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1. The atypical chemokine receptor 2 reduces T cell expansion and tertiary lymphoid tissue but does not limit autoimmune organ injury in lupus-prone B6lpr mice

Author: Wenkai Xia, Nuru Eltrich, and Volker Vielhauer
Subjects: systemic lupus erythematosus, lupus nephritis, autoimmune lung disease, chemokines, atypical chemokine receptors, Immunologic diseases. Allergy, RC581-607
Abstract: IntroductionThe atypical chemokine receptor 2 (ACKR2) is a chemokine scavenger receptor, which limits inflammation and organ damage in several experimental disease models including kidney diseases. However, potential roles of ACKR2 in reducing inflammation and tissue injury in autoimmune disorders like systemic lupus erythematosus (SLE) and lupus nephritis are unknown, as well as its effects on systemic autoimmunity. MethodsTo characterize functional roles of ACKR2 in SLE, genetic Ackr2 deficiency was introduced into lupus-prone C57BL/6lpr (Ackr2-/- B6lpr) mice. ResultsUpon inflammatory stimulation in vitro, secreted chemokine levels increased in Ackr2 deficient tubulointerstitial tissue but not glomeruli. Moreover, Ackr2 expression was induced in kidneys and lungs of female C57BL/6lpr mice developing SLE. However, female Ackr2-/- B6lpr mice at 28 weeks of age showed similar renal functional parameters as wildtype (WT)-B6lpr mice. Consistently, assessment of activity and chronicity indices for lupus nephritis revealed comparable renal injury. Interestingly, Ackr2-/- B6lpr mice showed significantly increased renal infiltrates of CD3+ T and B cells, but not neutrophils, macrophages or dendritic cells, with T cells predominantly accumulating in the tubulointerstitial compartment of Ackr2-/- B6lpr mice. In addition, histology demonstrated significantly increased peribronchial lung infiltrates of CD3+ T cells in Ackr2-/- B6lpr mice. Despite this, protein levels of pro-inflammatory chemokines and mRNA expression of inflammatory mediators were not different in kidneys and lungs of WT- and Ackr2-/- B6lpr mice. This data suggests compensatory mechanisms for sufficient chemokine clearance in Ackr2-deficient B6lpr mice in vivo. Analysis of systemic autoimmune responses revealed comparable levels of circulating lupus-associated autoantibodies and glomerular immunoglobulin deposition in the two genotypes. Interestingly, similar to kidney and lung CD4+ T cell numbers and activation were significantly increased in spleens of Ackr2-deficient B6lpr mice. In lymph nodes of Ackr2-/- B6lpr mice abundance of activated dendritic cells decreased, but CD4+ T cell numbers were comparable to WT. Moreover, increased plasma levels of CCL2 were present in Ackr2-/- B6lpr mice, which may facilitate T cell mobilization into spleens and peripheral organs. DiscussionIn summary, we show that ACKR2 prevents expansion of T cells and formation of tertiary lymphoid tissue, but is not essential to limit autoimmune tissue injury in lupus-prone B6lpr mice.
Published: 2024
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2. Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy

Author: Frederick W.K. Tam, James Tumlin, Jonathan Barratt, Brad H. Rovin, Ian S.D. Roberts, Candice Roufosse, H. Terence Cook, Gurjeet Bhangal, Alison L. Brown, Martin Busch, Fayaz Dudhiya, Anne-Marie Duliege, Donald J. Fraser, Daniel P. Gale, Chiu-Ching Huang, Ping-Chin Lai, Meng Lee, Esteban S. Masuda, Stephen P. McAdoo, Alexander R. Rosenkranz, Claudia Sommerer, Gere Sunder-Plassmann, Cheuk-Chun Szeto, Sydney C.W. Tang, Don E. Williamson, Lisa Willcocks, Volker Vielhauer, Min Jeong Kim, Leslie Todd, Hany Zayed, Sandra Tong-Starksen, and Richard Lafayette
Subjects: glomerulonephritis, IgA nephropathy, inflammation, kidney, macrophage, signaling, Diseases of the genitourinary system. Urology, RC870-923
Abstract: Introduction: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells. Methods: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors. The primary end point was reduction of proteinuria. Secondary end points included change from baseline in estimated glomerular filtration rate (eGFR) and kidney histology. Results: Although we could not detect significant reduction in proteinuria with fostamatinib overall, in a predetermined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27%, and 36% in the placebo, fostamatinib 100 mg, and 150 mg groups, respectively) in patients with baseline urinary protein-to-creatinine ratios (UPCR) more than 1000 mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well-tolerated. Side effects included diarrhea, hypertension, and increased liver enzymes. Thirty-nine patients underwent repeat biopsy showing reductions in SYK staining associated with therapy at low dose (−1.5 vs. 1.7 SYK+ cells/glomerulus in the placebo group, P < 0.05). Conclusions: There was a trend toward reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 mg/g. Further study may be warranted.
Published: 2023
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3. Elevated TG/HDL-C and non-HDL-C/HDL-C ratios predict mortality in peritoneal dialysis patients

Author: Wenkai Xia, Xiajuan Yao, Yan Chen, Jie Lin, Volker Vielhauer, and Hong Hu
Subjects: Triglyceride, High-density lipoprotein cholesterol, Peritoneal dialysis, Prognosis, Diseases of the genitourinary system. Urology, RC870-923
Abstract: Abstract Background and aims Dyslipidemia is common in patients with chronic kidney disease and particular prevalent in patients receiving peritoneal dialysis. However, whether markers of atherogenic dyslipidemia correlate with outcomes in dialysis patients as in the general population is uncertain. The aim of this study was to explore the prognostic value of the serum triglyceride/HDL cholesterol (TG/HDL-C) ratio and non-HDL-C/HDL-C ratio to predict mortality in peritoneal dialysis patients. Methods Two hundred fourteen peritoneal dialysis patients were retrospectively analyzed from January 2011 to December 2015, with a median follow-up of 59 months. We used receiver operating curves (ROC) to determine the optimal threshold for TG/HDL-C and non-HDL/HDL-C ratios at baseline to predict overall survival during follow-up. Prognostic values were accessed by univariate and multivariate COX regression analysis and Kaplan-Meier curve. A predictive nomogram was developed to predict prognosis for overall survival, and the predictive accuracy was evaluated by concordance index (c-index). Results The optimal cut-off values for TG/HDL-C ratio and non-HDL-C/HDL-C ratio to predict mortality were 1.94 and 2.86, respectively. A high TG/HDL-C ratio and a high non-HDL-C/HDL-C ratio strongly correlated with worse overall survival in peritoneal dialysis patients. Multivariate analysis demonstrated that elevated TG/HDL-C ratio (HR 3.57, 95% CI 1.99, 6.39, P
Published: 2020
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4. Extratubular Polymerized Uromodulin Induces Leukocyte Recruitment and Inflammation In Vivo

Author: Roland Immler, Bärbel Lange-Sperandio, Tobias Steffen, Heike Beck, Ina Rohwedder, Jonas Roth, Matteo Napoli, Georg Hupel, Frederik Pfister, Bastian Popper, Bernd Uhl, Hanna Mannell, Christoph A. Reichel, Volker Vielhauer, Jürgen Scherberich, Markus Sperandio, and Monika Pruenster
Subjects: uromodulin, damage associated molecular pattern (DAMP), inflammation, leukocyte recruitment, kidney disease, Immunologic diseases. Allergy, RC581-607
Abstract: Uromodulin (UMOD) is produced and secreted by tubular epithelial cells. Secreted UMOD polymerizes (pUMOD) in the tubular lumen, where it regulates salt transport and protects the kidney from bacteria and stone formation. Under various pathological conditions, pUMOD accumulates within the tubular lumen and reaches extratubular sites where it may interact with renal interstitial cells. Here, we investigated the potential of extratubular pUMOD to act as a damage associated molecular pattern (DAMP) molecule thereby creating local inflammation. We found that intrascrotal and intraperitoneal injection of pUMOD induced leukocyte recruitment in vivo and led to TNF-α secretion by F4/80 positive macrophages. Additionally, pUMOD directly affected vascular permeability and increased neutrophil extravasation independent of macrophage-released TNF-α. Interestingly, pUMOD displayed no chemotactic properties on neutrophils, did not directly activate β2 integrins and did not upregulate adhesion molecules on endothelial cells. In obstructed neonatal murine kidneys, we observed extratubular UMOD accumulation in the renal interstitium with tubular atrophy and leukocyte infiltrates. Finally, we found extratubular UMOD deposits associated with peritubular leukocyte infiltration in kidneys from patients with inflammatory kidney diseases. Taken together, we identified extratubular pUMOD as a strong inducer of leukocyte recruitment, underlining its critical role in mounting an inflammatory response in various kidneys pathologies.
Published: 2020
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5. Tumor necrosis factor superfamily ligand mRNA expression profiles differ between humans and mice during homeostasis and between various murine kidney injuries

Author: Satish Kumar Devarapu, Julia Felicitas Grill, Junhui Xie, Marc Weidenbusch, Mohsen Honarpisheh, Volker Vielhauer, Hans-Joachim Anders, and Shrikant R. Mulay
Subjects: Crystal nephropathy, Ischemia reperfusion injury, Chronic kidney injury, Anti-GBM, Tumor necrosis factor, Tumor necrosis factor ligands, Medicine
Abstract: Abstract Background Several tumour necrosis factor (TNF) based therapeutics have already been approved for human use and several others are emerging. Therefore, we determined the mRNA expression levels of the TNF superfamily ligands (TNFSF) – e.g. TNF-α, lymphotoxin (LT)-α, LT-β, Fas-L (CD95-L), TNF-related apoptosis-inducing ligand (TRAIL), TNF-related weak inducer of apoptosis (TWEAK), 4-1BBL, OX40-L (CD252) and amyloid precursor protein (APP) in healthy human and mouse solid organs. Methods We used quantitative real time-PCR to analyse mRNA expression levels of TNFSF ligands. Murine models of acute ischemic renal injury, chronic oxalate nephropathy, and immune complex glomerulonephritis were used. Renal injury was assessed by PAS staining, and infiltrating immune cells were analysed by immunohistochemistry. Data was analysed using non-parametric ANOVA (non-parametric; Kruskal-Wallis test). Results We observed significant differences in the mRNA expression levels of TNFSF ligands in human and mouse solid organs. Furthermore, we determined their mRNA expressions during acute and chronic kidney injuries in mice. Our data demonstrate that the mRNA expression levels of TNFSF vary depending on the type of tissue injury – for example, acute ischemic renal injury, chronic crystalline nephropathy, and immune complex glomerulonephritis. In addition, we observed that mRNA expressions of TNFSF ligands are differentially regulated during the course of a transient ischemic renal injury (IRI) and chronic kidney modelling. We observed that TNF-α, LT-β, and 4-1BBL were significantly upregulated during the progression of IRI and crystal-induced chronic kidney disease (CKD), whereas only 4-1BBL and TNF-α were significantly upregulated and LT-β was significantly downregulated during the progression of immune complex glomerulonephritis. The mRNA expression of Fas-L was higher during IRI whereas it decreased in a time dependent manner during the progression of crystal-induced CKD. Conclusion We conclude that the injury- and species-specific differences of TNFSF ligands must be considered in order to avoid the misinterpretation and wrong conclusions during data extrapolation between species.
Published: 2017
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6. Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis

Author: Shrikant R. Mulay, Jyaysi Desai, Santhosh V. Kumar, Jonathan N. Eberhard, Dana Thomasova, Simone Romoli, Melissa Grigorescu, Onkar P. Kulkarni, Bastian Popper, Volker Vielhauer, Gabriele Zuchtriegel, Christoph Reichel, Jan Hinrich Bräsen, Paola Romagnani, Rostyslav Bilyy, Luis E. Munoz, Martin Herrmann, Helen Liapis, Stefan Krautwald, Andreas Linkermann, and Hans-Joachim Anders
Subjects: Science
Abstract: Kidney stone disease is caused by accumulation of oxalate crystals, which trigger tissue injury, inflammation and cell death. Mulay et al. show that crystals induce cell death in the kidney through necroptosis, and propose that this pathway may be a target for the treatment of crystal-induced disease.
Published: 2016
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7. Hepatitis C virus induced endothelial inflammatory response depends on the functional expression of TNFα receptor subtype 2.

Author: Joachim Pircher, Thomas Czermak, Monika Merkle, Hanna Mannell, Florian Krötz, Andrea Ribeiro, Volker Vielhauer, Jonathan Nadjiri, Erik Gaitzsch, Markus Niemeyer, Stefan Porubsky, Hermann-Josef Gröne, and Markus Wörnle
Subjects: Medicine, Science
Abstract: In hepatitis C virus (HCV) infection, morbidity and mortality often result from extrahepatic disease manifestations. We provide evidence for a role of receptors of the innate immune system in virally induced inflammation of the endothelium in vitro and in vivo. Corresponding to the in vitro finding of an HCV-dependent induction of proinflammatory mediators in endothelial cells, mice treated with poly (I:C) exhibit a significant reduction in leukocyte rolling velocity, an increase in leukocyte adhesion to the vessel wall and an increased extravasation of leukocytes. HCV directly promotes activation, adhesion and infiltration of inflammatory cells into the vessel wall by activation of endothelial viral receptors. Poly (I:C) induces the expression of TLR3 in vivo and hereby allows for amplification of all of the aforementioned responses upon viral infection. Proinflammatory effects of viral RNA are specifically mediated by TLR3 and significantly enhanced by tumor necrosis factor alpha (TNFα). HCV-RNA induces the endothelial expression of TNFα and TNFα receptor subtype 2 and we provide evidence that leucocyte adhesion and transmigration in response to activation of viral RNA receptors seem to depend on expression of functional TNFR2. Our results demonstrate that endothelial cells actively participate in immune mediated vascular inflammation caused by viral infections.
Published: 2014
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8. Distinct contributions of TNF receptor 1 and 2 to TNF-induced glomerular inflammation in mice.

Author: Anela Taubitz, Martin Schwarz, Nuru Eltrich, Maja T Lindenmeyer, and Volker Vielhauer
Subjects: Medicine, Science
Abstract: TNF is an important mediator of glomerulonephritis. The two TNF-receptors TNFR1 and TNFR2 contribute differently to glomerular inflammation in vivo, but specific mechanisms of TNFR-mediated inflammatory responses in glomeruli are unknown. We investigated their expression and function in murine kidneys, isolated glomeruli ex vivo, and glomerular cells in vitro. In normal kidney TNFR1 and TNFR2 were preferentially expressed in glomeruli. Expression of both TNFRs and TNF-induced upregulation of TNFR2 mRNA was confirmed in murine glomerular endothelial and mesangial cell lines. In vivo, TNF exposure rapidly induced glomerular accumulation of leukocytes. To examine TNFR-specific inflammatory responses in intrinsic glomerular cells but not infiltrating leukocytes we performed microarray gene expression profiling on intact glomeruli isolated from wildtype and Tnfr-deficient mice following exposure to soluble TNF ex vivo. Most TNF-induced effects were exclusively mediated by TNFR1, including induced glomerular expression of adhesion molecules, chemokines, complement factors and pro-apoptotic molecules. However, TNFR2 contributed to TNFR1-dependent mRNA expression of inflammatory mediators in glomeruli when exposed to low TNF concentrations. Chemokine secretion was absent in TNF-stimulated Tnfr1-deficient glomeruli, but also significantly decreased in glomeruli lacking TNFR2. In vivo, TNF-induced glomerular leukocyte infiltration was abrogated in Tnfr1-deficient mice, whereas Tnfr2-deficiency decreased mononuclear phagocytes infiltrates, but not neutrophils. These data demonstrate that activation of intrinsic glomerular cells by soluble TNF requires TNFR1, whereas TNFR2 is not essential, but augments TNFR1-dependent effects. Previously described TNFR2-dependent glomerular inflammation may therefore require TNFR2 activation by membrane-bound, but not soluble TNF.
Published: 2013
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9. Anti-GBM glomerulonephritis involves IL-1 but is independent of NLRP3/ASC inflammasome-mediated activation of caspase-1.

Author: Julia Lichtnekert, Onkar P Kulkarni, Shrikant R Mulay, Khader Valli Rupanagudi, Mi Ryu, Ramanjaneyulu Allam, Volker Vielhauer, Dan Muruve, Maja T Lindenmeyer, Clemens D Cohen, and Hans-Joachim Anders
Subjects: Medicine, Science
Abstract: IL-1β and IL-18 are proinflammatory cytokines that contribute to renal immune complex disease, but whether IL-1β and IL-18 are mediators of intrinsic glomerular inflammation is unknown. In contrast to other cytokines the secretion of IL-1β and IL-18 requires a second stimulus that activates the inflammasome-ASC-caspase-1 pathway to cleave pro-IL-1β and -IL-18 into their mature and secretable forms. As the NLRP3 inflammasome and caspase-1 were shown to contribute to postischemic and postobstructive tubulointerstitial inflammation, we hypothesized a similar role for NLRP3, ASC, and caspase-1 in glomerular immunopathology. This concept was supported by the finding that lack of IL-1R1 reduced antiserum-induced focal segmental necrosis, crescent formation, and tubular atrophy when compared to wildtype mice. Lack of IL-18 reduced tubular atrophy only. However, NLRP3-, ASC- or caspase-1-deficiency had no significant effect on renal histopathology or proteinuria of serum nephritis. In vitro studies with mouse glomeruli or mesangial cells, glomerular endothelial cells, and podocytes did not reveal any pro-IL-1β induction upon LPS stimulation and no caspase-1 activation after an additional exposure to the NLRP3 agonist ATP. Only renal dendritic cells, which reside mainly in the tubulointerstitium, expressed pro-IL-1β and were able to activate the NLRP3-caspase-1 axis and secrete mature IL-1β. Together, the NLRP3-ASC-caspase-1 axis does not contribute to intrinsic glomerular inflammation via glomerular parenchymal cells as these cannot produce IL-1β during sterile inflammation.
Published: 2011
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10. Drug-induced CYP-induction as therapy for tacrolimus intoxication

Author: John M. Hoppe, Alexander Holderied, Ulf Schönermarck, Volker Vielhauer, Hans-Joachim Anders, and Michael Fischereder
Subjects: Geriatrics and Gerontology
Published: 2022
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11. 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, 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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, Irina, Rump, Lar, Stegbauer, Johanne, Pötz, Christine, Schemmelmann, Mara, Schmidt, Claudia, Koch, Michael, Aker, Sendogan, Küpper, Annika, Martin, Manuela, Pfab, Thiemo, Albert, Christian, Haase, Michael, Zander, Barbara, Schneider-Danwitz, Claudia, Seeger, Wolfgang, Seeger, Wolf-Adam, Zemann, Britta, Stellbrink, Christoph, Marx, Kristin, Stellbrink, Ekaterina, Brettschneider, Britta, Watson, Stephanie, Iselt, Marion, Klausmann, Gerhard, Kummer, Inga-Nadine, Kutschat, Auguste, Streitenberger, Simone, Girndt, Matthia, Markau, Silke, Girakossyan, Ina, Hanf, Claudia, Beige, Joachim, Wendt, Ralph, Schmidt, Ulrike, Schneider, Andrea, Veelken, Roland, Donhauser, Claudia, Becker, Lui, Miftari, Nexhat, Wolfling, Ricarda, Morlok, Sarah, Hugo, Christian, Paliege, Alexander, Passauer, Jen, Stumpf, Julian, Fleischer, Annegret, Haaser, Kerstin, Kraemer, Bernhard, Jochims, Jan, Kruger, Bernd, Foellinger, Claudia, Reisler, Anastassiya, Strutz, Frank, Haack, Stefan, Hohenstatt, Ursula, Busch, Martin, 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

12. Strategien zur effektiven und nebenwirkungsarmen Therapie ANCA-assoziierter Vaskulitiden

Author: Volker Vielhauer and Ulf Schönermarck
Subjects: Gynecology, medicine.medical_specialty, Anti-neutrophil cytoplasmic antibodies, business.industry, Eosinophilic granulomatosis with polyangiitis, ANCA-Associated Vasculitides, medicine.disease, Glukokortikoide, Eosinophile Granulomatose mit Polyangiitis, Transplant surgery, Granulomatose mit Polyangiitis, Nephrology, medicine, Leitthema, Effective treatment, Antineutrophile zytoplasmatische Antikörper, Mikroskopische Polyangiitis, Granulomatosis with polyangiitis, Microscopic polyangiitis, business, Glucocorticoids
Abstract: Die Pathogenese von ANCA(antineutrophile zytoplasmatische Antikorper)-assoziierten Vaskulitiden (AAV) ist komplex, das bessere Verstandnis der letzten Jahre hat jedoch neue therapeutische Ansatze ermoglicht. In den letzten Jahren stand die Minimierung toxischer Therapieeffekte im Vordergrund. In der Remissionsinduktion stehen fur die schwere Granulomatose mit Polyangiitis (GPA) und die mikroskopische Polyangiitis (MPA) neben Glukokortikoiden Cyclophosphamid und Rituximab zur Verfugung. Die aktuellen Empfehlungen ermoglichen eine raschere Reduktion der Steroiddosis und sehen den Einsatz der Plasmapherese zuruckhaltend. Zur Remissionserhaltung stehen Rituximab und Azathioprin zur Verfugung. Medikamentenwahl und Dauer der Remissionserhaltung richten sich insbesondere nach dem Rezidivrisiko. Der Stellenwert von niedrig dosierten Steroiden ist nicht endgultig geklart. Neue Therapieansatze wie der C5a-Rezeptor-Inhibitor Avacopan konnten in Zukunft eine steroidminimierte Therapie ermoglichen. Die Therapie der eosinophilen Granulomatose mit Polyangiitis (EGPA) ist weniger evidenzbasiert und beinhaltet Glukokortikoide, Immunsuppressiva je nach Erkrankungsschwere und zunehmend Biologika (z. B. Interleukin[IL]-5-Blockade). Supportive Masnahmen (Impfungen, Infektionsprophylaxe, kardiovaskulares Risikomanagement) gewinnen an Bedeutung. Zukunftige Therapiestrategien mussen das individuelle Risiko (z. B. ANCA-Subtyp, Rezidivrisiko) fur Auswahl und Dauer der Therapien besser berucksichtigen.
Published: 2021

13. Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy

Author: Jonathan Barratt, Richard Lafayette, Jens Kristensen, Andrew Stone, Daniel Cattran, Jürgen Floege, Vladimir Tesar, Hernán Trimarchi, Hong Zhang, Necmi Eren, Alexander Paliege, Brad H. Rovin, Guillermo Fragale, Alejandra Karl, Patricia Losisolo, Ivan Gonzalez Hoyos, Mauro Guillermo Lampo, Matias Monkowski, Jorge De La Fuente, Magdalena Alvarez, Daniela Stoppa, Carlos Chiurchiu, Pablo Antonio Novoa, Marcelo Orias, Maria Belen Barron, Ana Giotto, Mariano Arriola, Evelin Cassini, Rafael Maldonado, Maria Paula Dionisi, Jessica Ryan, Nigel Toussaint, Grant Luxton, Chen Au Peh, Vicki Levidiotis, Ross Francis, Richard Phoon, Elena Fedosiuk, Dmitry Toropilov, Ruslan Yakubtsevich, Elena Mikhailova, Christophe Bovy, Nathalie Demoulin, Jean-Michel Hougardy, Bart Maes, Marijn Speeckaert, Louis-Philippe Laurin, Sean Barbour, Melanie Masse, Michelle Hladunewich, Heather Reich, Serge Cournoyer, Karthik Tennankore, Jicheng Lv, Zhangsuo Liu, Caili Wang, Shaomei Li, Qun Luo, Zhaohui Ni, Tiekun Yan, Ping Fu, Hong Cheng, Bicheng Liu, Wanhong Lu, Jianqin Wang, Qinkai Chen, DeGuang Wang, Zuying Xiong, Menghua Chen, Yan Xu, Jiali Wei, Pearl Pai, Lianhua Chen, Jitka Rehorova, Dita Maixnerova, Roman Safranek, Ivan Rychlik, Miroslav Hruby, Satu Makela, Kati Vaaraniemi, Fernanda Ortiz, Eric Alamartine, Maite Daroux, Claire Cartery, Francois Vrtovsnik, Jean-Emmanuel Serre, Eleni Stamellou, Volker Vielhauer, Christian Hugo, Klemens Budde, Britta Otte, Martin Nitschke, Evangelia Ntounousi, Ioannis Boletis, Aikaterini Papagianni, Dimitrios Goumenos, Konstantinos Stylianou, Synodi Zermpala, Ciro Esposito, Mario Gennaro Cozzolino, Sara Maria Viganò, Loreto Gesualdo, Michal Nowicki, Tomasz Stompor, Ilona Kurnatowska, Sung Gyun Kim, Yong-Lim Kim, Ki-Ryang Na, Dong Ki Kim, Su-Hyun Kim, Luis Quintana Porras, Eva Rodriguez Garcia, Irene Agraz Pamplona, Alfons Segarra, Marian Goicoechea, Bengt Fellstrom, Sigrid Lundberg, Peter Hemmingsson, Gregor Guron, Anna Sandell, Cheng-Hsu Chen, Bulent Tokgoz, Soner Duman, Mehmet Riza Altiparmak, Metin Ergul, Peter Maxwell, Patrick Mark, Kieran McCafferty, Arif Khwaja, Chee Kay Cheung, Matthew Hall, Albert Power, Durga Kanigicherla, Richard Baker, Jim Moriarty, Amr Mohamed, Joseph Aiello, Pietro Canetta, Isabelle Ayoub, Derrick Robinson, Surabhi Thakar, Amy Mottl, Isaac Sachmechi, Bernard Fischbach, Harmeet Singh, Jeffrey Mulhern, Fahmeedah Kamal, Douglas Linfert, Dana Rizk, Shikha Wadhwani, Menaka Sarav, Kirk Campbell, Gaia Coppock, Randy Luciano, John Sedor, Rupali Avasare, Wai Lang Lau, Zermpala, Synodi, Esposito, Ciro, Cozzolino, Mario Gennaro, Viganò, Sara Maria, Gesualdo, Loreto, Nowicki, Michal, Stompor, Tomasz, Kurnatowska, Ilona, Kim, Sung Gyun, Kim, Yong-Lim, Na, Ki-Ryang, Kim, Dong Ki, Kim, Su-Hyun, Porras, Luis Quintana, Garcia, Eva Rodriguez, Pamplona, Irene Agraz, Segarra, Alfons, Goicoechea, Marian, Fellstrom, Bengt, Lundberg, Sigrid, Hemmingsson, Peter, Guron, Gregor, Sandell, Anna, Chen, Cheng-Hsu, Tokgoz, Bulent, Duman, Soner, Altiparmak, Mehmet Riza, Ergul, Metin, Maxwell, Peter, Mark, Patrick, Fragale, Guillermo, McCafferty, Kieran, Khwaja, Arif, Cheung, Chee Kay, Hall, Matthew, Power, Albert, Kanigicherla, Durga, Baker, Richard, Moriarty, Jim, Mohamed, Amr, Aiello, Joseph, Karl, Alejandra, Canetta, Pietro, Ayoub, Isabelle, Robinson, Derrick, Thakar, Surabhi, Mottl, Amy, Sachmechi, Isaac, Fischbach, Bernard, Singh, Harmeet, Mulhern, Jeffrey, Kamal, Fahmeedah, Losisolo, Patricia, Linfert, Douglas, Rizk, Dana, Wadhwani, Shikha, Sarav, Menaka, Campbell, Kirk, Coppock, Gaia, Luciano, Randy, Sedor, John, Avasare, Rupali, Lau, Wai Lang, Trimarchi, Hernán, Hoyos, Ivan Gonzalez, Lampo, Mauro Guillermo, Monkowski, Matias, De La Fuente, Jorge, Alvarez, Magdalena, Stoppa, Daniela, Chiurchiu, Carlos, Novoa, Pablo Antonio, Orias, Marcelo, Barron, Maria Belen, Giotto, Ana, Arriola, Mariano, Cassini, Evelin, Maldonado, Rafael, Dionisi, Maria Paula, Ryan, Jessica, Toussaint, Nigel, Luxton, Grant, Peh, Chen Au, Levidiotis, Vicki, Francis, Ross, Phoon, Richard, Fedosiuk, Elena, Toropilov, Dmitry, Yakubtsevich, Ruslan, Mikhailova, Elena, Bovy, Christophe, Demoulin, Nathalie, Hougardy, Jean-Michel, Maes, Bart, Speeckaert, Marijn, Laurin, Louis-Philippe, Barbour, Sean, Masse, Melanie, Hladunewich, Michelle, Reich, Heather, Cournoyer, Serge, Tennankore, Karthik, Lv, Jicheng, Liu, Zhangsuo, Wang, Caili, Li, Shaomei, Luo, Qun, Ni, Zhaohui, Yan, Tiekun, Fu, Ping, Cheng, Hong, Liu, Bicheng, Lu, Wanhong, Wang, Jianqin, Chen, Qinkai, Wang, DeGuang, Xiong, Zuying, Chen, Menghua, Xu, Yan, Wei, Jiali, Pai, Pearl, Chen, Lianhua, Rehorova, Jitka, Maixnerova, Dita, Safranek, Roman, Rychlik, Ivan, Hruby, Miroslav, Makela, Satu, Vaaraniemi, Kati, Ortiz, Fernanda, Alamartine, Eric, Daroux, Maite, Cartery, Claire, Vrtovsnik, Francois, Serre, Jean-Emmanuel, Stamellou, Eleni, Vielhauer, Volker, Hugo, Christian, Budde, Klemens, Otte, Britta, Nitschke, Martin, Ntounousi, Evangelia, Boletis, Ioannis, Papagianni, Aikaterini, Goumenos, Dimitrios, Stylianou, Konstantinos, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, and UCL - (SLuc) Service de néphrologie
Subjects: gut-associated lymphoid tissue, glucocorticoids, Nephrology, glomerular disease, IgA nephropathy
Abstract: Kidney international 103(2), 391-402 (2022). doi:10.1016/j.kint.2022.09.017, Published by Elsevier, New York, NY
Published: 2022
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14. Elevated TG/HDL-C and non-HDL-C/HDL-C ratios predict mortality in peritoneal dialysis patients

Author: Hong Hu, Yan Chen, Wenkai Xia, Volker Vielhauer, Xiajuan Yao, and Jie Lin
Subjects: Adult, Male, Nephrology, medicine.medical_specialty, Multivariate analysis, medicine.medical_treatment, Population, Peritoneal dialysis, 030232 urology & nephrology, 030204 cardiovascular system & hematology, lcsh:RC870-923, Gastroenterology, Triglyceride, 03 medical and health sciences, 0302 clinical medicine, High-density lipoprotein cholesterol, Internal medicine, medicine, Humans, Mortality, education, Triglycerides, Aged, education.field_of_study, business.industry, Proportional hazards model, Cholesterol, HDL, nutritional and metabolic diseases, Middle Aged, Nomogram, medicine.disease, Prognosis, lcsh:Diseases of the genitourinary system. Urology, Cholesterol, Kidney Failure, Chronic, Female, lipids (amino acids, peptides, and proteins), business, Dyslipidemia, Research Article, Kidney disease
Abstract: Background and aims Dyslipidemia is common in patients with chronic kidney disease and particular prevalent in patients receiving peritoneal dialysis. However, whether markers of atherogenic dyslipidemia correlate with outcomes in dialysis patients as in the general population is uncertain. The aim of this study was to explore the prognostic value of the serum triglyceride/HDL cholesterol (TG/HDL-C) ratio and non-HDL-C/HDL-C ratio to predict mortality in peritoneal dialysis patients. Methods Two hundred fourteen peritoneal dialysis patients were retrospectively analyzed from January 2011 to December 2015, with a median follow-up of 59 months. We used receiver operating curves (ROC) to determine the optimal threshold for TG/HDL-C and non-HDL/HDL-C ratios at baseline to predict overall survival during follow-up. Prognostic values were accessed by univariate and multivariate COX regression analysis and Kaplan-Meier curve. A predictive nomogram was developed to predict prognosis for overall survival, and the predictive accuracy was evaluated by concordance index (c-index). Results The optimal cut-off values for TG/HDL-C ratio and non-HDL-C/HDL-C ratio to predict mortality were 1.94 and 2.86, respectively. A high TG/HDL-C ratio and a high non-HDL-C/HDL-C ratio strongly correlated with worse overall survival in peritoneal dialysis patients. Multivariate analysis demonstrated that elevated TG/HDL-C ratio (HR 3.57, 95% CI 1.99, 6.39, P P = 0.003) were independent markers to predict reduced OS. A nomogram was constructed to predict overall survival, with a c-index for predictive accuracy of 0.795. Conclusion TG/HDL-C ratio and non-HDL-C/HDL-C may serve as potential prognostic biomarkers in PD patients.
Published: 2020
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15. Extratubular polymerized uromodulin induces leukocyte recruitment and inflammation in vivo

Author: Georg Hupel, Markus Sperandio, Monika Pruenster, Volker Vielhauer, Bastian Popper, Bernd Uhl, Jürgen E. Scherberich, Roland Immler, Hanna Mannell, Tobias Steffen, Jonas Roth, Bärbel Lange-Sperandio, Christoph A. Reichel, Heike Beck, and Frederik Pfister
Subjects: Kidney, Neutrophil extravasation, Tamm–Horsfall protein, biology, Chemistry, Damage-associated molecular pattern, Inflammation, Vascular permeability, medicine.disease, Cell biology, medicine.anatomical_structure, medicine, biology.protein, Tumor necrosis factor alpha, medicine.symptom, Infiltration (medical)
Abstract: Uromodulin (UMOD) is produced and secreted by tubular epithelial cells. Secreted UMOD polymerizes (pUMOD) within the lumen, where it regulates salt transport and protects the kidney from bacteria and stone formation. Under various pathological conditions, pUMOD accumulates within the tubular lumen and reaches extratubular sites where it may interact with renal interstitial cells. Here, we investigated the potential of extratubular pUMOD to act as a damage associated molecular pattern (DAMP) molecule thereby creating local inflammation. We found that intrascrotal and intraperitoneal injection of pUMOD induced leukocyte recruitment in vivo and led to TNF-α secretion by F4/80 positive macrophages. Additionally, pUMOD directly affected vascular permeability and increased neutrophil extravasation independent of macrophage-released TNF-α. Interestingly, pUMOD did not directly upregulate adhesion molecules on endothelial cells and did not directly activate β2 integrins on neutrophils. In obstructed neonatal murine kidneys, we observed extratubular UMOD accumulation with tubular atrophy and leukocyte infiltrates. Finally, we found extratubular UMOD deposits associated with peritubular leukocyte infiltration in kidneys from patients with inflammatory kidney diseases. Taken together, we identified extratubular pUMOD as a strong inducer of leukocyte recruitment, underlining its critical role in mounting an inflammatory response in various kidneys pathologies.
Published: 2020
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16. After ten years of follow-up, no difference between supportive care plus immunosuppression and supportive care alone in IgA nephropathy

Author: Thomas Rauen, Stephanie Wied, Christina Fitzner, Frank Eitner, Claudia Sommerer, Martin Zeier, Britta Otte, Ulf Panzer, Klemens Budde, Urs Benck, Peter R. Mertens, Uwe Kuhlmann, Oliver Witzke, Oliver Gross, Volker Vielhauer, Johannes F.E. Mann, Ralf-Dieter Hilgers, Jürgen Floege, Marcus J. Moeller, Horst Weihprecht, Harm Peters, Saban Elitok, Markus Bieringer, Ralf Schindler, Ulrich Frei, Sima Canaan–Kühl, Christiane Erley, Karsten Schlieps, Frans Zandvoort, Bernd Hohenstein, Christian Hugo, Catrin Palm, Karl Hilgers, Hermann Haller, Anna Bertram, Gunter Wolf, Martin Busch, Thomas Rath, Stephan Ziefle, Thomas Benzing, Franziska Grundmann, Stefan Westphalen, Uwe Göttmann, Michael Fischereder, Oliver Sarkar, Marianna Stefanidou, Hermann Pavenstädt, Bernhard Banas, Alexander Boeger, Nils Heyne, Ferruh Artunc, Helmut Reichel, Thomas Mettang, Christoph Wanner, and Thomas Metzger
Subjects: 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Medizin, 030232 urology & nephrology, Renal function, urologic and male genital diseases, Nephropathy, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, medicine, Clinical endpoint, Humans, Retrospective Studies, Immunosuppression Therapy, business.industry, Hazard ratio, Glomerulonephritis, IGA, Immunosuppression, Retrospective cohort study, medicine.disease, 3. Good health, Proteinuria, 030104 developmental biology, Nephrology, business, Immunosuppressive Agents, Follow-Up Studies, Glomerular Filtration Rate, Kidney disease
Abstract: The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.
Published: 2020

17. Effects of Two Immunosuppressive Treatment Protocols for IgA Nephropathy

Author: Britta Otte, Claudia Sommerer, Martin Zeier, Peter R. Mertens, Harm Peters, Uwe Kuhlmann, Ulf Panzer, Christina Fitzner, Volker Vielhauer, Frank Eitner, Ralf-Dieter Hilgers, Jürgen Floege, Urs Benck, Thomas Rauen, Oliver Witzke, Johannes F.E. Mann, and Oliver Gross
Subjects: Male, medicine.medical_treatment, Medizin, Anti-Inflammatory Agents, 030232 urology & nephrology, Azathioprine, 030204 cardiovascular system & hematology, Weight Gain, urologic and male genital diseases, Gastroenterology, 0302 clinical medicine, Adrenal Cortex Hormones, Prospective Studies, Proteinuria, Immunosuppression, General Medicine, Middle Aged, Intention to Treat Analysis, 3. Good health, Nephrology, Corticosteroid, Drug Therapy, Combination, Female, medicine.symptom, Immunosuppressive Agents, Glomerular Filtration Rate, medicine.drug, Adult, medicine.medical_specialty, Cyclophosphamide, medicine.drug_class, Prednisolone, Infections, Nephropathy, 03 medical and health sciences, Clinical Research, Internal medicine, Glucose Intolerance, medicine, Humans, Adverse effect, Immunosuppression Therapy, business.industry, Glomerulonephritis, IGA, Odds ratio, medicine.disease, business
Abstract: The role of immunosuppression in IgA nephropathy (IgAN) is controversial. In the Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) Trial, 162 patients with IgAN and proteinuria >0.75 g/d after 6 months of optimized supportive care were randomized into two groups: continued supportive care or additional immunosuppression (GFR≥60 ml/min per 1.73 m2: 6-month corticosteroid monotherapy; GFR=30–59 ml/min per 1.73 m2: cyclophosphamide for 3 months followed by azathioprine plus oral prednisolone). Coprimary end points were full clinical remission and GFR loss ≥15 ml/min per 1.73 m2 during the 3-year trial phase. In this secondary intention to treat analysis, we separately analyzed data from each immunosuppression subgroup and the corresponding patients on supportive care. Full clinical remission occurred in 11 (20%) patients receiving corticosteroid monotherapy and three (6%) patients on supportive care (odds ratio, 5.31; 95% confidence interval, 1.07 to 26.36; P=0.02), but the rate did not differ between patients receiving immunosuppressive combination and controls on supportive care (11% versus 4%, respectively; P=0.30). The end point of GFR loss ≥15 ml/min per 1.73 m2 did not differ between groups. Only corticosteroid monotherapy transiently reduced proteinuria at 12 months. Severe infections, impaired glucose tolerance, and/or weight gain in the first year were more frequent with either immunosuppressive regimen than with supportive care. In conclusion, only corticosteroid monotherapy induced disease remission in a minority of patients who had IgAN with relatively well preserved GFR and persistent proteinuria. Neither immunosuppressive regimen prevented GFR loss, and both associated with substantial adverse events.
Published: 2017
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18. Tumor necrosis factor superfamily ligand mRNA expression profiles differ between humans and mice during homeostasis and between various murine kidney injuries

Author: Hans-Joachim Anders, Satish Kumar Devarapu, Mohsen Honarpisheh, Volker Vielhauer, Shrikant R. Mulay, Junhui Xie, Marc Weidenbusch, and Julia Felicitas Grill
Subjects: 0301 basic medicine, Tumor necrosis factor, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Tumor necrosis factor ligands, lcsh:Medicine, Anti-GBM, Biology, Vascular endothelial growth inhibitor, Kidney, Ligands, Nephropathy, 03 medical and health sciences, Mice, Species Specificity, medicine, Animals, Homeostasis, Humans, Pharmacology (medical), RNA, Messenger, B-cell activating factor, Molecular Biology, TNF superfamily, Chronic kidney injury, Research, Biochemistry (medical), lcsh:R, Cell Biology, General Medicine, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Apoptosis, Organ Specificity, Crystal nephropathy, Immunology, Tumor Necrosis Factors, Cancer research, Tumor necrosis factor alpha, Lymphotoxin beta receptor, Transcriptome, Ischemia reperfusion injury, Kidney disease
Abstract: Background Several tumour necrosis factor (TNF) based therapeutics have already been approved for human use and several others are emerging. Therefore, we determined the mRNA expression levels of the TNF superfamily ligands (TNFSF) – e.g. TNF-α, lymphotoxin (LT)-α, LT-β, Fas-L (CD95-L), TNF-related apoptosis-inducing ligand (TRAIL), TNF-related weak inducer of apoptosis (TWEAK), 4-1BBL, OX40-L (CD252) and amyloid precursor protein (APP) in healthy human and mouse solid organs. Methods We used quantitative real time-PCR to analyse mRNA expression levels of TNFSF ligands. Murine models of acute ischemic renal injury, chronic oxalate nephropathy, and immune complex glomerulonephritis were used. Renal injury was assessed by PAS staining, and infiltrating immune cells were analysed by immunohistochemistry. Data was analysed using non-parametric ANOVA (non-parametric; Kruskal-Wallis test). Results We observed significant differences in the mRNA expression levels of TNFSF ligands in human and mouse solid organs. Furthermore, we determined their mRNA expressions during acute and chronic kidney injuries in mice. Our data demonstrate that the mRNA expression levels of TNFSF vary depending on the type of tissue injury – for example, acute ischemic renal injury, chronic crystalline nephropathy, and immune complex glomerulonephritis. In addition, we observed that mRNA expressions of TNFSF ligands are differentially regulated during the course of a transient ischemic renal injury (IRI) and chronic kidney modelling. We observed that TNF-α, LT-β, and 4-1BBL were significantly upregulated during the progression of IRI and crystal-induced chronic kidney disease (CKD), whereas only 4-1BBL and TNF-α were significantly upregulated and LT-β was significantly downregulated during the progression of immune complex glomerulonephritis. The mRNA expression of Fas-L was higher during IRI whereas it decreased in a time dependent manner during the progression of crystal-induced CKD. Conclusion We conclude that the injury- and species-specific differences of TNFSF ligands must be considered in order to avoid the misinterpretation and wrong conclusions during data extrapolation between species.
Published: 2017
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19. Exclusive expression of transmembrane TNF aggravates acute glomerulonephritis despite reduced leukocyte infiltration and inflammation

Author: Andrei Bideak, Martin B. Müller, Maja T. Lindenmeyer, John M. Hoppe, Volker Vielhauer, Nuru Eltrich, Susanna Müller, Moritz Lux, Bernhard Ryffel, University of Alberta, Division of nephrology and Institute of Physiology, Universität Zürich [Zürich] = University of Zurich (UZH), Immunologie et Embryologie Moléculaires (IEM), and Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Biopsy, Necroptosis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Interleukin-1beta, Kidney Glomerulus, 030232 urology & nephrology, Datasets as Topic, Apoptosis, Mice, Transgenic, Inflammation, Cell Line, Podocyte, Mice, 03 medical and health sciences, Glomerulonephritis, 0302 clinical medicine, Leukocytes, medicine, Animals, Humans, Receptors, Tumor Necrosis Factor, Type II, Gene Knock-In Techniques, ComputingMilieux_MISCELLANEOUS, Kidney, Tumor Necrosis Factor-alpha, business.industry, Cell Membrane, Endothelial Cells, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Cytokine, Nephrology, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, medicine.symptom, business, Nephritis
Abstract: Tumor necrosis factor-α (TNF) is a cytokine mediating inflammatory kidney diseases such as immune complex glomerulonephritis. Its two receptors, TNFR1 and TNFR2, play distinct roles in this process, with TNFR2 strongly required for induction of disease. In contrast to soluble TNF (sTNF), transmembrane TNF robustly activates TNFR2. Thus, we examined the functional role of transmembrane TNF by inducing heterologous nephrotoxic serum nephritis in wild-type and transgenic TNFΔ1-9,K11E knock-in mice expressing transmembrane TNF but no sTNF (memTNF mice). Compared to wild-type, nephritis was exacerbated in memTNF mice on day 5, indicated by increased albuminuria, higher serum urea levels, and more pronounced glomerular deposits, together with higher numbers of dying and proliferating glomerular cells. This was associated with greater loss of glomerular endothelial cells, increased podocyte stress, and signs of augmented necroptosis in memTNF kidneys. Aggravation of nephritis was dependent on transmembrane TNF expression in parenchymal cells, but not leukocytes. Surprisingly, increased kidney injury was associated with reduced renal leukocyte infiltration in memTNF mice, which correlated with decreased renal mRNA expression of pro-inflammatory mediators. This effect was also present in isolated memTNF glomeruli stimulated with interleukin-1β in vitro. Thus, uncleaved transmembrane TNF is an important mediator of renal tissue damage characterized by increased renal cell death and loss of glomerular endothelial cells in murine glomerulonephritis. In contrast, sTNF predominantly mediates renal leukocyte recruitment and inflammation. These findings highlight the importance of transmembrane TNF in inflammatory kidney disease as a possible therapeutic target.
Published: 2019
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20. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Author: Hiddo J L Heerspink, Hans-Henrik Parving, Dennis L Andress, George Bakris, Ricardo Correa-Rotter, Fan-Fan Hou, Dalane W Kitzman, Donald Kohan, Hirofumi Makino, John J V McMurray, Joel Z Melnick, Michael G Miller, Pablo E Pergola, Vlado Perkovic, Sheldon Tobe, Tingting Yi, Melissa Wigderson, Dick de Zeeuw, Alicia Elbert, Augusto Vallejos, Andres Alvarisqueta, Laura Maffei, Luis Juncos, Javier de Arteaga, Gustavo Greloni, Eduardo Farias, Alfredo Zucchini, Daniel Vogel, Ana Cusumano, Juan Santos, Margaret Fraenkel, Martin Gallagher, Tim Davis, Shamasunder Acharya, Duncan Cooke, Michael Suranyi, Simon Roger, Nigel Toussaint, Carol Pollock, Doris Chan, Stephen Stranks, Richard MacIsaac, Zoltan Endre, Alice Schmidt, Rudolf Prager, Gert Mayer, Xavier Warling, Michel Jadoul, Jean Hougardy, Chris Vercammen, Bruno Van Vlem, Pieter Gillard, Adriana Costa e Forti, Joao Lindolfo Borges, Luis Santos Canani, Freddy Eliaschewitz, Silmara Leite, Fadlo Fraige Filho, Raphael Paschoalin, Jose Andrade Moura Neto, Luciane Deboni, Irene de Lourdes Noronha, Cintia Cercato, Carlos Alberto Prompt, Maria Zanella, Nelson Rassi, Domingos D'Avila, Rosangela Milagres, Joao Felicio, Roberto Pecoits Filho, Miguel Carlos Riella, Joao Salles, Elizete Keitel, Sergio Draibe, Celso Amodeo, Joseph Youmbissi, Louise Roy, Serge Cournoyer, Shivinder Jolly, Vincent Pichette, Gihad Nesrallah, Harpreet Singh Bajaj, Hasnain Khandwala, Ronnie Aronson, Richard Goluch, Paul Tam, Christian Rabbat, Gordon Bailey, Stephen Chow, Alvaro Castillo, Alfredo Danin Vargas, Fernando Gonzalez, Rodrigo Munoz, Vicente Gutierrez, Gonzalo Godoy, Hongwen Zhao, Zhangsuo Liu, Minghui Zhao, Xiaohui Guo, Benli Su, Shuxia Fu, Yan Xu, Jinkui Yang, Bingyin Shi, Guanqing Xiao, Wei Shi, Chuanming Hao, Changying Xing, Fanfan Hou, Qun Luo, Yuxiu Li, Linong Ji, Li Zuo, Song Wang, Zhaohui Ni, Guohua Ding, Nan Chen, Jiajun Zhao, Weiping Jia, Shengqiang Yu, Jian Weng, Gang Xu, Ping Fu, Shiren Sun, Bicheng Liu, Xiaoqiang Ding, Ivan Rychlik, Alexandra Oplustilova, Dagmar Bartaskova, Vaclava Honova, Hana Chmelickova, Martin Petr, Petr Bucek, Vladimir Tesar, Emil Zahumensky, Johan Povlsen, Kenneth Egstrup, Anna Oczachowska-Kulik, Peter Rossing, Jorma Lahtela, Jorma Strand, Ilkka Kantola, Catherine Petit, Christian Combe, Philippe Zaoui, Vincent Esnault, Pablo Urena Torres, Jean-Michel Halimi, Bertrand Dussol, Tasso Bieler, Klemens Budde, Frank Dellanna, Thomas Segiet, Christine Kosch, Hans Schmidt-Guertler, Isabelle Schenkenberger, Volker Vielhauer, Frank Pistrosch, Mark Alscher, Christoph Hasslacher, Christian Hugo, Anja Muehlfeld, Christoph Wanner, Ploumis Passadakis, Theofanis Apostolou, Nikolaos Tentolouris, Ioannis Stefanidis, Konstantinos Mavromatidis, Vasilios Liakopoulos, Dimitrios Goumenos, Konstantinos Siamopoulos, Vincent Yeung, Risa Ozaki, Samuel Fung, Kathryn Tan, Sydney Tang, Sing Leung Lui, Siu Fai Cheung, Seamus Sreenan, Joseph Eustace, Donal O'Shea, Peter Lavin, Austin Stack, Yoram Yagil, Julio Wainstein, Hilla Knobler, Josef Cohen, Irina Kenis, Deeb Daoud, Yosefa Bar-Dayan, Victor Frajewicki, Faiad Adawi, Loreto Gesualdo, Domenico Santoro, Francesco Marino, Andrea Galfre, Chiara Brunati, Piero Ruggenenti, Giuseppe Rombola, Giuseppe Pugliese, Maura Ravera, Fabio Malberti, Giuseppe Pontoriero, Teresa Rampino, Salvatore De Cosmo, Ciro Esposito, Felice Nappi, Cataldo Abaterusso, Giuseppe Conte, Vincenzo Panichi, Davide Lauro, Giovambattista Capasso, Domenico Russo, Jiichi Anzai, Motoji Naka, Keita Ato, Tetsuro Tsujimoto, Toshinori Nimura, Eitaro Nakashima, Tetsuro Takeda, Shinya Fujii, Kunihisa Kobayashi, Hideaki Iwaoka, Koji Nagayama, Hiroyuki Harada, Hajime Maeda, Rui Kishimoto, Tadashi Iitsuka, Naoki Itabashi, Ryuichi Furuya, Yoshitaka Maeda, Daishiro Yamada, Nobuhiro Sasaki, Hiromitsu Sasaki, Shinichiro Ueda, Naoki Kashihara, Shuichi Watanabe, Takehiro Nakamura, Hidetoshi Kanai, Yuichiro Makita, Keiko Ono, Noriyuki Iehara, Daisuke Goto, Keiichiro Kosuge, Kenichi Tsuchida, Toshiaki Sato, Takashi Sekikawa, Hideki Okamoto, Tsuyoshi Tanaka, Naoko Ikeda, Takenobu Tadika, Koji Mukasa, Takeshi Osonoi, Fuminori Hirano, Motonobu Nishimura, Yuko Yambe, Yukio Tanaka, Makoto Ujihara, Takashi Sakai, Mitsuo Imura, Yutaka Umayahara, Shinya Makino, Jun Nakazawa, Yukinari Yamaguchi, Susumu Kashine, Hiroaki Miyaoka, Katsunori Suzuki, Toshihiko Inoue, Sou Nagai, Nobuyuki Sato, Masahiro Yamamoto, Noriyasu Taya, Akira Fujita, Akira Matsutani, Yugo Shibagaki, Yuichi Sato, Akira Yamauchi, Masahiro Tsutsui, Tamayo Ishiko, Shizuka Kaneko, Nobuyuki Azuma, Hirofumi Matsuda, Yasuhiro Hashiguchi, Yukiko Onishi, Mikiya Tokui, Munehide Matsuhisa, Arihiro Kiyosue, Junji Shinoda, Kazuo Ishikawa, Ghazali Ahmad, Shalini Vijayasingham, Nor Azizah Aziz, Zanariah Hussein, Yin Khet Fung, Wan Hasnul Halimi Wan Hassan, Hin Seng Wong, Bak Leong Goh, Norhaliza Mohd Ali, Nor Shaffinaz Yusuf Azmi Merican, Indralingam Vaithilingam, Nik Nur Fatnoon Nik Ahmad, Noor Adam, Norlela Sukor, V Paranthaman P Vengadasalam, Khalid Abdul Kadir, Mafauzy Mohamed, Karina Renoirte Lopez, Aniceto Leguizamo-Dimas, Alfredo Chew Wong, Jose Chevaile-Ramos, Jose Gonzalez Gonzalez, Raul Rico Hernandez, Jose Nino-Cruz, Leobardo Sauque Reyna, Guillermo Gonzalez-Galvez, Magdalena Madero Rovalo, Tomasso Bochicchio-Ricardelli, Jorge Aldrete, Jaime Carranza-Madrigal, Liffert Vogt, Peter Smak Gregoor, JNM Barendregt, Peter Luik, Ronald Gansevoort, Gozewijn Laverman, Helen Pilmore, Helen Lunt, John Baker, Steven Miller, Kannaiyan Rabindranath, Luis Zapata-Rincon, Rolando Vargas-Gonzales, Jorge Calderon Ticona, Augusto Dextre Espinoza, Jose Burga Nunez, Carlos Antonio Zea-Nunez, Benjamin Herrada Orue, Boris Medina-Santander, Cesar Delgado-Butron, Julio Farfan-Aspilcueta, Stanislaw Mazur, Miroslaw Necki, Michal Wruk, Katarzyna Klodawska, Grazyna Popenda, Ewa Skokowska, Malgorzata Arciszewska, Andrzej Wiecek, Kazimierz Ciechanowski, Michal Nowicki, Rita Birne, Antonio Cabrita, Aura Ramos, Manuel Anibal Antunes Ferreira, Evelyn Matta Fontanet, Altagracia Aurora Alcantara-Gonzalez, Angel Comulada-Rivera, Eugenia Galindo Ramos, Jose Cangiano, Luis Quesada-Suarez, Ricardo Calderon Ortiz, Jose Vazquez-Tanus, Rafael Burgos-Calderon, Carlos Rosado, Nicolae Hancu, Ella Pintilei, Cristina Mistodie, Gabriel Bako, Lavinia Ionutiu, Ligia Petrica, Romulus Timar, Liliana Tuta, Livia Duma, Adriana Tutescu, Svetlana Ivanova, Ashot Essaian, Konstantin Zrazhevskiy, Natalia Tomilina, Elena Smolyarchuk, Anatoly Kuzin, Olga Lantseva, Irina Karpova, Minara Shamkhalova, Natalia Liberanskaya, Andrey Yavdosyuk, Yuri Shvarts, Tatiana Bardymova, Olga Blagoveshchenskaya, Oleg Solovev, Elena Rechkova, Natalia Pikalova, Maria Pavlova, Elena Kolmakova, Rustam Sayfutdinov, Svetlana Villevalde, Natalya Koziolova, Vladimir Martynenko, Vyacheslav Marasaev, Adelya Maksudova, Olga Sigitova, Viktor Mordovin, Vadim Klimontov, Yulia Samoylova, Tatiana Karonova, Lee Ying Yeoh, Boon Wee Teo, Marjorie Wai Yin Foo, Adrian Liew, Ivan Tkac, Aniko Oroszova, Jozef Fekete, Jaroslav Rosenberger, Ida Obetkova, Alla Fulopova, Eva Kolesarova, Katarina Raslova, Peter Smolko, Adrian Oksa, Larry Distiller, Julien Trokis, Luthando Adams, Hemant Makan, Padaruth Ramlachan, Essack Mitha, Kathleen Coetzee, Zelda Punt, Qasim Bhorat, Puvenesvari Naiker, Graham Ellis, Louis Van Zyl, Kwan Woo Lee, Min Seon Kim, Soon-Jib Yoo, Kun Ho Yoon, Yong-Wook Cho, Tae-Sun Park, Sang Yong Kim, Moon-Gi Choi, Tae Keun Oh, Kang-Wook Lee, Ho Sang Shon, Sung Hwan Suh, Byung-Joon Kim, Kim Doo-Man, Joo Hark Yi, Sang Ah Lee, Ho Chan Cho, Sin-Gon Kim, Dae-Ryong Cha, Ji A Seo, Kyung Mook Choi, Jeong-Taek Woo, Kyu Jeung Ahn, Jae Hyuk Lee, In-Joo Kim, Moon-Kyu Lee, Hak Chul Jang, Kyong-Soo Park, Beom Seok Kim, Ji Oh Mok, Mijung Shin, Sun Ae Yoon, Il-Seong Nam-Goong, Choon Hee Chung, Tae Yang Yu, Hyoung Woo Lee, Alfonso Soto Gonzalez, Jaume Almirall, Jesus Egido, Francesca Calero Gonzalez, Gema Fernandez Fresnedo, Ildefonso Valera Cortes, Manuel Praga Terente, Isabel Garcia Mendez, Juan Navarro Gonzalez, Jose Herrero Calvo, Secundino Cigarran Guldris, Mario Prieto Velasco, Jose Ignacio Minguela Pesquera, Antonio Galan, Julio Pascual, Maria Marques Vidas, Judith Martins Munoz, Jose Rodriguez-Perez, Cristina Castro-Alonso, Josep Bonet Sol, Daniel Seron, Elvira Fernandez Giraldez, Javier Arrieta Lezama, Nuria Montero, Julio Hernandez-Jaras, Rafael Santamaria Olmo, Jose Ramon Molas Coten, Olof Hellberg, Bengt Fellstrom, Andreas Bock, Dee Pei, Ching-Ling Lin, Kai-Jen Tien, Ching-Chu Chen, Chien-Ning Huang, Ju-Ying Jiang, Du-An Wu, Chih-Hsun Chu, Shih-Ting Tseng, Jung-Fu Chen, Cho-Tsan Bau, Wayne Sheu, Mai-Szu Wu, Ramazan Sari, Siren Sezer, Alaattin Yildiz, Ilhan Satman, Betul Kalender, Borys Mankovskyy, Ivan Fushtey, Mykola Stanislavchuk, Mykola Kolenyk, Iryna Dudar, Viktoriia Zolotaikina, Orest Abrahamovych, Tetyana Kostynenko, Olena Petrosyan, Petro Kuskalo, Olga Galushchak, Oleg Legun, Ivan Topchii, Liliya Martynyuk, Vasyl Stryzhak, Svitlana Panina, Sergii Tkach, Vadym Korpachev, Peter Maxwell, Luigi Gnudi, Sui Phin Kon, Hilary Tindall, Phillip Kalra, Patrick Mark, Dipesh Patel, Mohamed El-Shahawy, Liqun Bai, Romanita Nica, Yeong-Hau Lien, Judson Menefee, Robert Busch, Alan Miller, Azazuddin Ahmed, Ahmed Arif, Joseph Lee, Sachin Desai, Shweta Bansal, Marie Bentsianov, Mario Belledonne, Charles Jere, Raul Gaona, Gregory Greenwood, Osvaldo Brusco, Mark Boiskin, Diogo Belo, Raffi Minasian, Naveen Atray, Mary Lawrence, John Taliercio, Pablo Pergola, David Scott, German Alvarez, Bradley Marder, Thomas Powell, Wa'el Bakdash, George Stoica, Christopher McFadden, Marc Rendell, Jonathan Wise, Audrey Jones, Michael Jardula, Ivy-Joan Madu, Freemu Varghese, Brian Tulloch, Ziauddin Ahmed, Melanie Hames, Imran Nazeer, Newman Shahid, Rekha John, Manuel Montero, David Fitz-Patrick, Lawrence Phillips, Antonio Guasch, Elena Christofides, Aijaz Gundroo, Mohammad Amin, Cynthia Bowman-Stroud, Michael Link, Laura Mulloy, Michael Nammour, Tarik Lalwani, Lenita Hanson, Adam Whaley-Connell, Lee Herman, Rupi Chatha, Sayed Osama, Kenneth Liss, Zeid Kayali, Anuj Bhargava, Ezra Israel, Alfredo Peguero-Rivera, Michael Fang, Judith Slover, Elena Barengolts, Jose Flores, Rosemary Muoneke, Virginia Savin, Stella Awua-Larbi, Andrew Levine, George Newman, Laden Golestaneh, Guillermo Bohm, Efrain Reisin, Lucita Cruz, Robert Weiss, Franklin Zieve, Edward Horwitz, Peale Chuang, James Mersey, John Manley, Ronald Graf, Fadi Bedros, Sudhir Joshi, Juan Frias, Ali Assefi, Andrew O'Shaughnessy, Roman Brantley, Todd Minga, David Tietjen, Samuel Kantor, Aamir Jamal, Ramon Guadiz, Kenneth Hershon, Peter Bressler, Nelson Kopyt, Harold Cathcart, Scott Bloom, Ronald Reichel, Samer Nakhle, Emily Dulude, Joshua Tarkan, Penelope Baker, Steven Zeig, Jaynier Moya Hechevarria, Armando Ropero-Cartier, Gilda De la Calle, Ankur Doshi, Fadi Saba, Teresa Sligh, Sylvia Shaw, Jayant Kumar, Harold Szerlip, George Bayliss, Alan Perlman, Lakhi Sakhrani, Steven Gouge, Georges Argoud, Idalia Acosta, John Elder, Sucharit Joshi, John Sensenbrenner, Steven Vicks, Roberto Mangoo-Karim, Claude Galphin, Carlos Leon-Forero, John Gilbert, Eric Brown, Adeel Ijaz, Salman Butt, Mariana Markell, Carlos Arauz-Pacheco, Lance Sloan, Odilon Alvarado, Serge Jabbour, Eric Simon, Anjay Rastogi, Sam James, Karen Hall, John Melish, Brad Dixon, Allen Adolphe, Csaba Kovesdy, Srinivasan Beddhu, Richard Solomon, Ronald Fernando, Ellis Levin, Charuhas Thakar, Brooks Robey, David Goldfarb, Linda Fried, Geetha Maddukuri, Stephen Thomson, Andrew Annand, Saeed Kronfli, Paramjit Kalirao, Rebecca Schmidt, Neera Dahl, Samuel Blumenthal, Debra Weinstein, Ove Ostergaard, Talia Weinstein, Yasuhiro Ono, Murat Yalcin, Shahana Karim, APH - Health Behaviors & Chronic Diseases, Nephrology, ACS - Amsterdam Cardiovascular Sciences, ACS - Microcirculation, Biomedical Signals and Systems, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Groningen Kidney Center (GKC), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Heerspink, H. J. L., Parving, H. -H., Andress, D. L., Bakris, G., Correa-Rotter, R., Hou, F. -F., Kitzman, D. W., Kohan, D., Makino, H., Mcmurray, J. J. V., Melnick, J. Z., Miller, M. G., Pergola, P. E., Perkovic, V., Tobe, S., Yi, T., Wigderson, M., de Zeeuw, D., Elbert, A., Vallejos, A., Alvarisqueta, A., Maffei, L., Juncos, L., de Arteaga, J., Greloni, G., Farias, E., Zucchini, A., Vogel, D., Cusumano, A., Santos, J., Fraenkel, M., Gallagher, M., Davis, T., Acharya, S., Cooke, D., Suranyi, M., Roger, S., Toussaint, N., Pollock, C., Chan, D., Stranks, S., Macisaac, R., Endre, Z., Schmidt, A., Prager, R., Mayer, G., Warling, X., Jadoul, M., Hougardy, J., Vercammen, C., Van Vlem, B., Gillard, P., Costa e Forti, A., Borges, J. L., Santos Canani, L., Eliaschewitz, F., Leite, S., Fraige Filho, F., Paschoalin, R., Moura Neto, J. A., Deboni, L., de Lourdes Noronha, I., Cercato, C., Prompt, C. A., Zanella, M., Rassi, N., D'Avila, D., Milagres, R., Felicio, J., Pecoits Filho, R., Riella, M. C., Salles, J., Keitel, E., Draibe, S., Amodeo, C., Youmbissi, J., Roy, L., Cournoyer, S., Jolly, S., Pichette, V., Nesrallah, G., Bajaj, H. S., Khandwala, H., Aronson, R., Goluch, R., Tam, P., Rabbat, C., Bailey, G., Chow, S., Castillo, A., Danin Vargas, A., Gonzalez, F., Munoz, R., Gutierrez, V., Godoy, G., Zhao, H., Liu, Z., Zhao, M., Guo, X., Su, B., Fu, S., Xu, Y., Yang, J., Shi, B., Xiao, G., Shi, W., Hao, C., Xing, C., Hou, F., Luo, Q., Li, Y., Ji, L., Zuo, L., Wang, S., Ni, Z., Ding, G., Chen, N., Zhao, J., Jia, W., Yu, S., Weng, J., Xu, G., Fu, P., Sun, S., Liu, B., Ding, X., Rychlik, I., Oplustilova, A., Bartaskova, D., Honova, V., Chmelickova, H., Petr, M., Bucek, P., Tesar, V., Zahumensky, E., Povlsen, J., Egstrup, K., Oczachowska-Kulik, A., Rossing, P., Lahtela, J., Strand, J., Kantola, I., Petit, C., Combe, C., Zaoui, P., Esnault, V., Urena Torres, P., Halimi, J. -M., Dussol, B., Bieler, T., Budde, K., Dellanna, F., Segiet, T., Kosch, C., Schmidt-Guertler, H., Schenkenberger, I., Vielhauer, V., Pistrosch, F., Alscher, M., Hasslacher, C., Hugo, C., Muehlfeld, A., Wanner, C., Passadakis, P., Apostolou, T., Tentolouris, N., Stefanidis, I., Mavromatidis, K., Liakopoulos, V., Goumenos, D., Siamopoulos, K., Yeung, V., Ozaki, R., Fung, S., Tan, K., Tang, S., Lui, S. L., Cheung, S. F., Sreenan, S., Eustace, J., O'Shea, D., Lavin, P., Stack, A., Yagil, Y., Wainstein, J., Knobler, H., Cohen, J., Kenis, I., Daoud, D., Bar-Dayan, Y., Frajewicki, V., Adawi, F., Gesualdo, L., Santoro, D., Marino, F., Galfre, A., Brunati, C., Ruggenenti, P., Rombola, G., Pugliese, G., Ravera, M., Malberti, F., Pontoriero, G., Rampino, T., De Cosmo, S., Esposito, C., Nappi, F., Abaterusso, C., Conte, G., Panichi, V., Lauro, D., Capasso, G., Russo, D., Anzai, J., Naka, M., Ato, K., Tsujimoto, T., Nimura, T., Nakashima, E., Takeda, T., Fujii, S., Kobayashi, K., Iwaoka, H., Nagayama, K., Harada, H., Maeda, H., Kishimoto, R., Iitsuka, T., Itabashi, N., Furuya, R., Maeda, Y., Yamada, D., Sasaki, N., Sasaki, H., Ueda, S., Kashihara, N., Watanabe, S., Nakamura, T., Kanai, H., Makita, Y., Ono, K., Iehara, N., Goto, D., Kosuge, K., Tsuchida, K., Sato, T., Sekikawa, T., Okamoto, H., Tanaka, T., Ikeda, N., Tadika, T., Mukasa, K., Osonoi, T., Hirano, F., Nishimura, M., Yambe, Y., Tanaka, Y., Ujihara, M., Sakai, T., Imura, M., Umayahara, Y., Makino, S., Nakazawa, J., Yamaguchi, Y., Kashine, S., Miyaoka, H., Suzuki, K., Inoue, T., Nagai, S., Sato, N., Yamamoto, M., Taya, N., Fujita, A., Matsutani, A., Shibagaki, Y., Sato, Y., Yamauchi, A., Tsutsui, M., Ishiko, T., Kaneko, S., Azuma, N., Matsuda, H., Hashiguchi, Y., Onishi, Y., Tokui, M., Matsuhisa, M., Kiyosue, A., Shinoda, J., Ishikawa, K., Ahmad, G., Vijayasingham, S., Aziz, N. A., Hussein, Z., Fung, Y. K., Hassan, W. H. H. W., Wong, H. S., Goh, B. L., Ali, N. M., Merican, N. S. Y. A., Vaithilingam, I., Nik Ahmad, N. N. F., Adam, N., Sukor, N., Vengadasalam, V. P. P., Abdul Kadir, K., Mohamed, M., Renoirte Lopez, K., Leguizamo-Dimas, A., Chew Wong, A., Chevaile-Ramos, J., Gonzalez Gonzalez, J., Rico Hernandez, R., Nino-Cruz, J., Sauque Reyna, L., Gonzalez-Galvez, G., Madero Rovalo, M., Bochicchio-Ricardelli, T., Aldrete, J., Carranza-Madrigal, J., Vogt, L., Smak Gregoor, P., Barendregt, J. N. M., Luik, P., Gansevoort, R., Laverman, G., Pilmore, H., Lunt, H., Baker, J., Miller, S., Rabindranath, K., Zapata-Rincon, L., Vargas-Gonzales, R., Calderon Ticona, J., Dextre Espinoza, A., Burga Nunez, J., Zea-Nunez, C. A., Herrada Orue, B., Medina-Santander, B., Delgado-Butron, C., Farfan-Aspilcueta, J., Mazur, S., Necki, M., Wruk, M., Klodawska, K., Popenda, G., Skokowska, E., Arciszewska, M., Wiecek, A., Ciechanowski, K., Nowicki, M., Birne, R., Cabrita, A., Ramos, A., Antunes Ferreira, M. A., Matta Fontanet, E., Alcantara-Gonzalez, A. A., Comulada-Rivera, A., Galindo Ramos, E., Cangiano, J., Quesada-Suarez, L., Calderon Ortiz, R., Vazquez-Tanus, J., Burgos-Calderon, R., Rosado, C., Hancu, N., Pintilei, E., Mistodie, C., Bako, G., Ionutiu, L., Petrica, L., Timar, R., Tuta, L., Duma, L., Tutescu, A., Ivanova, S., Essaian, A., Zrazhevskiy, K., Tomilina, N., Smolyarchuk, E., Kuzin, A., Lantseva, O., Karpova, I., Shamkhalova, M., Liberanskaya, N., Yavdosyuk, A., Shvarts, Y., Bardymova, T., Blagoveshchenskaya, O., Solovev, O., Rechkova, E., Pikalova, N., Pavlova, M., Kolmakova, E., Sayfutdinov, R., Villevalde, S., Koziolova, N., Martynenko, V., Marasaev, V., Maksudova, A., Sigitova, O., Mordovin, V., Klimontov, V., Samoylova, Y., Karonova, T., Yeoh, L. Y., Teo, B. W., Foo, M. W. Y., Liew, A., Tkac, I., Oroszova, A., Fekete, J., Rosenberger, J., Obetkova, I., Fulopova, A., Kolesarova, E., Raslova, K., Smolko, P., Oksa, A., Distiller, L., Trokis, J., Adams, L., Makan, H., Ramlachan, P., Mitha, E., Coetzee, K., Punt, Z., Bhorat, Q., Naiker, P., Ellis, G., Van Zyl, L., Lee, K. W., Kim, M. S., Yoo, S. -J., Yoon, K. H., Cho, Y. -W., Park, T. -S., Kim, S. Y., Choi, M. -G., Oh, T. K., Lee, K. -W., Shon, H. S., Suh, S. H., Kim, B. -J., Doo-Man, K., Yi, J. H., Lee, S. A., Cho, H. C., Kim, S. -G., Cha, D. -R., Seo, J. A., Choi, K. M., Woo, J. -T., Ahn, K. J., Lee, J. H., Kim, I. -J., Lee, M. -K., Jang, H. C., Park, K. -S., Kim, B. S., Mok, J. O., Shin, M., Yoon, S. A., Nam-Goong, I. -S., Chung, C. H., Yu, T. Y., Lee, H. W., Soto Gonzalez, A., Almirall, J., Egido, J., Calero Gonzalez, F., Fernandez Fresnedo, G., Valera Cortes, I., Praga Terente, M., Garcia Mendez, I., Navarro Gonzalez, J., Herrero Calvo, J., Cigarran Guldris, S., Prieto Velasco, M., Minguela Pesquera, J. I., Galan, A., Pascual, J., Marques Vidas, M., Martins Munoz, J., Rodriguez-Perez, J., Castro-Alonso, C., Bonet Sol, J., Seron, D., Fernandez Giraldez, E., Arrieta Lezama, J., Montero, N., Hernandez-Jaras, J., Santamaria Olmo, R., Molas Coten, J. R., Hellberg, O., Fellstrom, B., Bock, A., Pei, D., Lin, C. -L., Tien, K. -J., Chen, C. -C., Huang, C. -N., Jiang, J. -Y., Wu, D. -A., Chu, C. -H., Tseng, S. -T., Chen, J. -F., Bau, C. -T., Sheu, W., Wu, M. -S., Sari, R., Sezer, S., Yildiz, A., Satman, I., Kalender, B., Mankovskyy, B., Fushtey, I., Stanislavchuk, M., Kolenyk, M., Dudar, I., Zolotaikina, V., Abrahamovych, O., Kostynenko, T., Petrosyan, O., Kuskalo, P., Galushchak, O., Legun, O., Topchii, I., Martynyuk, L., Stryzhak, V., Panina, S., Tkach, S., Korpachev, V., Maxwell, P., Gnudi, L., Kon, S. P., Tindall, H., Kalra, P., Mark, P., Patel, D., El-Shahawy, M., Bai, L., Nica, R., Lien, Y. -H., Menefee, J., Busch, R., Miller, A., Ahmed, A., Arif, A., Lee, J., Desai, S., Bansal, S., Bentsianov, M., Belledonne, M., Jere, C., Gaona, R., Greenwood, G., Brusco, O., Boiskin, M., Belo, D., Minasian, R., Atray, N., Lawrence, M., Taliercio, J., Pergola, P., Scott, D., Alvarez, G., Marder, B., Powell, T., Bakdash, W., Stoica, G., Mcfadden, C., Rendell, M., Wise, J., Jones, A., Jardula, M., Madu, I. -J., Varghese, F., Tulloch, B., Ahmed, Z., Hames, M., Nazeer, I., Shahid, N., John, R., Montero, M., Fitz-Patrick, D., Phillips, L., Guasch, A., Christofides, E., Gundroo, A., Amin, M., Bowman-Stroud, C., Link, M., Mulloy, L., Nammour, M., Lalwani, T., Hanson, L., Whaley-Connell, A., Herman, L., Chatha, R., Osama, S., Liss, K., Kayali, Z., Bhargava, A., Israel, E., Peguero-Rivera, A., Fang, M., Slover, J., Barengolts, E., Flores, J., Muoneke, R., Savin, V., Awua-Larbi, S., Levine, A., Newman, G., Golestaneh, L., Bohm, G., Reisin, E., Cruz, L., Weiss, R., Zieve, F., Horwitz, E., Chuang, P., Mersey, J., Manley, J., Graf, R., Bedros, F., Joshi, S., Frias, J., Assefi, A., O'Shaughnessy, A., Brantley, R., Minga, T., Tietjen, D., Kantor, S., Jamal, A., Guadiz, R., Hershon, K., Bressler, P., Kopyt, N., Cathcart, H., Bloom, S., Reichel, R., Nakhle, S., Dulude, E., Tarkan, J., Baker, P., Zeig, S., Moya Hechevarria, J., Ropero-Cartier, A., De la Calle, G., Doshi, A., Saba, F., Sligh, T., Shaw, S., Kumar, J., Szerlip, H., Bayliss, G., Perlman, A., Sakhrani, L., Gouge, S., Argoud, G., Acosta, I., Elder, J., Sensenbrenner, J., Vicks, S., Mangoo-Karim, R., Galphin, C., Leon-Forero, C., Gilbert, J., Brown, E., Ijaz, A., Butt, S., Markell, M., Arauz-Pacheco, C., Sloan, L., Alvarado, O., Jabbour, S., Simon, E., Rastogi, A., James, S., Hall, K., Melish, J., Dixon, B., Adolphe, A., Kovesdy, C., Beddhu, S., Solomon, R., Fernando, R., Levin, E., Thakar, C., Robey, B., Goldfarb, D., Fried, L., Maddukuri, G., Thomson, S., Annand, A., Kronfli, S., Kalirao, P., Schmidt, R., Dahl, N., Blumenthal, S., Weinstein, D., Ostergaard, O., Weinstein, T., Ono, Y., Yalcin, M., Karim, S., Pathology/molecular and cellular medicine, Diabetes Pathology & Therapy, and Diabetes Clinic
Subjects: Male, endothelin, albuminuria, nephropathy, inhibition, Diabetes Mellitus, Type 2/drug therapy, Endocrinology, Diabetes and Metabolism, Placebo-controlled study, Administration, Oral, 030204 cardiovascular system & hematology, Settore MED/13 - Endocrinologia, chemistry.chemical_compound, 0302 clinical medicine, ENDOTHELIN, 80 and over, Diabetic Nephropathies, 030212 general & internal medicine, Renal Insufficiency, Chronic, Aged, 80 and over, Diabetic Nephropathies/blood, General Medicine, Middle Aged, Atrasentan/administration & dosage, Editorial Commentary, Treatment Outcome, Nephrology, Creatinine, Administration, young adult, Female, medicine.symptom, Glomerular filtration rate, Type 2, Endothelin A Receptor Antagonists/administration & dosage, medicine.drug, Glomerular Filtration Rate, Human, Oral, Adult, medicine.medical_specialty, ALBUMINURIA, Endothelin A Receptor Antagonists, NEPHROPATHY, Urology, INHIBITION, Renal function, Serum Albumin, Human, Placebo, Nephropathy, 03 medical and health sciences, Young Adult, Double-Blind Method, Atresentan, diabetes, chronic kidney disease, medicine, Diabetes Mellitus, Aged, Atrasentan, Diabetes Mellitus, Type 2, Humans, Renal Insufficiency, Chronic, Serum Albumin, business.industry, Creatinine/blood, medicine.disease, Serum Albumin, Human/urine, n/a OA procedure, chemistry, Albuminuria, Renal Insufficiency, Chronic/blood, business, aged, 80 and over, Kidney disease
Abstract: Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR = 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
Published: 2019
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21. C-C chemokine receptor type 2 mediates glomerular injury and interstitial fibrosis in focal segmental glomerulosclerosis

Author: Maja T. Lindenmeyer, Volker Vielhauer, Anne M Mühe, Nuru Eltrich, Bruno Luckow, Anja Wilkening, and Julia Krappe
Subjects: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, CCR2, Receptors, CCR2, 030232 urology & nephrology, urologic and male genital diseases, Kidney, Podocyte, Nephrin, Diabetic nephropathy, 03 medical and health sciences, Mice, 0302 clinical medicine, Focal segmental glomerulosclerosis, medicine, Animals, Inflammation, Mice, Knockout, Transplantation, Mice, Inbred BALB C, biology, urogenital system, business.industry, Glomerulosclerosis, Focal Segmental, Macrophages, Glomerulosclerosis, Glomerulonephritis, medicine.disease, Fibrosis, female genital diseases and pregnancy complications, 030104 developmental biology, medicine.anatomical_structure, Nephrology, biology.protein, Tubulointerstitial fibrosis, Chemokines, business
Abstract: Background Glomerulosclerosis and tubulointerstitial fibrosis are hallmarks of chronic kidney injury leading to end-stage renal disease. Inflammatory mechanisms contribute to glomerular and interstitial scarring, including chemokine-mediated recruitment of leucocytes. In particular, accumulation of C-C chemokine receptor type 2 (CCR2)-expressing macrophages promotes renal injury and fibrotic remodelling in diseases like glomerulonephritis and diabetic nephropathy. The functional role of CCR2 in the initiation and progression of primary glomerulosclerosis induced by podocyte injury remains to be characterized. Methods We analysed glomerular expression of CCR2 and its chemokine ligand C-C motif chemokine ligand 2 (CCL2) in human focal segmental glomerulosclerosis (FSGS). Additionally, CCL2 expression was determined in stimulated murine glomeruli and glomerular cells in vitro. To explore pro-inflammatory and profibrotic functions of CCR2 we induced adriamycin nephropathy, a murine model of FSGS, in BALB/c wild-type and Ccr2-deficient mice. Results Glomerular expression of CCR2 and CCL2 significantly increased in human FSGS. In adriamycin-induced FSGS, progressive glomerular scarring and reduced glomerular nephrin expression was paralleled by induced glomerular expression of CCL2. Adriamycin exposure stimulated secretion of CCL2 and tumour necrosis factor-α (TNF) in isolated glomeruli and mesangial cells and CCL2 in parietal epithelial cells. In addition, TNF induced CCL2 expression in all glomerular cell populations, most prominently in podocytes. In vivo, Ccr2-deficient mice with adriamycin nephropathy showed reduced injury, macrophage and fibrocyte infiltration and inflammation in glomeruli and the tubulointerstitium. Importantly, glomerulosclerosis and tubulointerstitial fibrosis were significantly ameliorated. Conclusions Our data indicate that CCR2 is an important mediator of glomerular injury and progression of FSGS. CCR2- targeting therapies may represent a novel approach for its treatment.
Published: 2018

22. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy

Author: Thomas, Rauen, Frank, Eitner, Christina, Fitzner, Claudia, Sommerer, Martin, Zeier, Britta, Otte, Ulf, Panzer, Harm, Peters, Urs, Benck, Peter R, Mertens, Uwe, Kuhlmann, Oliver, Witzke, Oliver, Gross, Volker, Vielhauer, Johannes F E, Mann, Ralf-Dieter, Hilgers, Jürgen, Floege, and Ellen, Irmler-Mercier
Subjects: Adult, Male, medicine.medical_specialty, Critical Care, medicine.medical_treatment, Medizin, Renal function, Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Type 2 Receptor Blockers, law.invention, Nephropathy, Renin-Angiotensin System, chemistry.chemical_compound, Randomized controlled trial, law, Internal medicine, Humans, Medicine, Treatment Failure, Immunosuppression, Intensive Supportive Care, IgA Nephropathy, Glucocorticoids, Immunosuppression Therapy, Creatinine, Proteinuria, business.industry, Glomerulonephritis, IGA, Glomerulonephritis, General Medicine, Middle Aged, medicine.disease, Combined Modality Therapy, 3. Good health, Blockade, Logistic Models, chemistry, Immunology, Female, medicine.symptom, business, Glomerular Filtration Rate
Abstract: BACKGROUND: The outcomes of immunosuppressive therapy, when added to supportive care, in patients with IgA nephropathy are uncertain. METHODS: We conducted a multicenter, open-label, randomized, controlled trial with a two-group, parallel, group-sequential design. During a 6-month run-in phase, supportive care (in particular, blockade of the renin-angiotensin system) was adjusted on the basis of proteinuria. Patients who had persistent proteinuria with urinary protein excretion of at least 0.75 g per day were randomly assigned to receive supportive care alone (supportive-care group) or supportive care plus immunosuppressive therapy (immunosuppression group) for 3 years. The primary end points in hierarchical order were full clinical remission at the end of the trial (protein-to-creatinine ratio
Published: 2015
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23. The Atypical Chemokine Receptor 2 Limits Progressive Fibrosis after Acute Ischemic Kidney Injury

Author: Nuru Eltrich, Volker Vielhauer, Martin B. Müller, Hermann Josef Gröne, Moritz Lux, Alexander Blaut, Andrei Bideak, Massimo Locati, and John M. Hoppe
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, T-Lymphocytes, 030232 urology & nephrology, Inflammation, Nephron, urologic and male genital diseases, Kidney, Pathology and Forensic Medicine, 03 medical and health sciences, Chemokine receptor, Mice, 0302 clinical medicine, Fibrosis, Renal fibrosis, Medicine, Animals, Renal Insufficiency, Chronic, Myofibroblasts, Chemokine CCL2, Mice, Knockout, urogenital system, business.industry, Macrophages, Acute kidney injury, Kidney metabolism, Acute Kidney Injury, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Reperfusion Injury, Receptors, Chemokine, medicine.symptom, business, Kidney disease
Abstract: Following renal ischemia-reperfusion injury (IRI), resolution of inflammation allows tubular regeneration, whereas ongoing inflammatory injury mediated by infiltrating leukocytes leads to nephron loss and renal fibrosis, typical hallmarks of chronic kidney disease. Atypical chemokine receptor 2 (ACKR2) is a chemokine decoy receptor that binds and scavenges inflammatory CC chemokines and reduces local leukocyte accumulation. We hypothesized that ACKR2 limits leukocyte infiltration, inflammation, and fibrotic tissue remodeling after renal IRI, thus preventing progression to chronic kidney disease. Compared with wild type, Ackr2 deficiency increases CC chemokine ligand 2 levels in tumor necrosis factor-stimulated tubulointerstitial tissue in vitro. In Ackr2-deficient mice with early IRI 1 or 5 days after transient renal pedicle clamping, tubular injury was similar to wild type, although accumulation of mononuclear phagocytes increased in postischemic Ackr2-/- kidneys. Regarding long-term outcomes, Ackr2-/- kidneys displayed more tubular injury 5 weeks after IRI, which was associated with persistently increased renal infiltrates of mononuclear phagocytes, T cells, Ly6Chigh inflammatory macrophages, and inflammation. Moreover, Ackr2 deficiency caused substantially aggravated renal fibrosis in Ackr2-/- kidneys 5 weeks after IRI, shown by increased expression of matrix molecules, renal accumulation of α-smooth muscle actin-positive myofibroblasts, and bone marrow-derived fibrocytes. ACKR2 is important in limiting persistent inflammation, tubular loss, and renal fibrosis after ischemic acute kidney injury and, thus, can prevent progression to chronic renal disease.
Published: 2017

24. The atypical chemokine receptor 2 limits renal inflammation and fibrosis in murine progressive immune complex glomerulonephritis

Author: Nuru Eltrich, Massimo Locati, Martin B. Müller, Alexander Blaut, John M. Hoppe, Andrei Bideak, Hermann Josef Gröne, Giuseppina Federico, and Volker Vielhauer
Subjects: 0301 basic medicine, CD4-Positive T-Lymphocytes, Male, Chemokine, Pathology, medicine.medical_specialty, Kidney Glomerulus, Inflammation, CCL2, Adaptive Immunity, Lymphocyte Activation, 03 medical and health sciences, Chemokine receptor, 0302 clinical medicine, Glomerulonephritis, Fibrosis, Medicine, Animals, Immune Complex Diseases, Mononuclear Phagocyte System, Cells, Cultured, Mice, Knockout, biology, business.industry, medicine.disease, Mice, Inbred C57BL, Chemotaxis, Leukocyte, Disease Models, Animal, 030104 developmental biology, Kidney Tubules, Nephrology, 030220 oncology & carcinogenesis, biology.protein, Disease Progression, Receptors, Chemokine, medicine.symptom, Inflammation Mediators, business, Nephritis, Immune complex disease, Signal Transduction
Abstract: The atypical chemokine receptor 2 (ACKR2), also named D6, regulates local levels of inflammatory chemokines by internalization and degradation. To explore potential anti-inflammatory functions of ACKR2 in glomerulonephritis, we induced autologous nephrotoxic nephritis in C57/BL6 wild-type and Ackr2 -deficient mice. Renal ACKR2 expression increased and localized to interstitial lymphatic endothelium during nephritis. At two weeks Ackr2 –/– mice developed increased albuminuria and urea levels compared to wild-type mice. Histological analysis revealed increased structural damage in the glomerular and tubulointerstitial compartments within Ackr2 −/− kidneys. This correlated with excessive renal leukocyte infiltration of CD4 + T cells and mononuclear phagocytes with increased numbers in the tubulointerstitium but not glomeruli in knockout mice. Expression of inflammatory mediators and especially markers of fibrotic tissue remodeling were increased along with higher levels of ACKR2 inflammatory chemokine ligands like CCL2 in nephritic Ackr2 –/– kidneys. In vitro , Ackr2 deficiency in TNF-stimulated tubulointerstitial tissue but not glomeruli increased chemokine levels. These results are in line with ACKR2 expression in interstitial lymphatic endothelial cells, which also assures efflux of activated leukocytes into regional lymph nodes. Consistently, nephritic Ackr2 –/– mice showed reduced adaptive cellular immune responses indicated by decreased regional T-cell activation. However, this did not prevent aggravated injury in the kidneys of Ackr2 –/– mice with nephrotoxic nephritis due to simultaneously increased tubulointerstitial chemokine levels, leukocyte infiltration and fibrosis. Thus, ACKR2 is important in limiting renal inflammation and fibrotic remodeling in progressive nephrotoxic nephritis. Hence, ACKR2 may be a potential target for therapeutic interventions in immune complex glomerulonephritis.
Published: 2017

25. Analysis of TNF-mediated recruitment and activation of glomerular dendritic cells in mouse kidneys by compartment-specific flow cytometry

Author: Ramanjaneyulu Allam, Nuru Eltrich, Anela Taubitz, Volker Vielhauer, Martin Schwarz, and Shrikant R. Mulay
Subjects: Male, Chemokine, Kidney Glomerulus, CD11c, chemical and pharmacologic phenomena, Cell Separation, Mice, Immune system, medicine, Animals, Receptors, Tumor Necrosis Factor, Type II, RNA, Messenger, Mice, Knockout, CD86, Phagocytes, CD40, biology, Tumor Necrosis Factor-alpha, Chemotaxis, hemic and immune systems, Dendritic Cells, Flow Cytometry, medicine.disease, Molecular biology, CD11c Antigen, Mice, Inbred C57BL, Disease Models, Animal, Phenotype, Receptors, Tumor Necrosis Factor, Type I, Nephrology, Immunology, biology.protein, Nephritis, Interstitial, Female, Tumor necrosis factor alpha, Chemokines, Inflammation Mediators, Cell Adhesion Molecules, Nephritis, Biomarkers, CD80, Signal Transduction, Ureteral Obstruction
Abstract: Renal dendritic cells (DCs) form an interstitial network contributing to inflammatory and adaptive immune responses in the kidney. The presence and functional role of DC-like glomerular CD11c(+) mononuclear phagocytes is a matter of debate. Using compartment-specific flow cytometry we found that healthy mouse kidneys contained 1.3 CD11c(+) cells per 100 glomeruli and these increased by 4.6-fold and 13-fold after TNF stimulation and immune complex deposition, respectively. Compartment-specific mRNA expression revealed a predominantly glomerular expression of TNF receptors, chemokines, and adhesion molecules; all upregulated after TNF exposure. Intraperitoneal TNF injection induced influx of neutrophils and mononuclear phagocytes including DC-like CD11c(+) cells into both the glomerular and tubulointerstitial compartments, but reduced in TNF receptor (Tnfr) 1-deficient mice. Additionally, Tnfr2 deficiency impaired glomerular infiltration of CD11c(+) cells, but not neutrophils. Interstitial CD11c(+) cells infiltrated in the presence of Tnfr1 or Tnfr2. TNF exposure also induced similar maturation of glomerular and interstitial CD11c(+) cells as demonstrated by increased surface expression of MHC II, CD54, and costimulatory molecules CD40, CD80, and CD86. Thus, by compartment-specific flow cytometry we could demonstrate the constitutive presence of DC-like CD11c(+) mononuclear phagocytes in normal mouse glomeruli and their TNF-induced accumulation and activation.
Published: 2013
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26. Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease

Author: Hans-Joachim Anders, Santhosh V. Kumar, Nicolai Burzlaff, Martin Hrabě de Angelis, Bernd Hoppe, Volker Vielhauer, Martin Herrmann, John R. Asplin, Wolfgang Hans, Jyaysi Desai, Shrikant R. Mulay, Maciej Lech, Andrew P. Evan, Nuru Eltrich, Marc Weidenbusch, Julian A. Marschner, Melissa Grigorescu, Lisa Müller, and Jonathan N. Eberhard
Subjects: 0301 basic medicine, medicine.medical_specialty, Urology, Necroptosis, 030232 urology & nephrology, Calcium oxalate, Inflammation, urologic and male genital diseases, Receptors, Tumor Necrosis Factor, Primary hyperoxaluria, 03 medical and health sciences, chemistry.chemical_compound, Kidney Calculi, Mice, 0302 clinical medicine, Internal medicine, medicine, Chronic Inflammation, Hyperoxaluria, Kidney Stone, Pathology, Animals, Humans, Receptors, Tumor Necrosis Factor, Type II, Receptor, business.industry, Cell adhesion molecule, Adhesion, General Medicine, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, chemistry, Kidney stone disease, Nephrology, Receptors, Tumor Necrosis Factor, Type I, Tumor necrosis factor alpha, Nephrocalcinosis, medicine.symptom, Brief Communications, business, Crystallization, Annexin A2
Abstract: Intrarenal crystals trigger inflammation and renal cell necroptosis, processes that involve TNF receptor (TNFR) signaling. Here, we tested the hypothesis that TNFRs also have a direct role in tubular crystal deposition and progression of hyperoxaluria-related CKD. Immunohistochemical analysis revealed upregulated tubular expression of TNFR1 and TNFR2 in human and murine kidneys with calcium oxalate (CaOx) nephrocalcinosis-related CKD compared with controls. Western blot and mRNA expression analyses in mice yielded consistent data. When fed an oxalate-rich diet, wild-type mice developed progressive CKD, whereas Tnfr1-, Tnfr2-, and Tnfr1/2-deficient mice did not. Despite identical levels of hyperoxaluria, Tnfr1-, Tnfr2-, and Tnfr1/2-deficient mice also lacked the intrarenal CaOx deposition and tubular damage observed in wild-type mice. Inhibition of TNFR signaling prevented the induced expression of the crystal adhesion molecules, CD44 and annexin II, in tubular epithelial cells in vitro and in vivo, and treatment with the small molecule TNFR inhibitor R-7050 partially protected hyperoxaluric mice from nephrocalcinosis and CKD. We conclude that TNFR signaling is essential for CaOx crystal adhesion to the luminal membrane of renal tubules as a fundamental initiating mechanism of oxalate nephropathy. Furthermore, therapeutic blockade of TNFR might delay progressive forms of nephrocalcinosis in oxalate nephropathy, such as primary hyperoxaluria.
Published: 2016

27. Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis

Author: Gabriele Zuchtriegel, Stefan Krautwald, Jonathan N. Eberhard, Volker Vielhauer, Hans-Joachim Anders, Onkar P. Kulkarni, Shrikant R. Mulay, Andreas Linkermann, Santhosh V. Kumar, Luis E. Muñoz, Christoph A. Reichel, Helen Liapis, Simone Romoli, Jan Hinrich Bräsen, Dana Thomasova, Jyaysi Desai, Melissa Grigorescu, Bastian Popper, Rostyslav Bilyy, Paola Romagnani, and Martin Herrmann
Subjects: 0301 basic medicine, oxalate crystal-related acute kidney injury, progenitors, nephrology, Programmed cell death, Necroptosis, Science, Calcium oxalate, General Physics and Astronomy, Apoptosis, Biology, Calcium Pyrophosphate, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, chemistry.chemical_compound, RIPK1, Mice, Necrosis, medicine, Animals, Humans, Progenitor cell, Phosphorylation, Protein kinase A, Mice, Inbred BALB C, Multidisciplinary, Calcium Oxalate, Tumor Necrosis Factor-alpha, Inflammasome, General Chemistry, 3. Good health, Cell biology, Uric Acid, Mice, Inbred C57BL, 030104 developmental biology, chemistry, Receptor-Interacting Protein Serine-Threonine Kinases, Kidney Diseases, Protein Kinases, medicine.drug
Abstract: Crystals cause injury in numerous disorders, and induce inflammation via the NLRP3 inflammasome, however, it remains unclear how crystals induce cell death. Here we report that crystals of calcium oxalate, monosodium urate, calcium pyrophosphate dihydrate and cystine trigger caspase-independent cell death in five different cell types, which is blocked by necrostatin-1. RNA interference for receptor-interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain like (MLKL), two core proteins of the necroptosis pathway, blocks crystal cytotoxicity. Consistent with this, deficiency of RIPK3 or MLKL prevents oxalate crystal-induced acute kidney injury. The related tissue inflammation drives TNF-α-related necroptosis. Also in human oxalate crystal-related acute kidney injury, dying tubular cells stain positive for phosphorylated MLKL. Furthermore, necrostatin-1 and necrosulfonamide, an inhibitor for human MLKL suppress crystal-induced cell death in human renal progenitor cells. Together, TNF-α/TNFR1, RIPK1, RIPK3 and MLKL are molecular targets to limit crystal-induced cytotoxicity, tissue injury and organ failure., Kidney stone disease is caused by accumulation of oxalate crystals, which trigger tissue injury, inflammation and cell death. Mulay et al. show that crystals induce cell death in the kidney through necroptosis, and propose that this pathway may be a target for the treatment of crystal-induced disease.
Published: 2016

28. Viral RNA Induces Type I Interferon-Dependent Cytokine Release and Cell Death in Mesangial Cells via Melanoma-Differentiation-Associated Gene-5

Author: Onkar P. Kulkarni, Julia Lichtnekert, Bruce Beutler, Martin Schwarz, Daniel Zecher, Hans-Joachim Anders, Ramanjaneyulu Allam, Katharina Flür, and Volker Vielhauer
Subjects: Small interfering RNA, Mesangial cell, Glomerular Mesangial Cell, Cellular differentiation, RNA, Biology, Virology, Pathology and Forensic Medicine, Cell biology, Interferon, TRIF, TLR3, medicine, medicine.drug
Abstract: Viral RNA can trigger interferon signaling in dendritic cells via the innate recognition receptors melanoma-differentiation-associated gene (MDA)-5 and retinod-inducible gene (RIG)-I in the cytosol or via Toll-like receptors (TLRs) in intracellular endosomes. We hypothesized that viral RNA would also activate glomerular mesangial cells to produce type I interferon (IFN) via TLR-dependent and TLR-independent pathways. To test this hypothesis, we examined Toll/Interleukin-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)-deficient mice, which lack a key adaptor for TLR3 signaling. In primary mesangial cells, poly I:C RNA-mediated IFN-β induction was partially TRIF dependent; however, when poly I:C RNA was complexed with cationic lipids to enhance cytosolic uptake, mesangial cells produced large amounts of IFN-α and IFN-β independent of TRIF. Mesangial cells expressed RIG-I and MDA-5 and their mitochondrial adaptor IFN-β promoter stimulator-1 as well, and small interfering RNA studies revealed that MDA5 but not RIG-I was required for cytosolic poly I:C RNA signaling. In addition, mesangial cells produced Il-6 on stimulation with IFN-α and IFN-β, suggesting an autocrine proinflammatory effect. Indeed, blockade of IFN-αβ or lack of the IFNA receptor reduced viral RNA-induced Il-6 production and apoptotic cell death in mesangial cells. Furthermore, viral RNA/cationic lipid complexes increased focal necrosis in murine nephrotoxic serum nephritis in association with increased renal mRNA expression of IFN-related genes. Thus, TLR-independent recognition of viral RNA is a potent inducer of type I interferon in mesangial cells, which can be an important mediator of virally induced glomerulonephritis.
Published: 2009
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29. CCR1 blockade reduces interstitial inflammation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome

Author: Stephan Segerer, Matthias Kretzler, Vaclav Eis, Frank Strutz, Richard Horuk, Hermann Josef Gröne, Volker Vielhauer, Elias Berning, Hans-Joachim Anders, and Detlef Schlöndorff
Subjects: Male, medicine.medical_specialty, Pathology, Nephrotic Syndrome, Receptors, CCR1, chemokines, Kidney, urologic and male genital diseases, Mice, Focal segmental glomerulosclerosis, Piperidines, Fibrosis, Internal medicine, Leukocytes, Renal fibrosis, Animals, Medicine, focal segmental glomerulosclerosis, Mice, Inbred BALB C, Antibiotics, Antineoplastic, progressive nephropathy, Glomerulosclerosis, Focal Segmental, business.industry, Phenylurea Compounds, fibrosis, Glomerulosclerosis, Glomerulonephritis, receptor blockade, medicine.disease, Obstructive Nephropathy, macrophages, Proteinuria, Endocrinology, Doxorubicin, Nephrology, Nephritis, Interstitial, Receptors, Chemokine, business, Nephritis, Nephrotic syndrome
Abstract: CCR1 blockade reduces interstitial inflammation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome. Background CC chemokines mediate leukocyte infiltration into inflamed tissue. We have recently shown that blockade of the CC chemokine receptor CCR1 reduces interstitial inflammation and fibrosis in murine obstructive nephropathy. However, it is not known whether CCR 1 blockade is protective in progressive renal injury associated with severe proteinuria. We therefore studied the effect of the small-molecule CCR1 antagonist BX471 in a murine model of adriamycin-induced focal segmental glomerulosclerosis (FSGS) with nephrotic syndrome and progressive interstitial inflammation and fibrosis. Methods Adriamycin nephropathy with persistent proteinuria was induced in male BALB/c mice by two intravenous injections of adriamycin (13 mg/kg) at day 0 and 14. BX471 treatment was started at day 14 when proteinuria and interstitial inflammation had developed. At 6 weeks, renal histology was studied by morphometry and immunohistochemistry. Results At week 6, adriamycin-treated mice showed FSGS, associated with tubulointerstitial injury consisting of tubular dilation and atrophy, interstitial leukocyte infiltration, and fibrosis. The mRNA expression of CCR1 and CC chemokines, including the CCR1 ligands CCL3 (MIP-1α) and CCL5 (RANTES), was up-regulated in diseased kidneys, with a prominent interstitial expression of CCL5. Compared to vehicle-treated controls BX471 significantly reduced the amount of macrophages and T lymphocytes in interstitial lesions by 51% and 22%, respectively. Markers of renal fibrosis such as interstitial fibroblasts (48%) and interstitial volume (23%) were significantly reduced by BX471 treatment. In contrast, the extent of proteinuria and glomerular sclerosis was not affected by BX471 treatment. Conclusion Blockade of CCR1 substantially reduced interstitial leukocyte accumulation and the subsequent renal fibrosis in a murine model of nephrotic syndrome and FSGS. These findings support a role for CCR1 in interstitial leukocyte recruitment and suggest that CCR1 blockade might be a new therapeutic strategy in progressive nephropathies such as FSGS.
Published: 2004
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30. Phenotyping Renal Leukocyte Subsets by Four-Color Flow Cytometry: Characterization of Chemokine Receptor Expression

Author: Matthias Mack, Bruno Luckow, Volker Vielhauer, Detlef Schlöndorff, Hans-Joachim Anders, and Guillermo Pérez de Lema
Subjects: CCR2, Pathology, medicine.medical_specialty, Receptors, CCR5, Receptors, CCR2, Physiology, Receptor expression, Lupus nephritis, Biology, Kidney, Immunophenotyping, Flow cytometry, Mice, Chemokine receptor, Leukocytes, Genetics, medicine, Animals, RNA, Messenger, Receptor, Cells, Cultured, In Situ Hybridization, Nephritis, medicine.diagnostic_test, Macrophages, General Medicine, Flow Cytometry, medicine.disease, Immunohistochemistry, Lupus Nephritis, Mice, Inbred C57BL, Disease Models, Animal, Nephrology, Immunoglobulin G, Female, Receptors, Chemokine, Cytometry, CD8
Abstract: To investigate mechanisms of cell-mediated injury in renal inflammatory disease it is critical to determine the surface phenotype of infiltrating renal leukocyte subsets. However, the cell-specific expression of many leukocyte receptors is difficult to characterize in vivo. Here, we report a protocol based on flow cytometry that allows simultaneous characterization of surface receptor expression on different subsets of infiltrating renal leukocytes. The described technique combines an adapted method to prepare single cell suspensions from whole kidneys with subsequent four-color flow cytometry. We recently applied this technique to determine the differential expression of murine chemokine receptors CCR2 and CCR5 on infiltrating renal leukocyte subsets. In this article, we summarize our current findings on the validity of the method as compared with immunohistology and in situ hybridization in two murine models of nonimmune (obstructive nephropathy) and immune-mediated (lupus nephritis) inflammatory renal disease. Flow cytometry analysis revealed an accumulation of CCR5-, but not CCR2-positive lymphocytes in inflamed kidneys, compared to the peripheral blood. Particularly renal CD8+ cells expressed CCR5 (79% in obstructed kidneys, 90% in lupus nephritis). In both models, infiltrating renal macrophages were positive for CCR2 and CCR5. These data corresponded to immunohistological and in situ hybridization results. They demonstrate that flow cytometric analysis of single cell suspensions prepared from inflamed kidneys is a rapid and reliable technique to characterize and quantify surface receptor expression on infiltrating renal leukocyte subsets.
Published: 2004
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31. Current paradigms about chemokines as therapeutic targets

Author: Volker Vielhauer, Detlef Schlöndorff, and Hans-Joachim Anders
Subjects: Inflammation, Transplantation, medicine.medical_specialty, Chemokine, Nephritis, biology, business.industry, medicine.medical_treatment, Bioinformatics, medicine.disease, Glomerulonephritis, Endocrinology, Nephrology, Internal medicine, Disease Progression, medicine, biology.protein, Humans, Hemodialysis, Chemokines, Current (fluid), business, Kidney disease
Published: 2004
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32. Identifying Chemokines as Therapeutic Targets in Renal Disease: Lessons from Antagonist Studies and Knockout Mice

Author: Vaclav Eis, Volker Vielhauer, Hans-Joachim Anders, and Detlef Schlöndorff
Subjects: Mice, Knockout, Chemokine, Kidney, biology, business.industry, Inflammation, General Medicine, Transplantation, Mice, Chemokine receptor, Immune system, medicine.anatomical_structure, Nephrology, Immunology, Knockout mouse, Leukocyte Trafficking, biology.protein, Animals, Medicine, Renal Insufficiency, Chemokines, medicine.symptom, Cardiology and Cardiovascular Medicine, business
Abstract: Chemokines, in concert with cytokines and adhesion molecules, play multiple roles in local and systemic immune responses. In the kidney, the temporal and spatial expression of chemokines correlates with local renal damage and accumulation of chemokine receptor-bearing leukocytes. Chemokines play important roles in leukocyte trafficking and blocking chemokines can effectively reduce renal leukocyte recruitment and subsequent renal damage. However, recent data indicate that blocking chemokine or chemokine receptor activity in renal disease may also exacerbate renal inflammation under certain conditions. An increasing amount of data indicates additional roles of chemokines in the regulation of innate and adaptive immune responses, which may adversively affect the outcome of interventional studies. This review summarizes available in vivo studies on the blockade of chemokines and chemokine receptors in kidney diseases, with a special focus on the therapeutic potential of anti-chemokine strategies, including potential side effects, in renal disease.
Published: 2004
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33. Chemokines and chemokine receptors are involved in the resolution or progression of renal disease

Author: Volker Vielhauer, Detlef Schlöndorff, and Hans-Joachim Anders
Subjects: Graft Rejection, Chemokine, medicine.medical_treatment, Inflammation, urologic and male genital diseases, Models, Biological, Nephropathy, tubular damage, end-stage renal failure, Chemokine receptor, Renal fibrosis, Medicine, Animals, Humans, CCR10, biology, business.industry, leukocyte recruitment, medicine.disease, Kidney Transplantation, renal fibrosis, Cytokine, Nephrology, Immunology, Chemokine secretion, biology.protein, Disease Progression, Kidney Diseases, Receptors, Chemokine, medicine.symptom, Chemokines, profibrotic cytokines, business, glomerulosclerosis
Abstract: Chemokines and chemokine receptors are involved in the resolution or progression of renal disease. Locally secreted chemokines mediate leukocyte recruitment during the initiation and amplification phase of renal inflammation. In turn, the infiltrating leukocytes contribute to renal damage by releasing inflammatory and profibrotic factors. Rapid down modulation of the chemokine signal will support resolution of acute inflammation, whereas progression occurs if ongoing or repeated renal injury maintains continuous local chemokine secretion and leukocyte influx into the glomerulus or the interstitial space. In glomerular injury proteinuria itself as well as glomerular secreted cytokines stimulate downstream tubular epithelial cells to also secrete chemokines. During primary tubular injury, tubular epithelial cells directly become a major site of chemokine production. This in turn supports leukocyte infiltration and activation. Infiltrating leukocytes stimulate fibroblast proliferation and matrix synthesis, leading to widening of the interstitial space. The specific and intricate renal vascular architecture renders the organ susceptible to ischemic damage as interstitial volume increases. Ischemia in turn serves as a stimulus for chemokine and cytokine production and matrix synthesis. The mutual stimulation between fibroblasts and infiltrating leukocytes supports progressive tubular damage, renal fibrosis, and glomerulosclerosis. Potentially this vicious circle leading to progression of chronic nephropathies offers the opportunity for therapeutic intervention. Interfering with the chemokine network that mediates leukocyte recruitment may represent a promising therapeutic option for progressive renal disorders and renal fibrosis. This article summarizes the present data on the role of chemokines in acute and chronic renal disease with special emphasis on their potential role in mediating resolution or progression of renal disease as well as on therapeutic options.
Published: 2003
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34. A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation

Author: Hans-Joachim, Anders, Volker, Vielhauer, Michael, Frink, Yvonne, Linde, Clemens D, Cohen, Simone M, Blattner, Matthias, Kretzler, Frank, Strutz, Matthias, Mack, Hermann-Josef, Gröne, James, Onuffer, Richard, Horuk, Peter J, Nelson, and Detlef, Schlöndorff
Subjects: Phenylurea Compounds, Receptors, CCR1, General Medicine, urologic and male genital diseases, Fibrosis, Article, Cell Line, Mice, Inbred C57BL, Mice, Cytosol, Kidney Tubules, Piperidines, Cell Movement, Leukocytes, Animals, Humans, Calcium, Kidney Diseases, Receptors, Chemokine, Ureter, Ligation, Protein Binding
Abstract: The expression of chemokines and their receptors is thought to contribute to leukocyte infiltration and progressive renal fibrosis after unilateral ureter obstruction (UUO). We hypothesized that blocking the chemokine receptor CCR1 using the nonpeptide antagonist BX471 could reduce leukocyte infiltration and renal fibrosis after UUO. UUO kidneys from BX471-treated mice (day 0–10 and day 6–10) revealed a 40–60% reduction of interstitial macrophage and lymphocyte infiltrate compared with controls. Treated mice also showed a marked reduction of CCR1 and CCR5 mRNA levels, and FACS analysis showed a comparable reduction of CD8+/CCR5+ T cells. Markers of renal fibrosis, such as interstitial fibroblasts, interstitial volume, mRNA and protein expression for collagen I, were all significantly reduced by BX471-treatment compared with vehicle controls. By contrast treatment was ineffective when the drug was supplied only from days 0 to 5. In summary, blockade of CCR1 substantially reduces cell accumulation and renal fibrosis after UUO. Most interestingly, late onset of treatment is also effective. We therefore conclude that CCR1 blockade may represent a new therapeutic strategy for reducing cellular infiltration and renal fibrosis as major factors in the progression to end-stage renal failure.
Published: 2002
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35. Hepatitis C Virus Induced Endothelial Inflammatory Response Depends on the Functional Expression of TNFα Receptor Subtype 2

Author: Erik Gaitzsch, Jonathan Nadjiri, Joachim Pircher, Hermann Josef Gröne, Volker Vielhauer, Stefan Porubsky, Markus Wörnle, Andrea Ribeiro, Monika Merkle, Florian Krötz, Thomas Czermak, Markus Niemeyer, and Hanna Mannell
Subjects: Interferon-Induced Helicase, IFIH1, Time Factors, Physiology, Gene Expression, lcsh:Medicine, Hepacivirus, Vascular Medicine, DEAD-box RNA Helicases, Medicine and Health Sciences, lcsh:Science, Cells, Cultured, Mice, Knockout, Multidisciplinary, Chemistry, Cell adhesion molecule, Reverse Transcriptase Polymerase Chain Reaction, Systems Biology, ddc, medicine.anatomical_structure, Host-Pathogen Interactions, Cytokines, Tumor necrosis factor alpha, RNA Interference, medicine.symptom, Research Article, Endothelium, Inflammatory Diseases, Blotting, Western, Immunology, Inflammation, Proinflammatory cytokine, Immune system, medicine, Animals, Humans, Receptors, Tumor Necrosis Factor, Type II, Leukocyte Rolling, Molecular Biology, Cell Proliferation, Innate immune system, Tumor Necrosis Factor-alpha, lcsh:R, Endothelial Cells, Biology and Life Sciences, Cell Biology, Toll-Like Receptor 3, Mice, Inbred C57BL, Poly I-C, TLR3, lcsh:Q
Abstract: In hepatitis C virus (HCV) infection, morbidity and mortality often result from extrahepatic disease manifestations. We provide evidence for a role of receptors of the innate immune system in virally induced inflammation of the endothelium in vitro and in vivo. Corresponding to the in vitro finding of an HCV-dependent induction of proinflammatory mediators in endothelial cells, mice treated with poly (I:C) exhibit a significant reduction in leukocyte rolling velocity, an increase in leukocyte adhesion to the vessel wall and an increased extravasation of leukocytes. HCV directly promotes activation, adhesion and infiltration of inflammatory cells into the vessel wall by activation of endothelial viral receptors. Poly (I:C) induces the expression of TLR3 in vivo and hereby allows for amplification of all of the aforementioned responses upon viral infection. Proinflammatory effects of viral RNA are specifically mediated by TLR3 and significantly enhanced by tumor necrosis factor alpha (TNFα). HCV-RNA induces the endothelial expression of TNFα and TNFα receptor subtype 2 and we provide evidence that leucocyte adhesion and transmigration in response to activation of viral RNA receptors seem to depend on expression of functional TNFR2. Our results demonstrate that endothelial cells actively participate in immune mediated vascular inflammation caused by viral infections.
Published: 2014

36. Cell type-specific induction of O 6 -alkylguanine-DNA alkyltransferase mRNA expression in rat liver during regeneration, inflammation and preneoplasia

Author: Hartmut M. Rabes, Volker Vielhauer, Marina Sarafoff, and Peter Gais
Subjects: Cancer Research, Pathology, medicine.medical_specialty, Transcription, Genetic, In situ hybridization, Biology, Dimethylnitrosamine, Malignant transformation, O(6)-Methylguanine-DNA Methyltransferase, Gene expression, DNA Repair Protein, medicine, Animals, Rats, Long-Evans, Rats, Wistar, In Situ Hybridization, Inflammation, General Medicine, Molecular biology, Liver regeneration, Liver Regeneration, Rats, medicine.anatomical_structure, Liver, Oncology, Tumor progression, Enzyme Induction, Hepatocyte, Precancerous Conditions, Alkyltransferase
Abstract: Purpose and Methods: To investigate the potential role of an aberrant cellular DNA repair in target cells during malignant transformation we studied cell type-specific mRNA expression of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (O6-AGT) in normal and regenerating rat liver, chronic hepatitis and preneoplastic liver lesions by in situ hybridization and semiautomatic image analysis. Results: O6-AGT mRNA expression was found to be four to five times higher in hepatocytes than in nonparenchymal cells. A 1.9-fold increase in O6-AGT mRNA was observed after partial hepatectomy. Intraperitoneal injection of diethylnitrosamine led to a 1.3-fold and 2.6-fold rise in periportal and perivenous hepatocytes, respectively. Ethylnitrosourea produced an enhancement of mRNA levels up to 1.6-fold in hepatocytes without regional differences. In megalocytic hepatocytes of Long-Evans Cinnamon rats with chronic hepatitis, a 4.4-fold mRNA induction was found. In small preneoplastic lesions induced after chronic diethylnitrosamine-exposure, O6-AGT mRNA expression was identical to that of adjacent normal tissue. Intermediate and large lesions revealed 1.5- to 1.6-fold higher mRNA levels. Conclusions: These results suggest an induction of O6-AGT mRNA expression in hepatocellular target tissue under conditions of increased carcinogen sensitivity . The O6-AGT expression in early preneoplastic lesions did not differ from normal surrounding liver tissue, thus excluding the possibility that progression of preneoplasia in rat liver is associated with a deficient mRNA expression of this DNA repair protein. On the contrary, enhanced O6-AGT mRNA expression in more advanced foci and early neoplastic nodules may confer a selective advantage upon early malignant hepatocytes with regard to further tumor progression.
Published: 2001
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37. Stavudine Versus Zidovudine and the Development of Lipodystrophy

Author: Renate A. Beckmann, Bernd Salzberger, Frank-D. Goebel, Lutz Wille, Johannes R. Bogner, Volker Vielhauer, and Gerlinde M. Michl
Subjects: Adult, Male, medicine.medical_specialty, Lipodystrophy, Anti-HIV Agents, HIV Infections, White People, Cohort Studies, Zidovudine, Risk Factors, Antiretroviral Therapy, Highly Active, Internal medicine, Odds Ratio, Prevalence, medicine, Humans, Pharmacology (medical), Lipoatrophy, business.industry, Stavudine, Age Factors, Lipohypertrophy, Odds ratio, Viral Load, medicine.disease, Virology, Confidence interval, Cholesterol, Infectious Diseases, Regression Analysis, Female, business, Viral load, medicine.drug
Abstract: The pathogenesis of some components of the lipodystrophy (LD) syndrome might be linked to the use of nucleosides. Earlier reports did not compare treatment regimens according to the nucleoside backbone. We studied a cohort of individuals who did not switch between stavudine and zidovudine. LD was defined to be present if one of three criteria was met: self-report by the patient, observation by an investigator who had known the patient since commencement of highly active antiretroviral therapy (HAART), or examination by a physician masked to therapy. The mean duration of therapy was 101 weeks (range: 26-234 weeks). Overall prevalence of LD was 48.7%. Lipoatrophy and lipohypertrophy occurred in 33.9% and 28.7% of patients, respectively. Logistic regression showed four parameters to be significantly associated with lipoatrophy: HAART longer than 2 years (p =.002, odds ratio OR 1 = 4.4, 95% confidence interval [CI]: 1.608-11.965), baseline viral load >100,000 copies/ml (p =.004, OR = 4.3, Cl: 1.726-1 1.197), age >40 years (p =.016, OR = 3.2. CI: 1.247-8.373), and white ethnicity (p =.041, OR = 5.4, CI: 1.070-28.184). Cholesterol levels of >200 mg/dl at baseline were associated with a risk reduction (p =.047, OR = 0.36, CI: 0.130-0.987). Use of lipohypertrophy as a dependent variable resulted in a significant association with HAART duration (p = 0.028, OR = 2.7, CI: 1.2-6.5) and protease inhibitor use (p =.014, OR = 3.8, CI: 1.3-11.2). LD prevalence is similar with both backbones using stavudine or zidovudine. This is the first time that baseline cholesterol was shown to be significantly associated with lipoatrophy.
Published: 2001
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38. Expression and Characterization of the Chemokine Receptors CCR2 and CCR5 in Mice

Author: Manfred Stangassinger, Michael Frink, Detlef Schlöndorff, Bruno Luckow, Volker Vielhauer, Christopher Simonis, Jir̆í Plachý, Amanda E. I. Proudfoot, Hans-Joachim Anders, Matthias Mack, Hilke Brühl, Josef Cihak, and Jochen Pfirstinger
Subjects: Receptors, CCR5, Receptors, CCR2, T-Lymphocytes, Immunology, Down-Regulation, CHO Cells, Peritonitis, Biology, Binding, Competitive, CCL8, CCL5, Mice, Glomerulonephritis, Antibody Specificity, Cricetinae, Leukocytes, Animals, Immunology and Allergy, CXCL10, CCL15, Rats, Wistar, Antibodies, Blocking, CCL13, Mice, Inbred BALB C, Antibodies, Monoclonal, Molecular biology, Rats, CXCL2, Thioglycolates, Apoferritins, CCR5 Receptor Antagonists, Receptors, Chemokine, CC chemokine receptors, CCL23, Injections, Intraperitoneal
Abstract: The chemokine receptors CCR2 and CCR5 play important roles in the recruitment of monocytes/macrophages and T cells. To better understand the role of both receptors in murine models of inflammatory diseases and to recognize potential problems when correlating these data to humans, we have generated mAbs against murine CCR2 and CCR5. In mice CCR2 is homogeneously expressed on monocytes and on 2–15% of T cells, closely resembling the expression pattern in humans. In contrast to humans, murine NK cells are highly CCR5 positive. In addition, CCR5 is expressed on 3–10% of CD4 and 10–40% of CD8-positive T cells and is weakly detectable on monocytes. Using a model of immune complex nephritis, we examined the effects of inflammation on chemokine receptor expression and found a 10-fold enrichment of CCR5+ and CCR2+ T cells in the inflamed kidneys. The activity of various chemokines and the antagonistic properties of the mAbs were measured by ligand-induced internalization of CCR2 and CCR5 on primary leukocytes. The Ab MC-21 (anti-CCR2) reduced the activity of murine monocyte chemotactic protein 1 by 95%, whereas the Ab MC-68 (anti-CCR5) blocked over 99% of the macrophage-inflammatory protein 1α and RANTES activity. MC-21 and MC-68 efficiently blocked the ligand binding to CCR2 and CCR5 with an IC50 of 0.09 and 0.6–1.0 μg/ml, respectively. In good correlation to these in vitro data, MC-21 almost completely prevented the influx of monocytes in thioglycollate-induced peritonitis. Therefore, both Abs appear as useful reagents to further study the role of CCR2 and CCR5 in murine disease models.
Published: 2001
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39. The apoptosis mediator mDAP-3 is a novel member of a conserved family of mitochondrial proteins

Author: Thorsten Berger, Matthias Kretzler, Manfred Brigl, Johannes M. Herrmann, Detlef Schlöndorff, Bruno Luckow, and Volker Vielhauer
Subjects: Ribosomal Proteins, Mitochondrial DNA, Embryo, Nonmammalian, Protein family, Recombinant Fusion Proteins, Molecular Sequence Data, Gene Expression, Apoptosis, Saccharomyces cerevisiae, Biology, Cell Fractionation, DNA, Mitochondrial, Mitochondrial apoptosis-induced channel, Mice, Sequence Analysis, Protein, Animals, Humans, Amino Acid Sequence, RNA, Messenger, Cloning, Molecular, Caenorhabditis elegans, Conserved Sequence, In Situ Hybridization, Adaptor Proteins, Signal Transducing, DAP3, Proteins, RNA-Binding Proteins, Cell Biology, Embryo, Mammalian, Fusion protein, Molecular biology, Mitochondria, Cell biology, Mitochondrial biogenesis, Organ Specificity, Mutation, DNAJA3, ATP–ADP translocase, Apoptosis Regulatory Proteins, Sequence Alignment
Abstract: Programmed cell death is essential for organ development and regeneration. To identify molecules relevant for this process, full length cDNA cloning of a short, developmentally regulated murine cDNA fragment, MERM-3, was performed and showed a 1.7 kb mRNA encoding a 45 kDa protein with an ATP/GTP binding motive (P-loop). Sequence analysis revealed an 82% amino acid identity to the human death associated protein 3 (hDAP-3), a positive mediator of apoptosis. The full length sequence being the murine orthologue of hDAP-3 is therefore referred to as mDAP-3. In situ hybridization and northern blot analysis showed an abundant mRNA expression with a pronounced expression in highly proliferative epithelial compartments. For mDAP-3, cytochrome c release and induction of cell death could be demonstrated by overexpression of a mDAP-3/EGFP fusion protein. DAP-3 mediated apoptosis was shown to depend on a functional P-loop. Intracellular localization studies using the mDAP-3/EGFP fusion protein, cell fractionation and protease protection experiments localized mDAP-3 to the mitochondrial matrix. DAP-3, in contrast to cytochrome c, retained its mitochondrial localization during apoptosis induction. A mutant of a putative yeast orthologue of mDAP-3, YGL129c, here referred to as yDAP-3, has been shown to exhibit disrupted mitochondrial function. yDAP-3 deficient mutants could be shown to progressively loose mitochondrial DNA. Loss of mitochondrial DNA in yDAP-3 was partially prevented by transfection of the yDAP-3 deficient mutant with mDAP-3, indicating functional complementation by murine DAP-3 in the yeast system. These data identify mDAP-3 as one of the first proapoptotic factors in the mitochondrial matrix and provide evidence for a critical, evolutionary conserved role of members of the DAP-3 protein family for mitochondrial biogenesis.
Published: 2000
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40. The NLRP3/ASC inflammasome promotes T-cell-dependent immune complex glomerulonephritis by canonical and noncanonical mechanisms

Author: Hans-Joachim Anders, Julia Lichtnekert, Nuru Eltrich, Kirstin Andersen, and Volker Vielhauer
Subjects: Time Factors, Genotype, Inflammasomes, T cell, T-Lymphocytes, Interleukin-1beta, Kidney, Lymphocyte Activation, Glomerulonephritis, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Albuminuria, Animals, Immune Complex Diseases, HMGB1 Protein, Receptor, Mice, Knockout, Receptors, Interleukin-1 Type I, integumentary system, Chemistry, Interleukin, Kidney metabolism, Inflammasome, Dendritic cell, medicine.disease, CARD Signaling Adaptor Proteins, Mice, Inbred C57BL, Chemotaxis, Leukocyte, medicine.anatomical_structure, Phenotype, Nephrology, Immunology, Myeloid Differentiation Factor 88, Signal transduction, Inflammation Mediators, Apoptosis Regulatory Proteins, Carrier Proteins, medicine.drug, Signal Transduction
Abstract: Interleukin (IL)-1β contributes to renal injury in immune complex glomerulonephritis. However, production of mature IL-1β depends on activation of the inflammasome that cleaves pro-IL-1β into its secretable form. A functional role of the NLRP3-containing inflammasome, which responds to various endogenous danger signals, was found in tubulointerstitial nephropathies, but its function in glomerular disease has not been established. To determine whether NLRP3 and its adapter molecule ASC contribute to glomerulonephritis, we induced T-cell-dependent autologous nephrotoxic serum nephritis in Nlrp3- and Asc-deficient mice. Renal expression of NLRP3/ASC inflammasome components and pro-IL-1β increased during nephrotoxic serum nephritis and was abundant in renal dendritic cells. This was associated with renal production of mature IL-1β, indicating inflammasome activation. Nlrp3 and Asc deficiency significantly attenuated glomerular injury, renal leukocyte infiltration, and T-cell activation. Production of mature IL-1β was abrogated in Asc-deficient mice, consistent with a loss of inflammasome-dependent IL-1β activation. Surprisingly, renal IL-1β secretion remained intact in Nlrp3-deficient mice, indicating noncanonical pro-inflammatory effects of NLRP3 in autologous nephrotoxic serum nephritis. This may include NLRP3-mediated glomerular release of pro-inflammatory high-mobility group box 1 protein as a noncanonical function of NLRP3/ASC in glomerulonephritis. Thus, therapeutic blockade of the NLRP3/ASC/IL-1β axis may be beneficial in glomerulonephritis.
Published: 2013

41. Distinct contributions of TNF receptor 1 and 2 to TNF-induced glomerular inflammation in mice

Author: Volker Vielhauer, Martin Schwarz, Anela Taubitz, Maja T. Lindenmeyer, Nuru Eltrich, University of Zurich, and Vielhauer, Volker
Subjects: Male, Chemokine, Mouse, Gene Expression, lcsh:Medicine, Kidney, urologic and male genital diseases, Mice, Molecular Cell Biology, Chronic Kidney Disease, Leukocytes, Membrane Receptor Signaling, 10035 Clinic for Nephrology, lcsh:Science, Immune Response, Oligonucleotide Array Sequence Analysis, Multidisciplinary, Mesangial cell, biology, Glomerulonephritis, Animal Models, respiratory system, Receptors, Tumor Necrosis Factor, Type I, Nephrology, Transforming Growth Factors, Chemokine secretion, Cytokines, Medicine, Tumor necrosis factor alpha, medicine.symptom, Research Article, Signal Transduction, Immunology, Inflammation, 610 Medicine & health, 1100 General Agricultural and Biological Sciences, Real-Time Polymerase Chain Reaction, Cell Line, Immune Activation, Model Organisms, In vivo, 1300 General Biochemistry, Genetics and Molecular Biology, medicine, Animals, Receptors, Tumor Necrosis Factor, Type II, Biology, 1000 Multidisciplinary, urogenital system, Gene Expression Profiling, lcsh:R, Immunity, medicine.disease, Molecular biology, Mice, Inbred C57BL, Immune System, biology.protein, lcsh:Q, Gene Deletion, Ex vivo
Abstract: TNF is an important mediator of glomerulonephritis. The two TNF-receptors TNFR1 and TNFR2 contribute differently to glomerular inflammation in vivo, but specific mechanisms of TNFR-mediated inflammatory responses in glomeruli are unknown. We investigated their expression and function in murine kidneys, isolated glomeruli ex vivo, and glomerular cells in vitro. In normal kidney TNFR1 and TNFR2 were preferentially expressed in glomeruli. Expression of both TNFRs and TNF-induced upregulation of TNFR2 mRNA was confirmed in murine glomerular endothelial and mesangial cell lines. In vivo, TNF exposure rapidly induced glomerular accumulation of leukocytes. To examine TNFR-specific inflammatory responses in intrinsic glomerular cells but not infiltrating leukocytes we performed microarray gene expression profiling on intact glomeruli isolated from wildtype and Tnfr-deficient mice following exposure to soluble TNF ex vivo. Most TNF-induced effects were exclusively mediated by TNFR1, including induced glomerular expression of adhesion molecules, chemokines, complement factors and pro-apoptotic molecules. However, TNFR2 contributed to TNFR1-dependent mRNA expression of inflammatory mediators in glomeruli when exposed to low TNF concentrations. Chemokine secretion was absent in TNF-stimulated Tnfr1-deficient glomeruli, but also significantly decreased in glomeruli lacking TNFR2. In vivo, TNF-induced glomerular leukocyte infiltration was abrogated in Tnfr1-deficient mice, whereas Tnfr2-deficiency decreased mononuclear phagocytes infiltrates, but not neutrophils. These data demonstrate that activation of intrinsic glomerular cells by soluble TNF requires TNFR1, whereas TNFR2 is not essential, but augments TNFR1-dependent effects. Previously described TNFR2-dependent glomerular inflammation may therefore require TNFR2 activation by membrane-bound, but not soluble TNF.
Published: 2013
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42. Renal co-morbidity in patients with rheumatic diseases

Author: Volker Vielhauer and Hans-Joachim Anders
Subjects: Nephrology, medicine.medical_specialty, business.industry, Immunology, Renal function, Arthritis, Comorbidity, Review, medicine.disease, Rheumatology, Autoimmune Diseases, Internal medicine, Rheumatic Diseases, medicine, Immunology and Allergy, Humans, In patient, Kidney Diseases, Complication, business, Kidney disease
Abstract: Renal co-morbidity is common in patients with rheumatic disease based on regular assessment of serum and urine parameters of renal function. When patients present with both arthritis and renal abnormalities the following questions have to be addressed. Is kidney disease a complication of rheumatic disease or its management, or are they both manifestations of a single systemic autoimmune disease? Is rheumatic disease a complication of kidney disease and its management? How do rheumatic disease and kidney disease affect each other even when they are unrelated? The present review provides an overview of how to address these questions in daily practice.
Published: 2011

43. Questions about chemokine and chemokine receptor antagonism in renal inflammation

Author: Volker Vielhauer, Hans-Joachim Anders, and Sufyan Ali Sayyed
Subjects: Nephrology, medicine.medical_specialty, Chemokine, Physiology, Kidney, Nephropathy, Chemokine receptor, Leukocyte Count, Internal medicine, Genetics, Medicine, Animals, Humans, Clinical Trials as Topic, Nephritis, biology, business.industry, General Medicine, medicine.disease, Immunology, biology.protein, Receptors, Chemokine, Chemokines, business, Antagonism, Homeostasis, Kidney disease
Abstract: Chemokines remain attractive therapeutic targets for modulating inflammatory diseases in all areas of medicine including acute and chronic kidney disease. Industry has launched huge programs for the development of chemokine antagonists, and clinical trials with chemokine and chemokine receptor antagonists are ongoing. However, chemokine biology remains an area of unexpected discoveries. Here we discuss a number of questions which need to be addressed to further explore the potential of chemokine antagonism in renal inflammation: Why does renal expression of chemokines and chemokine receptors not always correlate with their functional significance? Why does chemokine antagonism only partially reduce renal leukocyte counts? Will antagonist combinations be more effective in reducing renal inflammation? What are the functional roles of homeostatic chemokines and atypical, nonsignaling chemokine receptors in renal inflammation? And finally, what classes of chemokine antagonists are available to address these questions experimentally?
Published: 2009

44. Viral RNA and DNA trigger common antiviral responses in mesangial cells

Author: Anton G. Moll, Anela Taubitz, Ramanjaneyulu Allam, Julia Lichtnekert, Volker Vielhauer, and Hans-Joachim Anders
Subjects: Small interfering RNA, Chemokine, Glomerular Mesangial Cell, Gene Expression, Apoptosis, Nerve Tissue Proteins, Receptors, Cell Surface, Biology, Cell Line, Mice, Immune system, Glomerulonephritis, Animals, Immune Complex Diseases, Glycoproteins, Oligonucleotide Array Sequence Analysis, Mesangial cell, Interleukin-6, RNA, Membrane Proteins, RNA-Binding Proteins, General Medicine, Molecular biology, Chemokine CXCL10, Mice, Inbred C57BL, Basic Research, Nephrology, Cell culture, DNA, Viral, Mesangial Cells, biology.protein, RNA, Viral, CpG Islands, Female, Interferons, Immune complex disease
Abstract: Extrarenal viral infections commonly trigger glomerulonephritis, usually in association with immune complex disease. The Ig component of immune complexes can activate glomerular cell Fc receptors, but whether complexed viral nucleic acids contribute to glomerular inflammation remains unknown. Because of the types of Toll-like receptors (Tlrs) expressed by glomerular mesangial cells, we hypothesized that viral single-stranded RNA and DNA would activate mesangial cells via Tlr-independent pathways and trigger overlapping antiviral immune responses. Consistent with this hypothesis, 5'-triphosphate RNA (3P-RNA) and non-CpG DNA activated murine primary glomerular mesangial cells to secrete Cxcl10 and Il-6 even in cells derived from mice deficient in the Tlr adaptor proteins Myd88 and Trif. Transcriptome analysis revealed that 3P-RNA and non-CpG-DNA triggered almost identical gene expression programs, especially the proinflammatory cytokine Il-6, several chemokines, and genes related to type I IFN. We observed similar findings in glomerular preparations after injecting 3P-RNA and non-CpG-DNA in vivo. These effects depended on the formation of complexes with cationic lipids, which enhanced nucleic acid uptake into the cytosol of mesangial cells. Small interfering RNA studies revealed that 3P-RNA recognition involves Rig-1, whereas non-CpG-DNA did not require Rig-1 or Dai to activate glomerular mesangial cells. We conclude that 3P-RNA and double-stranded DNA trigger a common, TLR-independent, antiviral response in glomerular mesangial cells, which may promote glomerulonephritis in the setting of viral infection.
Published: 2009

45. Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice

Author: Klaus Buchner, Stephan Segerer, Werner Purschke, Hans-Joachim Anders, Volker Vielhauer, Sven Klussmann, Onkar P. Kulkarni, Dirk Eulberg, Volha Ninichuk, Norma Selve, and Rahul D. Pawar
Subjects: Mice, Inbred MRL lpr, T cell, Lupus nephritis, Inflammation, Autoimmunity, CCL2, medicine.disease_cause, Monocytes, Mice, Bone Marrow, medicine, Animals, skin and connective tissue diseases, Receptor, Chemokine CCL2, Systemic lupus erythematosus, Oligoribonucleotides, business.industry, Monocyte, General Medicine, DNA, Genetic Therapy, medicine.disease, Lupus Nephritis, Lymphoproliferative Disorders, Survival Rate, medicine.anatomical_structure, Nephrology, Immunology, Female, medicine.symptom, business
Abstract: The monocyte chemoattractant protein CCL2 is crucial for monocyte and T cell recruitment from the vascular to the extravascular compartment at sites of inflammation. CCL2 is expressed in human lupus nephritis and was shown to mediate experimental lupus; therefore, CCL2 antagonists may be beneficial for therapy. This study describes the l-enantiomeric RNA oligonucleotide mNOX-E36, a so-called Spiegelmer that binds murine CCL2 with high affinity and neutralizes its action in vitro and in vivo. The mirror image configuration of the Spiegelmer confers nuclease resistance and thus excellent biostability. mNOX-E36 does not induce type I IFN via Toll-like receptor-7 or cytosolic RNA receptors, as recently shown for certain synthetic D-RNA. Autoimmune-prone MRL(lpr/lpr) mice that were treated with a polyethylene glycol form of mNOX-E36 from weeks 14 to 24 of age showed prolonged survival associated with a robust improvement of lupus nephritis, peribronchial inflammation, and lupus-like inflammatory skin lesions. Thus, mNOX-E36-based inhibition of CCL2 represents a novel strategy for the treatment of autoimmune tissue injury, such as lupus nephritis.
Published: 2007

46. Expression of DARC, CXCR3 and CCR5 in giant cell arteritis

Author: Detlef Schlöndorff, M Weiss, Volker Vielhauer, Hilke Brühl, Stephan Segerer, and Matthias Mack
Subjects: Pathology, medicine.medical_specialty, Chemokine, Receptors, CXCR3, Receptors, CCR5, T-Lymphocytes, High endothelial venules, Giant Cell Arteritis, Gene Expression, Receptors, Cell Surface, CXCR3, CCL5, Monocytes, Polymyalgia rheumatica, Chemokine receptor, Rheumatology, medicine, Leukocytes, Humans, Pharmacology (medical), RNA, Messenger, skin and connective tissue diseases, Chemokine CCL5, biology, business.industry, hemic and immune systems, Middle Aged, medicine.disease, Temporal Arteries, Giant cell arteritis, Polymyalgia Rheumatica, Chemokines, CC, Immunology, biology.protein, Receptors, Chemokine, Vasculitis, business, Duffy Blood-Group System, Biomarkers
Abstract: Objectives. Leucocyte infiltration is the hallmark of vasculitis, chemokines being mainly responsible for leucocyte migration into inflamed tissues. The objective was to evaluate the local expression of chemokines and chemokine receptors in biopsies of patients with giant cell arteritis (GCA) compared with arteries from patients with polymyalgia rheumatica (PMR). We studied the expression of CCR5, CXCR3 and that of the Duffy antigen/receptor of chemokine (DARC), a chemokine internalizing receptor (interceptor), in parallel to the expression of the CCR5 ligand RANTES/CCL5. Methods. Paraffin-embedded tissue sections from six patients with GCA and five patients with PMR were available for immunohistological analysis of chemokine receptor expression. RANTES/CCL5 mRNA was detected in tissue sections by in situ hybridization. Results. In patients with biopsy-proven giant cell arteritis, CCR5 and CXCR3 were highly expressed by infiltrating leucocytes in involved tissue sections. Predominant clustering of CCR5 + and CXCR3 + leucocytes was found in the adventitia and was co-localized with the expression of CCL5/RANTES mRNA. Interestingly, we found marked expression of DARC on adventitial high endothelial venules in vasculitis lesions of patients with GCA, while in arteries from patients with PMR DARC was only expressed on a low number of vessels with flat lining endothelium. Conclusions. The co-localization of infiltrating CCR5 + and CXCR3 + leucocytes together with CCL5/RANTES and DARC in vasculitis lesions suggests a role for these chemokine receptors in leucocyte infiltration, possibly supported by DARC-mediated vascular presentation of chemokines.
Published: 2004

47. Chemokine receptor CCR1 but not CCR5 mediates leukocyte recruitment and subsequent renal fibrosis after unilateral ureteral obstruction

Author: Richard Horuk, Charles E. Alpers, Ji Liang Gao, Bruno Luckow, Hermann Josef Gröne, Kelly L. Hudkins, Hans-Joachim Anders, Matthias Mack, Vaclav Eis, Guillermo Pérez de Lema, Jens T. Siveke, Yvonne Linde, Matthias Kretzler, Philip M. Murphy, Volker Vielhauer, Clemens D. Cohen, Detlef Schlöndorff, and Stephan Segerer
Subjects: Nephrology, CCR1, medicine.medical_specialty, Pathology, Receptors, CCR5, T cell, Receptors, CCR1, urologic and male genital diseases, Kidney, Transforming Growth Factor beta1, Chemokine receptor, Mice, Fibrosis, Transforming Growth Factor beta, Internal medicine, medicine, Renal fibrosis, Leukocytes, Animals, RNA, Messenger, Cells, Cultured, business.industry, Macrophages, Kidney metabolism, General Medicine, medicine.disease, Mice, Inbred C57BL, Endocrinology, medicine.anatomical_structure, Receptors, Chemokine, business, Kidney disease, Ureteral Obstruction
Abstract: As chemokine receptor CCR1 and CCR5 expression on circulating leukocytes is thought to contribute to leukocyte recruitment during renal fibrosis, the authors examined the effects of unilateral ureteral obstruction (UUO) in mice deficient for CCR1 or CCR5. Analysis of UUO kidneys from CCR1-deficient mice revealed a reduction of interstitial macrophages and lymphocytes (35% and 55%, respectively) compared with wild-type controls. CCR1-deficient mice had reduced CCR5 mRNA levels in UUO kidneys, which correlated with a reduction of CCR5+ T cell infiltrate as determined by flow cytometry. Interstitial fibroblasts, renal TGF-beta1 mRNA expression, interstitial volume, and collagen I deposits were all significantly reduced in CCR1-deficient mice. In contrast, renal leukocytes and fibrosis were unaffected in CCR5-deficient mice with UUO. However, if treated with the CCR1 antagonist BX471, CCR5-deficient mice showed a similar reduction of renal leukocytes and fibrosis as CCR1-deficient mice. To determine the underlying mechanism labeled macrophages and T cells isolated from either wild-type, CCR1-deficient, or CCR5-deficient mice were injected into wild-type mice with UUO. Three hours later, renal cell recruitment was reduced for CCR1-deficient cells or cells pretreated with BX471 compared with CCR5-deficient or wild-type cells. Thus, CCR1 but not CCR5 is required for leukocyte recruitment and fibrosis after UUO in mice. Therefore, CCR1 is a promising target for therapeutic intervention in leukocyte-mediated fibrotic tissue injury, e.g. progressive renal fibrosis.
Published: 2004

48. Bacterial CpG-DNA aggravates immune complex glomerulonephritis: role of TLR9-mediated expression of chemokines and chemokine receptors

Author: Hans-Joachim Anders, Bernhard Banas, Detlef Schlöndorff, Matthias Kretzler, Yvonne Linde, Volker Vielhauer, Stefan Martin, Clemens D. Cohen, Lars Weller, and Hermann Josef Gröne
Subjects: CCR1, DNA, Bacterial, CCR2, Chemokine, Receptors, CCR5, Chemokine receptor CCR5, medicine.medical_treatment, 610 Medizin, Receptors, CCR1, Receptors, Cell Surface, CCL2, Kidney, CCL5, Cell Line, Chemokine receptor, Mice, Glomerulonephritis, medicine, Animals, Immune Complex Diseases, Tissue Distribution, RNA, Messenger, Mice, Inbred BALB C, biology, Macrophages, hemic and immune systems, General Medicine, Th1 Cells, DNA-Binding Proteins, Cytokine, Oligodeoxyribonucleotides, Nephrology, Toll-Like Receptor 9, Immunology, Antibody Formation, biology.protein, Female, Receptors, Chemokine, Chemokines
Abstract: Immune complex glomerulonephritis (GN) often deteriorates during infection with viruses and bacteria that, in contrast to mammals, have DNA that contains many unmethylated CpG motifs. Balb/c mice with horse apoferritin-induced GN (HAF-GN) were treated with either saline, CpG-oligodeoxynucleotides (ODN), or control GpC-ODN. Only CpG-ODN exacerbated HAF-GN with an increase of glomerular macrophages, which was associated with massive albuminuria and increased renal MCP-1/CCL2, RANTES/CCL5, CCR1, CCR2, and CCR5 mRNA expression. CpG-ODN induced a Th1 response as indicated by serum anti-HAF IgG(2a) titers, mesangial IgG(2a) deposits, and splenocyte IFN-gamma secretion. Messenger RNA for the CpG-DNA receptor Toll-like reeptor 9 (TLR9) was present in kidneys with HAF-GN but not in normal kidneys. The source of TLR9 mRNA in HAF-GN could be infiltrating macrophages or intrinsic renal cells, e.g., mesangial cells; but, in vitro, only murine J774 macrophages expressed TLR9. In J774 cells, CpG-ODN induced the chemokines MCP-1/CCL2 and RANTES/CCL5 and the chemokine receptors CCR1 and CCR5. It is concluded that CpG-DNA can aggravate preexisting GN via a shift toward a Th1 response but also by a novel pathway involving TLR9-mediated chemokine and chemokine receptor expression by macrophages, which may contribute to the enhanced glomerular macrophage recruitment and activation. This mechanism may be relevant during infection-triggered exacerbation of human immune-complex GN and other immune-mediated diseases in general.
Published: 2003

49. Chemokine expression precedes inflammatory cell infiltration and chemokine receptor and cytokine expression during the initiation of murine lupus nephritis

Author: Holger Maier, Elena Nieto, Bruno Luckow, Detlef Schlöndorff, Francisco Mampaso, Volker Vielhauer, and Guillermo Pérez de Lema
Subjects: CCR1, CCR2, Chemokine, Mice, Inbred MRL lpr, Time Factors, Lupus nephritis, Fluorescent Antibody Technique, Mice, Inbred Strains, Biology, urologic and male genital diseases, Kidney, Proinflammatory cytokine, Chemokine receptor, Mice, medicine, Animals, RNA, Messenger, In Situ Hybridization, General Medicine, medicine.disease, Lupus Nephritis, Mononuclear cell infiltration, Microscopy, Electron, Nephrology, Immunology, biology.protein, Cytokines, Receptors, Chemokine, Chemokines, Inflammation Mediators, Nephritis
Abstract: Lupus nephritis is characterized by immune complex deposition and inflammatory cell infiltration. Therefore, the initiation and progression of lupus nephritis in MRL/MpJ Fas(lpr/lpr) (MRL/lpr) mice were investigated, with a focus on the expression of several chemokines and chemokine receptors. Mice were monitored for proteinuria from 6 to 20 wk of age, and kidneys were examined every 2 wk by light microscopy, electron microscopy, and immunohistologic analyses. Furthermore, the expression of chemokines, chemokine receptors, and proinflammatory cytokines was analyzed in ribonuclease protection assays. MRL/lpr mice demonstrated increased expression of monocyte chemoattractant protein-1, regulated upon activation, normal T cell-expressed and -secreted protein, inducible protein of 10 kD, and macrophage inflammatory protein-1beta at week 8. At that time point, levels of circulating and glomerular immune complexes were increased, and no proteinuria or histopathologic signs of renal damage could be observed. As assessed in immunohistochemical and in situ hybridization analyses, monocyte chemoattractant protein-1 and regulated upon activation, normal T cell-expressed and -secreted protein expression was preferentially located in the glomeruli and interstitium. Mononuclear cell infiltration of the kidney was observed by weeks 10 to 12. At week 12, the renal expression of chemokine receptor 1 (CCR1), CCR2, and CCR5 was increased, mice became proteinuric, and renal damage was histologically evident. Finally, the expression of proinflammatory cytokines was detected (weeks 12 to 14). In summary, (1) chemokines are upregulated before inflammatory cell infiltration, proteinuria, and kidney damage are observed; (2) chemokine generation is restricted to sites of subsequent inflammatory cell infiltration, i.e., glomeruli and interstitium; (3) chemokine receptor expression parallels mononuclear cell infiltration; and (4) proinflammatory cytokines are upregulated later, in parallel with inflammatory cell infiltration and the onset of proteinuria. These results support the hypothesis that chemokines initiate leukocyte infiltration and precede proteinuria and renal damage in MRL/lpr mice.
Published: 2001

50. Obstructive nephropathy in the mouse: progressive fibrosis correlates with tubulointerstitial chemokine expression and accumulation of CC chemokine receptor 2- and 5-positive leukocytes

Author: Hans-Joachim Anders, Manfred Stangassinger, Hermann Josef Gröne, Detlef Schlöndorff, Bruno Luckow, Volker Vielhauer, Frank Strutz, Josef Cihak, and Matthias Mack
Subjects: CCR1, Pathology, medicine.medical_specialty, CCR2, Chemokine, 030232 urology & nephrology, CCL5, Immunoenzyme Techniques, 03 medical and health sciences, Chemokine receptor, Mice, 0302 clinical medicine, Leukocytes, Medicine, Animals, CCL15, RNA, Messenger, In Situ Hybridization, 030304 developmental biology, 0303 health sciences, biology, business.industry, General Medicine, Flow Cytometry, Fibrosis, Mice, Inbred C57BL, Disease Models, Animal, Nephrology, Chemokines, CC, biology.protein, Tubulointerstitial fibrosis, Nephritis, Interstitial, Female, Receptors, Chemokine, CC chemokine receptors, business, Ureteral Obstruction
Abstract: The infiltration of leukocytes plays a major role in mediating tubulointerstitial inflammation and fibrosis in chronic renal disease. CC chemokines participate in leukocyte migration and infiltration into inflamed renal tissue. Because CC chemokine-directed leukocyte migration is mediated by target cell expression of a group of CC chemokine receptors, this study examined the expression of CC chemokines and their receptors during initiation of tubulointerstitial fibrosis after unilateral ureteral obstruction in C57BL/6 mice. Obstructed kidneys developed hydronephrosis, tubular cell damage, interstitial inflammation, and fibrosis. From days 2 to 10, a progressive interstitial influx of F4/80+ macrophages and CD3+ lymphocytes occurred (macrophages, 4-fold; lymphocytes, 20-fold at day 10, compared with contralateral control kidneys). In parallel, the number of activated fibroblast-specific protein 1+ fibroblasts and interstitial collagen IV accumulation increased from days 2 to 10. The mRNA expression of CC chemokines (predominantly monocyte chemoattractant protein-1 [MCP-1]/CCL2, RANTES/CCL5) and their receptors CCR1, CCR2, CCR5 increased progressively from days 2 to 10. By in situ hybridization, a prominent interstitial mRNA expression of MCP-1 and RANTES and their receptors CCR2 and CCR5 localized to interstitial mononuclear cell infiltrates. MCP-1 and RANTES expression was also seen in tubular epithelial cells. Fluorescence-activated cell sorter analysis of single-cell suspensions from obstructed kidneys revealed a prominent expression of CCR2 and CCR5 by infiltrating macrophages, whereas most lymphocytes expressed CCR5 only. These data demonstrate an increased expression of MCP-1/CCL2 and RANTES/CCL5 at sites of tubulointerstitial damage and progressive fibrosis during unilateral ureteral obstruction that correlates with simultaneous accumulation of interstitial macrophages and T lymphocytes expressing the respective surface receptors CCR2 and CCR5. The chemokine receptor—mediated leukocyte influx into the tubulointerstitium could offer a new potential target for therapeutic intervention in progressive renal tubulointerstitial fibrosis.
Published: 2001

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