.12

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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. Reviewed International journal

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

Atherosclerosis   211 ( 2 )   399 - 403   2010.8

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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. Reviewed

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

Acta medica Okayama   63 ( 1 )   35 - 42   2009.2

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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. Reviewed International journal

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

Hypertension research : official journal of the Japanese Society of Hypertension   31 ( 1 )   51 - 8   2008.1

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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. Reviewed

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 nephrology   11 ( 1 )   77 - 87   2007.3

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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. Reviewed International journal

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 Association   21 ( 12 )   3475 - 80   2006.12

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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. Reviewed

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

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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. Reviewed International journal

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 Hypertension   27 ( 8 )   545 - 50   2004.8

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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. Reviewed International journal

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

Diabetes research and clinical practice   61 ( 2 )   137 - 41   2003.8

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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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