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1. Annual trends in atypical haemolytic uremic syndrome management in Japan and factors influencing early diagnosis and treatment: a retrospective study

Author

Yoshitaka Tatematsu, Takahiro Imaizumi, Nobuaki Michihata, Noritoshi Kato, Ryosuke Kumazawa, Hiroki Matsui, Kiyohide Fushimi, Hideo Yasunaga, and Shoichi Maruyama

Subjects
Atypical haemolytic uremic syndrome (aHUS), Thrombotic microangiopathy (TMA), Eculizumab, Plasma exchange, A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13), Thrombocytopenia, Medicine, Science
Abstract

Abstract Atypical haemolytic uremic syndrome (aHUS) is a rare disorder characterised by complement-mediated thrombotic microangiopathy (TMA). Despite clinical guidelines, the diagnosis and treatment of aHUS in its early stages remains challenging. This study examined the annual trends in aHUS clinical practices in Japan and explored factors influencing early diagnosis and treatment. Using data from the 2011–2020 Diagnosis Procedure Combination database, 3096 cases with the HUS disease code were identified, of which 217 were confirmed as aHUS and treated with eculizumab or plasma exchange. Early initiation, defined as starting eculizumab or plasma exchange within 7 days of admission, was the focus of the study. Our study revealed no significant changes over time in the number of aHUS diagnoses, cases treated with eculizumab, or early initiation cases. Early initiation cases underwent haemodialysis earlier and had ADAMTS13 activity measured earlier, shorter hospital stays, and lower hospitalisation costs than late initiation cases. In conclusion, we found no increase in the number of newly diagnosed aHUS cases or early treatment initiation over time. Early recognition of TMA and differentiation of the causative disease are crucial for identifying potential aHUS cases, which may lead to better patient prognoses.

Published
2024
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2. Case report: A family of atypical hemolytic uremic syndrome involving a CFH::CFHR1 fusion gene and CFHR3-1-4-2 gene duplication

Author

Yuko Tasaki, Hiroshi Tsujimoto, Tadafumi Yokoyama, Naotoshi Sugimoto, Shinji Kitajima, Hiroshi Fujii, Yoshihiko Hidaka, Noritoshi Kato, Shoichi Maruyama, Norimitsu Inoue, and Taizo Wada

Subjects
atypical hemolytic uremic syndrome, factor H, complement factor H-related, multiplex ligation-dependent probe amplification (MLPA), CFH::CFHR1 fusion gene, CFHR3-1-4-2 genes duplication, Immunologic diseases. Allergy, RC581-607
Abstract

Mutations in the complement factor H (CFH) gene are associated with complement dysregulation and the development of atypical hemolytic uremic syndrome (aHUS). Several fusion genes that result from genomic structural variation in the CFH and complement factor H-related (CFHR) gene regions have been identified in aHUS. However, one allele has both CFHR gene duplication and CFH::CFHR1 fusion gene have not been reported. An 8-month-old girl (proband) presented with aHUS and was treated with ravulizumab. Her paternal grandfather developed aHUS previously and her paternal great grandmother presented with anti-neutrophil cytoplasmic antibody-associated vasculitis and thrombotic microangiopathy (TMA). However, the proband’s parents have no history of TMA. A genetic analysis revealed the presence of CFH::CFHR1 fusion gene and a CFHR3-1-4-2 gene duplication in the patient, her father, and her paternal grandfather. Although several fusion genes resulting from structural variations of the CFH–CFHR genes region have been identified, this is the first report of the combination of a CFH::CFHR1 fusion gene with CFHR gene duplication. Because the CFH–CFHR region is highly homologous, we hypothesized that CFHR gene duplication occurred. These findings indicate a novel pathogenic genomic structural variation associated with the development of aHUS.

Published
2024
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3. Application of a scoring system in Japanese patients diagnosed with atypical hemolytic uremic syndrome to assess the relationship between the score and clinical responses to eculizumab

Author

Hideo Wada, Hirofumi Teranishi, Akihiko Shimono, Noritoshi Kato, Shoichi Maruyama, and Masanori Matsumoto

Subjects
Atypical hemolytic uremic syndrome, Classification, Diagnosis, Eculizumab, Thrombotic microangiopathy, Post-marketing surveillance, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Abstract Background Atypical hemolytic uremic syndrome (aHUS) is caused by complement dysregulation and is generally diagnosed by exclusion from other disorders of thrombotic microangiopathy (TMA). Eculizumab, a terminal complement inhibitor, has been approved for aHUS treatment since 2013 in Japan. Recently, a scoring system was published to support diagnosis of aHUS. Herein we modified this scoring system to apply it to patients diagnosed with aHUS and treated with eculizumab, and assessed the association between the score and clinical responses to eculizumab. Methods One hundred eighty-eight Japanese patients who were clinically diagnosed with aHUS, treated with eculizumab, and enrolled in post-marketing surveillance (PMS) were included in this analysis. Some of parameters in the original scoring system were replaced with clinically similar parameters collected in the PMS to modify the system, hereafter referred to as the TMA/aHUS score, which ranges from -15 to 20 points. Treatment responses within 90 days after eculizumab initiation were also assessed, and the relationship between treatment response and TMA/aHUS scores calculated at TMA onset was explored. Results The median (range) TMA/aHUS score was 10 (3–16). Receiver operating characteristic curve analysis showed that the cutoff value of TMA/aHUS score to predict treatment response to eculizumab was estimated as 10, and negative predictive value indicated that ≥ 5 points was appropriate to consider assessing the treatment response to eculizumab; 185 (98%) patients had ≥ 5 points and 3 (2%) had

Published
2023
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4. Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis

Author

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, and Hiroshi I. Suzuki

Subjects
Cotargeting, Evolution, MicroRNA, Seed, SLE, Biology (General), QH301-705.5
Abstract

Abstract 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.

Published
2022
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5. A novel renal perivascular mesenchymal cell subset gives rise to fibroblasts distinct from classic myofibroblasts

Author

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, and Shoichi Maruyama

Subjects
Medicine, Science
Abstract

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.

Published
2022
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6. The ISN/RPS 2016 classification predicts renal prognosis in patients with first-onset class III/IV lupus nephritis

Author

Asaka Hachiya, Munetoshi Karasawa, Takahiro Imaizumi, Noritoshi Kato, Takayuki Katsuno, Takuji Ishimoto, Tomoki Kosugi, Naotake Tsuboi, and Shoichi Maruyama

Subjects
Medicine, Science
Abstract

Abstract Lupus nephritis (LN) is a life-threatening complication of systemic lupus erythematosus. The 2003 pathological classification of LN was revised in 2016; it quantitatively evaluates the interstitium in addition to the glomeruli. We performed a retrospective multi-centre cohort study and investigated the utility of the 2016 classification—including the activity index (AI), chronicity index (CI), and each pathological component to predict complete remission or renal function decline, defined as 1.5-fold increase in serum creatinine levels—and compare with that of the 2003 classification. Ninety-one consecutive adult patients with first-onset class III/IV LN who were newly prescribed any immunosuppressants were enrolled and followed up for a median of 51 months from January 2004. Cox regression analysis demonstrated the subclasses based on the 2003 classification, which mainly evaluate glomerular lesions, were not associated with clinical outcomes. After adjustments for estimated glomerular filtration rate and urinary protein levels, higher CI and higher interstitial fibrosis and lower hyaline deposit scores were associated with renal functional decline. Similarly, higher CI and interstitial inflammation scores were associated with failure to achieve complete remission. Therefore, the 2016 classification can predict the clinical outcomes more precisely than the 2003 classification.

Published
2021
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7. Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis

Author

Akihiro Ryuge, Tomoki Kosugi, Kayaho Maeda, Ryoichi Banno, Yang Gou, Kei Zaitsu, Takanori Ito, Yuka Sato, Akiyoshi Hirayama, Shoma Tsubota, Takashi Honda, Kazuki Nakajima, Tomoya Ozaki, Kunio Kondoh, Kazuo Takahashi, Noritoshi Kato, Takuji Ishimoto, Tomoyoshi Soga, Takahiko Nakagawa, Teruhiko Koike, Hiroshi Arima, Yukio Yuzawa, Yasuhiko Minokoshi, Shoichi Maruyama, and Kenji Kadomatsu

Subjects
Hepatology, Metabolism, Medicine
Abstract

Monocarboxylates, such as lactate and pyruvate, are precursors for biosynthetic pathways, including those for glucose, lipids, and amino acids via the tricarboxylic acid (TCA) cycle and adjacent metabolic networks. The transportation of monocarboxylates across the cellular membrane is performed primarily by monocarboxylate transporters (MCTs), the membrane localization and stabilization of which are facilitated by the transmembrane protein basigin (BSG). Here, we demonstrate that the MCT/BSG axis sits at a crucial intersection of cellular metabolism. Abolishment of MCT1 in the plasma membrane was achieved by Bsg depletion, which led to gluconeogenesis impairment via preventing the influx of lactate and pyruvate into the cell, consequently suppressing the TCA cycle. This net anaplerosis suppression was compensated in part by the increased utilization of glycogenic amino acids (e.g., alanine and glutamine) into the TCA cycle and by activated ketogenesis through fatty acid β-oxidation. Complementary to these observations, hyperglycemia and hepatic steatosis induced by a high-fat diet were ameliorated in Bsg-deficient mice. Furthermore, Bsg deficiency significantly improved insulin resistance induced by a high-fat diet. Taken together, the plasma membrane–selective modulation of lactate and pyruvate transport through BSG inhibition could potentiate metabolic flexibility to treat metabolic diseases.

Published
2021
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10. Case report: A family of atypical hemolytic uremic syndrome involving a CFH:: CFHR1 fusion gene and CFHR3-1-4-2 gene duplication.

Author

Yuko Tasaki, Hiroshi Tsujimoto, Tadafumi Yokoyama, Naotoshi Sugimoto, Shinji Kitajima, Hiroshi Fujii, Yoshihiko Hidaka, Noritoshi Kato, Shoichi Maruyama, Norimitsu Inoue, and Taizo Wada

Subjects
HEMOLYTIC-uremic syndrome, GENE fusion, CHROMOSOME duplication, COMPLEMENT factor H, THROMBOTIC thrombocytopenic purpura
Abstract

Mutations in the complement factor H (CFH) gene are associated with complement dysregulation and the development of atypical hemolytic uremic syndrome (aHUS). Several fusion genes that result from genomic structural variation in the CFH and complement factor H-related (CFHR) gene regions have been identified in aHUS. However, one allele has both CFHR gene duplication and CFH::CFHR1 fusion gene have not been reported. An 8-month-old girl (proband) presented with aHUS and was treated with ravulizumab. Her paternal grandfather developed aHUS previously and her paternal great grandmother presented with anti-neutrophil cytoplasmic antibody-associated vasculitis and thrombotic microangiopathy (TMA). However, the proband's parents have no history of TMA. A genetic analysis revealed the presence of CFH::CFHR1 fusion gene and a CFHR3-1-4-2 gene duplication in the patient, her father, and her paternal grandfather. Although several fusion genes resulting from structural variations of the CFH-CFHR genes region have been identified, this is the first report of the combination of a CFH:: CFHR1 fusion gene with CFHR gene duplication. Because the CFH-CFHR region is highly homologous, we hypothesized that CFHR gene duplication occurred. These findings indicate a novel pathogenic genomic structural variation associated with the development of aHUS. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Empagliflozin in Patients with Chronic Kidney Disease

Author

Herrington, William G, Staplin, Natalie, Wanner, Christoph, Green, Jennifer B, Hauske, Sibylle J, Emberson, Jonathan R, Preiss, David, Judge, Parminder, Mayne, Kaitlin J, Ng, Sarah Y A, Sammons, Emily, Zhu, Doreen, Hill, Michael, Stevens, Will, Wallendszus, Karl, Brenner, Susanne, Cheung, Alfred K, Liu, Zhi-Hong, Li, Jing, Hooi, Lai Seong, Liu, Wen, Kadowaki, Takashi, Nangaku, Masaomi, Levin, Adeera, Cherney, David, Maggioni, Aldo P, Pontremoli, Roberto, Deo, Rajat, Goto, Shinya, Rossello, Xavier, Tuttle, Katherine R, Steubl, Dominik, Petrini, Michaela, Massey, Dan, Eilbracht, Jens, Brueckmann, Martina, Landray, Martin J, Baigent, Colin, Haynes, Richard, The EMPA-KIDNEY Collaborative Group: Colin Baigent, Martin J Landray, Christoph Wanner, William G Herrington, Richard Haynes, Jennifer B Green, Sibylle J Hauske, Martina Brueckmann, Mark Hopley, Maximillian von-Eynatten, Jyothis George, Susanne Brenner, Alfred K Cheung, David Preiss, Zhi-Hong Liu, Jing Li, Laiseong Hooi, Wen Liu, Takashi Kadowaki, Masaomi Nangaku, Adeera Levin, David Cherney, Roberto Pontremoli, Aldo P Maggioni, Natalie Staplin, Jonathan Emberson, Stefan Hantel, Shinya Goto, Rajat Deo, Katherine R Tuttle, Michael Hill, Parminder Judge, Kaitlin J Mayne, Sarah Y A Ng, Xavier Rossello, Emily Sammons, Doreen Zhu, Peter Sandercock, Rudolf Bilous, Charles Herzog, Paul Whelton, Janet Wittes, Derrick Bennett, Patricia Achiri, Chrissie Ambrose, Cristina Badin, Jill Barton, Richard Brown, Andy Burke, Sebastian Butler, Rejive Dayanandan, Pia Donaldson, Robert Dykas, Lucy Fletcher, Kate Frederick, Hannah Kingston, Mo Gray, Emily Harding, Akiko Hashimoto, Lyn Howie, Susan Hurley, Ryonfa Lee, Nik Luker, Kevin Murphy, Mariko Nakahara, John Nolan, Michelle Nunn, Sorcha Mulligan, Akiko Omata, Sandra Pickworth, YanRu Qiao, Shraddha Shah, Karen Taylor, Alison Timadjer, Monique Willett, Liz Wincott, Qin Yan, Hui Yu, Louise Bowman, Fang Chen, Robert Clarke, Michelle Goonasekera, Waseem Karsan, Marion Mafham, Christina Reith, Mohammed Zayed, Ritva Ellison, Rowan Moys, Will Stevens, Kevin Verdel, Karl Wallendszus, Chris Bowler, Anna Brewer, Andy Measor, Guanguo Cui, Charles Daniels, Angela Field, Bob Goodenough, Ashley Lawson, Youcef Mostefai, Dheeptha Radhakrishnan, Samee Syed, Shuang Xia, Ruth Adewuyi-Dalton, Thomas Arnold, Anne-Marie Beneat, Anoushka Bhatt, Chloe Bird, Andrew Breach, Laura Brown, Mark Caple, Tatyana Chavagnon, Karen Chung, Sarah Clark, Luminita Condurache, Katarzyna Eichstadt, Marta Espino Obrero, Scarlett Forest, Helen French, Nick Goodwin, Andrew Gordon, Joanne Gordon, Cat Guest, Tina Harding, Michal Hozak, Matthew Lacey, David MacLean, Louise Messinger, Stewart Moffat, Martin Radley, Claire Shenton, Sarah Tipper, Jon Tyler, Lesley Weaving, James Wheeler, Elissa Williams, Tim Williams, Hamish Woodhouse, Angela Chamberlain, Jo Chambers, Joanne Davies, Denise Donaldson, Pati Faria-Shayler, Denise Fleming-Brown, Jennifer Ingell, Carol Knott, Anna Liew, Helen Lochhead, Juliette Meek, Isabel Rodriguez-Bachiller, Andrea Wilson, Patrick Zettergren, Rach AitSadi, Ian Barton, Alex Baxter, Yonghong Bu, Lukasz Danel, Sonja Grotjahn, Rijo Kurien, Michael Lay, Archie Maskill, Aleksandra Murawska, Rachel Raff, Allen Young, Rebecca Sardell, Vladimir Cejka, Marcela Fajardo-Moser, Christian Hartner, Doris Poehler, Janina Renner, Franziska Scheidemantel, Miya Bryant, Anita Hepditch, Cassandra Johnson, Erin Latore, Yolanda Miller, Lauren Price, Merilee Whalen, Ashleigh Wheeler, Jenny Ingell, Yu An, Yinghua Chen, Peiling Chen, Hao Dai, Hong Du, Fang Feng, Qing Guo, Libo Hou, Wuhanbilige Hundei, Binbin Jin, Yan Li, Jiamin Liu, Xia Song, Yanping Wang, Yanwu Yu, Ning Zhang, Lingshan Zhao, Hui Zhong, Cheng Beng Goh, Ye Mun Low, Soon Yi Sor, Farah Hanis Zulkipli, Sarojini Sivanandam, Natsuki Arai, Ai Fukasawa, Mizue Furukawa, Keisuke Habuki, Shoko Hayashi, Wakako Isari, Saki Kanegae, Maria Kawai, Reiki Kobayashi, Takako Kuramae, Chika Kuribayashi, Sawako Maeno, Satoshi Masumoto, Tomoko Morisaki, Minoru Oda, Kazue Sawada, Kenta Sugamori, Ayana Tatsuzawa, Aiko Tomita, Kazuyuki Yuasa, Hiroko Inazawa, Amanda Axler, Kerri Gallo, Ester Baldini, Barbara Bartolomei Mecatti, Francesca Bianchini, Martina Ceseri, Laura Cipressa, Gianna Fabbri, Andrea Lorimer, Donata Lucci, Sharang Ghavampour, Anja Knoppe, Hans Schmidt-Gurtler, Hubert Dumann, Sybille Merscher, Margret Patecki, Georg Rainer Schlieper, Anke Torp, Bianca Weber, Maja Zietz, Bernd Hohenstein, Urs Benck, Diliana Draganova, Thomas Weinreich, Lothar Wolf, Jasmine Gaidu, Hanna Reiner, Mandy Visnjic, Daniel Steffl, Marie Breitenfeldt, Annette Kraemer-Guth, Christine Braun, Simone Hagge, Michael Schomig, Stephan Matthias, Dominik Stoffler, Beate Schumacher, Thomas Sitter, Louise Fuessl, Julia Krappe, Jerome Loutan, Volker Vielhauer, Luciano Andriaccio, Magdalena Maurer, Bernhard Winkelmann, Martin Dursch, Linda Seifert, Linda Tenbusch, Julia Weinmann-Menke, Simone Boedecker, Wiebke Kaluza-Schilling, Daniel Kraus, Carina Krieger, Margit Schmude, Anne Schreiber, Ewelina Eckrich, Diethelm Tschope, Abdulwahab Arbi, Young Lee-Barkey, Bernd Stratmann, Natalie Prib, Sina Rolfsmeier, Irina Schneider, Lars Rump, Johannes Stegbauer, Christine Pötz, Mara Schemmelmann, Claudia Schmidt, Michael Koch, Sendogan Aker, Annika Küpper, Manuela Martin, Thiemo Pfab, Christian Albert, Michael Haase, Barbara Zander, Claudia Schneider-Danwitz, Wolfgang Seeger, Wolf-Adam Seeger, Britta Zemann, Christoph Stellbrink, Kristin Marx, Ekaterina Stellbrink, Britta Brettschneider, Stephanie Watson, Marion Iselt, Gerhard Klausmann, Inga-Nadine Kummer, Auguste Kutschat, Simone Streitenberger, Matthias Girndt, Silke Markau, Ina Girakossyan, Claudia Hanf, Joachim Beige, Ralph Wendt, Ulrike Schmidt, Andreas Schneider, Roland Veelken, Claudia Donhauser, Luis Becker, Nexhat Miftari, Ricarda Wolfling, Sarah Morlok, Christian Hugo, Alexander Paliege, Jens Passauer, Julian Stumpf, Annegret Fleischer, Kerstin Haaser, Bernhard Kraemer, Jan Jochims, Bernd Kruger, Claudia Foellinger, Anastassiya Reisler, Frank Strutz, Stefan Haack, Ursula Hohenstatt, Martin Busch, Konstantin Herfurth, Gunter Wolf, Rainer Paul, Hermann Haller, Jessica Kaufeld, Jan Menne, Elisabeth Bahlmann-Kroll, Angela Bergner, Horst Weihprecht, Aydin Er, Florian Sonntag, Elif Turan, Michael Wittmann, Franziska Klauser, Eva Voigt, Volker Schettler, Egbert Schulz, Madlen Rohnstock, Elke Schettler, Bernd Schroppel, Rene van Erp, Martin Kachele, Ulla Ludwig, Lena Schulte-Kemna, Waltraud Kmietschak, Elke Preiss, Martina Ruocco, Gunnar Heine, Martin Brzoska, Sebastian Gabel, Christina Büttner, Asma Sabarai, Bernhard Banas, Tobias Bergler, Yvonne Ehrl, Franz Putz, Antonia Schuster, Stefanie Kuhn, Torsten Schramm, Stefan Degenhardt, Gerhard Schmidt, Lea Weiland, Ulrike Giebeln-Hudnell, Jan Kielstein, Gabriele Eden, Brigitte Fuchs, Gina Morig, Manuela Winkler, Harald Darius, Charalampos Kriatselis, Carl-Philipp Roesch, Astrid Maselli, Dominik Alscher, Markus Ketteler, Moritz Schanz, Severin Schricker, Bianka Rettenmaier, Andrea Schwab, Pablo Pergola, Irene Leal, Melissa Cagle, Anna Romo, Anthony Torres, Sucharit Joshi, Kulli Barrett, Alexis Africano, Vicki Dodds, Dorleena Gowen, Ashlee Morris, Juan Fernandez, Guillermo Jimenez, Ricardo Viera, Kendaling Bruce, Ryan Barrios, Maylin Garcia, Kerelyn Garcia, Iradis Leal, David Tietjen, David Bains, Carlo Castillo, Genielle Brewer, Justin Davis, Natalie Freking, Brittany Golson, Sally Ham, Jesslyn Roesch, Pusadee Suchinda, Shameem Beigh, Usah Lilavivat, Joyce Bilton, Kim Bocchicchia, Jeffrey Turner, Neera Dahl, Aldo Peixoto, Yasemin Kavak, Lauren Liberti, Hari Nair, Nicolas Page, Stephanie Rosenberg, Kathryn Simmons, Tamara Isakova, Rebecca Frazier, Rupal Mehta, Anand Srivastava, Patrick Fox, Jonathan Hecktman, Alexander Hodakowski, Carlos Martinez, Rachel Phillips, Alexis Stevenson, Reem Mustafa, Kyle Jansson, Cassandra Kimber, Jason Stubbs, Ahmad Tuffaha, Sri Yarlagadda, Debbie Griffin, Elisabeth Laundy, Zhuo Tang, Radica Alicic, Ann Cooper, Lisa Davis, Ashwini Gore, Rebecca Goldfaden, Leslie Harvill, Lisa Hichkad, Barry Johns, Thomas Jones, Kayla Merritt, Jennifer Sheldon, Jennifer Stanfield, Lindsay Alexander, Kaitlyn Preston, Lindsey Wood, Rajesh Pradhan, Roger DeRaad, Kelli McIntosh, Louis Raymond, Michael Shepperd, Susan McLaughlin, Mary Seifert, Andrew Shepherd, Joseph Aiello, William Durham, Laurie Loudermilk, John Manley, Sabrina Burnette, Stephanie Evans, Tara Johnson, Lance Sloan, Judy Ann Acosta, Stacy Gillham, Katia Sloan, SueAnn Squyres, Michael Rocco, Amret Hawfield, Ben Bagwell, Lauren Richmond, Joseph Soufer, Subha Clarke, Amanda Aliu, Kristine Calabrese, Amanda Davis, Veronica Poma, Tracy Spinola, James Magee, Ricardo Silva, Rushab Choksi, Lorraine Dajani, John Evans, Anil George, Prasanth Krish, Gerard Martins, Mae Sheikh-Ali, David Sutton, Freda Driver, Abraham Hanburry, Laura Hume, Amber Hurst, Matthew Taddeo, Marla Turner, Veronica Yousif, Srinivasan Beddhu, Laith Al-Rabadi, Nikita Abraham, Amalia Caamano, Judy Carle, Victoria Gonce, Kaitlyn Staylor, Na Zhou, Shweta Bansal, Manoj Bhattarai, Kumar Sharma, Subrata Debnath, Aliseiya Garza, Chakradhar Velagapudi, Sergio Rovner, Javier Almeida, Pablo Casares, Verlaine Stewart-Ray, Rene Almaraz, Renata Dayrell, Ana Moncada, Ricardo Pulido, Roxana Rodriquez, Wasim Deeb, Kathryn DeGoursey, Rodel Gloria, Trevor Greene, Robert Miller, Edward Pereira, Miguel Roura, Debbie Domingo, Sasha Dorestin, William Hodge, Cathy Jackson, Deborah Lund, Katrina Taylor, Kenneth Boren, Brittany Cleveland, Sandra Gaiser, Mandeep Sahani, Logan Aldrich, Exodus Edmerson, Edmond Limon, Cole Valletta, Patricia Vasquez, Christopher Provenzano, Navkiranjot Brar, Heather Henderson, Bellovich Keith, Qur Khai, Quresh Khairullah, Gail Makos, Joel Topf, Sherry Gasko, Rosemarie Henschel, Kaitlin Knapp, Teresa Kozlowski, Paula LaFleur, Ashwathy Varughese, Hui Xue, Patricia Wu, Olga Arechiga, Shan Darbeau, Michael Fechter, Stephanie Martinez, Lenita Hanson, Nyla Cooper, Arelis Madera, Jay Cadorna, Rita Sheridan, Helen Sparks, Bradley Eilerman, Susanne Bodine, Wael Eid, Rebecca Flora, Amber Avery, Cashmere Hardy, Mihaela Biscoveanu, Steven Nagelberg, Tracey Cummins, Frederic Rahbari-Oskoui, Anju Oommen, Zohreh Forghani, Stacie Hitchcock, Darya Hosein, Diane Watkins, Minesh Patel, Anthony Lambert, Elizabeth Newman, Autumn Wood, Tammy Ross, Stephany Topping, Jeffrey Mulhern, Lorna Murphy, Ann Vasseur, Gregory Greenwood, Alexander Hadley, Denise Laurienti, Christopher Marshall, Nicholas McLean, Scott Satko, Brandy Caudill, Jacob Maris, Janice Rogers, Cindy Vanhoy, George Thomas, Georges Nakhoul, John O'Toole, Jonathan Taliercio, Leslie Cooperman, Marina Markovic, Barbara Tucky, Devasmita Dev, Alia Hasan, Hima Yalamanchili, Namita Jain, Lesley McNeil, Eric Wines, Jean Park, Adline Ghazi, Mia Hamm, Tejas Patel, Amy Mottl, Emily Chang, Vimal Derebail, Emmie Cole, Anne Froment, Sara Kelley, Jordan Osmond Foster, Vahid Mahabadi, Golriz Jafari, Anita Kamarzarian, Wendy Arriaga, Daisy Arteaga, Rosario Machicado, Genesis Naverrete, Prashant Kumar, Imran Nazeer, Karina Urquia, Tammi Glider, Vickie Jones, Savannah Rucker, Jennifer Wiley, Rahul Pandey, Jesus Arroyo, Harish Pariani, Mohammad Ahmad, Shahin Mozaffari, Erika Perez, Matthew Budoff, Sion Roy, Divya Birudaraju, Ahmed Ghanem, Sajad Hamal, Stephen Aronoff, Elisa Joye Petr, Richard Sachson, Jaime Wiebel, Sana Akram, Laurie Jones, Curtis Knight, Maurie Tarlac, Shahbaz Ahmed, Harold Szerlip, Akinwande Akinfolarin, Ankit Mehta, Shana Camp, Cindy Castro, Zanaida Cooper, Jessica Terry, Ahmed Awad, Bhavya Kothapalli, Ryan Lustig, Serine Alfaress, Hyder Jasim, Mary Parrigon, Dennis Karounos, Sadiq Ahmed, Maggie Berry, Ruth Oremus, Carlos Hernandez-Cassis, Elias Ugwu, Nazia Junejo, Nancy Suazo, Mark Segal, Amir Kazory, Sherry Brown, Tristan Daniels, Sofia Dayi, Renee Hogan, Kathy McCray, Jennifer Stickley, Mahboob Rahman, Mirela Dobre, Lavinia Negrea, Aparna Padiyar, Nishigandha Pradhan, Arash Rashidi, Nagaraju Sarabu, Vicki Donley, Tricia Young, Godson Oguchi, Judepatricks Onyema, Kahla Damianik, Jack Dienes, Judith Plummer-Morgan, Marilyn Roman, Mauver Skipper, Stacey-Ann Villaruel, Krystle Williams, Danny Sugimoto, Jeffrey Dugas, Ismeal Ahmed, Jamie Bhairoo, Dolores Rijos, Huzaifa Salim, Madita Gavrila, Kathryn Lafferty, Ria Rabara, Sally Ruse, Maria Weetman, James Bushnell, Albert Power, Alison Jenkins, Stefanie Jones, Amanda Scott, Cath Byrne, Mark Jesky, Alison Cowley, Emma McHaffie, Holly Waterfall, Jo Taylor, Laura Bough, Thomas Phillips, Barbara Winter-Goodwin, Sui Phin Kon, Iain MacDougall, Eirini Lioudaki, Sapna Shah, Claire Sharpe, Francisco Aguilar, Abegail Hernandez Pena, Conception Pugay, Amelia Te, Hugh Finn, Wasim Hanif, Samiul Mostafa, Alice Aitken, Katharine Draxlbauer, Evelina Grobovaite, Jennifer Kearney, Theresa McCarthy, Giorgio Gentile, Duncan Browne, Palanichamy Chellamuthu, Tabinda 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Cipressa, Laura, Fabbri, Gianna, Lorimer, Andrea, Lucci, Donata, Ghavampour, Sharang, Knoppe, Anja, Schmidt-Gurtler, Han, Dumann, Hubert, Merscher, Sybille, Patecki, Margret, Rainer Schlieper, Georg, Torp, Anke, Weber, Bianca, Zietz, Maja, Hohenstein, Bernd, Benck, Ur, Draganova, Diliana, Weinreich, Thoma, Wolf, Lothar, Gaidu, Jasmine, Reiner, Hanna, Visnjic, Mandy, Steffl, Daniel, Breitenfeldt, Marie, Kraemer-Guth, Annette, Braun, Christine, Hagge, Simone, Schomig, Michael, Matthias, Stephan, Stoffler, Dominik, Schumacher, Beate, Sitter, Thoma, Fuessl, Louise, Krappe, Julia, Loutan, Jerome, Vielhauer, Volker, Andriaccio, Luciano, Maurer, Magdalena, Winkelmann, Bernhard, Dursch, Martin, Seifert, Linda, Tenbusch, Linda, Weinmann-Menke, Julia, Boedecker, Simone, Kaluza-Schilling, Wiebke, Kraus, Daniel, Krieger, Carina, Schmude, Margit, Schreiber, Anne, Eckrich, Ewelina, Tschope, Diethelm, Arbi, Abdulwahab, Lee-Barkey, Young, Stratmann, Bernd, Prib, Natalie, Rolfsmeier, Sina, Schneider, 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Herfurth, Konstantin, Wolf, Gunter, Paul, Rainer, Haller, Hermann, Kaufeld, Jessica, Menne, Jan, Bahlmann-Kroll, Elisabeth, Bergner, Angela, Weihprecht, Horst, Er, Aydin, Sonntag, Florian, Turan, Elif, Wittmann, Michael, Klauser, Franziska, Voigt, Eva, Schettler, Volker, Schulz, Egbert, Rohnstock, Madlen, Schettler, Elke, Schroppel, Bernd, van Erp, Rene, Kachele, Martin, Ludwig, Ulla, Schulte-Kemna, Lena, Kmietschak, Waltraud, Preiss, Elke, Ruocco, Martina, Heine, Gunnar, Brzoska, Martin, Gabel, Sebastian, Büttner, Christina, Sabarai, Asma, Banas, Bernhard, Bergler, Tobia, Ehrl, Yvonne, Putz, Franz, Schuster, Antonia, Kuhn, Stefanie, Schramm, Torsten, Degenhardt, Stefan, Schmidt, Gerhard, Weiland, Lea, Giebeln-Hudnell, Ulrike, Kielstein, Jan, Eden, Gabriele, Fuchs, Brigitte, Morig, Gina, Winkler, Manuela, Darius, Harald, Kriatselis, Charalampo, Roesch, Carl-Philipp, Maselli, Astrid, Alscher, Dominik, Ketteler, Marku, Schanz, Moritz, Schricker, Severin, Rettenmaier, Bianka, Schwab, Andrea, Pergola, Pablo, Leal, Irene, Cagle, Melissa, Romo, Anna, Torres, Anthony, Joshi, Sucharit, Barrett, Kulli, Africano, Alexi, Dodds, Vicki, Gowen, Dorleena, Morris, Ashlee, Fernandez, Juan, Jimenez, Guillermo, Viera, Ricardo, Bruce, Kendaling, Barrios, Ryan, Garcia, Maylin, Garcia, Kerelyn, Leal, Iradi, Tietjen, David, Bains, David, Castillo, Carlo, Brewer, Genielle, Davis, Justin, Freking, Natalie, Golson, Brittany, Ham, Sally, Roesch, Jesslyn, Suchinda, Pusadee, Beigh, Shameem, Lilavivat, Usah, Bilton, Joyce, Bocchicchia, Kim, Turner, Jeffrey, Dahl, Neera, Peixoto, Aldo, Kavak, Yasemin, Liberti, Lauren, Nair, Hari, Page, Nicola, Rosenberg, Stephanie, Simmons, Kathryn, Isakova, Tamara, Frazier, Rebecca, Mehta, Rupal, Srivastava, Anand, Fox, Patrick, Hecktman, Jonathan, Hodakowski, Alexander, Martinez, Carlo, Phillips, Rachel, Stevenson, Alexi, Mustafa, Reem, Jansson, Kyle, Kimber, Cassandra, Stubbs, Jason, Tuffaha, Ahmad, Yarlagadda, Sri, Griffin, Debbie, Laundy, Elisabeth, Tang, Zhuo, Alicic, Radica, Cooper, Ann, Davis, Lisa, Gore, Ashwini, Goldfaden, Rebecca, Harvill, Leslie, Hichkad, Lisa, Johns, Barry, Jones, Thoma, Merritt, Kayla, Sheldon, Jennifer, Stanfield, Jennifer, Alexander, Lindsay, Preston, Kaitlyn, Wood, Lindsey, Pradhan, Rajesh, Deraad, Roger, Mcintosh, Kelli, Raymond, Loui, Shepperd, Michael, Mclaughlin, Susan, Seifert, Mary, Shepherd, Andrew, Aiello, Joseph, Durham, William, Loudermilk, Laurie, Manley, John, Burnette, Sabrina, Evans, Stephanie, Johnson, Tara, Sloan, Lance, Ann Acosta, Judy, Gillham, Stacy, Sloan, Katia, Squyres, Sueann, Rocco, Michael, Hawfield, Amret, Bagwell, Ben, Richmond, Lauren, Soufer, Joseph, Clarke, Subha, Aliu, Amanda, Calabrese, Kristine, Davis, Amanda, Poma, Veronica, Spinola, Tracy, Magee, Jame, Silva, Ricardo, Choksi, Rushab, Dajani, Lorraine, Evans, John, George, Anil, Krish, Prasanth, Martins, Gerard, Sheikh-Ali, Mae, Sutton, David, Driver, Freda, Hanburry, Abraham, Hume, Laura, Hurst, Amber, Taddeo, Matthew, Turner, Marla, Yousif, Veronica, Beddhu, Srinivasan, Al-Rabadi, Laith, Abraham, Nikita, Caamano, Amalia, Carle, Judy, Gonce, Victoria, Staylor, Kaitlyn, Zhou, Na, Bansal, Shweta, Bhattarai, Manoj, Sharma, Kumar, Debnath, Subrata, Garza, Aliseiya, Velagapudi, Chakradhar, Rovner, Sergio, Almeida, Javier, Casares, Pablo, Stewart-Ray, Verlaine, Almaraz, Rene, Dayrell, Renata, Moncada, Ana, Pulido, Ricardo, Rodriquez, Roxana, Deeb, Wasim, Degoursey, Kathryn, Gloria, Rodel, Greene, Trevor, Miller, Robert, Pereira, Edward, Roura, Miguel, Domingo, Debbie, Dorestin, Sasha, Hodge, William, Jackson, Cathy, Lund, Deborah, Taylor, Katrina, Boren, Kenneth, Cleveland, Brittany, Gaiser, Sandra, Sahani, Mandeep, Aldrich, Logan, Edmerson, Exodu, Limon, Edmond, Valletta, Cole, Vasquez, Patricia, Provenzano, Christopher, Brar, Navkiranjot, Henderson, Heather, Keith, Bellovich, Khai, Qur, Khairullah, Quresh, Makos, Gail, Topf, Joel, Gasko, Sherry, Henschel, Rosemarie, Knapp, Kaitlin, Kozlowski, Teresa, Lafleur, Paula, Varughese, Ashwathy, Xue, Hui, Wu, Patricia, Arechiga, Olga, Darbeau, Shan, Fechter, Michael, Martinez, Stephanie, Hanson, Lenita, Cooper, Nyla, Madera, Areli, Cadorna, Jay, Sheridan, Rita, Sparks, Helen, Eilerman, Bradley, Bodine, Susanne, Eid, Wael, Flora, Rebecca, Avery, Amber, Hardy, Cashmere, Biscoveanu, Mihaela, Nagelberg, Steven, Cummins, Tracey, Rahbari-Oskoui, Frederic, Oommen, Anju, Forghani, Zohreh, Hitchcock, Stacie, Hosein, Darya, Watkins, Diane, Patel, Minesh, Lambert, Anthony, Newman, Elizabeth, Wood, Autumn, Ross, Tammy, Topping, Stephany, Mulhern, Jeffrey, Murphy, Lorna, Vasseur, Ann, Greenwood, Gregory, Hadley, Alexander, Laurienti, Denise, Marshall, Christopher, Mclean, Nichola, Satko, Scott, Caudill, Brandy, Maris, Jacob, Rogers, Janice, Vanhoy, Cindy, Thomas, George, Nakhoul, George, O'Toole, John, Taliercio, Jonathan, Cooperman, Leslie, Markovic, Marina, Tucky, Barbara, Dev, Devasmita, Hasan, Alia, Yalamanchili, Hima, Jain, Namita, Mcneil, Lesley, Wines, Eric, Park, Jean, Ghazi, Adline, Hamm, Mia, Patel, Teja, Mottl, Amy, Chang, Emily, Derebail, Vimal, Cole, Emmie, Froment, Anne, Kelley, Sara, Osmond Foster, Jordan, Mahabadi, Vahid, Jafari, Golriz, Kamarzarian, Anita, Arriaga, Wendy, Arteaga, Daisy, Machicado, Rosario, Naverrete, Genesi, Kumar, Prashant, Nazeer, Imran, Urquia, Karina, Glider, Tammi, Jones, Vickie, Rucker, Savannah, Wiley, Jennifer, Pandey, Rahul, Arroyo, Jesu, Pariani, Harish, Ahmad, Mohammad, Mozaffari, Shahin, Perez, Erika, Budoff, Matthew, Roy, Sion, Birudaraju, Divya, Ghanem, Ahmed, Hamal, Sajad, Aronoff, Stephen, Joye Petr, Elisa, Sachson, Richard, Wiebel, Jaime, Akram, Sana, Jones, Laurie, Knight, Curti, Tarlac, Maurie, Ahmed, Shahbaz, Szerlip, Harold, Akinfolarin, Akinwande, Mehta, Ankit, Camp, Shana, Castro, Cindy, Cooper, Zanaida, Terry, Jessica, Awad, Ahmed, Kothapalli, Bhavya, Lustig, Ryan, Alfaress, Serine, Jasim, Hyder, Parrigon, Mary, Karounos, Denni, Ahmed, Sadiq, Berry, Maggie, Oremus, Ruth, Hernandez-Cassis, Carlo, Ugwu, Elia, Junejo, Nazia, Suazo, Nancy, Segal, Mark, Kazory, Amir, Brown, Sherry, Daniels, Tristan, Dayi, Sofia, Hogan, Renee, Mccray, Kathy, Stickley, Jennifer, Rahman, Mahboob, Dobre, Mirela, Negrea, Lavinia, Padiyar, Aparna, Pradhan, Nishigandha, Rashidi, Arash, Sarabu, Nagaraju, Donley, Vicki, Young, Tricia, Oguchi, Godson, Onyema, Judepatrick, Damianik, Kahla, Dienes, Jack, Plummer-Morgan, Judith, Roman, Marilyn, Skipper, Mauver, Villaruel, Stacey-Ann, Williams, Krystle, Sugimoto, Danny, Dugas, Jeffrey, Ahmed, Ismeal, Bhairoo, Jamie, Rijos, Dolore, Salim, Huzaifa, Gavrila, Madita, Lafferty, Kathryn, Rabara, Ria, Ruse, Sally, Weetman, Maria, Bushnell, Jame, Power, Albert, Jenkins, Alison, Jones, Stefanie, Scott, Amanda, Byrne, Cath, Jesky, Mark, Cowley, Alison, Mchaffie, Emma, Waterfall, Holly, Taylor, Jo, Bough, Laura, Phillips, Thoma, Winter-Goodwin, Barbara, Phin Kon, Sui, Macdougall, Iain, Lioudaki, Eirini, Shah, Sapna, Sharpe, Claire, Aguilar, Francisco, Hernandez Pena, Abegail, Pugay, Conception, Te, Amelia, Finn, Hugh, Hanif, Wasim, Mostafa, Samiul, Aitken, Alice, Draxlbauer, Katharine, Grobovaite, Evelina, Kearney, Jennifer, Mccarthy, Theresa, Gentile, Giorgio, Browne, Duncan, Chellamuthu, Palanichamy, Dugal, Tabinda, Chant, Terri, Jones, Laura, Laity, Emily, Miners, Megan, Muir, Jame, Swanson, Elizabeth, Frankel, Andrew, Tomlinson, Jame, Alegata, Marlon, Almasarwah, Rashid, Apostolidi, Anthoula, Vourvou, Maria, Walters, Thoma, Taal, Maarten, Dukka, Hari, Kolhe, Nitin, Mcdonald, Carly, White, Kelly, Ugni, Shiva, Gunda, Smita, Oluyombo, Rotimi, Brindle, Vicki, Coutts, Ping, Fuller, Tracy, Nadar, Evelyn, Ramadoss, Suresh, Motherwell, Nichola, Pajak, Susannah, Tonks, Louise, Bhandari, Sunil, Bodington, Richard, Hazara, Adil, Fellowes, Dominic, Wong, Christopher, Goldsmith, Christopher, Barnes, Sherald, Bennett, Ann, Burston, Claire, Hope, Samantha, Hunt, Nicola, Kurian, Lini, Fish, Richard, Farrugia, Daniela, Lee, Judy, Sadler, Emma, Turner, Hannah, Hill, Christopher, Brown, Henry, Masengu, Agne, Maxwell, Peter, Bleakley, Nina, Murtagh, Hugh, Petchey, William, Yiu, Vivian, Kellett, Joanne, Williams, Angharad, Clarke, Helen, Carnall, Victoria, Benyon, Sarah, Blake, Caroline, Estcourt, Stephanie, Piper, Jane, Morgan, Neal, Hutchinson, Carolyn, Mckinley, Teresa, Woodman, Alastair, Graham, Judi, Leonard, Niall, Smyth, John, Adell, Vicki, Hagan, Samantha, Caplin, Ben, Oomatia, Amin, Damian, Eleanor, Sobande, Toluleyi, Doulton, Tim, Delaney, Michael, Montasser, Mahmoud, Hansen, Jenny, Loader, David, Moon, Angela, Morris, France, Sinha, Smeeta, Chukwu, Chukwuma, Hudson, Amy, Campbell, Diane, Kershaw, Melanie, Whittaker, Stephanie, Irtiza-Ali, Ayesha, Ghalli, Farid, Nosseir, Heba, Leslie, Allison, Trivedi, Kate, Fraser, Donald, Alhadj Ali, Mohammad, Griffin, Sian, Latif, Farah, Witczak, Justyna, Wonnacott, Alexa, Jeffers, Lynda, Webley, Yvette, Phelan, Paul, Miller-Hodges, Eve, Geddes, Ailsa, Glenwright, Margaret, Hunter, Amy, Pickett, Thoma, Moriarty, Jim, Hill, Linda, Tyler, Amanda, Ayub, Waqar, Evans, Gail, Hewins, Sue, Hewitt, Davina, Read, Kerry, Bell, Samira, Cosgrove, Leanne, Craik, Rachel, Murray, Shona, Bhandary, Nitin, Coles, Holly, Easow, Rashmi, Joseph, Maya, Khwaja, Arif, Jackson, Yvonne, Mbuyisa, Angeline, Sellars, Rachel, Chitalia, Nihil, Mohandas, Cynthia, Gherman, Anca, Kamundi, Charlotte, Olufuwa, Olumide, Mccafferty, Kieran, Adeleke, Adedolapo, Healy, Cara, Jeyarajah, Damini, Kinsella-Perks, Edward, Smith, Richard, Camilleri, Brian, Buckman, Carol, Finch, Jenny, Rivers, Vanessa, Connor, Andrew, Carr, Sheila, Shainberg, Lisa, Lewington, Andrew, Baker, Richard, Dorey, Suzannah, Tobin, Kay, Wheatley, Rosalyn, Banerjee, Debasish, Hull, Richard, Abat, Sharirose, Paul, Riny, Karim, Mahzuz, Htet, Zay, Tufail, Saad, Varma, Ravi, Convery, Karen, Fottrell-Gould, Deirdre, Hudig, Lisa, Tropman, Emily, Abdul-Samad, Thahir, Grace, Anne, Phipps, Marie, Suckling, Rebecca, Somalanka, Subash, Sood, Bhrigu, Swift, Pauline, Acheampong, Sarah, Ansu, Kwame, Augustin, Martia, Sampson, Anna, Vinall, Lynn, Wren, Kim, Wanninayake, Shamila, Wooding, Nichola, Edwards, Heather, Owen, Lydia, Bolton, Stephanie, Carson, Marion, Matthews, Michael, Brunskill, Nigel, Jesus-Silva, Jorge, Howson, Alex, Quashie-Akponeware, Mary, Tindall, Hilary, Nethaji, Chidambaram, Eldon, Helen, Patel, Rajan, Mark, Patrick, Rankin, Alastair, Sullivan, Michael, Forsyth, Kirsty, Mcdougall, Rowan, Dasgupta, Tanaji, Davies, Louisa, Ryder, Maggie, Grimmer, Philip, Macdonald, Clare, Webster, Mary, Newcastle, Newcastle, Ellam, Timothy, Wong, Edwin, Meshykhi, Christine, Webster, Andrea, Wilson, Peter, Vilar, Enric, Berdeprado, Jocelyn, Doctolero, Eunice, Wilkinson, Lily, Mccarroll, Frank, Ammar, Hesham, Kuan, Ying, Moran, Conor, Shivashankar, Girish, Campbell, Ryan, Glowski, Deborah, Mcdermott, Paula, Ali, Amar, Patel, Zuber, Bond, Christine, Whalley, Gillian, Zhang, Haitao, Yang, Liu, Zhang, Lihua, Kan, Tingting, Zhu, Ling, Zhao, Jinghong, Hou, Weiping, Wu, Jing, Cheng, Hong, Bian, Weijing, Zhao, Zhirui, Shao, Fengmin, Cao, Huixia, Jiao, Xiaojing, Niu, Peiyuan, Niu, Jianying, Chen, Yu, Zhang, Lihong, Zhu, Shenglang, Lin, Haiyan, Yao, Shaopeng, Chen, Jiehui, Jiang, Ying, Hu, Ying, Xiao, Huaying, Yang, Fuye, Zhang, Xinzhou, Guo, Baochun, Jin, Qiu, Liu, Lixia, Xiao, Xiangcheng, Xie, Yanyun, Meng, Ting, Xu, Chuanwen, Huang, Jie, Xu, Yanmei, Kong, Weixin, Wang, Xiaoliang, Liu, Qianpan, Wang, Xueying, Gao, Ming, Hu, Xiumei, Lu, Ying, Wang, Li, Peng, Kun, Wang, Wei, Gong, Qiuhong, Cai, Jianfang, Li, Xiaojue, Liu, Xuejiao, Zhou, Shuhan, Liu, Hong, Weng, Yao, Tang, Shuai, Yao, Yao, Zhao, Shi, Cheng, Chen, Wei, Wei, Li, Na, Aqashiah Mazlan, Sadanah, Zubaidah Bahtar, Alia, Katiman, Elliyyin, Othman, Noraini, Mushahar, Lily, Mazlan, Nurdiana, Sharafina Safiee, Nur, Ramasamy, Sarasa, Seng Wong, Hin, Ahmad Rosdi, Hajar, Zhao Zhi Tan, Esther, Fan Tay, Ju, Seng Teng, Kok, Yahaya, Hasnah, Jiun Liu, Wen, Wee Ee, Lik, Kay Leong Khoo, Kenneth, Mohd Yusoff, Yuana, Safhan Mohamad Nor, Fariz, Kamil Ahmad, Mohd, Ramli Seman, Mohd, Hui Hong Tan, Clare, Lui Sian Ngu, Laura, Yoke May Chan, Jaime, Peji, Javelin, Loong Loh, Chek, Yan Lee, Yee, Ramanaidu, Sridhar, Mean Thong, Kah, Hong Wong, Yik, Junus, Suria, Hua Ching, Chen, Faisal Asmee, Mohammad, Ruziana Ku Md Razi, Ku, Leong Low, Chun, Sze Bing Sim, Christopher, Duan Tham, Zhang, Kamila Abdullah, Noor, Meng Chen, Tai, Chieh Chan, Yong, Chang, Eason, Yean Kang, Huan, Quan Lee, Kai, Ann Lee, Sue, Kheng Lee, Aik, Vinathan, Jeevika, Abdul Cader, Rizna, Mustafar, Ruslinda, Kamaruzaman, Lydia, Mohd, Rozita, Ismail, Rahimah, Men Leong, Chong, Koon Low, Chee, Wei Wong, Liang, Adnan, Norlezah, Ibrahim, Sabariah, Zaimi Abdul Wahab, Mohamad, Bavanandan, Sunita, Shen Lim, Yik, Hazlina Wan Mohamad, Wan, Munirah Jaafar, Siti, Ashykeen Mohd Fauzi, Nur, Sudin, Aziee, Kun Lim, Soo, Chung Gan, Chye, Hing, Albert, Ahmad Faizal Alaidin Razali, Wan, Fong Liew, Yew, Bao Tyng Chan, Chelsia, Chih Cheng, Mei, Chen Ong, Yu, Meng Ong, Loke, Amalina Mohamed Affandi, Farah, Rahmat, Korina, Chai Peng, Ban, Amat, Masayu, Hadafi Ahmad, Nuzaimin, Yee Mah, Doo, Loon Tye, Yi, Azhari, Zaid, Nabilah Mohamad Zaini, Siti, Aidil Musa, Mohd, Ahmad Miswan, Norazinizah, Ramli, Rafizanur, Aziah Ahmad, Nor, Leong Goh, Bak, Izah Ahmad, Nurul, Huda Ibrahim, Fairol, Jian Ng, Tze, Shanmuganathan, Malini, Lian Tay, Li, Harun, Zaiha, Ramli, Salmi, 'Ain Yusof, Nurul, Abd Rahman, Rossenizal, Iqbal Abdul Hafidz, Muhammad, Hidayati Mohd Sharif, Nur, Yasmoon Awang, Irda, Nakashima, Eitaro, Imamine, Rui, Minatoguchi, Makiko, Miura, Yukari, Nakaoka, Miduki, Suzuki, Yoshiki, Yoshikawa, Hitomi, Shin, Koki, Fujita, Kanae, Iwasa, Misuzu, Sasajima, Haruka, Sato, Airi, Hamamoto, Yoshiyuki, Fujita, Yuki, Haraguchi, Takuya, Hyo, Takanori, Izumi, Kiyohiro, Komiya, Toshiyuki, Kubota, Sodai, Kurose, Takeshi, Kuwata, Hitoshi, Nakatani, Susumu, Oishi, Kaori, Okamoto, Saki, Okamura, Kaori, Takeoka, Jun, Tanaka, Nagaaki, Tanigaki, Katsuya, Toda, Naohiro, Watanabe, Koin, Komori, Hiromi, Kumuji, Rika, Takesada, Asako, Tanaka, Aya, Maruyama, Shoichi, Hasegawa, Tomonori, Ishiguro, Akiko, Ishimoto, Takuji, Ito, Kazuhiro, Kamimura, Yutaka, Kato, Noritoshi, Kato, Sawako, Kojima, Hiroshi, Kosugi, Tomoki, Maeda, Kayaho, Mizuno, Masasi, Saito, Shoji, Sato, Hitomi, Sato, Yuka, Suzuki, Yasuhiro, Tanaka, Akihito, Yasuda, Yoshinari, Hasegawa, Fujiko, Hayashi, Maiko, Higashi, Shizuka, Shimamura, Kaho, Sumi, Momoko, Tajima, Kazuki, Unekawa, Chimaki, Wakayama, Kana, Wakita, Yukiko, Otani, Takatoshi, Imai, Ayako, Kawashima, Sayaka, Kogure, Eri, Sato, Tomoe, Takezawa, Misato, Yoshida, Shinya, Araki, Hideo, Katsuda, Yuko, Konishi, Masahiro, Matsunaga, Takahiro, Oe, Masashi, Ogane, Kunihiro, Sakai, Masato, Takahashi, Tomoko, Yamano, Takahiro, Yokoyama, Takuya, Ito, Hitomi, Katayama, Masayo, Kuroda, Emi, Ikeda, Toru, Kojo, Takuma, Yoshidome, Etsuo, Mizumachi, Rieko, Yamamoto, Akane, Yamasaki, Narihisa, Yamasaki, Yoshihiko, Wada, Jun, Eguchi, Jun, Higuchi, Chigusa, Katayama, Akihiro, Kinomura, Masaru, Kitagawa, Masashi, Kitamura, Shinji, Miyamoto, Satoshi, Morinaga, Hiroshi, Nakatsuka, Atsuko, Nojima, Ichiro, Shikata, Kenichi, Sugiyama, Hitoshi, Tanabe, Katsuyuki, Tsuji, Kenji, Uchida, Haruhito, Watanabe, Mayu, Hashimoto, Chie, Kato, Takahiro, Yamamoto, Sayaka, Wada, Takehiko, Fukagawa, Masafumi, Hamano, Naoto, Koizumi, Masahiro, Komaba, Hirotaka, Nakagawa, Yosuke, Iwamoto, Michiyo, Masutani, Kosuke, Katanosaka, Akane, Kiyota, Mayu, Uchi, Hikari, Ueda, Yuka, Yamamoto, Sonoka, Nagasu, Hajime, Itano, Seiji, Iwakura, Tsukasa, Kadoya, Hiroyuki, Kanda, Eiichiro, Kashihara, Naoki, Kidokoro, Kengo, Kondo, Megumi, Sasaki, Tamaki, Satoh, Minoru, Tokuyama, Atsuyuki, Umeno, Reina, Wada, Yoshihisa, Yamamoto, Toshiya, Yamanouchi, Yu, Abe, Masumi, Inukai, Yoko, Ogawa, Wataru, Asahara, Shunichiro, Fujii, Hideki, Goto, Shunsuke, Hirota, Yushi, Hosooka, Tetsuya, Kono, Keiji, Nishi, Shinichi, Okada, Yuko, Sakaguchi, Kazuhiko, Sugawara, Kenji, Takahashi, Michiko, Takai, Tomoko, Tamori, Yoshikazu, Watanabe, Kentaro, Kitajima, Miyu, Nishi, Misaki, Wada, Junko, Ito, Yasuhiko, Kamiya, Hideki, Asai, Akimasa, Asai, Nao, Asano, Saeko, Banno, Shogo, Ejima, Yohei, Hase, Hanako, Hayami, Tomohide, Himeno, Tatsuhito, Ishikawa, Takahiro, Ito, Mayumi, Iwagaitsu, Shiho, Kasagi, Rina, Kato, Yoshiro, Kato, Makoto, Kato, Koichi, Katsuno, Takayuki, Kawai, Miyuka, Kinashi, Hiroshi, Kondo, Masaki, Koshino, Masako, Matsuoka, Naoya, Morishita, Yoshiaki, Motegi, Mikio, Nakamura, Jiro, Shimoda, Hiromi, Sugiyama, Hirokazu, Tsunekawa, Shin, Yamaguchi, Makoto, Takahashi, Kazuyo, Watada, Hirotaka, Funayama, Takashi, Furukawa, Yasuhiko, Gohda, Tomohito, Goto, Hiromasa, Kaga, Hideyoshi, Kanaguchi, Yasuhiko, Kanazawa, Akio, Kaneko, Kayo, Kano, Toshiki, Kihara, Masao, Kimura, Shogo, Kobayashi, Takashi, Maiguma, Masayuki, Makita, Yuko, Mano, Satoshi, Mita, Tomoya, Miyatsuka, Takeshi, Murakoshi, Maki, Muto, Masahiro, Nakata, Masami, Nakata, Junichiro, Nishida, Yuya, Nohara, Nao, Ogihara, Takeshi, Sato, Daisuke, Sato, Junko, Sato, Hiroaki, Suzuki, Yusuke, Suzuki, Ruka, Suzuki, Hitoshi, Takagi, Miyuki, Tamura, Yoshifumi, Uchida, Toyoyoshi, Ueda, Seiji, Asawa, Miki, Miyaji, Minako, Nagashima, Eri, Shibata, Yoshie, Yanagisawa, Eri, Yamauchi, Toshimasa, Hirakawa, Yosuke, Nishi, Hiroshi, Shojima, Nobuhiro, Horikawa, Satoko, Nakayama, Yukiko, Yamada, Naoko, Omori, Yuki, Yano, Shintaro, Ioka, Miyabi, Kuwabara, Nahoko, Nagano, Remi, Nozawa, Megumi, Osawa, Yumi, Maegawa, Hiroshi, Kume, Shinji, Araki, Shinichi, Miyazawa, Itsuko, Morino, Katsutaro, Kawai, Ikuko, Sobata, Masumi, Takaoka, Motoko, Iwaita, Yasushi, Udagawa, Takashi, Inamori, Ami, Kawase, Aya, Yamanaka, Aya, Shimano, Hitoshi, Fujita, Akiko, Iwasaki, Hitoshi, Kai, Hirayasu, Osaki, Yoshinori, Saito, Chie, Sekiya, Motohiro, Tsunoda, Ryoya, Yamagata, Kunihiro, Nakamura, Rikako, Yamada, Aiko, Ohsugi, Mitsuru, Awazawa, Motoharu, Bouchi, Ryotaro, Hashimoto, Shota, Hashimoto, Makiko, Hisatake, Tomoko, Ihana, Noriko, Ishizuka, Koko, Izumi, Kazuo, Kajio, Hiroshi, Kobayashi, Michi, Kodani, Noriko, Maruyama, Koji, Matsumoto, Michihiro, Matsushita, Maya, Nakamura, Tomoka, Sugiyama, Takehiro, Tanabe, Akiyo, Terakawa, Aiko, Ueki, Kojiro, Orimo, Yuko, Ozawa, Takako, Takahira, Eriko, Yamasaki, Yoshimitsu, Haneda, Masakazu, Tomita, Tadahiro, Akimoto, Saori, Fujimoto, Akihiro, Ishihara, Kenji, Murakami, Chiho, Nishiyama, Akiyo, Toyonaga, Yukiko, Uozumi, Kana, Yamaji, Yukihiro, Shigehara, Tetsuya, Okajyo, Jun, Shimizu, Yukihiro, Iwasaki, Shingo, Fukao, Yuki, Furusho, Megumi, Nunokawa, Shintaro, Katagiri, Hideki, Izumi, Tomohito, Kaneko, Keizo, Kodama, Shinjiro, Miyazaki, Mariko, Munakata, Yuichiro, Nagasawa, Tasuku, Oe, Yuji, Sugawara, Hiroto, Takahashi, Kei, Hirata, Kazushige, Inomata, Keiko, Otomo, Shoko, Uchida, Taeko, Yamashita, Chigusa, Kiyosue, Arihiro, Tamura, Ryota, Dube, Francoi, Bolduc, Marilene, Talbot, Marie-Christine, Cham, Leslie, Lai, Vesta, Tse, Josephine, Jolly, Shivinder, Duck, Tabbatha, Lyle, Scott, Epp, Rachel, Galloway, Camille, Haskett, Susan, Matvienko, Elizabeta, Paulsen, Liam, Moist, Louise, Lozon, Zabrina, Ramsey, Tina, Whitmore, Brittany, Al-Zeer, Bader, Macleod, Paula, O'Sullivan, Aoife, Sheriff, Zainab, Tholl, Sam, Pandey, Amritanshu, Armstrong, Samantha, Gebeyehu, Bethelihem, Toth, Patrick, Goldenberg, Ronald, Jahangiriesmaili, Mahsa, Sanguila, Shariff, Suresh, Neethi, Talsania, Tanvi, Zalunardo, Nadia, Agharazii, Mohsen, Roussel, Marie-Pier, Saillant, Annie, Samson, France, Bajaj, Harpreet, Bhavsar, Miken, Dhall, Parul, Dhillon, Gagandeep, Grewal, Bhupinder, Nimbkar, Taniya, Madore, Francoi, Marcotte, Guylaine, Steen, Oren, Bullen, Mathura, Raguwaran, Shayani, Valleteau, Andre, Langlois, Marie-France, Brown, Christine, Steele, Andrew, Garrity, Melissa, Ghate, Taneera, Robinson, Holly, Tolibas, Michael, Tailor, Chetna, Elliott, Lauren, McClary-Wright, Christine, Boreky, Fadia, Fikry, Sameh, Ali, Ayesha, Barot, Chintankumar, Basily, Wagdy, Saram, Thisun, Varad, Vinay, Khandwala, Hasnain, Aguilera, Alex, Alvarez, Patricia, Gill, Balwinder, Huda, Nazihah, Navivala, Aamir, Pinto, Daniel, Bevilacqua, Micheli, Fung, Elaine, Hernandez, Geraldine, Mann, Puneet, Saini, Jaskiran, Rabasa-Lhoret, Remi, Bovan, Danijela, Devaux, Marie, Barnini, Cecilia, Leoncini, Giovanna, Manco, Luca, Nobili, Giulia, Piemontese, Matteo, Aucella, Filippo, Grifa, Rachele, Totaro, Francesco, La Manna, Gaetano, Capelli, Irene, Cianciolo, Giuseppe, Lerario, Sarah, Zappulo, Fulvia, Rosati, Alberto, Fani, Filippo, Spatoliatore, Giuseppe, Gesualdo, Loreto, Pesce, Francesco, Russo, Maria, Zippo, Maria, Cafiero, Cesira, Motta, Daria, Bianco, Simona, Bilucaglia, Donatella, Messa, Piergiorgio, Pavone, Laura, Tripodi, Federica, Vettoretti, Simone, Fioretto, Paola, Carraro, Gianni, Farnia, Filippo, Postal, Anna, D'Amelio, Alessandro, Cardone, Antonio, Piccinni, Giovanni, Aloisi, Annalisa, Scolari, Francesco, Alberici, Federico, Guerini, Alice, Saccà, Chiara, Salviani, Chiara, Zani, Roberta, DE NICOLA, Luca, Garofalo, Carlo, Elena Liberti, Maria, Minutolo, Roberto, Pennino, Luigi, Polese, Lucio, Mené, Paolo, Barberi, Simona, Falcone, Clorinda, Russo, Francesco, Caroppo, Maurizio, Santorelli, Gennaro, Rivera, Rodolfo, Santoro, Domenico, Giuffrida, Alfio, Zirino, Fortunata, Calvi, Cristina, Estienne, Luca, Gambaro, Giovanni, Gangemi, Concetta, Ortalda, Vittorio, Pessolano, Giuseppina, Grandaliano, Giuseppe, Baccaro, Rocco, Ferraro, Pietro, Mangiacapra, Roberto, Melandri, Marco, Foligno, Nadia, Quartagno, Rita, Vezzoli, Giuseppe, Brioni, Elena, and Group, EMPA-KIDNEY Collaborative

Subjects
chronic renal disease, empagliflozin, empa-kidney, General Medicine
Abstract

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; PConclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110. opens in new tab; EudraCT number, 2017-002971-24. opens in new tab.)

Published
2023

14. X-chromosome inactivation patterns in females with Fabry disease examined by both ultra-deep RNA sequencing and methylation-dependent assay

Author

Shoichi Maruyama, Kandai Nozu, Tomohiko Yamamura, Tomoko Horinouchi, Takeshi Ninchoji, Yuya Aoto, Shinya Ishiko, Rini Rossanti, Shogo Minamikawa, Eri Okada, Keiji Kono, Atsushi Fukunaga, Noritoshi Kato, China Nagano, Kazumoto Iijima, Hideki Fujii, Nana Sakakibara, and Shinichi Nishi

Subjects
Adult, Nephrology, Heterozygote, medicine.medical_specialty, Physiology, 030232 urology & nephrology, 030204 cardiovascular system & hematology, Severity of Illness Index, X-inactivation, 03 medical and health sciences, 0302 clinical medicine, X Chromosome Inactivation, Physiology (medical), Internal medicine, medicine, Humans, Allele, Gene, Aged, Genetics, Chromosomes, Human, X, Sequence Analysis, RNA, business.industry, RNA, Methylation, DNA Methylation, Middle Aged, medicine.disease, Fabry disease, Phenotype, alpha-Galactosidase, Leukocytes, Mononuclear, Fabry Disease, Female, business
Abstract

Fabry disease is an X-linked inherited lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A. Males are usually severely affected, while females have a wide range of disease severity. This variability has been assumed to be derived from organ-dependent skewed X-chromosome inactivation (XCI) patterns in each female patient. Previous studies examined this correlation using the classical methylation-dependent method; however, conflicting results were obtained. This study was established to ascertain the existence of skewed XCI in nine females with heterozygous pathogenic variants in the GLA gene and its relationship to the phenotypes. We present five female patients from one family and four individual female patients with Fabry disease. In all cases, heterozygous pathogenic variants in the GLA gene were detected. The X-chromosome inactivation patterns in peripheral blood leukocytes and cells of urine sediment were determined by both classical methylation-dependent HUMARA assay and ultra-deep RNA sequencing. Fabry Stabilization Index was used to determine the clinical severity. Skewed XCI resulting in predominant inactivation of the normal allele was observed only in one individual case with low ⍺-galactosidase A activity. In the remaining cases, no skewing was observed, even in the case with the highest total severity score (99.2%). We conclude that skewed XCI could not explain the severity of female Fabry disease and is not the main factor in the onset of various clinical symptoms in females with Fabry disease.

Published
2021
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15. Acquired Fanconi Syndrome in a Patient with Nontyphoidal Salmonella Bacteremia

Author

Akihiro Ryuge, Noritoshi Kato, Takuji Ishimoto, Hiroshi Morioka, Tomoki Kosugi, Shoji Saito, Shoichi Maruyama, and Asaka Hachiya

Subjects
medicine.medical_specialty, Bacterial Gastroenteritis, business.industry, Acute kidney injury, nutritional and metabolic diseases, Fanconi syndrome, General Medicine, 030204 cardiovascular system & hematology, urologic and male genital diseases, medicine.disease, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Aminoaciduria, Bacteremia, Internal Medicine, medicine, Renal glycosuria, 030211 gastroenterology & hepatology, Hypouricemia, business, Hypophosphatemia
Abstract

Nontyphoidal Salmonella is a common cause of bacterial gastroenteritis, occasionally causing bacteremia. We herein report the case of an 80-year-old man who presented with bacteremia and pre-renal acute kidney injury (AKI) secondary to diarrhea caused by nontyphoidal Salmonella. Despite AKI improvement on fluid administration, some serological abnormalities, such as hypokalemia, hypophosphatemia, and hypouricemia, and abnormal urinary findings emerged, including renal glycosuria and aminoaciduria. Fractional excretion of phosphate and uric acid was increased, suggesting that the serological and urinary abnormalities may have arisen from Fanconi syndrome. Physicians should consider acquired Fanconi syndrome when patients with nontyphoidal Salmonella bacteremia present with electrolyte disorders.

Published
2021
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16. Refractory Hypotension Caused by Selenium Deficiency in a Patient on Peritoneal Dialysis

Author

Masashi Mizuno, Hangsoo Kim, Shoji Saito, Yasuhiro Suzuki, Akihiro Ryuge, Shoichi Maruyama, Noritoshi Kato, Masaki Okazaki, Takuji Ishimoto, Hiroshi Kojima, and Tomoki Kosugi

Subjects
inorganic chemicals, Male, medicine.medical_specialty, hypotension, medicine.medical_treatment, chemistry.chemical_element, Case Report, 030204 cardiovascular system & hematology, Gastroenterology, Peritoneal dialysis, 03 medical and health sciences, Selenium, 0302 clinical medicine, Selenium deficiency, Internal medicine, Serum selenium level, Internal Medicine, medicine, Humans, Aged, business.industry, selenium deficiency, Malnutrition, Bacterial pneumonia, food and beverages, General Medicine, Refractory hypotension, medicine.disease, Pneumonia, chemistry, peritoneal dialysis, Ecg findings, 030211 gastroenterology & hepatology, business
Abstract

Selenium is essential for human health; its deficiency leads to cardiac dysfunction. We herein report a 79-year-old man on peritoneal dialysis who presented with refractory hypotension caused by selenium deficiency. He was admitted to our hospital with bacterial pneumonia and hypotension and abnormal electrocardiogram (ECG) findings. Despite improvement of pneumonia, his hypotension continued, and intravenous noradrenalin could not be discontinued. His serum selenium level was extremely low, and he was started on intravenous selenium. His hypotension and ECG findings gradually improved, and noradrenalin was discontinued. Physicians should consider selenium deficiency when patients on peritoneal dialysis show refractory hypotension.

Published
2021

17. Ectopic Relapse of Anti-neutrophil Cytoplasmic Antibody-associated Pituitary Vasculitis with No Elevation of Anti-neutrophil Cytoplasmic Antibodies after Renal Remission

Author

Tetsuro Sameshima, Toshiyuki Akahori, Naokazu Sato, Reiko Muto, Noritoshi Kato, Yuka Nagakura, Shoichi Maruyama, Koji Inagaki, and Satoshi Baba

Subjects
Pituitary gland, Pathology, medicine.medical_specialty, viruses, Case Report, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, 030204 cardiovascular system & hematology, Kidney, pituitary, vasculitis, Antibodies, Antineutrophil Cytoplasmic, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Biopsy, Internal Medicine, Enlarged pituitary gland, Humans, Medicine, Anti-neutrophil cytoplasmic antibody, relapse, medicine.diagnostic_test, biology, ANCA, business.industry, pituitary gland, Remission Induction, General Medicine, medicine.disease, Titer, medicine.anatomical_structure, Giant cell, biology.protein, 030211 gastroenterology & hepatology, Antibody, ANCA-associated vasculitis, Rituximab, business, Vasculitis
Abstract

The relationship between anti-neutrophil cytoplasmic antibody (ANCA) titer levels and relapse risk in patients with ANCA-associated vasculitis (AAV) following clinical remission remains controversial. We herein report a case showing ectopic relapse of AAV in the pituitary with no ANCA elevation after renal remission. Magnetic resonance imaging revealed an enlarged pituitary gland. A pituitary biopsy showed geographic necrosis with multinucleated giant cells. We diagnosed this case as relapse of AAV in the pituitary. One month after rituximab therapy, the pituitary gland volume had decreased. The intensification of therapy due to the possibility of vasculitis relapse may facilitate better control of AAV.

Published
2020
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18. aHUS; pathology and clinical aspects

Author

Yoshitaka Tatematsu, Noritoshi Kato, and Shoichi Maruyama

Subjects
medicine.medical_specialty, business.industry, medicine, General Earth and Planetary Sciences, Intensive care medicine, business, General Environmental Science
Published
2020
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19. IgA-dominant glomerulonephritis with DNAJB9-negative fibrillar polytypic immunoglobulin deposits in the subepithelium

Author

Reiko Muto, Kayaho Maeda, Sosuke Fukui, Shoji Saito, Noritoshi Kato, Tomoki Kosugi, Akira Shimizu, and Shoichi Maruyama

Subjects
General Medicine
Abstract

Fibrillary glomerulonephritis (FGN), a rare disease is pathologically characterized by glomerular fibril accumulation ranging from 12 to 24 nm in diameter with negative Congo red staining. Recently, the identification of DnaJ homolog subfamily B member 9 (DNAJB9) as a highly sensitive and specific marker for FGN has revolutionized diagnosis of this disease. However, few recent studies have reported DNAJB9-negative glomerulonephritis with fibrillar deposits. As such, it remains unclear whether DNAJB9-negative cases can be considered equivalent to FGN. Here, we report the case of a 70-year-old woman who developed renal impairment and nephrotic-range proteinuria. Renal biopsy and pathological examination revealed focal glomerulonephritis with fibrocellular crescents. Immunofluorescence microscopy showed IgA-dominant deposition of polytypic IgG in the glomerulus. Electron microscopy revealed hump-like subepithelial electron dense deposits with fibrils of 15-25 nm in diameter. These findings were consistent with FGN; thus, Congo red and direct fast scarlet (DFS) staining, and immunohistochemistry for DNAJB9 were performed. In addition to negative Congo red/DFS/DNAJB9 staining, laser microdissection (LMD) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) resulted negative for DNAJB9, which is a highly sensitive and specific marker for FGN. The patient's renal function further declined, prompting administration of rituximab weekly for 2 weeks, similar to the treatment for FGN. This is a unique case of IgA-dominant glomerulonephritis with DNAJB9-negative fibrillar polytypic immunoglobulin deposits in the subepithelium, unlike previous DNAJB9-negative cases. Thus, DNAJB9-negative cases diagnosed based on accurate electron microscopic evaluation must be gathered, and LMD and LC-MS/MS must be used to analyze the organized fibrillar deposits to reveal the disease entity.

Published
2022

20. The 30-year Natural History of Non-classic Fabry Disease with an R112H Mutation

Author

Koji Inagaki, Reiko Muto, Toshiyuki Akahori, Noritoshi Kato, and Shoichi Maruyama

Subjects
business.industry, Clinical course, Globotriaosylceramide, General Medicine, Disease, medicine.disease, Fabry disease, Natural history, chemistry.chemical_compound, chemistry, alpha-Galactosidase, Immunology, Mutation (genetic algorithm), Mutation, Internal Medicine, Medicine, Fabry Disease, Humans, business, Gene
Abstract

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase A (GLA) gene that results in deficiency of the enzyme GLA and leads to the accumulation of globotriaosylceramide (GL-3) in cells. The accumulation of GL-3 may lead to life-threatening complications. Significant advances in genetic sequencing technology have led to a better understanding of genotype-phenotype interactions in Fabry disease. Fabry disease with an R112H mutation is known as the non-classic type. However, the long-term clinical course of the disease remains unknown. We herein report a patient with a 30-year natural history of non-classic Fabry disease with an R112H mutation.

Published
2021

21. Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis

Author

Yukio Yuzawa, Takashi Honda, Tomoyoshi Soga, Yasuhiko Minokoshi, Takanori Ito, Kayaho Maeda, Tomoki Kosugi, Kenji Kadomatsu, Akiyoshi Hirayama, Ryoichi Banno, Kunio Kondoh, Kazuo Takahashi, Tomoya Ozaki, Hiroshi Arima, Kei Zaitsu, Yang Gou, Teruhiko Koike, Takuji Ishimoto, Kazuki Nakajima, Yuka Sato, Shoichi Maruyama, Noritoshi Kato, Shoma Tsubota, Akihiro Ryuge, and Takahiko Nakagawa

Subjects
Alanine, Hepatology, Chemistry, Diabetes, Pyruvate transport, Gluconeogenesis, General Medicine, Metabolism, Cell biology, Fatty Liver, Glutamine, Citric acid cycle, Mice, Basigin, Ketogenesis, Animals, Humans, Insulin Resistance, Research Article
Abstract

Monocarboxylates, such as lactate and pyruvate, are precursors for biosynthetic pathways, including those for glucose, lipids, and amino acids via the tricarboxylic acid (TCA) cycle and adjacent metabolic networks. The transportation of monocarboxylates across the cellular membrane is performed primarily by monocarboxylate transporters (MCTs), the membrane localization and stabilization of which are facilitated by the transmembrane protein basigin (BSG). Here, we demonstrate that the MCT/BSG axis sits at a crucial intersection of cellular metabolism. Abolishment of MCT1 in the plasma membrane was achieved by Bsg depletion, which led to gluconeogenesis impairment via preventing the influx of lactate and pyruvate into the cell, consequently suppressing the TCA cycle. This net anaplerosis suppression was compensated in part by the increased utilization of glycogenic amino acids (e.g., alanine and glutamine) into the TCA cycle and by activated ketogenesis through fatty acid β-oxidation. Complementary to these observations, hyperglycemia and hepatic steatosis induced by a high-fat diet were ameliorated in Bsg-deficient mice. Furthermore, Bsg deficiency significantly improved insulin resistance induced by a high-fat diet. Taken together, the plasma membrane-selective modulation of lactate and pyruvate transport through BSG inhibition could potentiate metabolic flexibility to treat metabolic diseases.

Published
2021
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22. The ISN/RPS 2016 classification predicts renal prognosis in patients with first-onset class III/IV lupus nephritis

Author

Naotake Tsuboi, Takuji Ishimoto, Shoichi Maruyama, Asaka Hachiya, Noritoshi Kato, Tomoki Kosugi, Munetoshi Karasawa, Takayuki Katsuno, and Takahiro Imaizumi

Subjects
Adult, Male, medicine.medical_specialty, Science, Kidney Glomerulus, Remission, Spontaneous, 030232 urology & nephrology, Lupus nephritis, Renal function, Kidney, Severity of Illness Index, Gastroenterology, Article, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, Rheumatic diseases, 0302 clinical medicine, Internal medicine, Humans, Lupus Erythematosus, Systemic, Medicine, Renal Insufficiency, Pathological, Hyaline, Proportional Hazards Models, Retrospective Studies, 030203 arthritis & rheumatology, Creatinine, Multidisciplinary, business.industry, Proportional hazards model, Remission Induction, Middle Aged, Prognosis, medicine.disease, Lupus Nephritis, chemistry, Female, business, Complication, Glomerular Filtration Rate, Cohort study
Abstract

Lupus nephritis (LN) is a life-threatening complication of systemic lupus erythematosus. The 2003 pathological classification of LN was revised in 2016; it quantitatively evaluates the interstitium in addition to the glomeruli. We performed a retrospective multi-centre cohort study and investigated the utility of the 2016 classification—including the activity index (AI), chronicity index (CI), and each pathological component to predict complete remission or renal function decline, defined as 1.5-fold increase in serum creatinine levels—and compare with that of the 2003 classification. Ninety-one consecutive adult patients with first-onset class III/IV LN who were newly prescribed any immunosuppressants were enrolled and followed up for a median of 51 months from January 2004. Cox regression analysis demonstrated the subclasses based on the 2003 classification, which mainly evaluate glomerular lesions, were not associated with clinical outcomes. After adjustments for estimated glomerular filtration rate and urinary protein levels, higher CI and higher interstitial fibrosis and lower hyaline deposit scores were associated with renal functional decline. Similarly, higher CI and interstitial inflammation scores were associated with failure to achieve complete remission. Therefore, the 2016 classification can predict the clinical outcomes more precisely than the 2003 classification.

Published
2021
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23. X-chromosome inactivation patterns in females with Fabry disease examined by both ultra-deep RNA sequencing and methylation-dependent assay

Author

Rini Rossanti, Kandai Nozu, Atsushi Fukunaga, China Nagano, Tomoko Horinouchi, Tomohiko Yamamura, Nana Sakakibara, Shogo Minamikawa, Shinya Ishiko, Yuya Aoto, Eri Okada, Takeshi Ninchoji, Noritoshi Kato, Shoichi Maruyama, Shinichi Nishi, Kazumoto Iijima, and Hideki Fujii

Abstract

Background: Fabry disease is an X-linked inherited lysosomal storage disorder related to GLA mutations, gene encoding α-galactosidase A. In general, males has severe phenotype, while females has a wide spectrum of sign and symptoms, from asymptomatic to a more classical profile including cardiac, renal, and cerebrovascular manifestations. This variability has been assumed to be derived from organ-dependent skewed X-chromosome inactivation (XCI) patterns in each female patient. Some previous studies examined this correlation using the classical methylation-dependent method; however, conflicting results were obtained. This study was established to determine the existence of skewed XCI in nine females with heterozygous pathogenic variants in the GLA gene and its relationship to the phenotypes. Methods: We present five female patients from one family and four individual female patients with Fabry disease. In all cases, heterozygous pathogenic variants in the GLA gene were detected. The X-chromosome inactivation patterns in peripheral blood leukocytes and cells of urine sediment were determined by both classical methylation-dependent HUMARA assay and ultra-deep RNA sequencing, the latter being a method that we recently developed. Results: Among all cases, skewed XCI resulting in predominant inactivation of the normal allele was observed only in one individual case with a severe phenotype. In the other eight cases, no skewing was observed, even among cases with severe phenotypes. Conclusions: We conclude that skewed XCI could explain the severity of Fabry disease in only a limited number of female cases and is not the main factor in the onset of various clinical symptoms in females with Fabry disease.

Published
2020
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24. Acquired Fanconi Syndrome in a Patient with Nontyphoidal Salmonella Bacteremia

Author

Akihiro, Ryuge, Shoji, Saito, Hiroshi, Morioka, Asaka, Hachiya, Noritoshi, Kato, Takuji, Ishimoto, Tomoki, Kosugi, and Shoichi, Maruyama

Subjects
Aged, 80 and over, Male, hypophosphatemia, Fanconi syndrome, Salmonella, hypokalemia, nutritional and metabolic diseases, Humans, salmonella bacteremia, Bacteremia, Case Report, Acidosis, Renal Tubular, urologic and male genital diseases
Abstract

Nontyphoidal Salmonella is a common cause of bacterial gastroenteritis, occasionally causing bacteremia. We herein report the case of an 80-year-old man who presented with bacteremia and pre-renal acute kidney injury (AKI) secondary to diarrhea caused by nontyphoidal Salmonella. Despite AKI improvement on fluid administration, some serological abnormalities, such as hypokalemia, hypophosphatemia, and hypouricemia, and abnormal urinary findings emerged, including renal glycosuria and aminoaciduria. Fractional excretion of phosphate and uric acid was increased, suggesting that the serological and urinary abnormalities may have arisen from Fanconi syndrome. Physicians should consider acquired Fanconi syndrome when patients with nontyphoidal Salmonella bacteremia present with electrolyte disorders.

Published
2020

25. Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis

Author

Sara Lovisa, Janine Hensel, Ignacio Revuelta, Nagireddy Putluri, Elisabeth M. Zeisberg, Raghu Kalluri, Erica J. Lawson, Gangadhar Taduri, Eliot Fletcher-Sananikone, Sharmistha Lahiri, Noritoshi Kato, Valerie S. LeBleu, Roland L. Bassett, Chang-Jiun Wu, Alexandre Hertig, Hikaru Sugimoto, Michael Zeisberg, and Rajan Dewar

Subjects
Epithelial-Mesenchymal Transition, Kidney, Biochemistry, Article, TIE1, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Parenchyma, medicine, Humans, Endothelium, Molecular Biology, 030304 developmental biology, 0303 health sciences, Chemistry, Transdifferentiation, Mesenchymal stem cell, Cell Biology, Hypoxia (medical), medicine.disease, 3. Good health, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, SNAI1, Kidney Diseases, medicine.symptom
Abstract

Endothelial–to–mesenchymal transition (EndMT) is a cellular transdifferentiation program in which endothelial cells partially lose their endothelial identity and acquire mesenchymal-like features. Renal capillary endothelial cells can undergo EndMT in association with persistent damage of the renal parenchyma. The functional consequence(s) of EndMT in kidney fibrosis remains unexplored. Here, we studied the effect of Twist or Snail deficiency in endothelial cells on EndMT in kidney fibrosis. Conditional deletion of Twist1 (which encodes Twist) or Snai1 (which encodes Snail) in VE-cadherin(+) or Tie1(+) endothelial cells inhibited the emergence of EndMT and improved kidney fibrosis in two different kidney injury/fibrosis mouse models. Suppression of EndMT limited peritubular vascular leakage, reduced tissue hypoxia, and preserved tubular epithelial health and function. Hypoxia, which was exacerbated by EndMT, resulted in increased Myc abundance in tubular epithelial cells, enhanced glycolysis, and suppression of fatty acid oxidation. Pharmacological suppression or epithelial-specific genetic ablation of Myc in tubular epithelial cells ameliorated fibrosis and restored renal parenchymal function and metabolic homeostasis. Together, these findings demonstrate a functional role for EndMT in the response to kidney capillary endothelial injury and highlight the contribution of endothelial-epithelial crosstalk in the development of kidney fibrosis with a potential for therapeutic intervention.

Published
2020
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26. Acute Kidney Injury and Cytokines

Author

Noritoshi Kato, Tomoki Kosugi, Kazuhiro Furuhashi, and Shoichi Maruyama

Subjects
Chemokine, Cell signaling, biology, Chemistry, Monocyte, medicine.medical_treatment, Inflammation, Microvesicles, Cell biology, medicine.anatomical_structure, Cytokine, Basigin, medicine, biology.protein, Macrophage, medicine.symptom
Abstract

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.

Published
2020
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27. Therapeutic efficacy of rituximab for the management of adult-onset steroid-dependent nephrotic syndrome: a retrospective study

Author

Takayuki Katsuno, Tomohiro Masuda, Takuji Ishimoto, Yasuhiko Ito, Tomoki Kosugi, Shoji Saito, Shoichi Maruyama, Toyonori Tsuzuki, Hiroshi Kitamura, Naotake Tsuboi, Noritoshi Kato, and Sawako Kato

Subjects
Adult, Male, Nephrology, medicine.medical_specialty, Time Factors, Physiology, medicine.drug_class, 030232 urology & nephrology, 030204 cardiovascular system & hematology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Adrenal Cortex Hormones, Recurrence, immune system diseases, Interquartile range, hemic and lymphatic diseases, Physiology (medical), Internal medicine, medicine, Humans, Immunologic Factors, Age of Onset, Adverse effect, Retrospective Studies, business.industry, Nephrosis, Lipoid, Remission Induction, Steroid-dependent nephrotic syndrome, Retrospective cohort study, Middle Aged, medicine.disease, Treatment Outcome, Corticosteroid, Female, Rituximab, business, Nephrotic syndrome, Immunosuppressive Agents, medicine.drug
Abstract

Recent reports have described the efficacy of rituximab in treating steroid-dependent nephrotic syndrome (SDNS) in pediatric patients. However, few reports describe data regarding adult-onset SDNS. We investigated the efficacy of rituximab for the management of adult-onset SDNS. We performed a retrospective cohort study investigating eight patients with adult-onset SDNS who were treated with rituximab. Clinical data were obtained at the initiation of rituximab therapy. The primary outcomes evaluated were successful suppression of relapses and CD19+ cells after rituximab treatment. The corticosteroid- and immunosuppressant-sparing effect and adverse events were additionally evaluated. All eight patients were diagnosed with minimal change nephrotic syndrome and received immunosuppressants in addition to corticosteroid. Total number of relapses was 10.5 times as a median value. Rituximab administration was repeated in two patients, whereas six received single-dose rituximab. Three of eight (37.5%) patients showed relapse after rituximab therapy. A rituximab-induced depletion in CD19+ cells noted initially was followed by their reappearance in all patients. There were cases with no relapse after the reappearance of CD19+ cells. The median relapse time pre- and post-rituximab therapy showed a decrease from 1 time/year (interquartile range [IQR] 1–3 times/year) to 0 time/year (IQR 0–1 time/year). Rituximab treatment induced a significant reduction in the required doses of corticosteroid and cyclosporine (P

Published
2018
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28. Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice

Author

Takuji Ishimoto, Shoichi Maruyama, Miguel A. Lanaspa, Takahiro Hayasaki, Tomoyoshi Soga, Satsuki Ikeda, Tomoki Kosugi, Noritoshi Kato, Tomohito Doke, Naotake Tsuboi, Akiyoshi Hirayama, Richard J. Johnson, Kenji Kadomatsu, and Masako Hasebe

Subjects
0301 basic medicine, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030232 urology & nephrology, Kidney, medicine.disease_cause, Article, Diabetes Mellitus, Experimental, Fructokinases, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Polyol pathway, Internal medicine, Diabetes mellitus, medicine, Animals, Diabetic Nephropathies, Glycolysis, Mice, Knockout, Nicotinamide, business.industry, Streptozotocin, medicine.disease, Oxidative Stress, 030104 developmental biology, medicine.anatomical_structure, chemistry, NAD+ kinase, business, Oxidative stress, medicine.drug
Abstract

Objective Ketohexokinase (KHK), a primary enzyme in fructose metabolism, has two isoforms, namely, KHK-A and KHK-C. Previously, we reported that renal injury was reduced in streptozotocin-induced diabetic mice which lacked both isoforms. Although both isoforms express in kidney, it has not been elucidated whether each isoform plays distinct roles in the development of diabetic kidney disease (DKD). The aim of the study is to elucidate the role of KHK-A for DKD progression. Materials and Methods Diabetes was induced by five consecutive daily intraperitoneal injections of streptozotocin (50 mg/kg) in C57BL/6J wild-type mice, mice lacking KHK-A alone (KHK-A KO), and mice lacking both KHK-A and KHK-C (KHK-A/C KO). At 35 weeks, renal injury, inflammation, hypoxia, and oxidative stress were examined. Metabolomic analysis including polyol pathway, fructose metabolism, glycolysis, TCA (tricarboxylic acid) cycle, and NAD (nicotinamide adenine dinucleotide) metabolism in kidney and urine was done. Results Diabetic KHK-A KO mice developed severe renal injury compared to diabetic wild-type mice, and this was associated with further increases of intrarenal fructose, dihydroxyacetone phosphate (DHAP), TCA cycle intermediate levels, and severe inflammation. In contrast, renal injury was prevented in diabetic KHK-A/C KO mice compared to both wild-type and KHK-A KO diabetic mice. Further, diabetic KHK-A KO mice contained decreased renal NAD+ level with the increase of renal hypoxia-inducible factor 1-alpha expression despite having increased renal nicotinamide (NAM) level. Conclusion These results suggest that KHK-C might play a deleterious role in DKD progression through endogenous fructose metabolism, and that KHK-A plays a unique protective role against the development of DKD.

Published
2018
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30. Ratio of blood urea nitrogen to serum creatinine at initiation of dialysis is associated with mortality: a multicenter prospective cohort study

Author

Daijo, Inaguma, Shigehisa, Koide, Eri, Ito, Kazuo, Takahashi, Hiroki, Hayashi, Midori, Hasegawa, Yukio, Yuzawa, and Noritoshi, Kato

Subjects
Male, Nephrology, Time Factors, Physiology, medicine.medical_treatment, 030232 urology & nephrology, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Kidney, Gastroenterology, Blood Urea Nitrogen, chemistry.chemical_compound, 0302 clinical medicine, Japan, Risk Factors, Odds Ratio, Prospective Studies, Prospective cohort study, Blood urea nitrogen, Aged, 80 and over, Hazard ratio, Area under the curve, Middle Aged, Treatment Outcome, Area Under Curve, Creatinine, Female, Glomerular Filtration Rate, medicine.medical_specialty, Renal function, 03 medical and health sciences, Predictive Value of Tests, Renal Dialysis, Physiology (medical), Internal medicine, medicine, Humans, Renal Insufficiency, Chronic, Dialysis, Aged, Proportional Hazards Models, Chi-Square Distribution, business.industry, Surgery, ROC Curve, chemistry, Multivariate Analysis, business, Biomarkers
Abstract

Some studies have shown that the estimated glomerular filtration rate (eGFR) at the time of initiating dialysis was associated with mortality. However, the relationship between ratio of blood urea nitrogen to serum creatinine (BUN/Cr) and mortality is unknown. The study was a multicenter, prospective cohort analysis including 1520 patients. Patients were classified into four quartiles based on the BUN/Cr ratio at the dialysis initiation, with Q1 having the lowest ratio and Q4 the highest. All-cause mortality after initiating dialysis was compared using the log-rank test. All-cause mortality of Q1, Q2, and Q3 was compared with that of Q4 using multivariate Cox proportional hazard regression analysis. Moreover, we compared the renal parameters including BUN/Cr ratio, eGFR, and creatinine clearance for sensitivity and specificity using receiver operative characteristic (ROC) curve. Significant differences were observed in all-cause mortality among the four groups (p

Published
2017
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32. Fructose increases the activity of sodium hydrogen exchanger in renal proximal tubules that is dependent on ketohexokinase

Author

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

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Swine, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Clinical Biochemistry, 030232 urology & nephrology, Blood Pressure, Fructose, Biochemistry, Cell Line, Excretion, Fructokinases, Kidney Tubules, Proximal, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Animals, Molecular Biology, Saline, Mice, Knockout, Nutrition and Dietetics, Renal sodium reabsorption, Chemistry, Sodium-Hydrogen Exchanger 3, Sodium, Mice, Inbred C57BL, Sodium–hydrogen antiporter, 030104 developmental biology, Endocrinology, Blood pressure, Knockout mouse, Intracellular
Abstract

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.

Published
2018

33. miR-146a targeted to splenic macrophages prevents sepsis-induced multiple organ injury

Author

Shoichi Maruyama, Noritoshi Kato, Takuji Ishimoto, Kenji Kadomatsu, Naotake Tsuboi, Tomohiro Masuda, Yoshio Funahashi, Naoyuki Matsuda, Fumitoshi Nishio, Hiroki Kitai, and Tomoki Kosugi

Subjects
0301 basic medicine, Male, Lipopolysaccharide, Multiple Organ Failure, Inflammation, Pathology and Forensic Medicine, Proinflammatory cytokine, Sepsis, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Splenocyte, Medicine, Macrophage, Animals, Molecular Biology, business.industry, Macrophages, Interleukin, Cell Biology, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, MicroRNAs, 030104 developmental biology, RAW 264.7 Cells, chemistry, 030220 oncology & carcinogenesis, Cancer research, Tumor necrosis factor alpha, medicine.symptom, business, Spleen, Plasmids
Abstract

Development of a novel agent against life-threatening sepsis requires the in-depth understanding of the relevant pathophysiology and therapeutic targets. Given the function of microRNAs (miRNAs) as potent oligonucleotide therapeutics, here we investigated the pathophysiological role of exogenously applied miRNA in sepsis-induced multiple organ injury. In vitro, miR-16, miR-126, miR-146a, and miR-200b suppressed the production of pro-inflammatory cytokines in RAW264.7 macrophage cells after lipopolysaccharide (LPS) stimulation. Of these, miR-146a displayed the most highly suppressive effect, wherein the transcriptional activity of nuclear factor kappa B (NF-κB) was decreased via targeting of interleukin 1 receptor-associated kinase 1 and tumor necrosis receptor-associated factor 6. Sepsis was induced in mice via cecal ligation and puncture (CLP) and an intravenous injection of a complex of miR-146a-expressing plasmid and polyethyleneimine. Treatment with this complex significantly decreased the level of serum inflammatory cytokines, attenuated organ injury including kidney injury, and led to increased survival from polymicrobial sepsis induced by CLP. miR-146a-expressing plasmid was abundantly distributed in splenic macrophages, but not in renal parenchymal cells. CLP mice treated with miR-146a displayed significantly decreased NF-κB activation and splenocyte apoptosis. Splenectomy diminished the anti-inflammatory effects of miR-146a. The collective results support the conclusion that the induction of miR-146a expression in splenic macrophages prevents excessive inflammation and sepsis-induced multiple organ injury. This study establishes a novel and critical pathophysiological role for splenic macrophage interference in sepsis-related organ injury.

Published
2018

34. CD147/Basigin Deficiency Prevents the Development of Podocyte Injury through FAK Signaling

Author

Tomoharu Watanabe, Akihiro Ryuge, Kenji Kadomatsu, Takuji Ishimoto, Hiroshi Nagaya, Yuka Sato, Takayuki Katsuno, Tomohiro Masuda, Yukio Yuzawa, Shoichi Maruyama, Noritoshi Kato, Tomoki Yoshioka, Kayaho Maeda, and Tomoki Kosugi

Subjects
0301 basic medicine, Adult, Male, 030232 urology & nephrology, Motility, Pathology and Forensic Medicine, Podocyte, Focal adhesion, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, medicine, Gene silencing, Animals, Humans, Endothelial dysfunction, Mice, Knockout, Chemistry, Glomerulosclerosis, Focal Segmental, Podocytes, medicine.disease, Cell biology, Vascular endothelial growth factor, Disease Models, Animal, Proteinuria, 030104 developmental biology, medicine.anatomical_structure, NG-Nitroarginine Methyl Ester, Doxorubicin, Basigin, Focal Adhesion Kinase 1, Female, Transforming growth factor, Signal Transduction
Abstract

Podocytes, which are susceptible to injury by various stimuli and stress, are critical regulators of proteinuric kidney diseases, regardless of the primary disease and pathogenesis. We further confirmed a significant correlation between urinary CD147/basigin (Bsg) levels and proteinuria in patients with focal segmental glomerulosclerosis. However, the molecular mechanism of podocyte injury involving Bsg is not fully understood. Here, the involvement of Bsg in the pathogenesis of podocyte injury was elucidated. Healthy podocytes rarely express Bsg protein. In two independent mouse models, including adriamycin-induced nephropathy and Nω-nitro-l-arginine methyl ester (l-name)-induced endothelial dysfunction, Bsg induction in injured podocytes caused podocyte effacement, which led to development of proteinuria. Bsg silencing in cultured podocytes exposed to transforming growth factor-β suppressed focal adhesion rearrangement and cellular motility via the activation of β1 integrin-focal adhesion kinase-matrix metallopeptidase signaling. In addition, induction of vascular endothelial growth factor and endothelin-1, which are implicated in podocyte-to-endothelial cross-communication, was lower in the supernatants of cultured Bsg-silenced podocytes stimulated with transforming growth factor-β. In this setting, Bsg may be involved in a physiological positive feedback loop that accelerates podocyte cell motility and depolarization. The current study thus suggests that Bsg silencing via suppression of β1 integrin-focal adhesion kinase-matrix metallopeptidase signaling may be an attractive therapeutic strategy for the maintenance of podocytes in patients with proteinuric kidney diseases.

Published
2018

35. Increase of Antimyeloperoxidase Antineutrophil Cytoplasmic Antibody (ANCA) in Patients with Renal ANCA-associated Vasculitis: Association with Risk to Relapse

Author

Yasuhiko Ito, Noritoshi Kato, Masashi Mizuno, Waichi Sato, Shoichi Maruyama, Yoshinari Yasuda, Masahiko Ando, Takayuki Katsuno, Makoto Yamaguchi, Sawako Kato, Tomoki Kosugi, Seiichi Matsuo, and Naotake Tsuboi

Subjects
Male, Nephrology, medicine.medical_specialty, Immunology, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Enzyme-Linked Immunosorbent Assay, Kaplan-Meier Estimate, Kidney, Risk Assessment, Severity of Illness Index, Gastroenterology, Antibodies, Antineutrophil Cytoplasmic, Cohort Studies, Rheumatology, Predictive Value of Tests, Recurrence, Renal Dialysis, Interquartile range, Internal medicine, medicine, Humans, Immunology and Allergy, Aged, Proportional Hazards Models, Retrospective Studies, Anti-neutrophil cytoplasmic antibody, business.industry, Proportional hazards model, Granulomatosis with Polyangiitis, Plasmapheresis, Middle Aged, Prognosis, medicine.disease, Treatment Outcome, Predictive value of tests, Multivariate Analysis, Disease Progression, Female, Microscopic polyangiitis, business, Granulomatosis with polyangiitis, Vasculitis, Biomarkers, Immunosuppressive Agents
Abstract

Objective.The diagnostic values of antiproteinase 3 and antimyeloperoxidase tests using antineutrophil cytoplasmic antibodies (ANCA) are well established. Our study determined whether an increase in ANCA level was a predictor of disease flareup.Methods.Our study included 126 patients with ANCA-associated renal vasculitis treated at 9 nephrology centers in Japan. The relationship between increased ANCA levels and relapse was assessed using time-dependent multivariate Cox regression models adjusted for clinically relevant factors. The outcome of interest was the time from remission to first relapse.Results.During the observation period [median 41 mos, interquartile range (IQR) 23–66 mos], 118 patients (95.8%) achieved remission at least once. After achieving remission, 34 patients relapsed (21.7%). Time-dependent multivariate Cox regression models revealed that lung involvement (adjusted HR 2.29, 95% CI 1.13–4.65, p = 0.022) and increased ANCA levels (adjusted HR 17.4, 95% CI 8.42–36.0, p < 0.001) were significantly associated with relapse. The median time from ANCA level increase to relapse was 0.6 months (IQR 0–2.1 mos).Conclusion.In our study, an increase in ANCA level during remission was associated with a risk of disease relapse. A rise in ANCA level may be useful for guiding treatment decisions in appropriate subsets of patients with ANCA-associated vasculitis.

Published
2015
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36. CD147/Basigin Limits Lupus Nephritis and Th17 Cell Differentiation in Mice by Inhibiting the Interleukin-6/STAT-3 Pathway

Author

Waichi Sato, Masaaki Murakami, Yukio Yuzawa, Daisuke Kamimura, Noritoshi Kato, Kayaho Maeda, Naotake Tsuboi, Seiichi Matsuo, Tomoki Kosugi, Hiroshi Kojima, Kenji Kadomatsu, Yuka Sato, and Shoichi Maruyama

Subjects
medicine.medical_specialty, biology, Cellular differentiation, Immunology, Lupus nephritis, medicine.disease, Molecular biology, In vitro, Pathogenesis, Endocrinology, Rheumatology, In vivo, Internal medicine, Basigin, medicine, biology.protein, Immunology and Allergy, Antibody, Interleukin 6
Abstract

Objective Interleukin-17 (IL-17)-producing T cells (Th17 cells) play critical roles in the pathogenesis of immune-related diseases, including systemic lupus erythematosus. However, the fundamental mechanism regulating Th17 cell differentiation is not fully understood. Recently, we demonstrated that plasma levels of CD147/basigin (Bsg) in patients with lupus nephritis (LN) were closely associated with disease activity. but the molecular mechanism involving Bsg has been elusive. Here, we addressed the role of Bsg in the pathogenesis of LN. Methods Injections of pristane (2,6,10,14-tetramethylpentadecane [TMPD]) were administered to Bsg(-/-) or Bsg(+/+) mice to induce LN. The mice were killed 6 months after being injected, for histologic and biochemical analyses of the kidneys and spleens. Results Pristane induced LN more strikingly in Bsg(-/-) mice than in Bsg(+/+) mice, even though humoral autoimmunity was similarly increased in both genotypes. The increased number of Th17, but not Th1, Treg cells, was augmented in Bsg(-/-) mice. The expression of IL-17 was also increased in the kidneys of Bsg(-/-) mice, in proportion to LN disease activity. Furthermore, treatment with anti-IL-17 antibody reduced LN disease activity in Bsg(-/-) mice. Complementary to these phenotypes of Bsg(-/-) mice, Bsg expression was enhanced in activated CD4+ T cells in vivo and in vitro. Bsg deficiency selectively augmented in vitro differentiation of naive CD4+ T cells to Th17 cells and STAT-3 phosphorylation during this differentiation. Moreover, STAT-3 phosphorylation was suppressed by crosslinking of Bsg with its antibody. Conclusion Bsg plays an indispensable role in Th17 cell differentiation as a negative regulator by suppressing the IL-6/STAT-3 pathway.

Published
2015
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37. The efficacy of tolvaptan as a diuretic for chronic kidney disease patients

Author

Fumiko Sakata, Naotake Tsuboi, Sawako Kato, Akihito Tanaka, Yasuhiro Suzuki, Tomoki Kosugi, Noritoshi Kato, Takenori Ozaki, Yasuhiko Ito, Yoshinari Yasuda, Seiichi Matsuo, Takayuki Katsuno, Shoichi Maruyama, Masashi Mizuno, and Waichi Sato

Subjects
Adult, Male, medicine.medical_treatment, Tolvaptan, Urination, Renal function, Pharmacology, Arginine vasopressin receptor 2, medicine, Humans, Renal Insufficiency, Chronic, Diuretics, Aged, Retrospective Studies, Aged, 80 and over, Dose-Response Relationship, Drug, Reabsorption, business.industry, Sodium, General Medicine, Antidiuretic Hormone Receptor Antagonists, Benzazepines, Middle Aged, medicine.disease, Treatment Outcome, Heart failure, Female, Diuretic, Cardiology and Cardiovascular Medicine, business, Follow-Up Studies, Glomerular Filtration Rate, medicine.drug, Kidney disease
Abstract

Tolvaptan selectively binds to the vasopressin V2 receptor and inhibits reabsorption of free water. Although its efficacy for heart failure has been proven, its efficacy for chronic kidney disease (CKD) patients has not been assessed in detail.We examined 20 CKD patients (13 men and 7 women) who presented with volume overload and who were administered tolvaptan. We assessed urine volume (UV) and blood biochemistry before administration (dO), 1 day after administration (d1), and 7 to 14 days after administration (d7-14).The mean age was 74.0 +/- 13.1 years. Besides CKD, there were 9, 8, and 5 patients with heart failure, liver failure or liver cirrhosis, andsevere oedema, respectively. UV significantly increased from 959.0 +/- 503.8 mL/day at d0 to 1605.4 +/- 964.0 mL/day at d7-14 (P0.01). Serum creatinine levels were not exacerbated (3.89 +/- 3.43 mg/dL at d0 and 3.66 +/- 3.02 mg/dL at d7-14). Serum albumin (ALB) levels and urinary protein creatinine ratio (uPCR) did not correlate with UV change. Estimated glomerular filtration rate (eGFR) correlated with UV change from d0 to d1 (r=0.6619, P0.01). Serum sodium elevation correlated with increased UV (r=0.4951, P0.05).Tolvaptan is useful to reduce volume overload without exacerbation of the renal function; its effect does not depend on ALB or uPCR. the eGFR correlated with the efficacy of tolvaptan. If UV increases drastically after tolvaptan administration, serum Na levels should be carefully monitored.

Published
2015
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38. Investigation on the benefits of mycophenolate mofetil and therapeutic drug monitoring in the treatment of Japanese patients with lupus nephritis

Author

Takenori Ozaki, Takuji Ishimoto, Yasuhiko Ito, Masashi Mizuno, Hangsoo Kim, Takayuki Katsuno, Asaka Hachiya, Tomoki Kosugi, Naotake Tsuboi, Takaya Ozeki, Sawako Kato, Shoichi Maruyama, and Noritoshi Kato

Subjects
Nephrology, Adult, Male, medicine.medical_specialty, Adolescent, Physiology, 030232 urology & nephrology, Lupus nephritis, Therapeutic drug monitoring, Gastroenterology, 03 medical and health sciences, Young Adult, Systemic lupus erythematosus, 0302 clinical medicine, Physiology (medical), Internal medicine, medicine, Humans, Adverse effect, Retrospective Studies, 030203 arthritis & rheumatology, medicine.diagnostic_test, business.industry, Mycophenolate mofetil, Area under the curve, Retrospective cohort study, Middle Aged, Mycophenolic Acid, medicine.disease, Lupus Nephritis, Confidence interval, Area Under Curve, Trough level, Female, Drug Monitoring, business
Abstract

Background: Mycophenolate mofetil (MMF) is recommended as a first-line immunosuppressant to treat lupus nephritis (LN). Prognosis and therapeutic response in LN are known to vary depending on race. We investigated the benefits of MMF and therapeutic drug monitoring (TDM) in the treatment of Japanese LN patients. Methods: In this retrospective cohort study, a total of 20 patients with LN who started MMF treatment were included. Clinical data were collected regularly after MMF administration. We evaluated complete remission (CR) rate as the primary outcome. Predictors of CR were identified using univariate and multivariate analyses. In the research of TDM, the correlation with the area under the curve (AUC) was analyzed at MMF dose, single-point value, treatment response, and adverse events. Results: Overall, 70% of cases showed CR; both flare-ups and refractory cases had favorable results. Cases of LN with nephrotic syndrome (NS) or class III/IV + V showed a significantly lower CR rate (p, ファイル公開：2019/12/01

Published
2017

39. Single-dose Rituximab Therapy for Refractory Idiopathic Membranous Nephropathy: A Single-center Experience

Author

Hangsoo Kim, Takuji Ishimoto, Shinichi Akiyama, Shoichi Maruyama, Takenori Ozaki, Yasuhiko Ito, Noritoshi Kato, Naotake Tsuboi, Tomoki Kosugi, Yasuhiro Suzuki, and Takayuki Katsuno

Subjects
Adult, Male, medicine.medical_specialty, Cyclophosphamide, 030232 urology & nephrology, Case Report, 030204 cardiovascular system & hematology, Single Center, Mycophenolate, Gastroenterology, Glomerulonephritis, Membranous, 03 medical and health sciences, 0302 clinical medicine, rituximab, Refractory, Membranous nephropathy, Asian People, Adrenal Cortex Hormones, Internal medicine, hemic and lymphatic diseases, Internal Medicine, medicine, Humans, Glucocorticoids, Aged, Mizoribine, business.industry, nephrotic syndrome, membranous nephropathy, General Medicine, Mycophenolic Acid, medicine.disease, Cyclosporine, Rituximab, Ribonucleosides, business, Nephrotic syndrome, Immunosuppressive Agents, medicine.drug
Abstract

To date, a recognized treatment for refractory membranous nephropathy (MN) has not been established. Recently, several reports have indicated the efficacy of rituximab as a novel treatment option. However, only a few published accounts exist of rituximab therapy for idiopathic MN (IMN) in the Asian population. We present the cases of three IMN patients who were treated with single-dose rituximab after they showed no response to conventional therapies, including corticosteroids, cyclosporine, cyclophosphamide, mizoribine, and mycophenolate mofetil. Although one case showed no response, a complete or incomplete remission was achieved in the other two cases. Rituximab may therefore be a beneficial treatment option for IMN.

Published
2017

40. The clinical relevance of plasma CD147/basigin in biopsy-proven kidney diseases

Author

Hiroshi Nagaya, Takuji Ishimoto, Hiroshi Kojima, Mayuko Hori, Yukio Yuzawa, Yuka Sato, Yoshiko Mori, Shoichi Maruyama, Tomoki Kosugi, Tomohiro Masuda, Kayaho Maeda, Kenji Kadomatsu, Takayuki Katsuno, Noritoshi Kato, and Tomoki Yoshioka

Subjects
Nephrology, Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Physiology, Biopsy, 030232 urology & nephrology, 030204 cardiovascular system & hematology, urologic and male genital diseases, Kidney, Nephropathy, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Focal segmental glomerulosclerosis, Membranous nephropathy, Physiology (medical), Internal medicine, medicine, Humans, Aged, Inflammation, Aged, 80 and over, medicine.diagnostic_test, urogenital system, business.industry, Acute kidney injury, Glomerulonephritis, IGA, Middle Aged, medicine.disease, Proteinuria, medicine.anatomical_structure, Cross-Sectional Studies, CD147, Basigin, Female, Kidney Diseases, Renal biopsy, business, Kidney disease
Abstract

Background: Precise understanding of kidney disease activity is needed to design therapeutic strategies. CD147/basigin is involved in the pathogenesis of acute kidney injury and renal fibrosis through inflammatory cell infiltration. The present study examined the clinical relevance of CD147 in biopsy-proven kidney diseases that lead to the progression of chronic kidney disease. Methods: Kidney biopsy specimens and plasma and urine samples were obtained from patients with kidney diseases, including IgA nephropathy (IgAN), Henoch–Schönlein purpura nephritis (HSPN), diabetic kidney disease (DKD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN), who underwent renal biopsy between 2011 and 2014. Plasma and urinary CD147 levels were measured and evaluated for their ability to reflect histological features. Disease activity of IgAN tissues was evaluated according to the Oxford classification and the Japanese histological grading system. Results: In biopsy tissues, CD147 induction was detected in injured lesions representing renal inflammation. Plasma CD147 values correlated with eGFR in patients with inflammation-related kidney diseases such as IgAN, HSPN, and DKD. Particularly in IgAN patients, plasma CD147 levels were correlated with injured regions comprising more than 50% of glomeruli or with tubular atrophy/interstitial injury in biopsy tissues. Proteinuria showed a closer correlation with urinary values of CD147 and L-FABP. Of note, plasma and urinary CD147 levels showed a strong correlation with eGFR or proteinuria, respectively, only in DKD patients. Conclusion: Evaluation of plasma and urinary CD147 levels might provide key insights for the understanding of the activity of various kidney diseases., ファイル公開：2019/08/01

Published
2017

41. Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis

Author

Kayaho Maeda, Yukio Yuzawa, Waichi Sato, Kenji Kadomatsu, Yuka Sato, Shoichi Maruyama, Tomohiro Masuda, Takuji Ishimoto, Noritoshi Kato, Hiroshi Kojima, Kenji Uchimura, Tomoki Kosugi, Naotake Tsuboi, Nagoya University, and Fujita Health University

Subjects
0301 basic medicine, medicine.medical_specialty, T cell, Cellular differentiation, T-Lymphocytes, Kidney Glomerulus, Biology, Lymphocyte Activation, Models, Biological, Pathology and Forensic Medicine, 03 medical and health sciences, Interleukin 21, Mice, 0302 clinical medicine, Models, Internal medicine, medicine, Cytotoxic T cell, Animals, IL-2 receptor, STAT4, Inflammation, NFATC Transcription Factors, ZAP70, Midkine, NFAT, Cell Differentiation, Th1 Cells, Biological, Lupus Nephritis, Cell biology, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cytokines, Intercellular Signaling Peptides and Proteins, Spleen, Signal Transduction
Abstract

Activated T cells play crucial roles in the pathogenesis of autoimmune diseases, including lupus nephritis (LN). The activation of calcineurin/nuclear factor of activated T cells (NFAT) and STAT4 signaling is essential for T cells to perform various effector functions. Here, we identified the growth factor midkine (MK; gene name, Mdk) as a novel regulator in the pathogenesis of 2,6,10,14-tetramethylpentadecane-induced LN via activation of NFAT and IL-12/STAT4 signaling. Wild-type (Mdk+/+) mice showed more severe glomerular injury than MK-deficient (Mdk-/-) mice, as demonstrated by mesangial hypercellularity and matrix expansion, and glomerular capillary loops with immune-complex deposition. Compared with Mdk-/- mice, the frequency of splenic CD69+ T cells and T helper (Th) 1 cells, but not of regulatory T cells, was augmented in Mdk+/+ mice in proportion to LN disease activity, and was accompanied by skewed cytokine production. MK expression was also enhanced in activated CD4+ T cells in vivo and in vitro. MK induced activated CD4+ T cells expressing CD69 through nuclear activation of NFAT transcription and selectively increased in vitro differentiation of naive CD4+ T cells into Th1 cells by promoting IL-12/STAT4 signaling. These results suggest that MK serves an indispensable role in the NFAT-regulated activation of CD4+ T cells and Th1 cell differentiation, eventually leading to the exacerbation of LN.

Published
2017
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42. Cancer Exosomes Perform Cell-Independent MicroRNA Biogenesis and Promote Tumorigenesis

Author

Lev T. Perelman, Raghu Kalluri, Edward Vitkin, Cristina Ivan, Joyce T. O’Connell, Noritoshi Kato, Le Qiu, Anthony Lucci, Alberto Villanueva, George A. Calin, Sonia A. Melo, Carlos A. Melo, Hikaru Sugimoto, and August Vidal

Subjects
0303 health sciences, Cancer Research, biology, Cancer, Cell Biology, Argonaute, medicine.disease_cause, medicine.disease, Microvesicles, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, microRNA, Cancer cell, Immunology, biology.protein, medicine, Cancer research, Gene silencing, Carcinogenesis, 030304 developmental biology, Dicer
Abstract

SummaryExosomes are secreted by all cell types and contain proteins and nucleic acids. Here, we report that breast cancer associated exosomes contain microRNAs (miRNAs) associated with the RISC-Loading Complex (RLC) and display cell-independent capacity to process precursor microRNAs (pre-miRNAs) into mature miRNAs. Pre-miRNAs, along with Dicer, AGO2, and TRBP, are present in exosomes of cancer cells. CD43 mediates the accumulation of Dicer specifically in cancer exosomes. Cancer exosomes mediate an efficient and rapid silencing of mRNAs to reprogram the target cell transcriptome. Exosomes derived from cells and sera of patients with breast cancer instigate nontumorigenic epithelial cells to form tumors in a Dicer-dependent manner. These findings offer opportunities for the development of exosomes based biomarkers and therapies.

Published
2014
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43. CD147/basigin reflects renal dysfunction in patients with acute kidney injury

Author

Hiroki Hayashi, Yuka Sato, Hiroshi Kojima, Shoichi Maruyama, Waichi Sato, Takuji Ishimoto, Kayaho Maeda, Mayuko Maeda-Hori, Hiroshi Nagaya, Yukio Yuzawa, Seiichi Matsuo, Tomoki Kosugi, Noritoshi Kato, and Kenji Kadomatsu

Subjects
Adult, Male, Nephrology, medicine.medical_specialty, Pathology, Adolescent, Physiology, Fatty Acid-Binding Proteins, Kidney, urologic and male genital diseases, Pathogenesis, Necrosis, Young Adult, Ischemia, Fibrosis, Physiology (medical), Internal medicine, Humans, Medicine, Acute tubular necrosis, Aged, Renal ischemia, urogenital system, business.industry, Acute kidney injury, Kidney metabolism, Acute Kidney Injury, Middle Aged, medicine.disease, Case-Control Studies, Creatinine, Basigin, Female, business, Biomarkers
Abstract

Acute tubular necrosis (ATN) describes a form of intrinsic acute kidney injury (AKI) that results from persistent hypoperfusion and subsequent activation of the immune system. A glycosylated transmembrane protein, CD147/basigin, is involved in the pathogenesis of renal ischemia and fibrosis. The present study investigated whether CD147 can reflect pathological features and renal dysfunction in patients with AKI.Plasma and spot urine samples were collected from 24 patients (12 controls and 12 with ATN) who underwent renal biopsy between 2008 and 2012. In another study, patients undergoing open surgery to treat abdominal aortic aneurysms (AAAs) were enrolled in 2004. We collected urine and plasma samples from seven patients with AKI and 33 patients without AKI, respectively. In these experiments, plasma and urinary CD147, and urinary L-fatty acid-binding protein (L-FABP) levels were measured, and the former expression in kidneys was examined by immunostaining.In biopsy tissues of ATN with severe histological features, CD147 induction was strikingly present in inflammatory cells such as macrophages and lymphocytes in the injured interstitium, but not in damaged tubules representing atrophy. Both plasma and urinary CD147 levels were strikingly increased in ATN patients; both values showed greater correlations with renal dysfunction compared to urinary L-FABP. In patients who had undergone open AAA surgery, urinary and plasma CD147 values in AKI patients were significantly higher than in non-AKI patients at post-operative day 1, similar to the profile of urinary L-FABP.CD147 was prominent in its ability to detect AKI and may allow the start of preemptive medication.

Published
2013
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44. TGF-β1–Containing Exosomes from Injured Epithelial Cells Activate Fibroblasts to Initiate Tissue Regenerative Responses and Fibrosis

Author

Raghu Kalluri, Noritoshi Kato, Fernanda Borges, Vincent H. Gattone, Valerie S. LeBleu, Berna C. Özdemir, Caroline A. Miller, Sonia A. Melo, and Ignacio Revuelta

Subjects
Male, Pathology, medicine.medical_specialty, Biology, Exosomes, Kidney, Models, Biological, Transforming Growth Factor beta1, Mice, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Parenchyma, medicine, Animals, Humans, Regeneration, RNA, Messenger, Fibroblast, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Messenger RNA, Epithelial Cells, General Medicine, Fibroblasts, medicine.disease, Cell Hypoxia, Microvesicles, 3. Good health, Cell biology, Mice, Inbred C57BL, medicine.anatomical_structure, Nephrology, 030220 oncology & carcinogenesis, NIH 3T3 Cells, Type I collagen, Transforming growth factor
Abstract

Hypoxia is associated with tissue injury and fibrosis but its functional role in fibroblast activation and tissue repair/regeneration is unknown. Using kidney injury as a model system, we demonstrate that injured epithelial cells produce an increased number of exosomes with defined genetic information to activate fibroblasts. Exosomes released by injured epithelial cells promote proliferation, α-smooth muscle actin expression, F-actin expression, and type I collagen production in fibroblasts. Fibroblast activation is dependent on exosomes delivering TGF-β1 mRNA among other yet to be identified moieties. This study suggests that TGF-β1 mRNA transported by exosomes constitutes a rapid response to initiate tissue repair/regenerative responses and activation of fibroblasts when resident parenchyma is injured. The results also inform potential utility of exosome-targeted therapies to control tissue fibrosis.

Published
2013
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45. The E-Selectin Ligand Basigin/CD147 Is Responsible for Neutrophil Recruitment in Renal Ischemia/Reperfusion

Author

Kazuma Sakamoto, Yukio Yuzawa, Yuko Miwa, Kenji Kadomatsu, Waichi Sato, Seiichi Matsuo, Akinori Hobo, Noritoshi Kato, and Tomoki Kosugi

Subjects
Umbilical Veins, medicine.medical_specialty, Neutrophils, Ischemia, Inflammation, Kidney, Ligands, Mice, Cell Movement, Internal medicine, E-selectin, Cell Adhesion, medicine, Animals, Humans, Cells, Cultured, Mice, Knockout, biology, Renal ischemia, business.industry, General Medicine, Acute Kidney Injury, medicine.disease, Extravasation, Disease Models, Animal, Basic Research, Endocrinology, medicine.anatomical_structure, Nephrology, Reperfusion Injury, Basigin, Immunology, biology.protein, Endothelium, Vascular, medicine.symptom, E-Selectin, business, Cell Adhesion Molecules, Reperfusion injury
Abstract

E-selectin and its ligands are essential for extravasation of leukocytes in inflammation. Here, we report that basigin (Bsg)/CD147 is a ligand for E-selectin that promotes renal inflammation in ischemia/reperfusion. Compared with wild-type mice, Bsg-deficient (Bsg(-/-)) mice demonstrated striking suppression of neutrophil infiltration in the kidney after renal ischemia/reperfusion. Although E-selectin expression increased similarly between the two genotypes, Bsg(-/-) mice exhibited less renal damage, suggesting that Bsg on neutrophils contribute to renal injury in this model. Neutrophils expressed Bsg with N-linked polylactosamine chains and Bsg(-)(/)(-) neutrophils showed reduced binding to E-selectin. Bsg isolated from HL-60 cells bound to E-selectin, and tunicamycin treatment to abolish N-linked glycans from Bsg abrogated this binding. Furthermore, Bsg(-)(/)(-) neutrophils exhibited reduced E-selectin-dependent adherence to human umbilical vein endothelial cells in vitro. Injection of labeled neutrophils into mice showed that Bsg(-)(/)(-) neutrophils were less readily recruited to the kidney after renal ischemia/reperfusion than Bsg(+/+) neutrophils, regardless of the recipient's genotype. Taken together, these results indicate that Bsg is a physiologic ligand for E-selectin that plays a critical role in the renal damage induced by ischemia/reperfusion.

Published
2009
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46. Overexpression of Calmodulin in Pancreatic β Cells Induces Diabetic Nephropathy

Author

Waichi Sato, Yukio Yuzawa, Tomoki Kosugi, Noritoshi Kato, Motohiro Takeda, Futoshi Yoshida, Toshihide Kimura, Seiichi Matsuo, Shoichi Maruyama, Yukiko Kaneko, Jyunichiro Yamamoto, Ichiro Niki, Takahiko Nakagawa, and Yoshiaki Tagawa

Subjects
Vascular Endothelial Growth Factor A, medicine.medical_specialty, Nitric Oxide Synthase Type III, Thrombomodulin, Mice, Transgenic, Kidney, Nitric oxide, Pathogenesis, Diabetic nephropathy, Mice, chemistry.chemical_compound, Type IV collagen, Calmodulin, Insulin-Secreting Cells, Internal medicine, Animals, Medicine, Diabetic Nephropathies, Endothelial dysfunction, business.industry, General Medicine, medicine.disease, Immunohistochemistry, Capillaries, Vascular endothelial growth factor, Arterioles, Disease Models, Animal, Vascular endothelial growth factor A, Receptors, Vascular Endothelial Growth Factor, Basic Research, Endocrinology, chemistry, Nephrology, Female, business
Abstract

Recently, endothelial dysfunction induced by an uncoupling of vascular endothelial growth factor (VEGF) and nitric oxide has been implicated in the pathogenesis of diabetic nephropathy (DN). Investigating the pathogenesis of DN has been limited, however, because of the lack of animal models that mimic the human disease. In this report, pancreatic beta cell-specific calmodulin-overexpressing transgenic (CaMTg) mice, a potential new model of DN, are characterized with particular emphasis on VEGF and related molecules. CaMTg mice developed hyperglycemia at 3 wk and persistent proteinuria by 3 mo. Morphometric analysis showed considerable increases in the glomerular and mesangial areas with deposition of type IV collagen. Moreover, the pathologic hallmarks of human DN (mesangiolysis, Kimmelstiel-Wilson-like nodular lesions, exudative lesions, and hyalinosis of afferent and efferent arteries with neovascularization) were observed. In addition, increased VEGF expression was associated with an increased number of peritubular capillaries. Expression of endothelial nitric oxidase synthase was reduced and that of VEGF was markedly elevated in CaMTg mice kidney compared with nontransgenic mice. No differences in VEGF receptor-1 or VEGF receptor-2 expression were observed between CaMTg mice and nontransgenic kidneys. In summary, CaMTg mice develop most of the distinguishing lesions of human DN, and the elevated VEGF expression in the setting of diminished endothelial nitric oxide synthase expression may lead to endothelial proliferation and dysfunction. This model may prove useful in the study of the pathogenesis and treatment of DN.

Published
2008
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47. Midkine is involved in tubulointerstitial inflammation associated with diabetic nephropathy

Author

Yukio Yuzawa, Noritoshi Kato, Waichi Sato, Kenji Kadomatsu, Tomoki Kosugi, Seiichi Matsuo, Norihiko Suzuki, and Hanayo Arata-Kawai

Subjects
Adult, medicine.medical_specialty, medicine.medical_treatment, Inflammation, Diabetes Mellitus, Experimental, Pathology and Forensic Medicine, Pathogenesis, Diabetic nephropathy, Mice, Internal medicine, medicine, Animals, Humans, Diabetic Nephropathies, Osteopontin, Molecular Biology, Chemokine CCL2, Aged, Mice, Knockout, Midkine, biology, business.industry, Macrophages, Growth factor, Glomerulosclerosis, Cell Biology, Middle Aged, medicine.disease, Endocrinology, Case-Control Studies, Hyperglycemia, biology.protein, Cytokines, Nephritis, Interstitial, Female, medicine.symptom, business, Nephritis
Abstract

The concept that inflammation plays a crucial role in the pathogenesis of diabetic nephropathy has been recently emerging, although the principal pathology of diabetic nephropathy comprises glomerular sclerosis and associated changes in nephrons. Here, we identified the growth factor midkine (MK) as a novel key molecule involved in inflammation associated with Streptozotocin-induced diabetic nephropathy. The tubulointerstitial damage, as assessed as morphological changes, osteopontin expression, collagen I deposition and macrophage infiltration, were strikingly less in MK-deficient (Mdk(-/-)) mice than in Mdk(+/+) mice. Monocyte chemoattractant protein (MCP)-1 expression, but not that of intercellular adhesion molecule-1, was also lower in Mdk(-/-) mice. High glucose upregulated MK expression in primary-cultured tubular epithelial cells, and induced MCP-1 to a larger extent in Mdk(+/+) cells than in Mdk(-/-) cells. Correspondingly, the combination of exogenous MK and high glucose enhanced MCP-1 expression in Mdk(-/-) cells. Furthermore, high glucose and oxidant stress enhanced MK expression in macrophages. Consistent with the findings in the mouse model, MK expression was detected in the glomeruli, tubular epithelium and interstitium of kidneys from patients with diabetic nephropathy. Our data indicate that MK plays a critical role in the tubulointerstitial inflammation associated with diabetic nephropathy through activation of the MCP-1 pathway.

Published
2007
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49. Massive pleural effusion induced by internal jugular vein catheterization for hemodialysis

Author

Noritoshi Kato, Yukio Yuzawa, Shizunori Ichida, and Rieko Okada

Subjects
medicine.medical_specialty, Pleural effusion, business.industry, medicine.medical_treatment, Internal medicine, medicine, Cardiology, Hemodialysis, medicine.disease, business, Internal jugular vein, Surgery
Abstract

透析用ダブルルーメンカテーテルの右内頸静脈への長期留置が, 同側の胸水貯留の原因と考えられた症例を経験した. 症例は45歳男性, 10年前より糖尿病を指摘されており通院中, 急激な全身の浮腫が著明となり入院. 10g/日以上の高度蛋白尿および, 全身の浮腫と重度の低蛋白血症を伴ったネフローゼ症候群をきたしており, 腎生検組織型は糖尿病性腎症と膜性腎症の合併を認めた. 保存的な治療法に反応が乏しく心不全傾向が出現してきたため, 右内頸静脈にダブルルーメンカテーテルを留置しECUMを開始, 徐々に腎機能も増悪し血液透析へと移行した. シャントの作成が困難で, 長期間の右内頸静脈へのダブルルーメンカテーテル留置を余儀なくされた. カテーテル交換は随時施行していたが, 留置後45日目より急激な右胸水, 右頸部, 顔面の浮腫が出現した. 胸水は漏出性であり, トロッカーから, 一日1,500mL以上の胸水が流出した. 右内頸静脈からのDSAから, 右静脈角の狭窄の存在を確認した. カテーテル抜去後, 胸水および浮腫は速やかに消失した.本症例における胸水貯留の機序は, 右内頸静脈カテーテル存在下における右リンパ本幹の静脈角での閉塞により, 気管支縦隔リンパ本幹, 鎖骨下りンパ本幹, 頸リンパ本幹の静脈系への流入路が絶たれた可能性が考えられた.

Published
2004
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