Faculty Profiles - FURUHASHI Kazuhiro

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

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

CD150high 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

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

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

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

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

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

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

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

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

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

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

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

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

In vivo efficacy and safety of systemically administered serinol nucleic acid-modified antisense oligonucleotides in mouse kidney Reviewed

Tsuboi, T; Hattori, K; Ishimoto, T; Imai, K; Doke, T; Hagita, J; Ariyoshi, J; Furuhashi, K; Kato, N; Ito, Y; Kamiya, Y; Asanuma, H; Maruyama, S

MOLECULAR THERAPY NUCLEIC ACIDS Vol. 36 ( 1 ) page： 102387 2025.3

Urinary presepsin is a novel biomarker capable of directly assessing monocyte/macrophage infiltration in kidney diseases Reviewed

Niwa, S; Tanaka, A; Furuhashi, K; Hattori, K; Onogi, C; Sunohara, K; Owaki, A; Kato, A; Kawazoe, T; Watanabe, Y; Koshi-Ito, E; Kato, N; Kosugi, T; Maruyama, S

SCIENTIFIC REPORTS Vol. 14 ( 1 ) page： 30088 2024.12

Association between alpha blocker use and the risk of fractures in patients with chronic kidney disease: a cohort study Reviewed

Sunohara, K; Onogi, C; Tanaka, A; Furuhashi, K; Matsumoto, J; Hattori, K; Owaki, A; Kato, A; Kawazoe, T; Watanabe, Y; Koshi-Ito, E; Maruyama, S

BMC NEPHROLOGY Vol. 25 ( 1 ) page： 442 2024.12

A case of non-traumatic rectus sheath hematoma in a post-kidney transplant patient undergoing catheter embolization during anticoagulation treatment for atrial fibrillation Reviewed

Fujieda, K; Saito, S; Tanaka, A; Furuhashi, K; Ozeki, T; Yasuda, Y; Sano, Y; Ishida, S; Maruyama, S

CEN CASE REPORTS Vol. 13 ( 6 ) page： 528 - 533 2024.12

Language：English Publisher：CEN Case Reports

A 65-year-old man, a post living donor kidney transplant patient, was admitted to the intensive care unit (ICU) with a severe bacterial infection. He also tested positive for coronavirus disease and had a cough. On admission, heparin was administered for atrial fibrillation. On the third day of hospitalization, his general condition had recovered, and he was discharged from the ICU to the general ward. On the fourth day of hospitalization, he experienced abdominal pain, and a hard mass was palpated in the left lower abdomen. On the fifth day of hospitalization, contrast-enhanced computed tomography showed an extensive rectus sheath hematoma (RSH) extending from the left lower abdominal wall to the left side of the bladder, with extravasation from a small branch of the left inferior epigastric artery. Heparin was discontinued, and transcatheter arterial embolization was performed to control the bleeding. RSH is a rare disease, and cases of extensive hematoma in post-kidney transplant patients occur even less frequently. Patients taking anticoagulants and those with chronic kidney disease are at high risk for RSH, so physicians should be cognizant of this disease when these patients develop abdominal pain.

DOI： 10.1007/s13730-024-00890-2

Safety and Tolerability of ADR-001 Therapy for Immunoglobulin A Nephropathy. Reviewed International journal

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

Kidney360 Vol. 5 ( 11 ) page： 1692 - 1705 2024.11

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

BACKGROUND: Immunoglobulin A nephropathy often requires kidney replacement therapy because of its refractoriness and because corticosteroids pose infection risks. However, mesenchymal stem cells offer clinical benefits because of their regenerative and immunomodulatory properties. This prospective clinical trial assessed the safety and tolerability of adipose-derived mesenchymal stem cell therapy and evaluated its therapeutic efficacy. METHODS: This phase 1 study included adult patients with refractory immunoglobulin A nephropathy that was difficult to treat with traditional therapies. Adipose-derived mesenchymal stem cell therapy comprising one intravenous dose of 1 × 108 cells was administered to three to six patients in cohort 1. The same intravenous dose was administered twice with a 2-week interval to six patients in cohort 2. Heparin was administered simultaneously. This study continued for 52 weeks, and the primary endpoints were safety and tolerability during the 6-week period after treatment administration. Secondary endpoints included adverse events and efficacy measures such as clinical remission, partial remission, urine protein remission, hematuria remission, time to remission, changes in the urine protein and hematuria levels, and changes in the estimated glomerular filtration rate. RESULTS: The three patients in cohort 1 and six patients in cohort 2 who received adipose-derived mesenchymal stem cell therapy achieved the primary endpoints. No severe adverse clinical events were observed. Therefore, the safety and tolerability of adipose-derived mesenchymal stem cells were confirmed. Improvements such as significantly decreased kidney damage markers and urinary protein levels were observed immediately after adipose-derived mesenchymal stem cell administration. CONCLUSIONS: The safety and tolerability of adipose-derived mesenchymal stem cells are acceptable for patients with immunoglobulin A nephropathy. TRIAL REGISTRATION: This trial was registered with the Japan Registry of Clinical Trials (jRCT2043200002; registration date: April 14, 2020) and ClinicalTrials.gov (NCT04342325; registration date: April 13, 2020).

DOI： 10.34067/KID.0000000000000563

Meflin/ISLR is a marker of adipose stem and progenitor cells in mice and humans that suppresses white adipose tissue remodeling and fibrosis Reviewed

Ishihara, T; Kato, K; Matsumoto, K; Tanaka, M; Hara, A; Shiraki, Y; Morisaki, H; Urano, Y; Ando, R; Ito, K; Mii, S; Esaki, N; Furuhashi, K; Takefuji, M; Suganami, T; Murohara, T; Enomoto, A

GENES TO CELLS Vol. 29 ( 10 ) page： 902 - 920 2024.10

Language：English Publisher：Genes to Cells

Identifying specific markers of adipose stem and progenitor cells (ASPCs) in vivo is crucial for understanding the biology of white adipose tissues (WAT). PDGFRα-positive perivascular stromal cells represent the best candidates for ASPCs. This cell lineage differentiates into myofibroblasts that contribute to the impairment of WAT function. However, ASPC marker protein(s) that are functionally crucial for maintaining WAT homeostasis are unknown. We previously identified Meflin as a marker of mesenchymal stem cells (MSCs) in bone marrow and tissue-resident perivascular fibroblasts in various tissues. We also demonstrated that Meflin maintains the undifferentiated status of MSCs/fibroblasts. Here, we show that Meflin is expressed in WAT ASPCs. A lineage-tracing experiment showed that Meflin+ ASPCs proliferate in the WAT of obese mice induced by a high-fat diet (HFD), while some of them differentiate into myofibroblasts or mature adipocytes. Meflin knockout mice fed an HFD exhibited a significant fibrotic response as well as increases in adipocyte cell size and the number of crown-like structures in WAT, accompanied by impaired glucose tolerance. These data suggested that Meflin expressed by ASPCs may have a role in reducing disease progression associated with WAT dysfunction.

DOI： 10.1111/gtc.13154

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

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

CEN CASE REPORTS Vol. 13 ( 5 ) page： 346 - 350 2024.10

Language：English Publisher：CEN Case Reports

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

MPO-ANCA-positive rapidly progressive glomerulonephritis after COVID-19 vaccination during treatment of plaque psoriasis with bimekizumab Reviewed

Takuya Sugiura, Tomohito Doke, Akihito Tanaka, Yuka Sato, Kayaho Maeda, Kazuhiro Furuhashi, Noritoshi Kato, Tomoki Kosugi, Shoichi Maruyama

2024.9

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

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

THERAPEUTIC APHERESIS AND DIALYSIS Vol. 28 ( 4 ) page： 489 - 498 2024.8

Language：English Publisher：Therapeutic Apheresis and Dialysis

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

Detecting and exploring kidney-derived extracellular vesicles in plasma Reviewed

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 Vol. 28 ( 7 ) page： 617 - 628 2024.7

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

Prognosis of microscopic polyangiitis is well predictable in the first 2 weeks of treatment Reviewed

Owaki, A; Tanaka, A; Furuhashi, K; Watanabe, Y; Koshi-Ito, E; Imaizumi, T; Maruyama, S

CLINICAL AND EXPERIMENTAL NEPHROLOGY Vol. 28 ( 7 ) page： 701 - 706 2024.7

Language：English Publisher：Clinical and Experimental Nephrology

Background: Kidney and life outcomes remain unsatisfactory in patients with microscopic polyangiitis (MPA). Appropriate treatment intensity must be provided to the appropriate patients. To identify severe cases early, we investigated the factors related to kidney and life outcomes. Methods: We included patients diagnosed with MPA based on myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) positivity and kidney histopathology results after kidney biopsies between January 1, 2021, and May 11, 2023, at 10 affiliated centers, including our hospital. Death, maintenance dialysis, and estimated glomerular filtration rate (eGFR) < 15 after 6 months of treatment were defined as poor prognosis groups, and factors associated with these conditions were investigated. Results: We included 84 (36 men and 48 women) patients in this study. Median age was 73.8 (interquartile range: 71–81) years. After 6 months of treatment, the proportion of patients in the poor prognosis group was 16.7 %, with a mortality of 7.1 % and a poor kidney prognosis rate of 9.5 %. Area under the receiver operating characteristic curve showed that eGFR at 2 weeks had a comparable prognostic performance equal as eGFR at 4 weeks (area under the curve: 0.875 and 0.896, respectively). After adjustment by various factors, eGFR at 2 weeks was related with prognosis significantly (p = 0.031). Conclusion: Kidney function 2 weeks after the start of treatment for MPA can predict prognosis.

DOI： 10.1007/s10157-024-02522-6

Safety and Tolerability of adipose-derived mesenchymal stem cell "ADR-001" in the treatment of immunoglobulin A nephropathy Reviewed

Maruyama, S; Tanaka, A; Furuhashi, K; Fujieda, K; Maeda, K; Mimura, T; Saka, Y; Naruse, T; Ishimoto, T; Kosugi, T

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 39 page： I740 - I740 2024.5

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

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

CEN CASE REPORTS Vol. 13 ( 2 ) page： 128 - 134 2024.4

Language：English Publisher：CEN Case Reports

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.

DOI： 10.1007/s13730-023-00813-7

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

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

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

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

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 Reviewed

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 2024.2

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

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

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

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

Language：English Publisher：Journal of Pathology

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

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

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

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

Language：English Publisher：Therapeutic Apheresis and Dialysis

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

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

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

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

生体腎移植後にCOVID-19に罹患し、遅発性に重症肺炎を合併した1例

COVID-19罹患後,遅発性に重症肺炎を合併した生体腎移植レシピエントの1例

田中章仁, 齋藤尚二, 古橋和拡, 安田宜成, 佐野優太, 加藤真史, 丸山彰一

日本腎臓学会誌 Vol. 65 ( 6-W ) page： 792 - 792 2023.9

田中章仁, 齋藤尚二, 古橋和拡, 安田宜成, 佐野優太, 加藤真史, 丸山彰一

移植 Vol. 58 ( 総会臨時 ) page： 270 - 270 2023.9

TOPICS 腎臓内科学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 Invited

古橋和拡, 田中章仁, 丸山彰一

医学のあゆみ Vol. 285 ( 8 ) page： 755 - 756 2023.5

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

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

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

Language：English Publisher：BMC Nephrology

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.

DOI： 10.1186/s12882-023-03190-6

腎移植後患者におけるSARS-CoV-2 mRNAワクチン2回接種後から3回接種後までの抗体価の変化

藤枝久美子, 田中章仁, 菊地良介, 高井奈美, 齋藤尚二, 安田宜成, 藤田高史, 加藤真史, 古橋和拡, 丸山彰一

日本腎臓学会誌 Vol. 65 ( 3 ) page： 285 - 285 2023.5

腎移植後患者におけるSARS-CoV-2 mRNAワクチン2回接種後から3回接種後までの抗体価の変化

藤枝久美子, 田中章仁, 菊地良介, 高井奈美, 齋藤尚二, 安田宜成, 藤田高史, 加藤真史, 古橋和拡, 丸山彰一

日本腎臓学会誌 Vol. 65 ( 3 ) page： 285 - 285 2023.5

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

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

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.

DOI： 10.1016/j.omtn.2022.12.011

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

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

Language：English Publisher：Vaccines

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.

DOI： 10.3390/vaccines11010134

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

Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis. Reviewed 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

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

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.

DOI： 10.1186/s12915-022-01447-4

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

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

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

Language：English Publisher：Globalization and Health

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.

DOI： 10.1186/s12992-022-00883-9

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

生体腎移植実施し約10年経過後の血液透析再導入期に,右眼内移植後リンパ増殖性疾患(PTLD)を合併した1例

クロップ明日香, 齋藤尚二, 田中章仁, 鈴村文那, 牛田宏昭, 藤田高史, 加藤真史, 古橋和拡, 安田宜成, 丸山彰一

日本腎臓学会誌 Vol. 64 ( 6-W ) page： 757 - 757 2022.10

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

FRONTIERS IN MEDICINE Vol. 9 page： 899359 2022.5

Language：English Publisher：Frontiers in Medicine

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.

DOI： 10.3389/fmed.2022.899359

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. Reviewed 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

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

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.

DOI： 10.3389/fmed.2022.883168

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

血液透析歴30年を超えてから、夫婦間血液型不適合生体腎移植を施行した1例

田中章仁, 齋藤尚二, 古橋和拡, 安田宜成, 藤田高史, 加藤真史, 丸山彰一

日本透析医学会雑誌 Vol. 55 ( Suppl.1 ) page： 469 - 469 2022.5

腎移植後の患者におけるSARS-CoV-2 mRNAワクチン接種後の抗体獲得率

藤枝久美子, 田中章仁, 菊地良介, 高井奈美, 齋藤尚二, 安田宜成, 藤田高史, 加藤真史, 古橋和拡, 丸山彰一

日本透析医学会雑誌 Vol. 55 ( Suppl.1 ) page： 531 - 531 2022.5

当院通院中の腎移植後の患者におけるSARS-CoV-2 mRNAワクチン接種後の抗体獲得率

藤枝久美子, 田中章仁, 菊地良介, 高井奈美, 齋藤尚二, 安田宜成, 藤田高史, 加藤真史, 古橋和拡, 丸山彰一

日本腎臓学会誌 Vol. 64 ( 3 ) page： 235 - 235 2022.5

当院通院中の腎移植後の患者におけるSARS-CoV-2 mRNAワクチン接種後の抗体獲得率

藤枝久美子, 田中章仁, 菊地良介, 高井奈美, 齋藤尚二, 安田宜成, 藤田高史, 加藤真史, 古橋和拡, 丸山彰一

日本腎臓学会誌 Vol. 64 ( 3 ) page： 235 - 235 2022.5

当院通院中の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価の推移についての検討

田中章仁, 藤枝久美子, 菊地良介, 高井奈美, 齋藤尚二, 安田宜成, 藤田高史, 加藤真史, 古橋和拡, 丸山彰一

日本腎臓学会誌 Vol. 64 ( 3 ) page： 235 - 235 2022.5

当院通院中の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価の推移についての検討

田中章仁, 藤枝久美子, 菊地良介, 高井奈美, 齋藤尚二, 安田宜成, 藤田高史, 加藤真史, 古橋和拡, 丸山彰一

日本腎臓学会誌 Vol. 64 ( 3 ) page： 235 - 235 2022.5

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

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

Language：English Publisher：Scientific Reports

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.

DOI： 10.1038/s41598-022-10510-7

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

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

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

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+ 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+ PMCs to conventional α-SMA+ myofibroblasts is low, they give rise to fibroblasts with heterogeneous α-SMA expression patterns. Genetic ablation of Meflin+ 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.

DOI： 10.1038/s41598-022-09331-5

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

Language：Japanese Publisher：一般社団法人日本移植学会

【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 vaccination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。【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。【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。【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。

DOI： 10.11386/jst.57.supplement_s270_3

CiNii Research

A Case of TAFRO Syndrome with Two Consecutive Renal Biopsies Following the Pathological Course of the Kidney Reviewed

Kato, N; Hasegawa, T; Muto, R; Tanaka, A; Sato, Y; Maeda, K; Furuhashi, K; Saito, S; Kosugi, T; Maruyama, S

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Vol. 32 ( 10 ) page： 823 - 824 2021.10

ABO不適合生体腎移植後にisolated v lesionを認め、1年後にTCMRと診断された1例

田中章仁, 前田佳哉輔, 齋藤尚二, 古橋和拡, 加藤規利, 安田宜成, 加藤真史, 藤田高史, 丸山彰一

日本腎臓学会誌 Vol. 63 ( 6-W ) page： 835 - 835 2021.9

当院の生体腎移植術前検査における、麻疹、風疹、ムンプス、水痘帯状疱疹ウィルス抗体価の検討

田中章仁, 藤島由貴, 古橋和拡, 齋藤尚二, 安田宜成, 石田昇平, 藤田高史, 加藤真史, 丸山彰一

日本腎臓学会誌 Vol. 63 ( 4 ) page： 483 - 483 2021.6

手術前に低ナトリウム血症を補正して生体腎移植に臨んだ1例

田中章仁, 龍華章裕, 古橋和拡, 齋藤尚二, 鈴木康弘, 安田宜成, 藤田高史, 加藤真史, 丸山彰一

日本透析医学会雑誌 Vol. 54 ( Suppl.1 ) page： 325 - 325 2021.5

当院へ生体腎移植目的で紹介された症例の手術中止、延期に関連する因子の検討

田中章仁, 齋藤尚二, 古橋和拡, 安田宜成, 藤田高史, 加藤真史, 丸山彰一

日本透析医学会雑誌 Vol. 53 ( Suppl.1 ) page： 562 - 562 2020.10

Acute kidney injury and cytokines

Furuhashi K

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

Language：Japanese Publisher：Acute Kidney Injury and Regenerative Medicine

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.

DOI： 10.1007/978-981-15-1108-0_23