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1. New marker for chronic kidney disease progression and mortality in medical-word virtual space

Author

Eiichiro Kanda, Bogdan I. Epureanu, Taiji Adachi, Tamaki Sasaki, and Naoki Kashihara

Subjects
Medicine, Science
Abstract

Abstract A new marker reflecting the pathophysiology of chronic kidney disease (CKD) has been desired for its therapy. In this study, we developed a virtual space where data in medical words and those of actual CKD patients were unified by natural language processing and category theory. A virtual space of medical words was constructed from the CKD-related literature (n = 165,271) using Word2Vec, in which 106,612 words composed a network. The network satisfied vector calculations, and retained the meanings of medical words. The data of CKD patients of a cohort study for 3 years (n = 26,433) were transformed into the network as medical-word vectors. We let the relationship between vectors of patient data and the outcome (dialysis or death) be a marker (inner product). Then, the inner product accurately predicted the outcomes: C-statistics of 0.911 (95% CI 0.897, 0.924). Cox proportional hazards models showed that the risk of the outcomes in the high-inner-product group was 21.92 (95% CI 14.77, 32.51) times higher than that in the low-inner-product group. This study showed that CKD patients can be treated as a network of medical words that reflect the pathophysiological condition of CKD and the risks of CKD progression and mortality.

Published
2024
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2. IL-1β may be an indicator of peritoneal deterioration after healing of peritoneal dialysis-associated peritonitis

Author

Akira Hirano, Hiroyuki Kadoya, Yu Yamanouchi, Seiji Kishi, Tamaki Sasaki, and Naoki Kashihara

Subjects
Chronic inflammation, IL-1β, Inflammasome, Peritoneal dialysis, Peritonitis, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Abstract Background Peritoneal dialysis (PD) is an essential lifesaving treatment for end-stage renal disease. However, PD therapy is limited by peritoneal inflammation, which leads to peritoneal membrane failure because of progressive peritoneal deterioration. Peritonitis is the most common complication in patients undergoing PD. Thus, elucidating the mechanism of chronic peritoneal inflammation after PD-associated peritonitis is an urgent issue for patients undergoing PD. This first case report suggests that an increased interleukin-1β (IL-1β) expression in the peritoneal dialysate after healing of peritonitis can contribute to peritoneal deterioration. Case presentation A 64-year-old woman was diagnosed with diabetes mellitus 10 years ago and had been started on PD for end-stage renal disease. One day, the patient developed PD-associated acute peritonitis and was admitted to our hospital for treatment. Thus, treatment with antimicrobial agents was initiated for PD-associated peritonitis. Dialysate turbidity gradually disappeared after treatment with antimicrobial agents, and the number of cells in the PD fluid decreased. After 2 weeks of antimicrobial therapy, peritonitis was clinically cured, and the patient was discharged. Thereafter, the patient did not develop peritonitis; however, residual renal function tended to decline, and peritoneal function also decreased in a relatively short period. We evaluated pro-inflammatory cytokine levels before and after PD-associated peritonitis; interestingly, the levels of IL-1β remained high in the PD fluid, even after remission of bacterial peritonitis. In addition, it correlated with decreased peritoneal function. Conclusions This case suggests that inflammasome-derived pro-inflammatory cytokines may contribute to chronic inflammation-induced peritoneal deterioration after PD-related peritonitis is cured.

Published
2023
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3. The Impact of Potassium Binders on Mortality in Patients with Hyperkalemia: A Single-Center Study

Author

Hajime Nagasu, Atsuyuki Tokuyama, Eiichiro Kanda, Seiji Itano, Seiji Kishi, Tamaki Sasaki, and Naoki Kashihara

Subjects
chronic kidney disease, electronic medical record, hyperkalemia, potassium binder, Internal medicine, RC31-1245
Abstract

Hyperkalemia is associated with an increased risk of mortality and is a common complication in patients with chronic kidney disease (CKD). Despite the prevalence of hyperkalemia, current real-world data suggest that serum potassium levels are not effectively managed in clinical practice. The potential benefit of potassium binders in reducing the risk of death has not been thoroughly investigated. Therefore, this retrospective cohort study aimed to investigate the potential impact of potassium binders on mortality risk in patients with CKD by analyzing electronic medical records. The study included 1689 patients with CKD and hyperkalemia (serum potassium level > 5.0 mEq/L), who visited Kawasaki Medical School Hospital between January 2014 and December 2018. The patients were divided into two groups: those without CPS (calcium polystyrene sulphonate) treatment (CPS_OFF) and those with CPS treatment (CPS_ON). The results showed that the incidence of death was significantly higher in the CPS_OFF group than in the CPS_ON group (22.3% vs. 19.6%, p < 0.001). After propensity score matching, the CPS_ON group had a higher survival rate than the CPS_OFF group (log-rank test, p = 0.020). These results suggest that potassium binders may reduce the risk of death in patients with CKD and hyperkalemia. We hope that the results of this cohort study will be confirmed in future RCTs.

Published
2023
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4. Effect of zinc deficiency on chronic kidney disease progression and effect modification by hypoalbuminemia.

Author

Atsuyuki Tokuyama, Eiichiro Kanda, Seiji Itano, Megumi Kondo, Yoshihisa Wada, Hiroyuki Kadoya, Kengo Kidokoro, Hajime Nagasu, Tamaki Sasaki, and Naoki Kashihara

Subjects
Medicine, Science
Abstract

Serum zinc (Zn) levels tend to be low in chronic kidney disease (CKD) patients. This cohort study was conducted to investigate the relationship between zinc deficiency and CKD progression. Patients were classified into two groups based on Zn levels < 60 μg/dl (low-Zn group, n = 160) and ≥ 60 μg/dl (high-Zn group, n = 152). The primary outcome was defined as end-stage kidney disease (ESKD) or death and was examined over a 1-year observation period. Overall, the mean Zn level was 59.6 μg/dl and the median eGFR was 20.3 ml/min/1.73 m2. The incidence of the primary outcome was higher in the low-Zn group (p

Published
2021
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5. Impact of heavy rains of 2018 in western Japan: disaster-induced health outcomes among the population of Innoshima Island

Author

Srinivas Bandaru, Shunji Sano, Yurika Shimizu, Yuka Seki, Yoshikazu Okano, Tamaki Sasaki, Hideho Wada, Takemi Otsuki, and Tatsuo Ito

Subjects
Epidemiology, Occupational health, Public health, Quality of life, Japan heavy Rain, Water outage, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

Southwestern Japan suffered its worst rains in 2018 causing floods and mudslides, claiming 225 lives and forcing millions for evacuations. Referred as “Heisei san-jū-nenshichi-gatsugōu”, the disaster was the result of incessant precipitation caused by the interaction of typhoon “Prapiroon” with the seasonal rain front ''Baiu''. The present epidemiological study aims to investigate disaster-induced health issues in 728 residents of Innoshima island in the Hiroshima Prefecture by comparing their clinical data in pre-disaster (2017) and disaster-hit (2018) years which was obtained from annual health screening. Comparison of data showed a significant increase in the urine protein concentration in victims following the disaster. Probing further into the household conditions, showed that a total of 59,844 households were affected with water outage during the heavy rains, which was accompanied by severe damage of sewerage pipelines with complete recovery process taking two weeks. This two weeks of the crisis forced victims to refrain from using restrooms which in turn led to infrequent urination, thereby explaining the increased urine protein concentration in victims following the disaster. The present study addresses the acute health implications caused by the water crisis and serves as a precautionary measure for disaster management council to provide enhanced aftercare services in victims in further events of natural disasters.

Published
2020
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6. Endothelial Dysfunction Accelerates Impairment of Mitochondrial Function in Ageing Kidneys via Inflammasome Activation

Author

Yoshihisa Wada, Reina Umeno, Hajime Nagasu, Megumi Kondo, Atsuyuki Tokuyama, Hiroyuki Kadoya, Kengo Kidokoro, Shun’ichiro Taniguchi, Masafumi Takahashi, Tamaki Sasaki, and Naoki Kashihara

Subjects
inflammasome, senescence-associated secretory phenotype, macrophages, mitochondria dysfunction, ASC-deficient mice, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Chronic kidney disease is a common problem in the elderly and is associated with increased mortality. We have reported on the role of nitric oxide, which is generated from endothelial nitric oxide synthase (eNOS), in the progression of aged kidneys. To elucidate the role of endothelial dysfunction and the lack of an eNOS-NO pathway in ageing kidneys, we conducted experiments using eNOS and ASC-deficient mice. C57B/6 J mice (wild type (WT)), eNOS knockout (eNOS KO), and ASC knockout (ASC KO) mice were used in the present study. Then, eNOS/ASC double-knockout (eNOS/ASC DKO) mice were generated by crossing eNOS KO and ASC KO mice. These mice were sacrificed at 17−19 months old. The Masson positive area and the KIM-1 positive area tended to increase in eNOS KO mice, compared with WT mice, but not eNOS/ASC DKO mice. The COX-positive area was significantly reduced in eNOS KO mice, compared with WT and eNOS/ASC DKO mice. To determine whether inflammasomes were activated in infiltrating macrophages, the double staining of IL-18 and F4/80 was performed. IL-18 and F4/80 were found to be co-localised in the tubulointerstitial areas. Inflammasomes play a pivotal role in inflammaging in ageing kidneys. Furthermore, inflammasome activation may accelerate cellular senescence via mitochondrial dysfunction. The importance of endothelial function as a regulatory mechanism suggests that protection of endothelial function may be a potential therapeutic target.

Published
2021
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7. Infiltration of M1, but not M2, macrophages is impaired after unilateral ureter obstruction in Nrf2-deficient mice

Author

Yuji Sogawa, Hajime Nagasu, Shigeki Iwase, Chieko Ihoriya, Seiji Itano, Atsushi Uchida, Kengo Kidokoro, Shun’ichiro Taniguchi, Masafumi Takahashi, Minoru Satoh, Tamaki Sasaki, Takafumi Suzuki, Masayuki Yamamoto, Tiffany Horng, and Naoki Kashihara

Subjects
Medicine, Science
Abstract

Abstract Chronic inflammation can be a major driver of the failure of a variety of organs, including chronic kidney disease (CKD). The NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been shown to play a pivotal role in inflammation in a mouse kidney disease model. Nuclear factor erythroid 2-related factor 2 (Nrf2), the master transcription factor for anti-oxidant responses, has also been implicated in inflammasome activation under physiological conditions. However, the mechanism underlying inflammasome activation in CKD remains elusive. Here, we show that the loss of Nrf2 suppresses fibrosis and inflammation in a unilateral ureter obstruction (UUO) model of CKD in mice. We consistently observed decreased expression of inflammation-related genes NLRP3 and IL-1β in Nrf2-deficient kidneys after UUO. Increased infiltration of M1, but not M2, macrophages appears to mediate the suppression of UUO-induced CKD symptoms. Furthermore, we found that activation of the NLRP3 inflammasome is attenuated in Nrf2-deficient bone marrow–derived macrophages. These results demonstrate that Nrf2-related inflammasome activation can promote CKD symptoms via infiltration of M1 macrophages. Thus, we have identified the Nrf2 pathway as a promising therapeutic target for CKD.

Published
2017
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8. The eNOS-NO pathway attenuates kidney dysfunction via suppression of inflammasome activation in aldosterone-induced renal injury model mice.

Author

Yuji Sogawa, Hajime Nagasu, Seiji Itano, Kengo Kidokoro, Shun'ichiro Taniguchi, Masafumi Takahashi, Hiroyuki Kadoya, Minoru Satoh, Tamaki Sasaki, and Naoki Kashihara

Subjects
Medicine, Science
Abstract

Hypertension causes vascular complications, such as stroke, cardiovascular disease, and chronic kidney disease (CKD). The relationship between endothelial dysfunction and progression of kidney disease is well known. However, the relationship between the eNOS-NO pathway and chronic inflammation, which is a common pathway for the progression of kidney disease, remains unexplored. We performed in vivo experiments to determine the role of the eNOS-NO pathway by using eNOS-deficient mice in a hypertensive kidney disease model. All mice were unilateral nephrectomized (Nx). One week after Nx, the mice were randomly divided into two groups: the aldosterone infusion groups and the vehicle groups. All mice also received a 1% NaCl solution instead of drinking water. The aldosterone infusion groups were treated with hydralazine to correct blood pressure differences. After four weeks of drug administration, all mice were euthanized, and blood and kidney tissue samples were collected. In the results, NLRP3 inflammasome activation was elevated in the kidneys of the eNOS-deficient mice, and tubulointerstitial fibrosis was accelerated. Suppression of inflammasome activation by knocking out ASC prevented tubulointerstitial injury in the eNOS knockout mice, indicating that the eNOS-NO pathway is involved in the development of kidney dysfunction through acceleration of NLRP3 inflammasome in macrophages. We revealed that endothelial function, particularly the eNOS-NO pathway, attenuates the progression of renal tubulointerstitial injury via suppression of inflammasome activation. Clinically, patients who develop vascular endothelial dysfunction have lifestyle diseases, such as hypertension or diabetes, and are known to be at risk for CKD. Our study suggests that the eNOS-NO pathway could be a therapeutic target for the treatment of chronic kidney disease associated with endothelial dysfunction.

Published
2018
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9. The Impact of Potassium Binders on Mortality in Patients with Hyperkalemia: A Single-Center Study

Author

Kashihara, Hajime Nagasu, Atsuyuki Tokuyama, Eiichiro Kanda, Seiji Itano, Seiji Kishi, Tamaki Sasaki, and Naoki

Subjects
chronic kidney disease, electronic medical record, hyperkalemia, potassium binder
Abstract

Hyperkalemia is associated with an increased risk of mortality and is a common complication in patients with chronic kidney disease (CKD). Despite the prevalence of hyperkalemia, current real-world data suggest that serum potassium levels are not effectively managed in clinical practice. The potential benefit of potassium binders in reducing the risk of death has not been thoroughly investigated. Therefore, this retrospective cohort study aimed to investigate the potential impact of potassium binders on mortality risk in patients with CKD by analyzing electronic medical records. The study included 1689 patients with CKD and hyperkalemia (serum potassium level > 5.0 mEq/L), who visited Kawasaki Medical School Hospital between January 2014 and December 2018. The patients were divided into two groups: those without CPS (calcium polystyrene sulphonate) treatment (CPS_OFF) and those with CPS treatment (CPS_ON). The results showed that the incidence of death was significantly higher in the CPS_OFF group than in the CPS_ON group (22.3% vs. 19.6%, p < 0.001). After propensity score matching, the CPS_ON group had a higher survival rate than the CPS_OFF group (log-rank test, p = 0.020). These results suggest that potassium binders may reduce the risk of death in patients with CKD and hyperkalemia. We hope that the results of this cohort study will be confirmed in future RCTs.

Published
2023
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10. 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

11. A rare case of amyloid light-chain amyloidosis with bilateral perirenal hematoma shortly after initiation of peritoneal dialysis

Author

Naoki Kashihara, Toshiya Yamamoto, Eriko Urabe, Hiroyuki Kadoya, Tamaki Sasaki, and Seiji Itano

Subjects
medicine.medical_specialty, business.industry, medicine.medical_treatment, Amyloidosis, Renal Hemorrhage, 030232 urology & nephrology, Case Report, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, Surgery, Peritoneal dialysis, Angiopathy, 03 medical and health sciences, 0302 clinical medicine, medicine, Renal replacement therapy, Hemodialysis, Hemoperitoneum, medicine.symptom, business, Kidney disease
Abstract

Peritoneal dialysis (PD) is valuable for patients starting on renal replacement therapy because it preserves residual renal function, maintains hemodynamic stability, and affords higher quality of life than hemodialysis. Amyloid-related kidney disease is a rare condition and a cause of end-stage renal disease, the incidence of which appears to be rising in recent years. Hemoperitoneum is a common complication of PD. In some cases, it requires urgent treatment and careful monitoring for deterioration and potential complications. Although the kidney is a retroperitoneal organ, renal hemorrhage can cause bloody peritoneal dialysate. We encountered a rare case of amyloid light-chain amyloidosis where bilateral perirenal hematoma occurred shortly after initiation of PD. Amyloid angiopathy with increased blood vessel fragility and impaired vasoconstriction may promote bleeding. Therefore, hemoperitoneum in a patient on PD with disease causing fragile blood vessels, such as amyloidosis, should alert the physician to the possibility of underlying angiopathy.

Published
2021

13. Klotho is a novel therapeutic target in peritoneal fibrosis via Wnt signaling inhibition

Author

Hajime Nagasu, Kengo Kidokoro, Megumi Kondo, Minoru Satoh, Yoshihisa Wada, Tamaki Sasaki, Hiroyuki Kadoya, Yuji Sogawa, Naoki Kashihara, and Yuko Nishi

Subjects
0301 basic medicine, Transgene, 030232 urology & nephrology, Mice, Transgenic, Mice, 03 medical and health sciences, 0302 clinical medicine, Peritoneum, Fibrosis, Animals, Humans, Medicine, Klotho Proteins, Peritoneal Fibrosis, Klotho, beta Catenin, Glucuronidase, Transplantation, business.industry, Wnt signaling pathway, medicine.disease, Eukaryotic translation elongation factor 1 alpha 1, Mice, Inbred C57BL, Wnt Proteins, 030104 developmental biology, medicine.anatomical_structure, Nephrology, Cancer research, Signal transduction, business, Peritoneal Dialysis
Abstract

Background Long-term exposure to bioincompatible peritoneal dialysate causes the loss of mesothelial cells and accumulation of matrix proteins, leading to an increase in the thickness of the submesothelial layer, thereby limiting the long-term effectiveness of peritoneal dialysis (PD). However, the detailed molecular mechanisms underlying the process of peritoneal fibrosis have not been clearly elucidated. Wnt/β-catenin signaling pathway activation has been suggested to play a pivotal role in the development of organ fibrosis. Moreover, Klotho protein can regulate Wnt/β-catenin signaling. We examined the role of Klotho protein in reducing peritoneal fibrosis by inhibiting Wnt/β-catenin signaling. Methods The β-catenin-activated transgenic (BAT) driving expression of nuclear β-galactosidase reporter transgenic (BAT-LacZ) mice, the alpha-Klotho gene under control of human elongation factor 1 alpha promoter [Klotho transgenic (KLTG) and C57BL/6 background] and C57BL/6 mice [wild-type (WT)] were used. The mice received daily intraperitoneal (i.p.) injections of 4.25% glucose with lactate (PD solution) or saline as a control for 4 weeks. Other mice received daily i.p. injections of the same volume of saline (normal control). Results After exposure to PD, Wnt signal activation was observed on the peritoneal mesothelial cells in WT-PD mice. The peritoneal fibrosis was also accelerated in WT-PD mice. The protein expression of β-catenin and Wnt-inducible genes were also remarkably increased in WT-PD mice. On the other hand, KLTG-PD mice attenuated activation of Wnt/β-catenin signaling after exposure to PD and ameliorated the progression of peritoneal fibrosis. Conclusions Overexpression of Klotho protein protects the peritoneal membrane through attenuation of the Wnt/β-catenin signaling pathway. The availability of recombinant Klotho protein would provide a novel potential therapeutic target in peritoneal fibrosis.

Published
2020

15. Renal cell carcinoma sharply captured by imaging technology at an early stage in a hemodialysis patient: Usefulness of noninvasive monochrome superb microvascular imaging

Author

Atsuyuki Tokuyama, Atsushi Obata, Takahiro Obata, Hiroyuki Kadoya, Naoki Kashihara, Rie Ohsawa, Tamaki Sasaki, and Hideaki Kaneto

Subjects
medicine.medical_specialty, renal cell carcinoma, medicine.medical_treatment, 030232 urology & nephrology, Case Report, Type 2 diabetes, Case Reports, 030204 cardiovascular system & hematology, Malignancy, urologic and male genital diseases, 03 medical and health sciences, 0302 clinical medicine, Vascularity, Renal cell carcinoma, medicine, Stage (cooking), hemodialysis, business.industry, monochrome superb microvascular imaging, Hematology, Blood flow, ultrasonography, medicine.disease, Nephrology, Imaging technology, Radiology, Hemodialysis, type 2 diabetes, medicine.symptom, business
Abstract

It has been drawing much attention that type 2 diabetes mellitus is closely associated with increased incidence of numerous cancers and their poor prognosis. Consequently, malignancy has been recently recognized as one of diabetic complications in addition to various conventional complications. Furthermore, it is well known that the prevalence of renal cell carcinoma (RCC) is drastically increased in hemodialysis (HD) patients. Therefore, screening of RCCs in HD patients is a very important and urgent issue as there are no highly sensitive tumor markers for RCCs. Monochrome superb microvascular imaging (mSMI) is a relatively new Doppler ultrasound technique and is useful especially when evaluating very slow blood flow state, because this allows for imaging microvessels with low velocity in the absence of a contrast agent. Thus, mSMI might be also useful when contrast enhancement is not obvious on CT and/or contrast‐enhanced ultrasonography using perflubutane or contrast agents are contraindicated. Moreover, it has been reported that mSMI could effectively detect vascularity of renal malignant tumor than benign renal mass in nondialysis patients. We propose that mSMI of ultrasonography could become one of the very useful methods for detecting RCCs at an early stage with high sensitivity in HD patients.

Published
2021

16. Endothelial Dysfunction Accelerates Impairment of Mitochondrial Function in Ageing Kidneys via Inflammasome Activation

Author

Megumi Kondo, Shun'ichiro Taniguchi, Yoshihisa Wada, Atsuyuki Tokuyama, Hiroyuki Kadoya, Masafumi Takahashi, Tamaki Sasaki, Kengo Kidokoro, Reina Umeno, Naoki Kashihara, and Hajime Nagasu

Subjects
Male, Aging, Inflammasomes, Kidney, chemistry.chemical_compound, Mice, Enos, Endothelial dysfunction, Biology (General), Spectroscopy, Mice, Knockout, biology, Inflammasome, General Medicine, Computer Science Applications, Mitochondria, macrophages, Chemistry, senescence-associated secretory phenotype, medicine.drug, medicine.medical_specialty, Nitric Oxide Synthase Type III, QH301-705.5, Mice, Transgenic, Nitric Oxide, Catalysis, Article, Nitric oxide, Inorganic Chemistry, inflammasome, Internal medicine, medicine, Animals, mitochondria dysfunction, Endothelium, Vascular Diseases, Physical and Theoretical Chemistry, Molecular Biology, QD1-999, business.industry, Organic Chemistry, Wild type, ASC-deficient mice, medicine.disease, biology.organism_classification, Mice, Inbred C57BL, Endocrinology, chemistry, Ageing, business, Function (biology), Kidney disease
Abstract

Chronic kidney disease is a common problem in the elderly and is associated with increased mortality. We have reported on the role of nitric oxide, which is generated from endothelial nitric oxide synthase (eNOS), in the progression of aged kidneys. To elucidate the role of endothelial dysfunction and the lack of an eNOS-NO pathway in ageing kidneys, we conducted experiments using eNOS and ASC-deficient mice. C57B/6 J mice (wild type (WT)), eNOS knockout (eNOS KO), and ASC knockout (ASC KO) mice were used in the present study. Then, eNOS/ASC double-knockout (eNOS/ASC DKO) mice were generated by crossing eNOS KO and ASC KO mice. These mice were sacrificed at 17−19 months old. The Masson positive area and the KIM-1 positive area tended to increase in eNOS KO mice, compared with WT mice, but not eNOS/ASC DKO mice. The COX-positive area was significantly reduced in eNOS KO mice, compared with WT and eNOS/ASC DKO mice. To determine whether inflammasomes were activated in infiltrating macrophages, the double staining of IL-18 and F4/80 was performed. IL-18 and F4/80 were found to be co-localised in the tubulointerstitial areas. Inflammasomes play a pivotal role in inflammaging in ageing kidneys. Furthermore, inflammasome activation may accelerate cellular senescence via mitochondrial dysfunction. The importance of endothelial function as a regulatory mechanism suggests that protection of endothelial function may be a potential therapeutic target.

Published
2021

17. Roxadustat and thyroid-stimulating hormone suppression

Author

Tamaki Sasaki, Atsushi Obata, Atsuyuki Tokuyama, Hiroyuki Kadoya, Naoki Kashihara, and Takahiro Obata

Subjects
medicine.medical_specialty, endocrine system, Darbepoetin alfa, endocrine system diseases, medicine.medical_treatment, 030232 urology & nephrology, Levothyroxine, Exceptional Cases, End stage renal disease, 03 medical and health sciences, 0302 clinical medicine, Thyroid-stimulating hormone, Internal medicine, medicine, AcademicSubjects/MED00340, Transplantation, Thyroid hormone receptor, end-stage renal disease, hemodialysis, business.industry, roxadustat, medicine.disease, levothyroxine sodium hydrate, Endocrinology, Nephrology, Hemodialysis, hypothyroidism, business, hypoxia-inducible factor prolyl-hydroxylase inhibitor, Kidney disease, medicine.drug, Hormone
Abstract

Hypoxia-inducible factor prolyl-hydroxylase inhibitors belong to a new class of orally administered drugs for treating anemia in patients with chronic kidney disease (CKD). The prevalence of hypothyroidism is disproportionately high in patients with CKD on hemodialysis. We report a rapid suppression of thyroid-stimulating hormone (TSH) and decrease in free triiodothyronine (T3) and free tetraiodothyronine levels after switching from darbepoetin alfa to roxadustat in a hemodialysis patient with hypothyroidism on levothyroxine therapy. This was reversed after stopping roxadustat. Roxadustat has structural similarity with T3 and is a selective activating ligand for thyroid hormone receptor-β possibly suppressing TSH release.

Published
2021

19. Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function

Author

Masayuki Yamamoto, Naoki Kashihara, Toshiya Yamamoto, Tamaki Sasaki, Joel W. Proksch, Kengo Kidokoro, W. Christian Wigley, Yuji Sogawa, Minoru Satoh, Colin J. Meyer, Takafumi Suzuki, Hajime Nagasu, and Seiji Itano

Subjects
0301 basic medicine, Mitochondrial ROS, Male, NF-E2-Related Factor 2, Nephrosis, Inflammation, Mitochondrion, Biochemistry, Nrf2, Kidney Tubules, Proximal, 03 medical and health sciences, Mice, 0302 clinical medicine, dh404, Genetics, medicine, Animals, Humans, Bardoxolone methyl, Oleanolic Acid, reactive oxidative species, Molecular Biology, Cells, Cultured, chemistry.chemical_classification, Reactive oxygen species, Mice, Inbred ICR, Activator (genetics), Research, Glomerulonephritis, medicine.disease, Cell biology, Mitochondria, Proteinuria, 030104 developmental biology, chemistry, inflammation, medicine.symptom, Reactive Oxygen Species, 030217 neurology & neurosurgery, Biotechnology
Abstract

Multiple clinical studies have shown that bardoxolone methyl, a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2), is effective in increasing glomerular filtration rate in patients with chronic kidney disease. However, whether an Nrf2 activator can protect tubules from proteinuria-induced tubular damage via anti-inflammatory and antioxidative stress mechanisms is unknown. Using an Institute of Cancer Research-derived glomerulonephritis (ICGN) mouse model of nephrosis, we examined the effects of dihydro-CDDO-trifluoroethyl amide (dh404), a rodent-tolerable bardoxolone methyl analog, in protecting the tubulointerstitium; dh404 markedly suppressed tubular epithelial cell damage in the renal interstitium of ICGN mice. The tubular epithelial cells of ICGN mice showed a decrease in the size and number of mitochondria, as well as the breakdown of the crista structure, whereas the number and ultrastructure of mitochondria were maintained by the dh404 treatment. To further determine the effect of dh404 on mitochondrial function, we used human proximal tubular cells in vitro. Stimulation with albumin and free fatty acid increased mitochondrial reactive oxygen species (ROS). However, dh404 administration diminished mitochondrial ROS. Our data show that dh404 significantly reduced proteinuria-induced tubular cell mitochondrial damage, suggesting that improved redox balance and mitochondrial function and suppression of inflammation underlie the cytoprotective mechanism of Nrf2 activators, including bardoxolone methyl, in diabetic kidney disease.-Nagasu, H., Sogawa, Y., Kidokoro, K., Itano, S., Yamamoto, T., Satoh, M., Sasaki, T., Suzuki, T., Yamamoto, M., Wigley, W. C., Proksch, J. W., Meyer, C. J., Kashihara, N. Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function.

Published
2019

20. 5‐Aminolevulinic acid exerts renoprotective effect via Nrf2 activation in murine rhabdomyolysis‐induced acute kidney injury

Author

Kengo Kidokoro, Yuji Sogawa, Naoki Kashihara, Tamaki Sasaki, Seiji Itano, Atsushi Uchida, Minoru Satoh, and Hajime Nagasu

Subjects
Glycerol, Male, Antioxidant, NF-E2-Related Factor 2, medicine.medical_treatment, 030232 urology & nephrology, Apoptosis, 030204 cardiovascular system & hematology, Pharmacology, medicine.disease_cause, Antioxidants, Rhabdomyolysis, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Animals, Humans, Medicine, Cells, Cultured, business.industry, Macrophages, Acute kidney injury, Aminolevulinic Acid, General Medicine, Acute Kidney Injury, medicine.disease, Cytoprotection, Mice, Inbred C57BL, Disease Models, Animal, Oxidative Stress, Kidney Tubules, Biochemistry, Nephrology, Cytokines, Inflammation Mediators, business, Intramuscular injection, Heme Oxygenase-1, Oxidative stress, Signal Transduction, Kidney disease
Abstract

Aim Acute kidney injury (AKI) is associated with chronic kidney disease, as well as high mortality, but effective treatments for AKI are still lacking. A recent study reported the prevention of renal injury, such as ischemia-reperfusion injury, by 5-aminolevulinic acid (ALA), which induces an antioxidant effect. The current study aimed to investigate the effect of ALA in a rhabdomyolysis-induced mouse model of AKI created by intramuscular injection of 50% glycerol. Methods Rhabdomyolysis-induced AKI was induced by an intramuscular injection of glycerol (5 mL/kg body weight) into mice. Administration of ALA (30 mg/kg, by gavage) was started from 48 h before or 24 h after glycerol injection. The mice were sacrificed at 72 h after glycerol injection. The roles of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), which is one of the Nrf2-related antioxidants, were further investigated through in vivo and in vitro methods. Results 5-aminolevulinic acid markedly reduced renal dysfunction and tubular damage in mice with rhabdomyolysis-induced AKI. ALA administration decreased oxidative stress, macrophage infiltration, and inflammatory cytokines and apoptosis. The expression of Nrf2 was upregulated by ALA administration. However, administration of Zinc protoporphyrin-9 (ZnPPIX) to inhibit HO-1 activity did not abolish these improvements by ALA. The expression of Nrf2-associated antioxidant factors other than HO-1 was also increased. Conclusion These findings indicate that ALA exerts its antioxidant activity via Nrf2-associated antioxidant factors to provide a renoprotective effect against rhabdomyolysis-induced AKI.

Published
2018

21. Non-purine selective xanthine oxidase inhibitor ameliorates glomerular endothelial injury in Ins(Akita) diabetic mice

Author

Naoki Kashihara, Takayo Murase, Yashpal S. Kanwar, Hiroyuki Kadoya, Minoru Satoh, Seiji Itano, Tamaki Sasaki, and Takashi Nakamura

Subjects
medicine.medical_specialty, endocrine system, Xanthine Oxidase, endocrine system diseases, Physiology, medicine.drug_class, Kidney Glomerulus, Kidney, Diabetes Mellitus, Experimental, Pathogenesis, Diabetic nephropathy, chemistry.chemical_compound, Mice, Internal medicine, Diabetes mellitus, medicine, Ameloblasts, Albuminuria, Animals, Diabetic Nephropathies, Endothelial dysfunction, Xanthine oxidase, Xanthine oxidase inhibitor, Proteinuria, business.industry, NADPH Oxidases, medicine.disease, Uric Acid, Topiroxostat, Disease Models, Animal, Oxidative Stress, Endocrinology, chemistry, medicine.symptom, business, hormones, hormone substitutes, and hormone antagonists, Research Article
Abstract

Endothelial dysfunction represents a predominant early feature of diabetes, rendering patients with diabetes prone to renal complications, e.g., proteinuria. Recent studies have indicated a possible role for xanthine oxidase (XO) in the pathogenesis of vascular dysfunctions associated with diabetes. In the present study, we investigated the contribution of XO activation on the progression of diabetic nephropathy in a mouse model using selective XO inhibitors. Male Ins2Akita heterozygous mice were used with wild-type mice as controls. Akita mice were treated with topiroxostat (Topi) or vehicle for 4 wk. Serum uric acid levels were significantly reduced in Akita + Topi mice compared with Akita + vehicle mice. The Akita + Topi group had a significant reduction in urinary albumin excretion compared with the Akita + vehicle group. Mesangial expansion, glomerular collagen type IV deposition, and glomerular endothelial injury (assessed by lectin staining and transmission electron microscopy) were considerably reduced in the Akita + topi group compared with the Akita + vehicle group. Furthermore, glomerular permeability was significantly higher in the Akita + vehicle group compared with the wild-type group. These changes were reduced with the administration of Topi. We conclude that XO inhibitors preserve glomerular endothelial functions and rescue compromised glomerular permeability, suggesting that XO activation plays a vital role in the pathogenesis of diabetic nephropathy.

Published
2020

22. SO021EFFECTS OF SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITOR, CANAGLIFLOZIN ON GLOMERULAR HYPERFILTRATION AND OXIDATIVE STRESS IN MICE WITH TYPE 2 DIABETES

Author

Atsuyuki Tokuyama, Yoshihisa Wada, Naoki Kashihara, Hiroyuki Kadoya, Tamaki Sasaki, Kengo Kidokoro, and Megumi Kondo

Subjects
Canagliflozin, Transplantation, medicine.medical_specialty, business.industry, Type 2 diabetes, medicine.disease, medicine.disease_cause, Endocrinology, Nephrology, Internal medicine, medicine, Sodium-Glucose Cotransporter 2 Inhibitor, business, Glomerular hyperfiltration, Oxidative stress, medicine.drug
Abstract

Background and Aims In most developed countries, diabetic kidney disease (DKD) is the most common cause of chronic kidney disease, which can lead to end-stage renal disease. In recent clinical trials, sodium–glucose cotransporter 2 inhibitors (SGLT2is) slowed the progression of kidney disease as compared with a placebo in patients with type 2 diabetes. One of the main mechanisms of the renoprotective effects of SCLT2is in DKD is considered the ability of these inhibitors to improve glomerular hyperfiltration. We previously demonstrated that the adenosine/adenosine A1 receptor pathway played a pivotal role in the tubuloglomerular feedback(TGF) system in a type 1 diabetic model, Akita mice (Circulation, 2019). We also reported that increased oxidative stress was involved in the pathogenesis of diabetic vascular complications. Uncoupling of endothelial nitric oxide (NO) synthase (eNOS) via oxidation of tetrahydrobiopterin (BH4), a cofactor required for NO production, played a major role in generation of oxidative stress (AJPRP, 2005; JASN, 2013). In the present study, we explored the renal protective effects of SGLT2 inhibition, with a focus on glomerular hemodynamics and glomerular oxidative stress. Method This study used type 2 diabetic db/db mice and db/m+ mice as a control (male, 8wk old). We developed a novel method to measure the glomerular filtration rate of single nephrons (SNGFRs) in mice using multiphoton laser microscopy. In the first experiment, we measured the SNGFRs in 12 wk-old db/db and db/m+ mice to confirm glomerular hyperfiltration. Next, we evaluated the SNGFRs change before and after the administration of a single dose of canagliflozin (CANA) (10 mg/kg). The SNGFRs, glomerular permeability of macromolecules, glomerular reactive oxygen species (ROS) and NO production, and tetrahydrobiopterin (BH4) level in serum and kidney were evaluated after the CANA treatment for 8 wk. Finally, human glomerular endothelial cells (hGECs) were exposed to normal glucose (5 mmol/L), high glucose (30 mmol/L of D-glucose), or a hyperosmotic control (5 mmol/L of D-glucose plus 25 mmol/L of L-glucose) in the presence or absence of CANA (10 μmol/L). Results The CANA treatment ameliorated glomerular hyperfiltration in the db/db mice. In the db/db mice, glomerulus ROS production increased, and NO production decreased as compared with the levels in the control mice. CANA improved the imbalance between ROS and NO production. The serum and kidney concentrations of BH4 declined in the non-treated db/db mice, whereas the CANA treatment preserved the BH4 level. Leakage of 70-kD FITC-labeled albumin into the urinary space was observed in the db/db mice. The CANA treatment reduced the amount of FITC-labeled albumin in the urinary space of the db/db mice. The CANA treatment also alleviated vascular endothelial damage in glomeruli. BH4 levels decreased in the hGECs exposed to high glucose. CANA did not improved BH4 level in the hGECs exposed to high glucose. Conclusion SGLT2i ameliorated glomerular hyperfiltration, preserving BH4 levels and improving the glomerular ROS/NO imbalance in type 2 diabetic mice.

Published
2020

23. P0089KEAP1/NRF2 PATHWAY REGULATES GFR BY INCREASING THE GLOMERULAR EFFECTIVE AREA WITHOUT AFFECTING THE AFFERENT/EFFERENT ARTERIOLE RATIO

Author

Chris Wigley, Kengo Kidokoro, Yoshihisa Wada, Joel W. Proksch, Megumi Kondo, Naoki Kashihara, Seiji Itano, Atsuyuki Tokuyama, Colin J. Meyer, and Tamaki Sasaki

Subjects
Efferent arteriole, Transplantation, medicine.anatomical_structure, Nephrology, business.industry, Afferent, Nrf2 pathway, medicine, business, Neuroscience
Abstract

Background and Aims The Keap1/Nrf2 pathway regulates the expression of a series of cytoprotective, anti-inflammatory and antioxidant genes. The Nrf2 activator, bardoxolone methyl (BARD), has consistently increased estimated GFR (eGFR) in clinical studies in patients with chronic kidney disease. BARD demonstrated improvement of renal function assessed by inulin clearance, the clinical gold standard for measuring GFR, in diabetic kidney disease patients. These findings suggest the Keap1/Nrf2 system is deeply involved in the regulatory mechanisms of GFR. However, the precise mechanisms are not fully elucidated. We pharmacologically and genetically investigated the mechanisms of GFR regulation by Keap1/Nrf2 system using in vivo multiphoton microscope (MPM) imaging techniques. Method C57BL/6 (Cont), Nrf2 knockout (Nrf2-KO), and Nrf2-activated Keap1-knockdown mice (Keap1-KD) were used. The mice were treated the synthetic triterpenoid RTA dh404 (10 mg/kg/day by gavage) which is a Nrf2 activator for rodents, for a week. We successfully developed the technique to evaluate single-nephron GFR (SNGFR) using MPM (Circulation 2019). The glomerular hemodynamics, diameter of the afferent/efferent arterioles and glomerular permeability were also evaluated. The calcium influx into cells in response to ATP and angiotensin II stimulation and the effect on [Ca2+]i by RTAdh404 were evaluated using Fluo 4 and Fura red in cultured mesangial cells and podocytes. Production of reactive oxygen species and nitric oxide (NO) availability were assessed by fluorescent method using CellROX® Deep Red and diaminofluorescein-FM diacetate (DAF-FM DA) upon the exposure to these stimuli. Results SNGFR in Keap1-KD mice was significantly higher than in the control (9.13±0.55 vs 4.40±0.39 nl/min, Figure 1). RTA dh404 increased SNGFR in the control but not in the Nrf2-KO mice (6.00±0.40 vs 4.66±0.35 nl/min, Figure 1). There was no significant change in the ratio of the glomerular afferent/efferent arteriole diameter in all groups. RTA dh404 treatment increased glomerular volume but did not affect the glomerular permeability of albumin and 40kd-dextran. RTA dh404-treatment inhibited calcium influx into cultured podocytes and mesangial cells induced by angiotensin II or ATP, thereby affecting contractile responses. Oxidative stress and NO-bioavailablity were also ameliorated with RTA dh404. Conclusion The Keap1/Nrf2 pathway plays a pivotal role in controlling GFR and presumably underlies the effect of BARD on GFR in patients.

Published
2020

24. SO022EVALUATION OF GLOMERULAR HEMODYNAMIC CHANGES BY SGLT2 INHIBITION IN TYPE 2 DIABETIC RATS USING IN VIVO IMAGING TECHNIQUES

Author

Megumi Kondo, Atsuyuki Tokuyama, Kengo Kidokoro, Yoshihisa Wada, Naoki Kashihara, Hiroyuki Kadoya, Tamaki Sasaki, and Hajime Nagasu

Subjects
Transplantation, Pathology, medicine.medical_specialty, Kidney, business.industry, Insulin, medicine.medical_treatment, Renal function, Hemodynamics, medicine.disease, Diabetic nephropathy, medicine.anatomical_structure, Nephrology, Diabetes mellitus, medicine, business, Preclinical imaging, Tubuloglomerular feedback
Abstract

Background and Aims In recent clinical trials, the SGLT2 inhibitor (SGLT2i) slowed the progression of kidney disease compared with the placebo in patients with type 2 diabetes. Improvement of glomerular hyperfiltration via tubuloglomerular feedback (TGF) is considered to be one of the possible pathways for renal protection with SGLT2 inhibition (SGLT2i) in diabetic kidney disease (DKD). We have successfully developed the novel method to measure single-nephron GFR (SNGFR) in mice using multiphoton laser microscopy and demonstrated that the adenosine/adenosine A1 receptor (A1aR) pathway plays a pivotal role in the TGF mechanism in the type 1 diabetic model, Akita mice (Kengo Kidokoro, David Z. I. Cherney et al. Circulation. 2019). It has been suggested that the mechanism of improvement effects in glomerular hyperfiltration by SGLT2i is different in type 1 diabetes and type 2 diabetes. However, the detailed regulatory mechanism of GFR by SGLT2i is not fully understood in type 2 diabetes. This study aims to clarify the effects of SGLT2i on glomerular hemodynamics in type 2 diabetic rats. Method Zucker lean (ZL) rats and Zucker diabetic fatty (ZDF) rats were used. In the first experiment, SNGFR and diameters of glomerular afferent/efferent arterioles were measured in both groups. Next, we examined the change of SNGFR and diameters of glomerular afferent/efferent arterioles, as well as urinary excretions of glucose and sodium in ZDF after a single-dose administration of SGLT2i (luseogliflozin; 10mg/kg, gavage) for 120 minutes, which generated the following three groups: SGLT2i group, SGLT2i + adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1mg/kg) group, and insulin group. Results SNGFR in the ZDF group was significantly higher than in the ZL group. The diameter of the afferent arteriole and efferent arteriole was also wider in ZDF rats than in ZL rats. The SNGFR and diameter of the afferent arteriole were significantly decreased after a single-dose administration of SGLT2i in ZDF. However, there was no significant diameter change in the efferent arteriole. Moreover, a decrease of SNGFR was not observed in the A1aR antagonist group after SGLT2i administration. Urinary excretions of glucose and sodium showed a similar pattern in the SGLT2i and SGLT2i+ A1aR antagonist groups. Conclusion The adenosine/A1aR pathway plays an important role in the regulation of the tonus of the afferent arteriole and is involved in the suppression of glomerular hyperfiltration by SGLT2 inhibition in type 2 diabetes.

Published
2020

26. Effect of zinc deficiency on chronic kidney disease progression and effect modification by hypoalbuminemia

Author

Tamaki Sasaki, Naoki Kashihara, Megumi Kondo, Seiji Itano, Yoshihisa Wada, Hiroyuki Kadoya, Kengo Kidokoro, Eiichiro Kanda, Atsuyuki Tokuyama, and Hajime Nagasu

Subjects
Male, 0301 basic medicine, Epidemiology, Kaplan-Meier Estimate, Cardiovascular Medicine, Biochemistry, Gastroenterology, Medical Conditions, Japan, Risk Factors, Chronic Kidney Disease, Medicine and Health Sciences, Hypoalbuminemia, Aged, 80 and over, Multidisciplinary, Nutritional Deficiencies, Hazard ratio, Middle Aged, Zinc, Chemistry, Proteinuria, Nephrology, Cardiovascular Diseases, Micronutrient Deficiencies, Physical Sciences, Disease Progression, Medicine, Female, Glomerular Filtration Rate, Research Article, Chemical Elements, medicine.medical_specialty, Science, Cardiology, Renal function, 03 medical and health sciences, Signs and Symptoms, Albumins, Internal medicine, Renal Diseases, medicine, Humans, Renal Insufficiency, Chronic, Risk factor, Propensity Score, Serum Albumin, Aged, Retrospective Studies, Nutrition, 030102 biochemistry & molecular biology, business.industry, Proportional hazards model, Biology and Life Sciences, Proteins, Retrospective cohort study, medicine.disease, 030104 developmental biology, Medical Risk Factors, Zinc deficiency, Kidney Failure, Chronic, Clinical Medicine, business, Kidney disease
Abstract

Serum zinc (Zn) levels tend to be low in chronic kidney disease (CKD) patients. This cohort study was conducted to investigate the relationship between zinc deficiency and CKD progression. Patients were classified into two groups based on Zn levels < 60 μg/dl (low-Zn group, n = 160) and ≥ 60 μg/dl (high-Zn group, n = 152). The primary outcome was defined as end-stage kidney disease (ESKD) or death and was examined over a 1-year observation period. Overall, the mean Zn level was 59.6 μg/dl and the median eGFR was 20.3 ml/min/1.73 m2. The incidence of the primary outcome was higher in the low-Zn group (pp = 0.026). The results of this study indicate that zinc deficiency is a risk factor for CKD progression.

Published
2021

27. Colchicine attenuates renal fibrosis in a murine unilateral ureteral obstruction model

Author

Tamaki Sasaki, Yuji Sogawa, Hiroyuki Kadoya, Minoru Satoh, Atsushi Uchida, Seiji Itano, and Naoki Kashihara

Subjects
Male, 0301 basic medicine, Cancer Research, Pathology, medicine.medical_specialty, Cell Survival, Stimulation, 030204 cardiovascular system & hematology, Pharmacology, urologic and male genital diseases, Biochemistry, Cell Line, Fibroblast migration, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cell Movement, Genetics, Renal fibrosis, Animals, Medicine, Colchicine, Fibroblast, Molecular Biology, Oncogene, urogenital system, business.industry, Angiotensin II, Fibroblasts, Fibrosis, Immunohistochemistry, Molecular medicine, Rats, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Oncology, chemistry, Apoptosis, Molecular Medicine, Kidney Diseases, rhoA GTP-Binding Protein, business, Biomarkers, Ureteral Obstruction
Abstract

The present study aimed to assess the effects of colchicine, a known anti‑inflammatory agent, on renal fibrosis using a murine model of unilateral ureteral obstruction (UUO). Male C57BL/6 mice were divided into two groups, vehicle‑ and colchicine‑treated. Colchicine (0.5 mg/kg/day) was administered by osmotic pump, and the UUO procedure was performed on the left kidney 7 days later. The mice were sacrificed at 14 days following UUO. Colchicine treatment suppressed interstitial fibrosis of the UUO kidneys. In addition, fibrogenic gene expression in the UUO kidneys was decreased by colchicine administration. NRK‑49F normal rat kidney fibroblasts were cultured with or without colchicine under angiotensin II stimulation, following which a wound‑healing assay and actin fiber staining were performed to evaluate the effects of colchicine in vitro. Colchicine was demonstrated to inhibit angiotensin II‑induced fibroblast migration in vitro in a concentration‑dependent manner. Colchicine treatment also suppressed the angiotensin II‑induced activation of Ras homolog gene family member A in NRK‑49F cells. In conclusion, colchicine treatment significantly inhibited fibroblast activity in vitro and attenuated renal fibrosis in vivo in UUO‑operated mice. Therefore, the prevention of renal fibrosis following injury may represent a novel therapeutic application for colchicine.

Published
2017

28. Proteinuria in neuronal intranuclear inclusion disease

Author

Daisuke Yorimitsu, Yutaka Ohsawa, Tamaki Sasaki, Yoshihide Sunada, Naoki Kashihara, Yuta Fukai, Yumiko Kutoku, and Hirotake Nishimura

Subjects
Pathology, medicine.medical_specialty, Proteinuria, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, 03 medical and health sciences, NEURONAL INTRANUCLEAR INCLUSION DISEASE, 0302 clinical medicine, Neurology, 030502 gerontology, Medicine, Neurology (clinical), Renal biopsy, medicine.symptom, 0305 other medical science, business, 030217 neurology & neurosurgery
Published
2018

29. SP433Investigation of the suppressive effects of an SGLT2 inhibitor on glomerular hyperfiltration and oxidative stress in mice with diabetic kidney disease

Author

Naoki Kashihara, Minoru Satoh, Kengo Kidokoro, Megumi Kondo, and Tamaki Sasaki

Subjects
Transplantation, medicine.medical_specialty, Diabetic kidney, business.industry, Disease, medicine.disease_cause, Endocrinology, Nephrology, Internal medicine, medicine, SGLT2 Inhibitor, business, Glomerular hyperfiltration, Oxidative stress
Published
2019

31. A case of endogenous endophthalmitis due to group G Streptococcus in a septic hemodialysis patient

Author

Yuka Kobayashi, Toshihiko Nagasawa, Tamaki Sasaki, Tadashi Matsumura, Hiroko Nagase-Sasamoto, Osamu Uchikoga, and Yuji Sogawa

Subjects
medicine.medical_specialty, business.industry, medicine.medical_treatment, Endogenous endophthalmitis, 030232 urology & nephrology, Group G streptococcus, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, 030221 ophthalmology & optometry, Medicine, Hemodialysis, business, Intensive care medicine
Published
2016

32. Klotho attenuates renal hypertrophy and glomerular injury in Ins2Akita diabetic mice

Author

Hiroyuki Kadoya, Naoki Kashihara, Yoshisuke Haruna, Tamaki Sasaki, and Minoru Satoh

Subjects
0301 basic medicine, Physiology, Renal Hypertrophy, Kidney Glomerulus, urologic and male genital diseases, Bioinformatics, Diabetic nephropathy, Diabetic Nephropathies, Klotho, Cells, Cultured, Glucuronidase, biology, Calpain, female genital diseases and pregnancy complications, Phenotype, 8-Hydroxy-2'-Deoxyguanosine, Nephrology, Inflammation Mediators, medicine.symptom, medicine.medical_specialty, Genotype, Urinary system, Mice, Transgenic, Transfection, Proinflammatory cytokine, 03 medical and health sciences, Physiology (medical), Internal medicine, Diabetes mellitus, Diabetes Mellitus, medicine, Albuminuria, Animals, Humans, Klotho Proteins, business.industry, Macrophages, Deoxyguanosine, Hypertrophy, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, Glucose, 030104 developmental biology, Endocrinology, biology.protein, business, Biomarkers
Abstract

Expression of klotho, the renoprotective anti-aging gene, is decreased in diabetic model kidneys. We hypothesized that klotho protein attenuates renal hypertrophy and glomerular injury in a mouse model of diabetic nephropathy. Klotho transgenic (KLTG) mice were crossed with spontaneously diabetic Ins2Akita (AKITA) mice. Glomerular morphology, macrophage infiltration, urinary albumin excretion and urinary 8-hydroxy-2-deoxy guanosine excretion were examined. In vitro, human glomerular endothelial cells were stimulated with high glucose with or without recombinant klotho, and calpain activity and proinflammatory cytokine expressions were measured. We found that klotho protein overexpression attenuates renal hypertrophy and glomerular injury in this mouse model of diabetic nephropathy. Klotho overexpression attenuated renal hypertrophy, albuminuria, glomerular mesangial expansion, and endothelial glycocalyx loss in the AKITA mice. AKITA mice exhibit high levels of urinary 8-hydroxy-2-deoxy guanosine excretion. In the presence of klotho overexpression, this effect was reversed. In addition, the glomerular macrophage infiltration characteristic of AKITA mice was attenuated in KLTG-AKITA mice. In human glomerular endothelial cells, high glucose induced calpain activity. This effect was suppressed by expression of recombinant klotho, which also suppressed the induction of proinflammatory cytokines. Our data suggest klotho protein protects against diabetic nephropathy through multiple pathways.

Published
2015

33. Impact of heavy rains of 2018 in western Japan: disaster-induced health outcomes among the population of Innoshima Island

Author

Takemi Otsuki, Srinivas Bandaru, Tamaki Sasaki, Yuka Seki, Yoshikazu Okano, Shunji Sano, Tatsuo Ito, Hideho Wada, and Yurika Shimizu

Subjects
0301 basic medicine, Quality of life, medicine.medical_specialty, Epidemiology, Population, Article, Occupational safety and health, Water scarcity, Urinary protein, 03 medical and health sciences, 0302 clinical medicine, Sewerage, medicine, Edemiology, Japan heavy Rain, lcsh:Social sciences (General), lcsh:Science (General), Natural disaster, education, Socioeconomics, Health checkup, education.field_of_study, Public health, Multidisciplinary, Emergency management, Occupational health, business.industry, 030104 developmental biology, Geography, Typhoon, Health impact, lcsh:H1-99, business, Water outage, 030217 neurology & neurosurgery, lcsh:Q1-390
Abstract

Southwestern Japan suffered its worst rains in 2018 causing floods and mudslides, claiming 225 lives and forcing millions for evacuations. Referred as “Heisei san-jū-nenshichi-gatsugōu”, the disaster was the result of incessant precipitation caused by the interaction of typhoon “Prapiroon” with the seasonal rain front "Baiu". The present epidemiological study aims to investigate disaster-induced health issues in 728 residents of Innoshima island in the Hiroshima Prefecture by comparing their clinical data in pre-disaster (2017) and disaster-hit (2018) years which was obtained from annual health screening. Comparison of data showed a significant increase in the urine protein concentration in victims following the disaster. Probing further into the household conditions, showed that a total of 59,844 households were affected with water outage during the heavy rains, which was accompanied by severe damage of sewerage pipelines with complete recovery process taking two weeks. This two weeks of the crisis forced victims to refrain from using restrooms which in turn led to infrequent urination, thereby explaining the increased urine protein concentration in victims following the disaster. The present study addresses the acute health implications caused by the water crisis and serves as a precautionary measure for disaster management council to provide enhanced aftercare services in victims in further events of natural disasters., Epidemiology; Occupational health; Public health; Quality of life; Japan heavy Rain, Water outage, Health impact, Urinary protein, Health checkup

Published
2020

34. The eNOS-NO pathway attenuates kidney dysfunction via suppression of inflammasome activation in aldosterone-induced renal injury model mice

Author

Masafumi Takahashi, Kengo Kidokoro, Hiroyuki Kadoya, Naoki Kashihara, Minoru Satoh, Seiji Itano, Yuji Sogawa, Tamaki Sasaki, Hajime Nagasu, and Shun'ichiro Taniguchi

Subjects
0301 basic medicine, Male, Hypertension, Renal, Inflammasomes, Vasodilator Agents, lcsh:Medicine, Blood Pressure, Pathology and Laboratory Medicine, Kidney, Biochemistry, Vascular Medicine, chemistry.chemical_compound, White Blood Cells, Mice, Animal Cells, Chronic Kidney Disease, Medicine and Health Sciences, Medicine, Lipid Hormones, Molecular Targeted Therapy, Endothelial dysfunction, lcsh:Science, Aldosterone, Immune Response, Mice, Knockout, Multidisciplinary, Immune System Proteins, Inflammasome, Animal Models, Hydralazine, Hypertensive kidney disease, medicine.anatomical_structure, Experimental Organism Systems, Nephrology, Hypertension, Cellular Types, Anatomy, medicine.drug, Research Article, medicine.medical_specialty, Nitric Oxide Synthase Type III, Immune Cells, Immunology, Primary Cell Culture, Mouse Models, Research and Analysis Methods, Nitric Oxide, 03 medical and health sciences, Model Organisms, Signs and Symptoms, Diagnostic Medicine, Internal medicine, Diabetes mellitus, NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Humans, Endothelium, Renal Insufficiency, Chronic, Antihypertensive Agents, Inflammation, Blood Cells, business.industry, Macrophages, lcsh:R, Biology and Life Sciences, Proteins, Kidneys, Cell Biology, Renal System, medicine.disease, Fibrosis, Hormones, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, chemistry, Tubulointerstitial fibrosis, Animal Studies, lcsh:Q, business, Kidney disease
Abstract

Hypertension causes vascular complications, such as stroke, cardiovascular disease, and chronic kidney disease (CKD). The relationship between endothelial dysfunction and progression of kidney disease is well known. However, the relationship between the eNOS-NO pathway and chronic inflammation, which is a common pathway for the progression of kidney disease, remains unexplored. We performed in vivo experiments to determine the role of the eNOS-NO pathway by using eNOS-deficient mice in a hypertensive kidney disease model. All mice were unilateral nephrectomized (Nx). One week after Nx, the mice were randomly divided into two groups: the aldosterone infusion groups and the vehicle groups. All mice also received a 1% NaCl solution instead of drinking water. The aldosterone infusion groups were treated with hydralazine to correct blood pressure differences. After four weeks of drug administration, all mice were euthanized, and blood and kidney tissue samples were collected. In the results, NLRP3 inflammasome activation was elevated in the kidneys of the eNOS-deficient mice, and tubulointerstitial fibrosis was accelerated. Suppression of inflammasome activation by knocking out ASC prevented tubulointerstitial injury in the eNOS knockout mice, indicating that the eNOS-NO pathway is involved in the development of kidney dysfunction through acceleration of NLRP3 inflammasome in macrophages. We revealed that endothelial function, particularly the eNOS-NO pathway, attenuates the progression of renal tubulointerstitial injury via suppression of inflammasome activation. Clinically, patients who develop vascular endothelial dysfunction have lifestyle diseases, such as hypertension or diabetes, and are known to be at risk for CKD. Our study suggests that the eNOS-NO pathway could be a therapeutic target for the treatment of chronic kidney disease associated with endothelial dysfunction.

Published
2018

35. Relationship between vascular function indexes, renal arteriolosclerosis, and renal clinical outcomes in chronic kidney disease

Author

Naoki Kashihara, Daisuke Yorimitsu, Tamehachi Namikoshi, Tamaki Sasaki, Chieko Ihoriya, Yasuo Fujimoto, Sohachi Fujimoto, and Norio Komai

Subjects
medicine.medical_specialty, Creatinine, medicine.diagnostic_test, biology, business.industry, Urinary system, Urology, Arteriolosclerosis, Renal function, General Medicine, urologic and male genital diseases, medicine.disease, chemistry.chemical_compound, Endocrinology, medicine.anatomical_structure, chemistry, Cystatin C, Nephrology, Internal medicine, medicine, biology.protein, Vascular resistance, Renal biopsy, business, Kidney disease
Abstract

Aim Hypertension contributes critically to the development of renal arteriolosclerosis in chronic kidney disease (CKD), but the impact of vascular function indexes including central blood pressure on renal arteriolosclerosis has not been investigated. We determined whether vascular function indexes were related to renal arteriolosclerosis and renal clinical outcomes in CKD. Methods This cross-sectional study was implemented in our hospital. Subjects were in-patients with CKD aged ≥20 years who underwent a renal biopsy. Vascular function indexes included central systolic blood pressure (SBP), cardio–ankle vascular index (CAVI), and renal resistive index. Central SBP was measured non-invasively using an automated device. Arteriolosclerosis was assessed histologically. Renal clinical outcomes included estimated glomerular filtration rate using serum creatinine (eGFRcreat) or cystatin C (eGFRcys), and the urinary albumin–creatinine ratio. Results Among vascular function indexes, central SBP was weakly correlated with renal arteriolosclerosis (n = 55). Renal arteriolosclerosis was increased in hypertensive or hyperuricaemic patients, and negatively correlated with serum high-density lipoprotein (HDL) cholesterol and eGFRcys, which were independent risk factors for renal arteriolosclerosis in a stepwise multivariate regression analysis. Of the vascular function indexes, CAVI showed the strongest correlation with all renal clinical outcomes. Central SBP was correlated with only urinary albumin–creatinine ratio, while renal resistive index was correlated with eGFRcreat and urinary albumin–creatinine ratio. Conclusion Decreased serum HDL cholesterol was independently and most closely associated with renal arteriolosclerosis. Of the vascular function indexes, CAVI had the greatest impact on renal clinical outcomes, although it was not associated with renal arteriolosclerosis.

Published
2015

36. Prevalence of gastroesophageal reflux disease symptoms and effects of esomeprazole on the quality of life related to reflux and dyspepsia in patients on maintenance hemodialysis

Author

Tamaki Sasaki, Masahiro Mori, Takehiko Tokura, Sohachi Fujimoto, Kazuhiro Harada, Hidekazu Hatta, Naoki Kashihara, Takaaki Fueki, Tetsuichi Nishizaki, Yoshiyuki Oshiro, Daisuke Yorimitsu, Tamehachi Namikoshi, Chieko Ihoriya, Yoshisuke Haruna, Atsunori Kuwabara, Yasuo Fujimoto, Seiji Itano, Takahiro Obata, Hiroyuki Kadoya, and Norio Komai

Subjects
Adult, Male, medicine.medical_specialty, Time Factors, Physiology, medicine.medical_treatment, Disease, Gastroenterology, Esomeprazole, 03 medical and health sciences, 0302 clinical medicine, Japan, Quality of life, Renal Dialysis, Surveys and Questionnaires, Physiology (medical), Internal medicine, Prevalence, Humans, Medicine, 030212 general & internal medicine, Dyspepsia, Aged, Aged, 80 and over, business.industry, Remission Induction, Reflux, Proton Pump Inhibitors, Middle Aged, medicine.disease, humanities, digestive system diseases, Clinical trial, Cross-Sectional Studies, Logistic Models, Treatment Outcome, Nephrology, Multivariate Analysis, Gastroesophageal Reflux, Quality of Life, GERD, Female, Kidney Diseases, 030211 gastroenterology & hepatology, Hemodialysis, business, Cohort study, medicine.drug
Abstract

The prevalence of gastroesophageal reflux disease (GERD) symptoms has not been investigated in patients on maintenance hemodialysis in Japan, and few studies have reported the effect of proton pump inhibitors (PPIs) in hemodialysis patients with GERD symptoms. Here, we investigated the prevalence of GERD symptoms and the effects of the PPI esomeprazole on the quality of life related to reflux and dyspepsia in patients on maintenance hemodialysis. This was a cross-sectional/cohort study of hemodialysis outpatients implemented in 10 Japanese medical facilities from October 2012 to March 2014. The trial was registered in the UMIN Clinical Trial Registry (UMIN000009124). Forty-one of 385 patients (11 %) reported GERD symptoms on the Global Overall Symptom (GOS) questionnaire. Multivariate logistic regression analysis identified the independent prognostic factors for GERD symptoms as a history of gastric ulcer and use of sevelamer hydrochloride or calcium polystyrene sulfonate. Participants with GERD symptoms completed the Quality of Life in Reflux and Dyspepsia, Japanese version (QOLRAD-J) questionnaire and were assigned to receive 4-week esomeprazole treatment (20 mg/day). This PPI therapy significantly improved all QOLRAD-J domains in the full analysis set (n = 28) and improved the GERD symptoms listed in the GOS questionnaire. Significantly impaired disease-specific quality of life (QOL) in the QOLRAD-J domains was observed in 44.4–74.1 % of patients who had symptoms before treatment. The mean GOS and QOLRAD-J scores correlated significantly. Therapy with 20 mg/day esomeprazole appears to be efficacious for improving disease-specific QOL and GERD symptoms in Japanese patients on maintenance hemodialysis.

Published
2015

39. Non-purine selective xanthine oxidase inhibitor ameliorates glomerular endothelial injury in InsAkita diabetic mice.

Author

Seiji Itano, Hiroyuki Kadoya, Minoru Satoh, Takashi Nakamura, Takayo Murase, Tamaki Sasaki, Kanwar, Yashpal S., and Naoki Kashihara

Subjects
XANTHINE oxidase, URIC acid, LECTINS, DIABETIC nephropathies, MICE, TRANSMISSION electron microscopy, PATHOLOGY
Abstract

Non-purine selective xanthine oxidase inhibitor ameliorates glomerular endothelial injury in InsAkita diabetic mice. Am J Physiol Renal Physiol 319: F765-F772, 2020. First published September 21, 2020; doi:10.1152/ajprenal.00236.2020.--Endothelial dysfunction represents a predominant early feature of diabetes, rendering patients with diabetes prone to renal complications, e.g., proteinuria. Recent studies have indicated a possible role for xanthine oxidase (XO) in the pathogenesis of vascular dysfunctions associated with diabetes. In the present study, we investigated the contribution of XO activation on the progression of diabetic nephropathy in a mouse model using selective XO inhibitors. Male Ins2Akita heterozygous mice were used with wild-type mice as controls. Akita mice were treated with topiroxostat (Topi) or vehicle for 4 wk. Serum uric acid levels were significantly reduced in Akita + Topi mice compared with Akita + vehicle mice. The Akita + Topi group had a significant reduction in urinary albumin excretion compared with the Akita + vehicle group. Mesangial expansion, glomerular collagen type IV deposition, and glomerular endothelial injury (assessed by lectin staining and transmission electron microscopy) were considerably reduced in the Akita + topi group compared with the Akita + vehicle group. Furthermore, glomerular permeability was significantly higher in the Akita + vehicle group compared with the wild-type group. These changes were reduced with the administration of Topi. We conclude that XO inhibitors preserve glomerular endothelial functions and rescue compromised glomerular permeability, suggesting that XO activation plays a vital role in the pathogenesis of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Published
2020
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40. Infiltration of M1, but not M2, macrophages is impaired after unilateral ureter obstruction in Nrf2-deficient mice

Author

Kengo Kidokoro, Tiffany Horng, Minoru Satoh, Masayuki Yamamoto, Shigeki Iwase, Shun'ichiro Taniguchi, Naoki Kashihara, Tamaki Sasaki, Atsushi Uchida, Yuji Sogawa, Hajime Nagasu, Seiji Itano, Takafumi Suzuki, Chieko Ihoriya, and Masafumi Takahashi

Subjects
0301 basic medicine, Inflammasomes, NF-E2-Related Factor 2, Science, Inflammation, Kidney, urologic and male genital diseases, Pyrin domain, Article, Mice, 03 medical and health sciences, Fibrosis, medicine, Animals, Transcription factor, Mice, Knockout, Multidisciplinary, business.industry, Gene Expression Profiling, Macrophages, Kidney metabolism, Inflammasome, Macrophage Activation, medicine.disease, female genital diseases and pregnancy complications, Disease Models, Animal, 030104 developmental biology, Immunology, Medicine, medicine.symptom, business, Infiltration (medical), Ureteral Obstruction, medicine.drug, Kidney disease
Abstract

Chronic inflammation can be a major driver of the failure of a variety of organs, including chronic kidney disease (CKD). The NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been shown to play a pivotal role in inflammation in a mouse kidney disease model. Nuclear factor erythroid 2-related factor 2 (Nrf2), the master transcription factor for anti-oxidant responses, has also been implicated in inflammasome activation under physiological conditions. However, the mechanism underlying inflammasome activation in CKD remains elusive. Here, we show that the loss of Nrf2 suppresses fibrosis and inflammation in a unilateral ureter obstruction (UUO) model of CKD in mice. We consistently observed decreased expression of inflammation-related genes NLRP3 and IL-1β in Nrf2-deficient kidneys after UUO. Increased infiltration of M1, but not M2, macrophages appears to mediate the suppression of UUO-induced CKD symptoms. Furthermore, we found that activation of the NLRP3 inflammasome is attenuated in Nrf2-deficient bone marrow–derived macrophages. These results demonstrate that Nrf2-related inflammasome activation can promote CKD symptoms via infiltration of M1 macrophages. Thus, we have identified the Nrf2 pathway as a promising therapeutic target for CKD.

Published
2017

41. Restricted nutrition-induced low birth weight, low number of nephrons and glomerular mesangium injury in Japanese quail

Author

Hiroko Nishimura, Y. Ouchi, Yohei Ikezumi, Masaaki Nameta, M. Sato, Tamaki Sasaki, Eishin Yaoita, Chieko Ihoriya, Naoki Kashihara, Ken'ichi Yamaguchi, Tadashi Yamamoto, Linning Zhao, and Hiroshi Kawachi

Subjects
0301 basic medicine, medicine.medical_specialty, Medicine (miscellaneous), Coturnix, Egg Proteins, Dietary, 03 medical and health sciences, chemistry.chemical_compound, Corticosterone, biology.animal, Internal medicine, medicine, Animals, biology, Coturnix japonica, Body Weight, Malnutrition, Glomerular mesangium, Embryo, Nephrons, Infant, Low Birth Weight, biology.organism_classification, Quail, Glomerular Mesangium, 030104 developmental biology, Endocrinology, chemistry, Mesangium, Podocin, biology.protein, Female, Glucocorticoid, medicine.drug
Abstract

Insufficient nutrition during the perinatal period causes structural alterations in humans and experimental animals, leading to increased vulnerability to diseases in later life. Japanese quail,Coturnix japonica, in which partial (8–10%) egg white was withdrawn (EwW) from eggs before incubation had lower birth weights than controls (CTs). EwW birds also had reduced hatching rates, smaller glomeruli and lower embryo weight. In EwW embryos, the surface condensate area containing mesenchymal cells was larger, suggesting that delayed but active nephrogenesis takes place. In mature EwW quail, the number of glomeruli in the cortical region (mm2) was significantly lower (CT 34.7±1.4, EwW 21.0±1.2); capillary loops showed focal ballooning, and mesangial areas were distinctly expanded. Immunoreactive cell junction proteins,N-cadherin and podocin, and slit diaphragms were clearly seen. With aging, the mesangial area and glomerular size continued to increase and were significantly larger in EwW quail, suggesting compensatory hypertrophy. Furthermore, apoptosis measured by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling analysis was higher in EwWs than in CTs on embryonic day 15 and postnatal day 4 (D4). Similarly, plasma glucocorticoid (corticosterone) was higher (P

Published
2017

42. Clearance Gap: Does It Really Matter for the Evaluation of Vascular Access Function?

Author

Jun-Ichi, Ono, Yujiro, Shiraga, Fumika, Yoshikawa, Yoshisuke, Haruna, Tamaki, Sasaki, and Seiichi, Mochizuki

Subjects
Renal Dialysis, Humans, Constriction, Pathologic, Models, Theoretical, Blood Flow Velocity, Vascular Access Devices
Abstract

Vascular access (VA) stenosis increases the risk of VA obstruction due to the gradual progress of intimal thickening. Therefore, we should try to detect VA stenosis early. However, we do not have a cutoff for when a difference between prescribed Kt/V and delivered Kt/V reflects a clinical issue. Thus, we have devised a new index, the 'clearance gap' (CL-Gap), which quantifies the difference between the effective clearance (eCL) of a hemodialysis (HD) patient and the theoretical clearance (tCL) of a dialyzer to detect a decrease in dialysis efficiency due to VA dysfunction.We propose a qualitative technique of analyzing dialysis (the CL-Gap method) concerning Kt/V by estimating the eCL based on the delivered Kt/V and the difference with the tCL based on the dialyzer. When VA recirculation and blood removal failure occurs, the eCL decreases, and it is expected that the CL-Gap increases. On the contrary, if uniform internal removal occurs, the eCL rises when we overestimate the delivered Kt/V and the CL-Gap is expected to decrease. However, we cannot judge whether a high CL-Gap indicates VA dysfunction immediately because it is necessary to consider not only VA dysfunction, but also the effect of other factors on the CL-Gap. Key Messages: We believe that it is important to think about VA function in a qualitative manner when managing the dose using the CL-Gap to achieve better dialysis treatment.

Published
2016

43. Clearance Gap: Does It Really Matter for the Evaluation of Vascular Access Function?

Author

Seiichi Mochizuki, Tamaki Sasaki, Junichi Ono, Yoshisuke Haruna, Yujiro Shiraga, and Fumika Yoshikawa

Subjects
medicine.medical_specialty, business.industry, medicine.medical_treatment, 030232 urology & nephrology, Vascular access, 030204 cardiovascular system & hematology, medicine.disease, Surgery, 03 medical and health sciences, Stenosis, 0302 clinical medicine, Internal medicine, Cardiology, medicine, Hemodialysis, Thickening, business, Dialysis
Abstract

Backgrounds: Vascular access (VA) stenosis increases the risk of VA obstruction due to the gradual progress of intimal thickening. Therefore, we should try to detect VA stenosis early. However, we do not have a cutoff for when a difference between prescribed Kt/V and delivered Kt/V reflects a clinical issue. Thus, we have devised a new index, the ‘clearance gap' (CL-Gap), which quantifies the difference between the effective clearance (eCL) of a hemodialysis (HD) patient and the theoretical clearance (tCL) of a dialyzer to detect a decrease in dialysis efficiency due to VA dysfunction. Summary: We propose a qualitative technique of analyzing dialysis (the CL-Gap method) concerning Kt/V by estimating the eCL based on the delivered Kt/V and the difference with the tCL based on the dialyzer. When VA recirculation and blood removal failure occurs, the eCL decreases, and it is expected that the CL-Gap increases. On the contrary, if uniform internal removal occurs, the eCL rises when we overestimate the delivered Kt/V and the CL-Gap is expected to decrease. However, we cannot judge whether a high CL-Gap indicates VA dysfunction immediately because it is necessary to consider not only VA dysfunction, but also the effect of other factors on the CL-Gap. Key Messages: We believe that it is important to think about VA function in a qualitative manner when managing the dose using the CL-Gap to achieve better dialysis treatment.

Published
2016

49. Hypertension promotes islet morphological changes with vascular injury on pre-diabetic status in SHRsp rats

Author

Minoru Satoh, Hajime Nagasu, Hiroyuki Kadoya, Tamaki Sasaki, Naoki Kashihara, Yoshisuke Haruna, and Chieko Ihoriya

Subjects
Male, endocrine system, medicine.medical_specialty, endocrine system diseases, Physiology, Tetrazoles, Blood Pressure, Prediabetic State, Islets of Langerhans, Irbesartan, Fibrosis, Rats, Inbred SHR, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Animals, Epithelial–mesenchymal transition, Antihypertensive Agents, geography, geography.geographical_feature_category, business.industry, Biphenyl Compounds, High fat diet, General Medicine, Vascular System Injuries, Hydralazine, medicine.disease, Islet, Disease Models, Animal, Endocrinology, Hypertension, Angiotensin Receptor Blockers, business, medicine.drug
Abstract

Hypertensive patients have a higher incidence of new-onset diabetic mellitus than normotensive subjects, and we hypothesized that hypertension induces morphological changes in islets via vascular injury. To test our hypothesis, we administrated hydralazine or irbesartan to spontaneously hypertensive stroke-prone (SHRsp) rats. A greater islet fibrosis was observed in SHRsp rats compared with controls, and irbesartan significantly ameliorated the fibrosis. High fat diet induced glucose intorelance in SHRsp rats and irbesartan but not hydralazine improved glucose torelance. We demonstrate islet morphological changes in hypertensive rats, and our data suggest that angiotensin receptor blockers have the potential to prevent islet injury.

Published
2013

50. Selective estrogen receptor modulation attenuates proteinuria-induced renal tubular damage by modulating mitochondrial oxidative status

Author

Hiroyuki Kadoya, Tamaki Sasaki, Kengo Kidokoro, Hajime Nagasu, Minoru Satoh, Naoki Kashihara, Chieko Ihoriya, and Yuko Nishi

Subjects
Selective Estrogen Receptor Modulators, medicine.medical_specialty, Inflammasomes, Ovariectomy, Estrogen receptor, Apoptosis, Nephritis, Hereditary, Oxidative phosphorylation, Mitochondrion, Biology, Kidney Tubules, Proximal, Mice, Glomerulonephritis, Internal medicine, medicine, Animals, Humans, Respiratory function, Raloxifene, Cells, Cultured, chemistry.chemical_classification, Mice, Inbred ICR, Reactive oxygen species, Macrophages, NF-kappa B, Inflammasome, Fibrosis, Mitochondria, Disease Models, Animal, Oxidative Stress, Proteinuria, Endocrinology, Gene Expression Regulation, chemistry, Selective estrogen receptor modulator, Nephrology, Raloxifene Hydrochloride, Cytokines, Female, Lipid Peroxidation, Atrophy, Inflammation Mediators, Oxidation-Reduction, medicine.drug
Abstract

Proteinuria is an independent risk factor for progressive renal diseases because it initiates or aggravates tubulointerstitial injury. Clinically, females are less susceptible to progression of chronic kidney disease; however, the mechanisms underlying the renoprotective effect of estrogen receptor stimulation have yet to be clarified. Recently, inflammasome-dependent inflammatory responses were shown to be triggered by free fatty acids, and mitochondria-derived reactive oxygen species were shown to be required for this response. Albumin-bound free fatty acids trigger inflammasome activation through mitochondrial reactive oxygen species production in human proximal tubule epithelial cells in vitro, an effect inhibited by raloxifene. Female ICR-derived glomerulonephritic mice (mice with hereditary nephritic syndrome) were ovariectomized and treated with raloxifene, a selective estrogen receptor modulator. Ovariectomized mice showed activation of tubular inflammasomes and elevated levels of inflammasome-dependent cytokines. Raloxifene attenuated these changes ameliorating tubulointerstitial damage, reduced production of reactive oxygen species, averted morphological changes, and improved respiratory function in mitochondria. The expression of genes that encode rate-limiting enzymes in the mitochondrial β-oxidation pathway was reduced by ovariectomy but enhanced by raloxifene. Thus, inflammasomes may be a novel and promising therapeutic target for proteinuria-induced renal injury.

Published
2013
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