Updated on 2024/03/14

写真a

 
FURUHASHI Kazuhiro
 
Organization
Nagoya University Hospital Nephrology Lecturer of hospital
Title
Lecturer of hospital

Degree 1

  1. 医学博士 ( 2013.5   名古屋大学 ) 

Research Interests 5

  1. 腎臓

  2. 再生医療

  3. 免疫学

  4. 腎臓

  5. 再生医療

Research Areas 3

  1. Life Science / Nephrology  / Nephrology

  2. Life Science / Nephrology  / Nephrology

  3. Life Science / Immunology

Current Research Project and SDGs 2

  1. 再生医療

  2. 腎臓内科

Research History 10

  1. Nagoya University   Nagoya University Hospital Nephrology   Lecturer of hospital

    2021.6

  2. Nagoya University   Nagoya University Hospital Nephrology   Assistant Professor

    2020.4 - 2021.5

  3. Nagoya University   Nagoya University Hospital Department of Blood Purification   Assistant professor of hospital

    2019.4 - 2020.3

  4. Nagoya University   Graduate School of Medicine Center for Research of Laboratory Animals and Medical Research Engineering Division   Designated assistant professor

    2018.8 - 2019.3

  5. Columbia University   Columbia Center for Translational Immunology   Research Scientist

    2015.9 - 2018.7

  6. Harvard Medical School and Brigham and Women's Hospital   Pathology   Postdoc

    2014.1 - 2015.8

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    Country:United States

  7. 名古屋大学大学院医学系研究科   腎臓内科

    2008.4 - 2014.1

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    Country:Japan

  8. 中津川市民病院   腎臓内科

    2007.4 - 2008.3

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    Country:Japan

  9. 春日井市民病院   腎臓内科

    2003.4 - 2007.3

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    Country:Japan

  10. 春日井市民病院   研修医

    2001.5 - 2003.3

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    Country:Japan

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Education 2

  1. Nagoya University   Graduate School, Division of Medical Sciences

    - 2011.3

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    Country: Japan

  2. Nagoya University   Faculty of Medicine

    1995.4 - 2001.3

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    Country: Japan

Professional Memberships 6

  1. The Japanese Society of Internal Medicine

  2. The Japanese Society of Internal Medicine

  3. The Japanese Society for Dialysis Therapy

  4. Japanese Society of Nephrology

  5. The Japanese Society of Inflammation and Regeneration

  6. American Society of Nephrology

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Awards 6

  1. 進行性腎炎におけるTNFR1,TNFR2の役割

    2013   アステラス病態代謝研究会  

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:Japan

  2. 脂肪由来間葉系幹細胞を用いた壊死性半月体形成性腎炎への新たな治療法の確立とその作用機序の解明

    2011   第3回腎疾患と高血圧研究会  

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:Japan

  3. 急速進行性糸球体腎炎における免疫調整性(M2)マクロファージの役割― マクロファージに関するパラダイムシフト

    2010   愛知腎臓財団  

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:Japan

  4. 脂肪由来間葉系幹細胞(ASC)を用いた難治性腎疾患・自己免疫疾患への新たな治療開発

    2010   分子腎臓フォーラム  

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:Japan

  5. New Strategy for autoimmune disease and nephritis MSCs have immunoregulatory properties

    2009   愛知腎臓財団  

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:Japan

  6. 慢性腎臓疾患に対する新規再生医療の開発

    2007   那古野医学振興会研究奨励金  

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    Award type:Award from publisher, newspaper, foundation, etc.  Country:Japan

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Papers 42

  1. Monocytes transition to macrophages within the inflamed vasculature via monocyte CCR2 and endothelial TNFR2.

    Mysore V, Tahir S, Furuhashi K, Arora J, Rosetti F, Cullere X, Yazbeck P, Sekulic M, Lemieux ME, Raychaudhuri S, Horwitz BH, Mayadas TN

    The Journal of experimental medicine   Vol. 219 ( 5 )   2022.5

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    DOI: 10.1084/jem.20210562

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  2. Photoactivatable Cre recombinase 3.0 for in vivo mouse applications. International journal

    Morikawa K, Furuhashi K, de Sena-Tomas C, Garcia-Garcia AL, Bekdash R, Klein AD, Gallerani N, Yamamoto HE, Park SE, Collins GS, Kawano F, Sato M, Lin CS, Targoff KL, Au E, Salling MC, Yazawa M

    Nature communications   Vol. 11 ( 1 ) page: 2141 - 2141   2020.5

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    Optogenetic genome engineering tools enable spatiotemporal control of gene expression and provide new insight into biological function. Here, we report the new version of genetically encoded photoactivatable (PA) Cre recombinase, PA-Cre 3.0. To improve PA-Cre technology, we compare light-dimerization tools and optimize for mammalian expression using a CAG promoter, Magnets, and 2A self-cleaving peptide. To prevent background recombination caused by the high sequence similarity in the dimerization domains, we modify the codons for mouse gene targeting and viral production. Overall, these modifications significantly reduce dark leak activity and improve blue-light induction developing our new version, PA-Cre 3.0. As a resource, we have generated and validated AAV-PA-Cre 3.0 as well as two mouse lines that can conditionally express PA-Cre 3.0. Together these new tools will facilitate further biological and biomedical research.

    DOI: 10.1038/s41467-020-16030-0

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  3. Generation of functional lungs via conditional blastocyst complementation using pluripotent stem cells.

    Mori M, Furuhashi K, Danielsson JA, Hirata Y, Kakiuchi M, Lin CS, Ohta M, Riccio P, Takahashi Y, Xu X, Emala CW, Lu C, Nakauchi H, Cardoso WV

    Nature medicine   Vol. 25 ( 11 ) page: 1691 - 1698   2019.11

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    DOI: 10.1038/s41591-019-0635-8

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  4. CD150<sup>high</sup> Bone Marrow Tregs Maintain Hematopoietic Stem Cell Quiescence and Immune Privilege via Adenosine. Reviewed

    Hirata Y, Furuhashi K, Ishii H, Li HW, Pinho S, Ding L, Robson SC, Frenette PS, Fujisaki J

    Cell stem cell   Vol. 22 ( 3 ) page: 445 - 453.e5   2018.3

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    DOI: 10.1016/j.stem.2018.01.017

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  5. Microanatomical dissection of human intestinal T-cell immunity reveals site-specific changes in gut-associated lymphoid tissues over life.

    Senda T, Dogra P, Granot T, Furuhashi K, Snyder ME, Carpenter DJ, Szabo PA, Thapa P, Miron M, Farber DL

    Mucosal immunology   Vol. 12 ( 2 ) page: 378 - 389   2019.3

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    DOI: 10.1038/s41385-018-0110-8

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  6. Neutrophil Fc gamma RIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases Reviewed

    Hiroshi Nishi, Kazuhiro Furuhashi, Xavier Cullere, Gurpanna Saggu, Mark J. Miller, Yunfeng Chen, Florencia Rosetti, Samantha L. Hamilton, Lihua Yang, Spencer P. Pittman, Jiexi Liao, Jan M. Herter, Jeffrey C. Berry, Daniel J. DeAngelo, Cheng Zhu, George C. Tsokos, Tanya N. Mayadas

    JOURNAL OF CLINICAL INVESTIGATION   Vol. 127 ( 10 ) page: 3810 - 3826   2017.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMER SOC CLINICAL INVESTIGATION INC  

    The kidney glomerular capillaries are frequent sites of immune complex deposition and subsequent neutrophil accumulation in post-infectious and rapidly progressive glomerulonephritis. However, the mechanisms of neutrophil recruitment remain enigmatic, and there is no targeted therapeutic to avert this proximal event in glomerular inflammation. The uniquely human activating Fc receptor Fc gamma RIIA promotes glomerular neutrophil accumulation and damage in anti-glomerular basement membrane-induced (anti-GBM-induced) glomerulonephritis when expressed on murine neutrophils. Here, we found that neutrophils are directly captured by immobilized IgG antibodies under physiological flow conditions in vitro through Fc gamma RIIA-dependent, Abl/Src tyrosine kinase-mediated F-actin polymerization. Biophysical measurements showed that the lifetime of Fc gamma RIIA-IgG bonds increased under mechanical force in an F-actin-dependent manner, which could enable the capture of neutrophils under physiological flow. Kidney intravital microscopy revealed that circulating neutrophils, which were similar in diameter to glomerular capillaries, abruptly arrested following anti-GBM antibody deposition via neutrophil Fc gamma RIIA and Abl/Src kinases. Accordingly, inhibition of Abl/Src with bosutinib reduced Fc gamma RIIA-mediated glomerular neutrophil accumulation and renal injury in experimental, crescentic anti-GBM nephritis. These data identify a pathway of neutrophil recruitment within glomerular capillaries following IgG deposition that may be targeted by bosutinib to avert glomerular injury.

    DOI: 10.1172/JCI94039

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  7. Fructose increases the activity of sodium hydrogen exchanger in renal proximal tubules that is dependent on ketohexokinase International journal

    Hayasaki Takahiro, Ishimoto Takuji, Doke Tomohito, Hirayama Akiyoshi, Soga Tomoyoshi, Furuhashi Kazuhiro, Kato Noritoshi, Kosugi Tomoki, Tsuboi Naotake, Lanaspa Miguel A, Johnson Richard J, Maruyama Shoichi, Kadomatsu Kenji

    JOURNAL OF NUTRITIONAL BIOCHEMISTRY   Vol. 71   page: 54 - 62   2019.9

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    High fructose intake has been known to induce metabolic syndrome in laboratory animals and humans. Although fructose intake enhances sodium reabsorption and elevates blood pressure, role of fructose metabolism in this process has not been studied. Here we show that by ketohexokinase - the primary enzyme of fructose - is involved in regulation of renal sodium reabsorption and blood pressure via activation of the sodium hydrogen exchanger in renal proximal tubular cells. First, wild-type and ketohexokinase knockout mice (Male, C57BL/6) were fed fructose water or tap water with or without a high salt diet. Only wild type mice fed the combination of fructose water and high salt diet displayed increased systolic blood pressure and decreased urinary sodium excretion. In contrast, ketohexokinase knockout mice were protected. Second, urinary sodium excretion after intraperitoneal saline administration was reduced with the decreased phosphorylation of sodium hydrogen exchanger 3 in fructose-fed WT; these changes were not observed in the ketohexokinase knockout mice, however. Third, knockdown of ketohexokinase attenuated fructose-mediated increases of NHE activity with decreased cAMP levels in porcine renal proximal tubular cells (LLC-PK1). In conclusion, fructose metabolism by ketohexokinase increases sodium hydrogen exchanger activity in renal proximal tubular cells via decreased intracellular cAMP level, resulting in increased renal sodium reabsorption and blood pressure in mice.

    DOI: 10.1016/j.jnutbio.2019.05.017

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  8. Serum-Starved Adipose-Derived Stromal Cells Ameliorate Crescentic GN by Promoting Immunoregulatory Macrophages Reviewed

    Furuhashi K, Tsuboi N, Shimizu A, Katsuno T, Kim H, Saka Y, Ozaki T, Sado Y, Imai E, Matsuo S, Maruyama S.

    Journal of the American Society of nephrology   Vol. 24   page: 587-603   2013.3

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1681

  9. Adipose derived stromal cells cultured in a low serum medium, but not bone marrow derived stromal cells, impede xenoantibody production. Reviewed

    5. Saka Y, Furuhashi K, Katsuno T, Kim H, Ozaki T, Iwasaki K, Haneda M, Sato W, Tsuboi N, Ito Y, Matsuo S, Kobayashi T, Maruyama S.

    Xenotransplantation   Vol. 18   page: 196-208   2011.6

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    DOI: 10.1111

  10. Mesenchymal stem cells exert renoprotection via extracellular vesicle-mediated modulation of M2 macrophages and spleen-kidney network. International journal

    Yuko Shimamura, Kazuhiro Furuhashi, Akihito Tanaka, Munetoshi Karasawa, Tomoya Nozaki, Shintaro Komatsu, Kenshi Watanabe, Asuka Shimizu, Shun Minatoguchi, Makoto Matsuyama, Yuriko Sawa, Naotake Tsuboi, Takuji Ishimoto, Hiroshi I Suzuki, Shoichi Maruyama

    Communications biology   Vol. 5 ( 1 ) page: 753 - 753   2022.7

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    Adipose-derived mesenchymal stem cells (ASCs) have shown therapeutic potentials against refractory diseases. However, the detailed therapeutic mechanisms remain unclear. Here, we report the therapeutic actions of human ASCs in nephritis, focusing on cellular dynamics and multi-organ networks. Intravenously-administered ASCs accumulated in spleen but not kidneys. Nevertheless, ASCs increased M2 macrophages and Tregs in kidneys and drove strong renoprotection. Splenectomy abolished these therapeutic effects. ASC-derived extracellular vesicles (EVs) were transferred to M2 macrophages, which entered the bloodstream from spleen. EVs induced the transcriptomic signatures of hyperpolarization and PGE2 stimulation in M2 macrophages and ameliorated glomerulonephritis. ASCs, ASC-derived EVs, and EV-transferred M2 macrophages enhanced Treg induction. These findings suggest that EV transfer from spleen-accumulated ASCs to M2 macrophages and subsequent modulation of renal immune-environment underlie the renoprotective effects of ASCs. Our results provide insights into the therapeutic actions of ASCs, focusing on EV-mediated modulation of macrophages and the spleen-kidney immune network.

    DOI: 10.1038/s42003-022-03712-2

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  11. Detecting and exploring kidney-derived extracellular vesicles in plasma

    Komatsu, S; Kato, N; Kitai, H; Funahashi, Y; Noda, Y; Tsubota, S; Tanaka, A; Sato, Y; Maeda, K; Saito, S; Furuhashi, K; Ishimoto, T; Kosugi, T; Maruyama, S; Kadomatsu, K

    CLINICAL AND EXPERIMENTAL NEPHROLOGY     2024.3

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    Language:English   Publisher:Clinical and Experimental Nephrology  

    Background: Extracellular vesicles (EVs) have received considerable attention as ideal biomarkers for kidney diseases. Most reports have focused on urinary EVs, that are mainly derived from the cells in the urinary tract. However, the detection and the application of kidney-derived EVs in plasma remains uncertain. Methods: We examined the kidney-derived small EVs (sEVs) in plasma that were supposedly released from renal mesangial and glomerular endothelial cells, using clinical samples from healthy controls and patients with kidney transplants. Plasma from healthy controls underwent ultracentrifugation, followed by on-bead flow cytometry, targeting α8 integrin, an antigen-specific to mesangial cells. To confirm the presence of kidney-derived sEVs in peripheral blood, plasma from ABO-incompatible kidney transplant recipients was ultracentrifuged, followed by western blotting for donor blood type antigens. Results: Immunohistochemistry and immunoelectron microscopy confirmed α8 integrin expression in kidney mesangial cells and their sEVs. The CD9-α8 integrin double-positive sEVs were successfully detected using on-bead flow cytometry. Western blot analysis further revealed transplanted kidney-derived sEVs containing blood type B antigens in non-blood type B recipients, who had received kidneys from blood type B donors. Notably, a patient experiencing graft kidney loss exhibited diminished signals of sEVs containing donor blood type antigens. Conclusion: Our findings demonstrate the potential usefulness of kidney-derived sEVs in plasma in future research for kidney diseases.

    DOI: 10.1007/s10157-024-02464-z

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  12. Changes in antibody titer after four and five doses of the SARS-CoV-2 vaccine in Japanese post-kidney transplant patients

    Fujieda, K; Tanaka, A; Kikuchi, R; Takai, N; Saito, S; Yasuda, Y; Sano, Y; Kato, M; Furuhashi, K; Maruyama, S

    THERAPEUTIC APHERESIS AND DIALYSIS     2024.2

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    Introduction: Immunosuppressed patients exhibit low antibody acquisition rates following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Kidney transplant recipients previously exhibited low antibody acquisition rates after two vaccine doses, which increased after the third dose. We evaluated antibody titers of Japanese post-kidney transplant patients after the fourth and fifth vaccinations. Methods: Antibody titers for SARS-CoV-2 spike protein were measured between 3 weeks and 3 months after the fourth or fifth vaccination. Results: Increased antibody acquisition rates were observed after the fourth (75.0% antibody-positive) and fifth (81.5% antibody-positive) vaccinations. The antibody-acquired group after the fourth vaccination exhibited a higher body mass index and estimated glomerular filtration rate (eGFR) than the non-acquired group. A higher eGFR was associated with antibody acquisition after the fifth vaccination. Conclusion: In Japanese post-kidney transplant patients, the antibody acquisition rate increased with each vaccine additional dose. Additional vaccinations are recommended to protect against SARS-CoV-2 infection.

    DOI: 10.1111/1744-9987.14114

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  13. A case of late-onset organizing pneumonia following COVID-19 infection in a post-kidney transplant patient

    Fujieda, K; Saito, S; Tanaka, A; Furuhashi, K; Yasuda, Y; Sano, Y; Kato, M; Maruyama, S

    CEN CASE REPORTS     2024.2

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    A 50-year-old man who had undergone a living-donor kidney transplant 12 years prior for chronic renal failure due to autosomal dominant polycystic kidney disease contracted coronavirus disease 19 (COVID-19). He had a positive antigen test, mild symptoms, sore throat, and fever of 37.9 ℃. The patient was treated with molnupiravir for 5 days, and the symptoms disappeared 5 days after onset. However, 10 days after onset, he developed a fever of approximately 37 ℃ and a non-productive cough; 27 days after onset, the patient was hospitalized for anorexia and a worsening respiratory condition. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen test results on admission were negative, and no antiviral medications were administered against SARS-CoV-2. Computed tomography revealed extensive ground-glass opacities in both lung fields. The patient was treated with steroid pulse therapy, ceftriaxone, atovaquone, azithromycin, and respiratory management using a high-flow nasal cannula. The combined therapies were successful, and the patient was managed with a nasal oxygen cannula after 3 days. Oxygen administration was discontinued after 6 days of hospitalization, and the patient was discharged after 14 days. Based on the laboratory findings, bacterial, interstitial, and Pneumocystis pneumonia were unlikely. The success of the steroid pulse therapy suggested that respiratory failure was caused by pneumonia due to the immune response after COVID-19 infection.

    DOI: 10.1007/s13730-023-00849-9

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  14. Mortality and hyperkalaemia-associated hospitalisation in patients with chronic kidney disease: comparison of sodium zirconium cyclosilicate and sodium/calcium polystyrene sulfonate

    Onogi, C; Watanabe, Y; Tanaka, A; Furuhashi, K; Maruyama, S

    CLINICAL KIDNEY JOURNAL   Vol. 17 ( 2 ) page: sfae021   2024.2

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    Language:English   Publisher:Clinical Kidney Journal  

    Background. Sodium zirconium cyclosilicate( SZC) , a novel drug used for treating hyperkalaemia, is effective in reducing serum potassium levels. The effects of potassium adsorbents on the mortality and hyperkalaemia-associated hospitalisation rates remain unclear. We aimed to examine how mortality and hyperkalaemia-associated hospitalisation rates vary with usage of various potassium adsorbents. Methods. This retrospective study used patients' data between April 2008 and August 2021 obtained from a large-scale Japanese medical claims database. Consecutive patients with chronic kidney disease( CKD) prescribed potassium adsorbents were enrolled and divided into three groups according to the adsorbent type [SZC, calcium polystyrene sulfonate( CPS) , and sodium polystyrene sulfonate( SPS) ] and were observed for 1 year. The primary outcome was a composite of mortality and hyperkalaemia-associated hospitalisation. Results. In total, 234, 54 183, and 18 692 patients were prescribed SZC, CPS, and SPS, respectively. The SZC group showed a higher event-free survival rate than the other two groups. The hazard ratio for the primary outcome in the CPS and SPS groups was similar in the analyses of the subgroups of patients who did not receive renal replacement therapy and those who received haemodialysis. The SZC group had a higher renin-angiotensin-aldosterone system inhibitors( RAASi) continuation rate compared to CPS and SPS groups, the difference being especially significant for SPS. Conclusions. This real-world study demonstrated the therapeutic effect of SZC in reducing mortality and hyperkalaemia-associated hospitalisations. The high RAASi continuation rate in the SZC group might be a contributing factor for improvement of the primary outcome.

    DOI: 10.1093/ckj/sfae021

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  15. Meflin is a marker of pancreatic stellate cells involved in fibrosis and epithelial regeneration in the pancreas

    Ando, R; Shiraki, Y; Miyai, Y; Shimizu, H; Furuhashi, K; Minatoguchi, S; Kato, K; Kato, A; Iida, T; Mizutani, Y; Ito, K; Asai, N; Mii, S; Esaki, N; Takahashi, M; Enomoto, A

    JOURNAL OF PATHOLOGY   Vol. 262 ( 1 ) page: 61 - 75   2024.1

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    Pancreatic stellate cells (PSCs) are stromal cells in the pancreas that play an important role in pancreatic pathology. In chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC), PSCs are known to get activated to form myofibroblasts or cancer-associated fibroblasts (CAFs) that promote stromal fibroinflammatory reactions. However, previous studies on PSCs were mainly based on the findings obtained using ex vivo expanded PSCs, with few studies that addressed the significance of in situ tissue-resident PSCs using animal models. Their contributions to fibrotic reactions in CP and PDAC are also lesser-known. These limitations in our understanding of PSC biology have been attributed to the lack of specific molecular markers of PSCs. Herein, we established Meflin (Islr), a glycosylphosphatidylinositol-anchored membrane protein, as a PSC-specific marker in both mouse and human by using human pancreatic tissue samples and Meflin reporter mice. Meflin-positive (Meflin+) cells contain lipid droplets and express the conventional PSC marker Desmin in normal mouse pancreas, with some cells also positive for Gli1, the marker of pancreatic tissue-resident fibroblasts. Three-dimensional analysis of the cleared pancreas of Meflin reporter mice showed that Meflin+ PSCs have long and thin cytoplasmic protrusions, and are localised on the abluminal side of vessels in the normal pancreas. Lineage tracing experiments revealed that Meflin+ PSCs constitute one of the origins of fibroblasts and CAFs in CP and PDAC, respectively. In these diseases, Meflin+ PSC-derived fibroblasts showed a distinctive morphology and distribution from Meflin+ PSCs in the normal pancreas. Furthermore, we showed that the genetic depletion of Meflin+ PSCs accelerated fibrosis and attenuated epithelial regeneration and stromal R-spondin 3 expression, thereby implying that Meflin+ PSCs and their lineage cells may support tissue recovery and Wnt/R-spondin signalling after pancreatic injury and PDAC development. Together, these data indicate that Meflin may be a marker specific to tissue-resident PSCs and useful for studying their biology in both health and disease. © 2023 The Pathological Society of Great Britain and Ireland.

    DOI: 10.1002/path.6211

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  16. Current status of low-density lipoprotein apheresis treatment for patients with peripheral artery disease and chronic kidney disease in Japanese clinical database

    Watanabe, Y; Tanaka, A; Furuhashi, K; Maruyama, S

    THERAPEUTIC APHERESIS AND DIALYSIS   Vol. 27 ( 6 ) page: 1000 - 1009   2023.12

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    Introduction: Patients with peripheral arterial disease (PAD) have a poorer prognosis than those without PAD. PAD complications worsen the prognosis of patients with chronic kidney disease (CKD), especially those on maintenance dialysis. Although low-density lipoprotein apheresis (LDL-A) is expected to be effective in treating severe PAD, there are no large-scale reports on the prognosis of patients undergoing LDL-A. Methods: We obtained a clinical database from April 2008 to August 2021 and selected 924 238 patients with CKD. We selected patients with disease codes of lower limb arteriosclerosis obliterans, arteriosclerosis obliterans, and critical limb ischemia or foot ulcer. Patients who were prescribed antithrombotic medications were included. Patients who used steroids were excluded. Among these patients, those undergoing blood purification considered LDL-A were selected, and their current status was investigated. Results: We included 147 patients (113 males and 34 females). The mean patient age was 70 ± 10 years. Diabetes mellitus was present in 86%, ischemic heart disease in 34%, and stroke in 48%. Maintenance dialysis patients accounted for 86% of the patients. Statins were administered to 40% of the patients, and bypass surgery was performed in 2.7%. The median observation period was 812 days, and the mortality rate was 41%. Conclusion: LDL-A was performed in a small population of patients with CKD with the most severe form of PAD. The prognosis for these patients is extremely poor. Therefore, strategies to improve prognosis are important.

    DOI: 10.1111/1744-9987.14046

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  17. Mesenchymal stem/stromal cells generated from induced pluripotent stem cells are highly resistant to senescence

    Aoi, T; Tanaka, A; Furuhashi, K; Ikeya, M; Shimizu, A; Arioka, Y; Kushima, I; Ozaki, N; Maruyama, S

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 85 ( 4 ) page: 682 - 690   2023.11

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    Language:English   Publisher:Nagoya Journal of Medical Science  

    The use of mesenchymal stem/stromal cells (MSCs) has attracted attention in the field of regenerative medicine based on their anti-inflammatory and tissue repair-promoting effects. Bone marrow is widely used as a source of MSCs; however, the performance of bone marrow (BM)-MSCs deteriorates as the cells age along with cell passaging. Recently, it has been reported that MSCs can be generated from induced pluripotent stem cells (iPSCs), which is expected to represent a new source of MSCs. However, few studies have investigated aging in iPSC-derived MSCs (iMSCs) and their functions. In this study, we investigated whether iMSCs overcome cellular senescence compared to that in BM-MSCs. Cellular senescence was quantitatively evaluated by staining iMSCs and BM-MSCs with fluorescein di-b-D-galactopyranoside (FDG) and following flow cytometer analysis. The hepatocyte growth factor (HGF) concentration in the culture supernatant was also measured as a factor in the therapeutic efficacy of nephritis. The iMSCs did not reach their proliferation limit and their morphology did not change even after 10 passages. The FDG positivity of BM-MSCs increased with passaging, whereas that in iMSCs did not increase. The HGF concentration increased with passaging in iMSCs. In conclusion, our results suggest that iMSCs may be less susceptible to senescence than BM-MSCs and may be used in clinical applications.

    DOI: 10.18999/nagjms.85.4.682

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  18. Establishment of an adverse effect prevention protocol on plasma exchange using fresh frozen plasma prior to ABO-incompatible living donor kidney transplantation at our hospital

    Akihito Tanaka, Yu Watanabe, Kazuhiro Furuhashi, Shoji Saito, Yoshinari Yasuda, Tomoki Kosugi, Yuta Sano, Masashi Kato, Shoichi Maruyama

    Therapeutic Apheresis and Dialysis   Vol. 28 ( 1 ) page: 152 - 157   2023.9

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    Introduction: Simple plasma exchange (PE) with fresh-frozen plasma replacement allows antibody removal for ABO-incompatible living donor kidney transplantation, but is associated with a high incidence of allergic reactions. We developed, implemented, and evaluated a protocol for safe preoperative PE. Methods: The protocol comprised pretreatment (125 mg methylprednisolone infusion, 400 mg acetaminophen and 30 mg diphenhydramine orally) with a replacement fluid rate < 20 mL/min. Allergic reaction incidence was investigated in controls who underwent ABO-incompatible living donor kidney transplantation between 2016 and March 2020 (group C) and patients who underwent the protocol and procedure between April 2020 and February 2023 (group N). Results: Ten (group C) and 19 (group N) patients performed 11 and 30 sessions of PE, respectively. Allergic reactions occurred in 81.8% and 36.7% (p = 0.014), respectively, with an odds ratio of the protocol was 0.056 (95% CI 0.0059–0.5380, P = 0.013). Conclusion: Our protocol resulted in a significantly lower incidence of allergic reactions.

    DOI: 10.1111/1744-9987.14071

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  19. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits and atypical pathological findings treated with corticosteroid and rituximab

    Mori, M; Tanaka, A; Maeda, K; Saito, S; Furuhashi, K; Maruyama, S

    CEN CASE REPORTS     2023.8

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    A 16-year-old girl with fever that appeared after taking the second COVID-19 vaccine presented to the clinic with a serum creatinine of 0.89 mg/dL and C-reactive protein of 6.9 mg/dL. She had proteinuria and microscopic hematuria, with slowly worsening kidney function. Her kidney biopsy showed fibrocellular crescents in seven of nine glomeruli that were observed under light microscopy. Another glomerulus showed endocapillary hypercellularity and mesangial cell proliferation. Electron-dense deposits were significant in the mesangial area, with monoclonal IgG1-κ and C3 deposition by immunofluorescence. The patient was diagnosed with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and atypical pathological finding of diffuse crescent formation. The treatment regimen for PGNMID has not yet been established, and the appropriate duration of treatment is unknown. In our case, considering that rituximab acts by binding to CD20 on the surface of B cells through its crystallizable fragment, it was administered in addition to prednisolone, which successfully decreased the proteinuria over time.

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  20. Prognosis and incidence of infections in chronic kidney disease patients with membranous nephropathy enrolled in a large Japanese clinical claims database

    Matsuzaki, T; Watanabe, Y; Tanaka, A; Furuhashi, K; Saito, S; Maruyama, S

    BMC NEPHROLOGY   Vol. 24 ( 1 ) page: 126   2023.5

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    Background: The treatment of membranous nephropathy involves a combination of conservative approaches, steroids, and immunosuppressive agents. Infection is an adverse effect of these treatments and its incidence is a critical issue for patients with membranous nephropathy, as many of them are older adults. However, the incidence of infections remains unclear; hence, this study investigated this issue using data from a large Japanese clinical claims database. Methods: From a database of patients with chronic kidney disease (n = 924,238), those diagnosed with membranous nephropathy from April 2008 to August 2021 with a history of one or more prescriptions and undergoing medical care were included. Patients who had undergone kidney replacement therapy were excluded. Patients were divided into three groups based on their prescriptions after diagnosis: prednisolone(PSL), who received steroids; PSL + IS, who were prescribed steroids and immunosuppressive agents; and C, who were treated without steroid or immunosuppressive agent use. The primary outcome was death or the initiation of kidney replacement therapy. The secondary outcome was death or hospitalization due to infection. Infectious diseases such as sepsis, pneumonia, urinary tract infections, cellulitis, cytomegalovirus infection, colitis, or hepatitis were defined as infections. Hazard ratios were expressed using group C as a reference. Results: Of 1,642 patients, the incidence of the primary outcome occurred in 62/460 individuals in the PSL group, 81/635 individuals in the PSL + IS group, and 47/547 individuals in the C group. The Kaplan–Meier survival curve showed no significant differences (P = 0.088). The incidence of secondary outcomes occurred in 80/460 individuals, 102/635 individuals, and 37/547 individuals in the PSL, PSL + IS, and C groups, respectively. The incidence of secondary outcomes was significantly higher in the PSL group (hazard ratio [HR] 2.43 [95% confidence interval [CI] 1.64–3.62, P < 0.01]) and PSL + IS group (HR 2.23 [95% CI 1.51–3.30, P < 0.01]). Conclusions: The outcome of membranous nephropathy was not completely satisfactory. Patients who use steroids and immunosuppressive agents have a high incidence of infection and may require close monitoring during the course of treatment.High-efficacy treatment with a low incidence of infections is desirable. The significance of this study lies in the fact that the impressions of membranous nephropathy, which have been recognized as tacit knowledge, were quantified using a clinical database.

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  21. Long non-coding RNA lnc-CHAF1B-3 promotes renal interstitial fibrosis by regulating EMT-related genes in renal proximal tubular cells. Reviewed International journal

    Kentaro Imai, Takuji Ishimoto, Tomohito Doke, Toshiki Tsuboi, Yu Watanabe, Keisuke Katsushima, Miho Suzuki, Hideto Oishi, Kazuhiro Furuhashi, Yasuhiko Ito, Yutaka Kondo, Shoichi Maruyama

    Molecular therapy. Nucleic acids   Vol. 31   page: 139 - 150   2023.3

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    Renal interstitial fibrosis (RIF) is a common pathological manifestation of chronic kidney diseases. Epithelial-mesenchymal transition (EMT) of tubular epithelial cells is considered a major cause of RIF. Although long non-coding RNAs (lncRNAs) are reportedly involved in various pathophysiological processes, the roles and underlying molecular mechanisms of lncRNAs in the progression of RIF are poorly understood. In this study, we investigated the function of lncRNAs in RIF. Microarray assays showed that expression of the lncRNA lnc-CHAF1B-3 (also called claudin 14 antisense RNA 1) was significantly upregulated in human renal proximal tubular cells by both transforming growth factor-β1 (TGF-β1) and hypoxic stimulation, accompanied with increased expression of EMT-related genes. Knockdown of lnc-CHAF1B-3 significantly suppressed TGF-β1-induced upregulated expression of collagen type I alpha 1, cadherin-2, plasminogen activator inhibitor-1, snail family transcriptional repressor I (SNAI1) and SNAI2. Quantitative reverse transcriptase PCR analyses of paraffin-embedded kidney biopsy samples from IgA nephropathy patients revealed lnc-CHAF1B-3 expression was correlated positively with urinary protein levels and correlated negatively with estimated glomerular filtration rate. In situ hybridization demonstrated that lnc-CHAF1B-3 is expressed only in proximal tubules. These findings suggest lnc-CHAF1B-3 affects the progression of RIF by regulating EMT-related signaling. Thus, lnc-CHAF1B-3 is a potential target in the treatment of RIF.

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  22. Assessment of Antibody-Titer Changes after Second and Third Severe Acute Respiratory Syndrome Coronavirus 2 mRNA Vaccination in Japanese Post-Kidney-Transplant Patients

    Fujieda, K; Tanaka, A; Kikuchi, R; Takai, N; Saito, S; Yasuda, Y; Fujita, T; Kato, M; Furuhashi, K; Maruyama, S

    VACCINES   Vol. 11 ( 1 )   2023.1

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    Post-renal-transplant patients have a relatively low antibody-acquisition rate following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination. In this study, antibody titers were measured 5–6 months and 3 weeks to 3 months after the second and third SARS-CoV-2 mRNA vaccinations, respectively. Post-renal-transplant patients visiting our hospital who had received three SARS-CoV-2 mRNA vaccine doses were included in the study. SARS-CoV-2 immunoglobulin G antibody titers were measured three times: between 3 weeks and 3 months after the second vaccination, 5–6 months after the second vaccination, and between 3 weeks and 3 months after the third vaccination. A total of 62 (40 men and 22 women) were included, 44 of whom (71.0%) were antibody positive after their third vaccination. On comparing the antibody-acquired and antibody-non-acquired groups, body mass index (BMI, odds ratio [OR]: 1.44, 95% confidence interval [CI]: 1.07–1.93, p < 0.05) and the estimated glomerular filtration rate (eGFR, OR: 1.14, 95% CI: 1.06–1.24, p < 0.01) were associated with antibody acquisition. Therefore, in Japanese post-kidney-transplant patients, increases in the antibody-acquisition rate and absolute antibody titer after the third vaccination were observed, with BMI and eGFR associated with the antibody-acquisition rate.

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  23. 重症患者の免疫・血栓学的プロファイルの異質性に着目した持続的腎代替療法の回路早期閉塞発生メカニズムの探索

    加藤 孝昭, 沖 尚弥, 春日井 大介, 古橋 和拡

    日本透析医学会雑誌   Vol. 56 ( 6 ) page: 251 - 252   2023

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    DOI: 10.4009/jsdt.56.251

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  24. Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis. International journal

    Hiroki Kitai, Noritoshi Kato, Koichi Ogami, Shintaro Komatsu, Yu Watanabe, Seiko Yoshino, Eri Koshi, Shoma Tsubota, Yoshio Funahashi, Takahiro Maeda, Kazuhiro Furuhashi, Takuji Ishimoto, Tomoki Kosugi, Shoichi Maruyama, Kenji Kadomatsu, Hiroshi I Suzuki

    BMC biology   Vol. 20 ( 1 ) page: 248 - 248   2022.11

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    BACKGROUND: Combinatorial gene regulation by multiple microRNAs (miRNAs) is widespread and closely spaced target sites often act cooperatively to achieve stronger repression ("neighborhood" miRNA cotargeting). While miRNA cotarget sites are suggested to be more conserved and implicated in developmental control, the pathological significance of miRNA cotargeting remains elusive. RESULTS: Here, we report the pathogenic impacts of combinatorial miRNA regulation on inflammation in systemic lupus erythematosus (SLE). In the SLE mouse model, we identified the downregulation of two miRNAs, miR-128 and miR-148a, by TLR7 stimulation in plasmacytoid dendritic cells. Functional analyses using human cell lines demonstrated that miR-128 and miR-148a additively target KLF4 via extensively overlapping target sites ("seed overlap" miRNA cotargeting) and suppress the inflammatory responses. At the transcriptome level, "seed overlap" miRNA cotargeting increases susceptibility to downregulation by two miRNAs, consistent with additive but not cooperative recruitment of two miRNAs. Systematic characterization further revealed that extensive "seed overlap" is a prevalent feature among broadly conserved miRNAs. Highly conserved target sites of broadly conserved miRNAs are largely divided into two classes-those conserved among eutherian mammals and from human to Coelacanth, and the latter, including KLF4-cotargeting sites, has a stronger association with both "seed overlap" and "neighborhood" miRNA cotargeting. Furthermore, a deeply conserved miRNA target class has a higher probability of haplo-insufficient genes. CONCLUSIONS: Our study collectively suggests the complexity of distinct modes of miRNA cotargeting and the importance of their perturbations in human diseases.

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  25. Influence of COVID-19 on the 10-year carbon footprint of the Nagoya University Hospital and medical research centre

    Morooka, H; Yamamoto, T; Tanaka, A; Furuhashi, K; Miyagawa, Y; Maruyama, S

    GLOBALIZATION AND HEALTH   Vol. 18 ( 1 ) page: 92   2022.11

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    Background:: Amidst the climate crisis, a key goal of the medical sector is to reduce its large carbon footprint. Although the Coronavirus disease 2019 (COVID-19) pandemic greatly impacted the medical sector, its influence on carbon footprints remains unknown. Therefore, the aim of this study was to evaluate changes in the carbon footprint of a university hospital with a medical research centre over the past 10 years. Methods:: Data on electricity, gas, and water usage, pharmaceutical and medical supply costs, and waste amounts were recorded for Nagoya University Hospital from April 2010 to March 2021. The relevant emission factors were obtained from the Japanese government and the overall monthly carbon footprint was reported according to the Greenhouse Gas Protocol. The effect of the COVID-19 pandemic on the carbon footprint was then compared for three types of emission sources. Moreover, a regression model was used to plot quadratic functions as approximate functions using monthly carbon emissions and monthly average external temperatures. Finally, the monthly carbon footprint was calculated per hospital admission. Results:: The overall carbon footprint of the hospital was 73,546 tCO2e in 2020, revealing an increase of 26.60% over the last 10 years. Carbon emissions from electricity consumption represented 26% of total emissions. The individual carbon footprints of pharmaceuticals, medical supplies, waste, and water usage also increased from 2010 to 2020. The overall monthly carbon footprint was positively correlated with the average monthly temperature (R2 = 0.7566, p < 0.001). Compared with 2019, the overall carbon footprint decreased by 2.19% in 2020. Moreover, the monthly carbon footprint per hospital admission increased significantly between 2018 (0.24 tCO2e/admission) and 2020 (0.26 tCO2e/admission) (p = 0.002). Conclusion:: The overall carbon footprint of the hospital generally increased over the last decade. During the COVID-19 epidemic in 2020, the carbon footprint decreased slightly, likely because of the reduced number of patients. However, the carbon footprint per admission increased, which was attributed to more complicated patient backgrounds because of the ageing population. Therefore, evaluation of carbon emissions in the medical sector is urgently required in order to act on the climate crisis as soon as possible.

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  26. Mortality and Cardiovascular Events in Patients With Chronic Kidney Disease and Sleep Apnea Syndrome

    Watanabe, Y; Tanaka, A; Furuhashi, K; Saito, S; Maruyama, S

    FRONTIERS IN MEDICINE   Vol. 9   page: 899359   2022.5

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    Background: The incidence of sleep apnea syndrome (SAS) is reported to be markedly high in patients with chronic kidney disease (CKD). Therefore, it is extremely important to know whether SAS affects prognosis in patients with CKD. Further, it is imperative to understand the prognostic impact of home continuous positive airway pressure (CPAP) therapy, which is one of the most common treatments for SAS. Materials and Methods: We used a clinical database to identify patients with CKD using diagnosis codes. We included patients with CKD aged 20 years or more, not on renal replacement therapy, with a known change in renal function for at least 1 year. The propensity score was used to compare event rates for patients with SAS and those without SAS. In addition, the prognostic impact of CPAP therapy was investigated. The primary outcome is a composite of death, initiation of renal replacement therapy, hospitalization for heart failure, ischemic heart disease, and cerebrovascular disease. Results: From the database, 31,294 patients with CKD without SAS and 1,026 with SAS were found to be eligible. Of these, 419 (41%) patients with SAS and 10,713 (34%) patients without SAS (P < 0.01) reached the primary outcome. After adjustment with the propensity score, the SAS group was found to have a similarly poor prognosis (P < 0.01): the hazard ratio for the primary outcome was 1.26 (95% CI, 1.08–1.45, P < 0.01) in the group with SAS compared with the group without SAS. Conversely, in patients with SAS and using CPAP, the hazard ratio was lower and did not differ significantly (HR 0.96, 95% CI: 0.76–1.22, P = 0.76). Conclusion: In patients with CKD and SAS, the risk of death and cardiovascular disease is high. In addition, patients treated with CPAP may have improved life expectancy.

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  27. Protocol for a Phase 1, Open-Label, Multiple-Center, Dose-Escalation Study to Evaluate the Safety and Tolerability of ADR-001 in the Treatment of Immunoglobulin A Nephropathy. International journal

    Akihito Tanaka, Kazuhiro Furuhashi, Kumiko Fujieda, Kayaho Maeda, Shoji Saito, Tetsushi Mimura, Yosuke Saka, Tomohiko Naruse, Takuji Ishimoto, Tomoki Kosugi, Fumie Kinoshita, Yachiyo Kuwatsuka, Shinobu Shimizu, Yasuhiro Nakai, Shoichi Maruyama

    Frontiers in medicine   Vol. 9   page: 883168 - 883168   2022.5

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    Introduction: Immunoglobulin A (IgA) nephropathy is a disease that presents with urinary symptoms such as glomerular hematuria and urinary protein positivity, with predominant deposition of IgA in the mesangial region of the glomerulus. Corticosteroids are mainly used for treatment; however, infection is a serious adverse event, and evidence regarding therapeutic efficacy is insufficient, thus new treatments are strongly desired. Mesenchymal stem cells (MSCs) contribute to the amelioration of inflammation and recovery of organ function in inflammatory environments by converting the character of leukocytes from inflammatory to anti-inflammatory and inducing the proliferation and differentiation of organ component cells, respectively. These properties of MSCs have led to their clinical application in various inflammatory diseases, but this study is the first clinical trial of MSCs for refractory glomerulonephritis in the world. This study is registered and assigned the number, jRCT2043200002 and NCT04342325. Methods: This will be a phase 1, open-label, multiple-center, dose-escalation study of adult patients with refractory IgA nephropathy resistant to or difficult to treat with existing therapies. ADR-001 will be administered intravenously to from three to six patients at a dose of 1 × 108 cells once in the first cohort and to six patients twice at 2-week intervals in the second cohort, and observation will continue until 52 weeks. The primary endpoint will be the evaluation of adverse events up to 6 weeks after the start of ADR-001 administration. Secondary endpoints will be the respective percentages of patients with adverse events, clinical remission, partial remission, remission of urine protein, remission of hematuria, time to remission, changes in urine protein, hematuria, and estimated glomerular filtration rate. Results: Following the administration of ADR-001 to patients with IgA nephropathy, the respective percentages of patients with adverse events, asymptomatic pulmonary emboli, clinical remission, partial remission, urine protein remission, hematuria remission, their time to remission, changes in urine protein, hematuria, and glomerular filtration rate will be determined. Conclusion: This study will evaluate the safety and tolerability of ADR-001 and confirm its therapeutic efficacy in adult patients with refractory IgA nephropathy.

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  28. Monocytes transition to monocyte‐macrophages within the inflamed vasculature via CCR2 on monocytes and endothelial TNFR2 Invited Reviewed

    Vijayashree Sathyanarayana Mysore, Suhail Tahir, Kazuhiro Furuhashi, Jatin Arora, Florencia Rosetti, Xavier Cullere, Pascal Yazbeck, Miroslav Sekulic, Madeleine E Lemieux, Soumya Raychaudhuri, Bruce Horwitz, Tanya Mayadas

      Vol. 36   2022.5

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  29. Antibody response to double SARS-CoV-2 mRNA vaccination in Japanese kidney transplant recipients

    Fujieda, K; Tanaka, A; Kikuchi, R; Takai, N; Saito, S; Yasuda, Y; Fujita, T; Kato, M; Furuhashi, K; Maruyama, S

    SCIENTIFIC REPORTS   Vol. 12 ( 1 ) page: 6850   2022.4

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    Immunocompromised patients, especially those who undergo kidney transplantation, have lower antibody levels following SARS-CoV-2 mRNA vaccination. The situation of transplant treatment, such as transplant source and immunosuppressive drugs, is different in Japan than that in other countries. Therefore, it is necessary to clarify whether antibody acquisition rates differ between Japan and other countries. This retrospective study included patients with post-kidney transplant who were attending at the Nagoya University Hospital. The anti-SARS-CoV-2 IgG antibody titers were measured between 3 weeks and 3 months after vaccination. Seventy-three patients (45 men and 28 women) were included. Of these, 23 (31.5%) showed antibody presence, and the rates of antibody acquisition were very low than those in the control group (100.0% vs. 31.5%, P < 0.05). Antibody acquisition rates were associated with body mass index (odds ratio [OR]: 1.21, 95% confidence interval [CI]: 1.04–1.39, P < 0.05) and the duration between transplantation and vaccination (OR: 1.01, 95% CI: 1.00–1.02, P < 0.05). The immunosuppressive drugs used were: prednisolone in all cases, tacrolimus in 89.0%, cyclosporine in 9.6%, and mofetil mycophenolate in 97.3%. None of the patients were excluded from receiving two doses of the vaccine due to adverse effects. The study indicated that vaccination-induced antibody acquisition rates against SARS-CoV-2 were extremely low in Japanese patients who underwent post-kidney transplantation. Thus, despite two doses of vaccination, it is necessary to closely monitor infection control in such patients.

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  30. A novel renal perivascular mesenchymal cell subset gives rise to fibroblasts distinct from classic myofibroblasts

    Shun Minatoguchi, Shoji Saito, Kazuhiro Furuhashi, Yuriko Sawa, Masaki Okazaki, Yuko Shimamura, Ahmad Baseer Kaihan, Yusaku Hashimoto, Yoshinari Yasuda, Akitoshi Hara, Yasuyuki Mizutani, Ryota Ando, Noritoshi Kato, Takuji Ishimoto, Naotake Tsuboi, Nobutoshi Esaki, Makoto Matsuyama, Yukihiro Shiraki, Hiroki Kobayashi, Naoya Asai, Atsushi Enomoto, Shoichi Maruyama

    Scientific Reports   Vol. 12 ( 1 ) page: 5389   2022.3

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    Abstract

    Perivascular mesenchymal cells (PMCs), which include pericytes, give rise to myofibroblasts that contribute to chronic kidney disease progression. Several PMC markers have been identified; however, PMC heterogeneity and functions are not fully understood. Here, we describe a novel subset of renal PMCs that express Meflin, a glycosylphosphatidylinositol-anchored protein that was recently identified as a marker of fibroblasts essential for cardiac tissue repair. Tracing the lineage of Meflin<sup>+</sup> PMCs, which are found in perivascular and periglomerular areas and exhibit renin-producing potential, showed that they detach from the vasculature and proliferate under disease conditions. Although the contribution of Meflin<sup>+</sup> PMCs to conventional α-SMA<sup>+</sup> myofibroblasts is low, they give rise to fibroblasts with heterogeneous α-SMA expression patterns. Genetic ablation of Meflin<sup>+</sup> PMCs in a renal fibrosis mouse model revealed their essential role in collagen production. Consistent with this, human biopsy samples showed that progressive renal diseases exhibit high Meflin expression. Furthermore, Meflin overexpression in kidney fibroblasts promoted bone morphogenetic protein 7 signals and suppressed myofibroblastic differentiation, implicating the roles of Meflin in suppressing tissue fibrosis. These findings demonstrate that Meflin marks a PMC subset that is functionally distinct from classic pericytes and myofibroblasts, highlighting the importance of elucidating PMC heterogeneity.

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  31. 腎移植レシピエントにおけるSARS-CoV-2 mRNAワクチン接種後の抗体獲得率

    安田 宜成, 田中 章仁, 菊地 良介, 高井 奈美, 齋藤 尚二, 藤田 高史, 加藤 真史, 古橋 和拡, 丸山 彰一

    移植   Vol. 57 ( Supplement ) page: s270_3 - s270_3   2022

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    <p>【背景】腎移植レシピエントでは免疫抑制療法のためSARS-CoV-2 mRNA vaccinat</p><p>ionによる抗体獲得率が低いと報告されている。本邦では諸外国と比較し、生体腎移植が多く、免疫抑制薬の治療レジメなどが異なる。日本人腎移植レシピエントのワクチン接種後の交代獲得率を調査した。</p><p>【方法】対象は名古屋大学医学部付属病院へ通院中の日本人腎移植レシピエントのうち、SARS-CoV-2 mRNAワクチンを受けて、抗体価を測定した106名。抗体価は2回のワクチン接種後3週間から3か月の間にSARS-CoV-2 IgG II Quant Reagent Kit(R)により測定し、50 AU/mL以上を陽性とした。</p><p>【結果】対象者106名中で陽性は41名(38.6%)であった。抗体獲得率に関連する因子として、BMI(OR 1.24, 95% CI 1.08-1.41, P<0.05)、移植からの期間(OR 1.01, 95% CI 1.00-1.02, P<0.05)、eGFR(OR 1.07, 95% CI 1.02-1.11, P<0.05)が関連した。</p><p>【結論】腎移植レシピエントはSARS-CoV-2 mRNAワクチン接種後の抗体獲得率が低く、ワクチン接種後も厳重な感染対策を継続しなければならない。加えて免疫抑制治療中の患者において抗体獲得率を高めるSARS-CoV-2 mRNAワクチン接種方法の検討が必要である。</p>

    DOI: 10.11386/jst.57.supplement_s270_3

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  32. Acute kidney injury and cytokines

    Furuhashi K

    Acute Kidney Injury and Regenerative Medicine     page: 333 - 351   2020.1

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    Cytokines and chemokines are potential signaling molecules that maintain homeostasis by activating intracellular communication. Cytokines orchestrate various processes, ranging from cellular survival, proliferation, and chemotaxis for tissue repair to regulation of inflammation. Extracellular vesicles (EVs), which are cell-derived membrane particles such as exosomes and microvesicles, may also play crucial roles similar to cytokines. The kidneys are highly susceptible to intrinsic oxidative stress resulting from ischemia and to the excessive inflammatory response resulting from systemic autoimmunity. These types of stress may eventually result in the development of acute kidney injury (AKI). In this setting, the skewed cytokine profile produced by macrophages and lymphocytes disrupts the reciprocal relationship for regulating tissue repair and remodeling due to amplification of a physiological vicious loop. We have so far shown that AKI induces the secretion of midkine (MK) and CD147/basigin, which are responsible for skewed cytokine production. MK and CD147/basigin secreted by tubular epithelial cells promote the recruitment of macrophages and neutrophils, respectively, which are accompanied by monocyte chemotactic protein- 1, transforming growth factor-β, E cadherin, and extracellular matrix metalloproteinase inducer. This chapter will present the functions of macrophage-related cytokines and EVs and summarize our findings on how MK and CD147/basigin are involved in the pathogenesis of AKI.

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  33. Therapeutic Application of Adipose Derived Mesenchymal Stem Cells for Kidney Diseases

    Furuhashi Kazuhiro, Maruyama Shoichi

    Nihon Naika Gakkai Zasshi   Vol. 109 ( 4 ) page: 812 - 818   2020

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    DOI: 10.2169/naika.109.812

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  34. Adenosine from Niche-Associated Tregs Maintains Hematopoietic Stem Cell Quiescence Reviewed

    Hirata Y, Furuhashi K, Ishi H, Li H, Pinho S,Ding L, Frenette P, Fujisaki J.

    Blood   ( 130 ) page: 91   2017.12

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    DOI: https://doi.org/10.1182/blood.V130.Suppl_1.91.91

  35. Urinary soluble CD163 level reflects glomerular inflammation in human lupus nephritis Reviewed

    Endo N, Tsuboi N, Furuhashi K, Shi Y, Du Q, Abe T, Hori M, Imaizumi T, Kim H, Katsuno T, Ozaki T, Kosugi T, Matsuo S,Maruyama S.

    Nephrology Dialysis Transplantation   Vol. 31   page: 2023-2033   2016.12

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    DOI: 10.1093

  36. Transfusion of CD206+ M2 Macrophages Ameliorates Antibody Mediated Glomerulonephritis in Mice Reviewed

    Du Q, Tsuboi N, Shi Y, Ito S, Sugiyama Y, Furuhashi K, Endo N, Kim H, Katsuno T, Akiyama S, Matsuo S, Isobe K, Maruyama S.

    The American Journal of Pathology   Vol. 186   page: 3176-3188   2016.8

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  37. Midkine Regulates BP through Cytochrome P450 Derived Eicosanoids Reviewed

    Sato Y, Sato W, Maruyama S, Wilcox C, Falck J, Masuda T, Kosugi T, Kojima H, Maeda K, Furuhashi K, Ando M, Imai E, Matsuo S, Kadomatsu K.

    Journal of the American Society of nephrology   Vol. 26   page: 1806-1815   2015.8

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  38. Pristane-Induced Granulocyte Recruitment Promotes Phenotypic Conversion of Macrophages and Protects against Diffuse Pulmonary Hemorrhage in Mac-1 Deficiency Reviewed

    Shi Y, Tsuboi N, Furuhashi K, Du Q, Horinouchi A, Maeda K, Kosugi T, Matsuo S, Maruyama S.

    The Journal of Immunology     page: 5129-5139   2014.11

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    DOI: 10.4049

  39. Rat adipose tissue derived stem cells attenuate peritoneal injuries in rat zymosan induced peritonitis accompanied by complement activation Reviewed

    Kim H, Mizuno M, Furuhashi K, Katsuno T, Ozaki T, Yasuda K, Tsuboi N, Sato W, Suzuki Y, Matsuo S, Ito Y, Maruyama S.

    Cytotherapy   Vol. 16   page: 357-368   2013.12

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  40. Low Serum Cultured Adipose Tissue-Derived Stromal Cells Ameliorate Acute Kidney Injury in Rats Reviewed

    Katsuno T, Ozaki T, Saka Y, Furuhashi K, Kim H, Yasuda K, Yamamoto T, Sato W, Tsuboi N, Mizuno M, Ito Y, Imai E, Matsuo S, Maruyama S.

    Cell transplantation   Vol. 22   page: 287-297   2013.2

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    DOI: 10.3727

  41. Clinical survey of hepatitis in patients treated at 7 hospitals located in Kasugai city Including the effects of patient transfer according to the hospital network Reviewed

    Kazuhiro Furuhashi, Yasuyuki Asano, Makoto Tsujita, Yohsuke Saka, Yoshimichi Urahama, Takao Yaomura, Kiyonari Kato, Tomohiko Naruse, Yuzo Watanabe

    Nihon Toseki Igakkai Zasshi   Vol. 38 ( 4 ) page: 291 - 296   2005.4

  42. Central cervical cord injury after a mild contusion due to syncopal attack caused by complete AV block in a maintenance hemodialysis patient: A case report Reviewed

    Yosuke Saka, Yasuyuki Asano, Makoto Tsujita, Kazuhiro Furuhashi, Tomohiko Naruse, Yuzo Watanabe, Shigeo Sugino, Akihiro Terasawa, Kimiko Hibino

      Vol. 38 ( 3 ) page: 227 - 231   2005.3

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: https://doi.org/10.4009/jsdt.38.227

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Books 8

  1. 脂肪由来間葉系幹細胞による重症腎炎改善メカニズムの解明

    古橋和拡、 田中章仁, 丸山彰一( Role: Joint author)

    医学のあゆみ  2023 

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    Language:Japanese Book type:Scholarly book

  2. 脂肪由来幹細胞を用いた腎炎の治療

    田中章仁( Role: Joint author)

    医学のあゆみ・医歯薬出版  2020.10 

  3. 間葉系幹細胞を用いた腎疾患治療法の開発

    古橋和拡・田中章仁・唐澤宗稔・丸山彰一( Role: Joint author)

    科学評論社  2020.8 

  4. Acute Kidney Injury and Cytokines

    ( Role: Joint author)

    Acute Kidney Injury and Regenerative Medicine  2020.5 

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    Total pages:p333-351   Language:English

  5. Acute Kidney Injury and Cytokines

    ( Role: Joint author)

    Acute Kidney Injury and Regenerative Medicine  2020.5 

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    Total pages:p333-351   Language:English

  6. 脂肪由来間葉系幹細胞を用いた腎疾患治療

    古橋和拡, 丸山彰一( Role: Joint author)

    日本内科学会雑誌  2020.4 

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    Language:Japanese

  7. 脂肪由来間葉系幹細胞を用いた腎疾患治療

    古橋和拡・丸山彰一( Role: Joint author)

    日本内科学会雑誌  2020.4 

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    Language:Japanese

  8. Annual Review 腎臓

    古橋和拡、丸山彰一、坪井直毅( Role: Joint author)

    中外医学社  2012.1 

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    Language:Japanese Book type:Scholarly book

    脂肪由来間葉系幹細胞(ASC)を用いた難治性腎疾患・自己免疫疾患への新たな治療開発

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MISC 2

  1. CD150<sup>high</sup> Bone Marrow Tregs Maintain Hematopoietic Stem Cell Quiescence and Immune Privilege via Adenosine. Reviewed

    Hirata Y, Furuhashi K, Ishii H, Li HW, Pinho S, Ding L, Robson SC, Frenette PS, Fujisaki J

    Cell stem cell   Vol. 22 ( 3 ) page: 445 - 453.e5   2018.3

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    Language:English   Publishing type:Rapid communication, short report, research note, etc. (scientific journal)  

    DOI: 10.1016/j.stem.2018.01.017

    PubMed

  2. Neutrophil Fc gamma RIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases Reviewed

    Hiroshi Nishi, Kazuhiro Furuhashi, Xavier Cullere, Gurpanna Saggu, Mark J. Miller, Yunfeng Chen, Florencia Rosetti, Samantha L. Hamilton, Lihua Yang, Spencer P. Pittman, Jiexi Liao, Jan M. Herter, Jeffrey C. Berry, Daniel J. DeAngelo, Cheng Zhu, George C. Tsokos, Tanya N. Mayadas

    JOURNAL OF CLINICAL INVESTIGATION   Vol. 127 ( 10 ) page: 3810 - 3826   2017.10

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    Language:English   Publishing type:Rapid communication, short report, research note, etc. (scientific journal)   Publisher:AMER SOC CLINICAL INVESTIGATION INC  

    The kidney glomerular capillaries are frequent sites of immune complex deposition and subsequent neutrophil accumulation in post-infectious and rapidly progressive glomerulonephritis. However, the mechanisms of neutrophil recruitment remain enigmatic, and there is no targeted therapeutic to avert this proximal event in glomerular inflammation. The uniquely human activating Fc receptor Fc gamma RIIA promotes glomerular neutrophil accumulation and damage in anti-glomerular basement membrane-induced (anti-GBM-induced) glomerulonephritis when expressed on murine neutrophils. Here, we found that neutrophils are directly captured by immobilized IgG antibodies under physiological flow conditions in vitro through Fc gamma RIIA-dependent, Abl/Src tyrosine kinase-mediated F-actin polymerization. Biophysical measurements showed that the lifetime of Fc gamma RIIA-IgG bonds increased under mechanical force in an F-actin-dependent manner, which could enable the capture of neutrophils under physiological flow. Kidney intravital microscopy revealed that circulating neutrophils, which were similar in diameter to glomerular capillaries, abruptly arrested following anti-GBM antibody deposition via neutrophil Fc gamma RIIA and Abl/Src kinases. Accordingly, inhibition of Abl/Src with bosutinib reduced Fc gamma RIIA-mediated glomerular neutrophil accumulation and renal injury in experimental, crescentic anti-GBM nephritis. These data identify a pathway of neutrophil recruitment within glomerular capillaries following IgG deposition that may be targeted by bosutinib to avert glomerular injury.

    DOI: 10.1172/JCI94039

    Web of Science

    PubMed

Presentations 11

  1. Elucidation of therapeutic mechanism of adipose-derived mesenchymal stem cells against glomerulonephritis model by focusing on in vivo cell dynamics Invited

    Kazuhiro Furuhashi

    2021.12.3 

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    Event date: 2021.12

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Country:Japan  

  2. 脂肪間葉系幹細胞を用いた腎炎治療の可能性 〜治療特性とその作用機序〜 Invited

    古橋和拡

    再生医療学会  2021.3.13 

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    Event date: 2021.3

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

  3. MESENCHYMAL STEM CELLS EXERT RENOPROTECTION VIA EXTRACELLULAR VESICLE- MEDIATED MODULATION OF M2 MACROPHAGES AND SPLEEN-KIDNEY NETWORK International conference

    Kazuhiro Furuhashi

    The International Society for Stem Cell Research (ISSCR)   2021.10.28  The International Society for Stem Cell Research (ISSCR)

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    Event date: 2021.10

    Language:English   Presentation type:Poster presentation  

    Venue:Tokyo   Country:Japan  

  4. Evaluation of the safety and efficacy of adipose derived mesenchymal stem cell (ADR-001) treatment for refractory IgA nephropathy International conference

    The 17th International Symposium on IgA Nephropathy   2023.9.30 

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    Event date: 2023.9

    Language:English   Presentation type:Symposium, workshop panel (public)  

  5. 腎臓への入口である血管内皮を 介したmonocytes教育 Invited

    古橋 和拡

    66回日本腎臓学会学術総会 シンポジウム10  2023.6.9 

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    Event date: 2023.6

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

  6. 間葉系幹細胞の心疾患・腎疾患への作用点における共通性 Invited

    古橋 和拡

    第66回日本腎臓学会学術総会 シンポジウム6  2023.6.9 

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    Event date: 2023.6

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

  7. Serum-starved adipose-derived stromal cells ameliorate rat crescentic glomerulonephritis by promoting immunoregulatory macrophages International conference

    Kazuhiro Furuhashi, Naotake Tsuboi, Asuka Shimizu, Yiqin Shi, Hangsoo Kim, Takayuki Katsuno, Yosuke Saka, Takenori Ozaki, Waichi Sato, Enyu Imai, Seiichi Matsuo, Shoichi Maruyama

    The Asia Pacifific Meeting of Vasculitis and ANCA Workshop 2012 5th International Conference on Autoimmunity: Mechanisms and Novel Treatments International Society for Stem Cell Research 10th Annual Meeting International Society for Stem Cell Research 11th Annual Meeting 

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    Event date: 2013.12

    Language:English   Presentation type:Poster presentation  

    Country:United States  

  8. 脂肪由来間葉系幹細胞を用いた壊死性半月体形成性腎炎への新たな治療法の確立とその作用機序の解明

    古橋 和拡,坪井 直毅,清水明日花,勝野 敬之,金  恒秀,松尾 清一,丸山 彰一

    第33回日本炎症・再生医学会 

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    Event date: 2012.7

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

    Country:Japan  

  9. LOW SERUM CULTURED ADIPOSE-DERIVED MESENCHYMAL STEM CELLS AMELIORATE CRESCENTIC GLOMERULONEPHRITIS BY FUNCTIONAL POLARIZATION OF MACROPHAGES INTO IMMUNOREGULATORY M2 PHENOTYPE International conference

    Furuhashi, Kazuhiro, Tsuboi, Naotake, Shimizu, Asuka, Kim, Hangsoo, Katsuno, Takayuki, Saka, Yosuke, Maruyama, Shoichi

    International Society for Stem Cell Research 10th Annual Meeting 

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    Event date: 2012.6

    Language:English   Presentation type:Poster presentation  

    Country:Greece  

  10. Low Serum Cultured Adipose-derived Mesenchymal Stem Cells Ameliorate Crescentic Glomerulonephritis by Functional Polarization of Macrophages into Immunoregulatory M2 Phenotype International conference

    Kazuhiro Furuhashi, Naotake Tsuboi, Asuka Shimizu, Yiqin Shi, Hangsoo Kim, Takayuki Katsuno, Yosuke Saka, Takenori Ozaki, Waichi Sato, Enyu Imai, Seiichi Matsuo, Shoichi Maruyama

    The Asia Pacifific Meeting of Vasculitis and ANCA Workshop 2012 

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    Event date: 2012.3

    Language:English   Presentation type:Oral presentation (general)  

    Country:Japan  

  11. Low serum cultured adipose-derived mesenchymal stromal cells, but not bone-marrow derived mesenchymal stem cells, ameliorate rat crescentic glomerulonephritis by functional polarization of macrophages into immunoregulatory M2 phenotype International conference

    Kazuhiro Furuhashi, Naotake Tsuboi, Seiichi Matsuo, and Shoichi Maruyama

    5th International Conference on Autoimmunity: Mechanisms and Novel Treatments 

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    Event date: 2011.9

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

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Research Project for Joint Research, Competitive Funding, etc. 2

  1. 生体がもつ巧妙な炎症制御機構の解明から治療応用へ

    2021.4 - 2028.3

    国立研究開発法人科学技術振興機構(JST)  創発的研究支援事業 

    古橋和拡

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    Authorship:Principal investigator  Grant type:Competitive

  2. 間葉系幹細胞治療用中空糸膜カラムの開発

    2021.4 - 2024.3

    AMED: 国立研究開発法人日本医療研究開発機構  再生医療実現拠点ネットワークプログラム(技術開発個別課題) 

    古橋和拡

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    Authorship:Principal investigator  Grant type:Competitive

KAKENHI (Grants-in-Aid for Scientific Research) 15

  1. 生体がもつ巧妙な炎症制御機構の解明から治療応用へ

    2021.4 - 2028.3

    国立研究開発法人科学技術振興機構(JST)  創発的研究支援事業 

    古橋和拡

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    Authorship:Principal investigator  Grant type:Competitive

  2. 間葉系幹細胞治療用中空糸膜カラムの開発

    2021.4 - 2024.3

    AMED: 国立研究開発法人日本医療研究開発機構  再生医療実現拠点ネットワークプログラム(技術開発個別課題) 

    古橋和拡

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    Authorship:Principal investigator  Grant type:Competitive

  3. 腎所属リンパ節を標的とするAKI-to-CKD transitionの新規治療戦略の構築

    Grant number:23K07716  2023.4 - 2026.3

    科学研究費助成事業  基盤研究(C)

    佐藤 由香, 古橋 和拡, 堀口 道子

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    Authorship:Coinvestigator(s) 

    AKI to CKD transitionの機序として「AKIによる尿細管細胞の大量ネクローシスの結果、障害腎の一部が抗原と認識され、リンパ節で“炎症がメモリー化”されることで、腎臓での炎症が慢性的に持続しCKDに進展する」という仮説を立て、以下の研究計画を遂行する。①KLN内で、どの免疫細胞が、どんな免疫反応を介して、腎障害を遷延させるかを解明し、②リンパ節HEVにのみ特異的に結合する抗体で標識したナノパーティクル(NP)を作成し、リンパ節特異的なDrug Delivery System(DDS)を確立する。そして、③リンパ節での免疫応答抑制を介したCKD進展抑制の新規治療戦略を構築する 。

  4. 糸球体周囲マクロファージは基底膜を貫く樹状突起によりポドサイト恒常性を維持する

    Grant number:22K19523  2022.6 - 2024.3

    科学研究費助成事業  挑戦的研究(萌芽)

    古橋 和拡, 丸山 彰一, 田中 章仁

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    Authorship:Principal investigator 

    Grant amount:\6370000 ( Direct Cost: \4900000 、 Indirect Cost:\1470000 )

    本研究では、通常の組織学的観察で見出せず、最新のイメージング技術である生体顕微鏡・臓器透明化を用いることで初めて観察することができたマクロファージのユニークな構造と細胞間networkに関して、その生物学的意味を解明する。独自に開発した生体顕微鏡技術・組織固定技術・組織透明化技術を融合することで、本課題の科学的問いは初めて解決することができるため、独自性の高い挑戦的な研究である。本課題は組織幹細胞niche研究に細胞形態学・細胞動態学を取り入れた新たな研究フィールドを創生し、細胞形態に関わる蛋白を治療ターゲットとした新たな治療法へと発展させ、ポドサイト再生に関わる因子の同定することを目指す。

  5. 間葉系幹細胞カラムとiPS細胞・遺伝子編集技術を融合した新規治療システム

    Grant number:22H03087  2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    古橋 和拡, 高須 正規, 平山 明由, 鈴木 洋, 丸山 彰一, 田中 章仁, 森 崇

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    Authorship:Principal investigator 

    Grant amount:\17550000 ( Direct Cost: \13500000 、 Indirect Cost:\4050000 )

    これまでの間葉系幹細胞(MSC)研究を通して、臨床応用時の問題点の解決と治療特性に関わる作用機序について解明を進めてきた。循環動態が悪い際の経静脈的な細胞投与は細胞塞栓の危険があり、この問題を解決するために、新たな治療装置としてMSCカラムの開発を進めている。さらに、細胞ソースの問題を解決するため、iPS細胞からMSCを作成する研究を進めている。
    本課題では、iPS細胞、MSCカラム、解明した治療機序を融合した新規治療システムを開発し、将来的に遺伝編集技術・細胞治療が新たに創生する治療フィールドを見据えた基盤技術へと発展させる。

  6. aHUS早期診断及び抗補体薬の適応判断に必要な補体機能検査開発

    Grant number:22K08349  2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    加藤 規利, 前田 佳哉輔, 丸山 彰一, 水野 正司, 古橋 和拡, 小杉 智規

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    aHUSは血液中ではなく、血管内皮細胞膜上での無秩序な補体活性化が問題であり、単純な採血で評価できないところに検査開発の難しさがある。我々は、2020年より開始したaHUS全国調査研究で登録のあった症例の血漿から、細胞外小胞(Exosomes)を精製し、Exosomes上の補体関連タンパクを測定し、細胞膜上の補体活性を評価する。またex vivoでaHUS患者の血漿と血管内皮細胞株との反応系にエクリズマブを添加することにより、実際に薬剤を投与する前に、治療反応性を見極める。
    我々は、非典型溶血性尿毒症症候群(aHUS)の疾患事務局を、2020年より東京大学から引き継ぎ、医療施設からの症例相談を受けるとともに、奈良県立医科大学にて開発されたヒツジ赤血球溶血試験(補体機能検査)を行ったり、抗H因子抗体(抗CFH抗体)価を測定するなどして研究、臨床の両面から知見を蓄積してきた。2020年度は62症例の臨床相談を受け、91検体の解析を行った。2021年度は65症例の臨床相談を受け、81検体の解析を行った。そして本研究を開始した2022年度は1月までに66症例の相談、77検体の解析を行った。
    当方で33例のaHUSの診断に至り、内補体関連遺伝子の病的バリアント保有例は19症例、バリアント未検出は10症例、未検査4症例であった。病的バリアント保有割合は65%(19/29)という数字は、過去の報告と同等~やや高めの値で、概ね妥当な数値と考えられる。
    19症例のバリアントの内訳は、CFH:7例、C3:9例、CD46:3例、CFI:1例(1例のC3, CD46重複例を含む)であった。世界的にはCFHの病的バリアント保有例の割合が高いが、本邦ではC3、特にC3 I1157Tバリアントの割合が高いことは、既に報告(Clin Exp Nephrol . 2018 Oct;22(5):1088-1099.)があり、同じ傾向であった。
    上記の様に、疾患の概要、特に本邦における特徴が明らかになっている。課題の1つであるヒツジ赤血球溶血試験に関しては、CFH病的バリアント保有例の7例の内、6例で測定が行われ5例で陽性と診断され、遺伝学的検査の前にaHUSへの診断につなげることが出来た。一方で他の遺伝子バリアントでは、C3 I1157Tバリアントの1例で陽性になったのみで、他のバリアントでは陰性となり、aHUSの早期診断には繋がらず、課題の残る結果であった。
    aHUSは希少疾患であり、本研究(非典型溶血性尿毒症症候群(aHUS)全国調査研究)は、現在日本で行われているaHUSの最大のコホート研究であると言える。上述のように33症例の診断に寄与してきた実績があり、本年度の症例数も例年と同じ水準~やや多めの数を記録している。aHUSのみならず他のTMA(STEC-HUS, TTP, 二次性TMA)の症例も含まれていることが、本コホート研究の強みである。つまり、aHUSの診断に寄与する検査方法を、他のTMAを引き起こす疾患と比較することができる。
    現状では血漿中のC5b-9は、エクリズマブ治療を行うと完全に抑制されるが、血漿交換を数回行った状況では、そこまで抑えられていないことがわかっている。また興味深いことに未発症者の検体でもC5b-9は基準値を上回っており、あきらかなTMAによる臓器症状がない状況においても異常値を取っていることの意義は、今後検証をしていく必要があるものと思われる。また、aHUS以外のTMAであるTTPにおいても血漿C5b-9が異常高値であったことは、C5b-9の診断的価値の検討に置いて大切な結果である。つまり補体が一義的に関与するaHUSのみならず、別要因で血管内皮細胞障害を引き起こす疾患でも、二次的に補体の活性化が起きている可能性は示唆される。これら問題点に置いて、更に症例数を重ねて検証を続けていく。
    基本的には現在のaHUS疾患事務局を通した症例の解析を続けていく。名古屋大学医学部腎臓内科学のホームページにおいて事務局の案内をするとともに、動画などの説明資材を用いて疾患の啓蒙を続ける。
    目的の検査に関しては、ある程度の数のaHUS症例、及び、STEC-HUS, TTP,
    二次性TMAの症例が蓄積した時点で、更にエクソソームの抽出を行う。またin vitroにおけるエクリズマブ抑制試験は、ヒツジ赤血球溶血試験においては既に数多く行っている。フローサイトメトリーによる解析を通して、生体内における補体活性化の量的解析、つまり定量性をもたせることによって、実臨床に置いて発症、再発診断、治療効果判定、のみならず抗C5抗体薬(エクリズマブ、ラブリズマブ)投与前に治療効果予測を行えるようになることは、医療資源の適切な利用に関わる問題として非常に重要な知見となると考える。

  7. 塩基性ヘリックスループヘリックス転写機構制御と細胞治療を融合する神経再生治療開発

    Grant number:22K09280  2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    西村 由介, 永島 吉孝, 夏目 敦至, 古橋 和拡

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    申請者らは『損傷脊髄を完全に再生する驚異的な能力を持つアフリカツメガエル幼生期に強く発現し、脊髄再生に関わるNeurod4などの塩基性ヘリックスループヘリックス(bHLH)神経転写因子を歯髄幹細胞に遺伝子導入してラット脊髄損傷モデルに投与することで、歯髄幹細胞自体をニューロンへ分化させ神経回路を再構築し、神経栄養因子分泌による脊髄再生効果に相加的かつ加速度的な神経機能回復が得られる』という仮説を立て、これを実証する。
    ① bHLH神経転写因子の遺伝子導入、 in vitroでの神経栄養因子の測定:アフリカツメガエル幼生期に高発現している脊髄再生に関わるNeurod4(bHLH神経転写因子)をシュードウイルスベクターでSHED(ヒト由来歯髄幹細胞)に良好に遺伝子導入し(Neurod4-SHED)、ウエスタンブロットでNeurod4が発現されていることが確認できた。その後、in vitroで培養し、神経栄養因子の分泌(培養上清での測定)を測定し、Neurod4-SHEDをnaiveのSHEDと比較した結果、MCP-1、TGF-βが有意に上昇していることがつきとめられた。これらが炎症惹起するM1マクロファージより炎症抑制するM2マクロファージを活性化する機能を有するため、マクロファージの動態を解析することを現在行っている。
    ② ラットへのSHED投与、機能評価、組織学的解析:胸髄損傷ラットモデルを用い、SHEDを胸髄内に投与した。下肢運動機能スコア(BBBスコア)で良好な下肢の運動機能回復がnaiveのSHEDとの比較で有意差をもって確認された。
    ③ Neurod4-SHEDの造腫瘍性試験:Neurod4-SHEDを移植して8週間の時点では、ラットの健康状態には問題がなく、造腫瘍性も否定されている。
    基本的にはおおむね順調に進展しており、予測された通り遺伝子改変した歯髄幹細胞(Neurod4-SHED)を投与したラットでは有意な下肢運動機能改善が認められた。そのメカニズムの解析の第1段階として、神経栄養因子の分泌(培養上清での測定)を測定し、naiveのSHEDと比較した結果、MCP-1、TGF-βが有意に上昇していることがつきとめられた。これらが炎症惹起するM1マクロファージより炎症抑制するM2マクロファージを活性化する機能を有するため、現在マクロファージの動態の研究を進めているが、今のところウエスタンブロットではnaiveのSHEDと比較して、Neurod4-SHEDがM2マクロファージを有意に誘導することが証明できておらずやや時間を要している。
    マクロファージの動態に関しては、マクロファージとSHEDの共培養を行い、M2マクロファージがNeurod4-SHEDにより有意に誘導されることを証明する。また、Neurod4-SHEDマイクロアレイ解析を行うことにより、ラット運動機能の有意な改善に寄与した神経再生に関わる因子の同定を行う予定である。また、運動機能が改善したラット脊髄の病理学的な解析、損傷脊髄移植8週間後のNeurod4-SHEDの動態と分化の解析も行う。

  8. ヒトiPS細胞由来間葉系幹細胞を用いた新規腎疾患治療法の開発

    Grant number:21K08253  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    田中 章仁, 石本 卓嗣, 丸山 彰一, 古橋 和拡

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    間葉系幹細胞(MSC)は様々な疾患に対する治療効果が示されている。しかし、MSCは品質のばらつきがあるため、治療効果の担保が大きな問題となっている。本課題では、iPS細胞からMSCを分化誘導し、腎炎に対する治療効果が安定して高いことを確認し、MSCの欠点を克服する。さらに治療効果を高める操作を加え、これまでのMSCよりも、腎炎に対して各段に高い治療効果を得る。最終的には、既存の治療法を凌駕する、難治性腎疾患に対する全く新しい細胞治療を確立する。
    ヒト人工多能性幹細胞(iPS細胞)から分化誘導した間葉系幹細胞(MSC)を用いて実験を行った。もともと当教室ではMSC、特に低血清培養脂肪由来MSC(LASC)の研究が精力的に行われており、LASC研究での実績を参考に、実験に用いるモデル動物の作製、細胞の投与プロトコルや、治療効果を評価するプロトコルの確立も行った。iPS細胞から分化誘導したMSC(iMSC)を用いた腎疾患モデル動物への治療実験を行っていく中で、一定の治療有効性は示された。その実験の中で、細胞側の条件として、iMSCは、骨髄由来MSCに比較して老化しにくく、長期間継代が可能であり、また継代と共にその性質を変化させていくことも明らかになった。そのため、iMSC投与に際して、その治療効果を最大とする、最適な細胞条件の検討を進めている。また治療効果と関連する機序解明についても、有効性の異なる細胞条件ごとに、有効性と関連付けながら、確認を進めている。
    研究の今後の発展を見据えて、大型モデル動物の作製を進めている。大型モデル動物への治療効果を踏まえ、最終的にはヒトへの応用を進めていくことを計画している。
    iPS細胞から誘導したMSCの、腎疾患に対する有効性については確信を得つつある。また、iMSCは老化しにくく継代を長期間継続することが可能であるため、ヒトへの応用を考えた際に、大量の細胞数を確保する点に関して、有利であることが明らかになった。ただし細胞側の条件により、その有効性の高さには変化があるようであり、最適な条件を確立していくための実験を継続している。さらに有効性の高さと関連付けて、機序解析などを進めている。
    今後はiMSCの、腎疾患に対する最も高い有効性を得られる細胞条件を決定し、それを用いたiMSCによる腎疾患モデル動物の治療方法を確立する。大型モデル動物へも展開し、最終的にはヒトへの応用を目指す。また、解明された機序から、iMSC治療をさらに洗練させていく。

  9. 間葉系幹細胞の微小環境での炎症制御機構に着眼した次世代型免疫・炎症制御法の創成

    Grant number:21H04824  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業  基盤研究(A)

    丸山 彰一, 石本 卓嗣, 平山 明由, 榎本 篤, 秋山 真一, 田中 章仁, 杉浦 悠毅, 古橋 和拡

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    既存の免疫抑制薬は過剰免疫抑制による感染症などの副作用が問題となっている。間葉系幹細胞(MSC)は、障害部位の炎症強度に応じた自律的かつ局所での炎症制御が可能なことから、次世代の免疫制御療法として期待されている。しかし、その作用機序は十分解明されておらず、その実用化に際しては課題が多い。新概念として『障害部位に到達したMSC由来細胞外小胞が炎症細胞から放出される炎症性物質と微小空間で会合した時にのみ免疫抑制物質が生成されて局所での抗炎症作用が出現する』という着想に至った。本研究では、この新概念を検証して、効果的で安全な次世代型免疫・炎症制御療法の開発に取り組む。

  10. フルクトース代謝を標的とした糖尿病性腎臓病の病態解明と新規治療法の開発

    Grant number:21K08254  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    石本 卓嗣, 小杉 智規, 古橋 和拡, 平山 明由

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    これまでに、グルコースより内因性に産生される過剰なフルクトース代謝が糖尿病性腎臓病(DKD)およびメタボリック症候群・脂肪肝を進展させることを報告し、フルクトース代謝酵素KHK-Cを抑制する治療法の開発に取り組んできた。本研究は、①腎尿細管のKHK-C依存的フルクトース代謝の抑制によるDKDの進展抑制効果およびその機序を解明し、②高い酵素耐性を持つ非環状型人工核酸を用いたKHK-Cを阻害する核酸医薬を開発する。
    1) KHK-C依存的フルクトース代謝の抑制による、異常解糖系の改善・DKDの進展抑制効果を解明する。 CRISPR-Cas9システムにより作成したKHK-Cのみを欠損するKHK-C KOマウスおよびKHK-A KOマウス、KHK-A/C KOマウス、野生型マウスを用い、ストレ プトゾトシン誘導性の糖尿病モデルを作成した。経時的に採尿し、尿NGAL・尿アルブミン濃度をモニターしつつ、当初予定よりも観察期間を延長し、生後10-11ヶ月時点で採血・採尿・各種臓器の採取を行った。現在、腎障害の評価を開始している。また、KHK-Cを強制発現した不死化近位尿細 管細胞HK-2にフルクトース・グルコース刺激を行い、過剰なフルクトース代謝の解糖系(ECAR)・ミトコンドリア呼吸(OCR)への影響を、細胞外フラックスア ナライザーにより解析した。
    2)KHK-Cを選択的に阻害する核酸医薬を作成し、DKDおよびMS・脂肪肝に対する新規治療法を開発する。 KHK-Cを選択的に阻害するsiRNAを作成し、KHK-Cのノックダウン効率およびKHK-Aへの影響を含めたオフターゲット効果を評価した。同様の配列を用い、KHK-Cを 選択的に阻害するアンチセンスオリゴヌクレオチドを作成した。同時に、アンチセンスオリゴヌクレオチドの腎尿細管細胞への導入効果を評価するため、先行して用意していたSGLT2を標的としたアンチセンスオリゴヌクレオチドをマウスに投与し、腎における発現抑制効果およびその体内分布の評価を行っている。
    KHK-Cノックアウトマウスを含めた複数のノックアウトマウス(KHK-C KO、KHK-A KO、KHK-A/C KO)のコロニーを拡大し、野生型マウス含めてストレプトゾトシ ン誘導性の糖尿病モデルを作成しており、経時的に尿NGAL・尿アルブミン濃度を測定することで遺伝子改変マウスにおける腎障害を評価し、組織検体採取・評価時期の検討を行った。結果として、当初計画より長期の病態モデルとなったことから、評価開始時期もやや遅れることとなった。
    また、KHK-Cを選択的に阻害する核酸については、siRNAにおいて有用な配列が同定でき、またアンチセンスオリゴヌクレオチドについても有効性を確認出来ている。並行して行っていたSGLT2を標的としたアンチセンスオリゴヌクレオチドのマウスへの全身投与における検討にて、副作用を回避するアンチセンスオリゴヌクレオチドの修飾および投与量の検討に予定以上の時間を要した。
    1)KHK-C依存的フルクトース代謝の抑制による、異常解糖系の改善・DKDの進展抑制効果を解明する。
    ストレプトゾトシン誘導性の糖尿病モデルについて、想定よりも病態モデルの維持期間が延長したもののすでに全群の屠殺は終了した。今後は採取した組織・血液・尿検体の解析を進める。培養細胞を用いたフラックスアナライザーによる検討については、結果の取りまとめを行う。
    2)KHK-Cを選択的に阻害する核酸医薬および低分子化合物を作成し、DKDおよびMS・脂肪肝に対する新規治療法を開発する。
    マウスへの全身投与において、腎尿細管においてmRNA発現抑制効果を有しかつ他臓器含めた副作用を抑制したアンチセンスオリゴヌクレオチドの作成を進める。その後、病態モデルマウスへのアンチセンスオリゴヌクレオチドの全身投与による治療効果を検討する。

  11. Analysis of function and novel therapy of mesenchymal mesenchymal stem cell marker Meflin

    Grant number:20K08589  2020.4 - 2023.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Saito Shoji

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    Analysis was performed using normal mice, Meflin knockout mice, and Meflin-CreERT2;Rosa26-LSL-tdtomato mice.
    We also analysed Meflin-positive cells by using Meflin-ZsGreen-DTR-Cre mice and clarified its role.
    By using these methods, we found out that Meflin is could be a molecule with anti-fibrotic effects and can be a marker for a new subgroup of perivascular mesenchymal cells in the kidney, and also was suggested to contribute to tissue repair.

  12. Screening of humoral pathogenesis of idiopathic focal segmental glomerulosclerosis by proteinuria visualized transparent model animal

    Grant number:19K22618  2019.6 - 2023.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Challenging Research (Exploratory)

    Maruyama Shoichi

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    Idiopathic focal segmental glomerulosclerosis (FSGS) is an extremely difficult-to-treat renal disease in which half of patients relapse within a few days after kidney transplantation. To understand the pathogenesis of FSGS, this study challenged the identification of the humoral etiologic agent responsible for FSGS, the molecule predicted to be present in patient blood based on previous findings. In this study, the in vivo assay using nephron-visible transparent zebrafish, which was invented by us, was used as the technical basis for the search for the humoral factors. As a result, although we could not identify the liquid factor within the study period, we found that a part of plasma from patients with FSGS and other renal diseases induced proteinuria in the said zebrafish, providing collateral evidence for the presence of the liquid factor in the patients' blood.

  13. Novel CaMK4-mediated podocyte-specific therapy in refractory renal disease

    Grant number:19K08723  2019.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Maeda Kayaho

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    We elucidated the role of CaMK4 in refractory nephrotic syndrome such as focal segmental glomerulosclerosis, and developed podocyte-specific therapy. The findings using podocyte-specific CaMK4-deficient mice showed that CaMK4 in podocytes is involved in podocyte cell death and induces more proteinuria, and podocyte-directed nanoparticles with a CaMK4 inhibitor showed the efficacy compared to administration without nanoparticles.

  14. Development of new cell therapy columns to solve current problems in mesenchymal stem cell therapy

    Grant number:19K08722  2019.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Furuhashi Kazuhiro

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    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

    In the clinical application of mesenchymal stem cells (MSCs), pulmonary embolism is a serious side effect when MSCs are administered intravenously. To solve this problem, we are developing an MSC therapeutic hollow fiber membrane column (MSC column) in which only liquid factors secreted from MSCs are administered into the body without directly injecting cells into the body. We have selected the optimal material for MSCs packed outside the hollow fiber membrane in the column. Furthermore, the cells in the created MSC columns were able to secrete many growth factors, leading to the MSC columns ameliorating the rat nephritis model.

  15. Development of a treatment for septic AKI using microRNAs and adipose stem cell-derived exosomes.

    Grant number:19K08676  2019.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Noritoshi Kato

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    In our previous studies, we have succeeded in suppressing hypercytokinemia and improving survival in sepsis model mice by systemic administration of a plasmid expressing miR-146a, which was mainly taken up by the spleen.
    In this study, we focused on the spleen as a target for the treatment of sepsis and investigated the therapeutic effect of local injection into the spleen. We found that most of the nucleic acids after administration were taken up by the spleen, especially by splenic macrophages. While the therapeutic effect was protective against organ damage such as kidney and liver damage, this did not improve the survival rate. Therefore, the target disease and therapeutic miRNAs were changed, and the inhibitory effect on renal fibrosis caused by folic acid nephropathy was examined, and a certain inhibitory effect on fibrosis was confirmed.

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Industrial property rights 6

  1. 間葉系幹細胞の培養方法

    古橋和拡/田中章仁/丸山彰一/高須正規/春原隆司/山口悟

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    Applicant:名古屋大学/ニプロ株式会社

    Application no:PCT/JP2023/ 12386  Date applied:2023.3

  2. 間葉系幹細胞の培養方法

    古橋和拡 丸山彰一 田中章仁 高須正規 春原隆司 山口悟

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    Applicant:国立大学法人東海国立大学機構・ニプロ株式会社

    Application no:特願2022-054023  Date applied:2022.3

    Date published:2023

  3. 腎臓中のCD25陽性の制御性T細胞増加剤

    東海国立大学機構,ロート製薬

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    Date applied:2021.4

    Announcement no:WO2021/210515  Date announced:2021.10

    Country of applicant:Foreign country   Country of acquisition:Foreign country

  4. 尿細管間質障害の検出用バイオマーカー並びにその用途

    古橋和拡, 丸山彰一, 田中章仁, 澤由里子, LSIメディエンス

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    Application no:特願2021-108341  Date applied:2021

  5. 脂肪由来間葉系幹細胞ADR-001による腎疾患治療法の開発

    古橋和拡

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    Application no:特願2020- 71737  Date applied:2020.4

    Rights holder:古橋和拡・丸山彰一・田中章仁・唐澤宗稔・ロート株式会社

  6. IMMUNOSUPPRESSING AGENT COMPRISING MESENCHYMAL STEM CELL DERIVED FROM ADIPOSE TISSUE, AND USE THEREOF

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    Application no:PCT/JP2010/064682  Date applied:2010.8

    Date announced:2011.4

    Country of applicant:Domestic  

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Teaching Experience (On-campus) 3

  1. 腎臓内科

    2023

  2. 腎臓内科

    2021

  3. 腎臓内科

    2020