{"rowid": 65, "title": "[\"Biomarker-guided implementation of the KDIGO guidelines to reduce the occurrence of acute kidney injury in patients after cardiac surgery (PrevAKI-multicentre): protocol for a multicentre, observational study followed by randomised controlled feasibility trial\"]", "DOI": "10.1136/bmjopen-2019-034201", "URL": "http://dx.doi.org/10.1136/bmjopen-2019-034201", "created": "2020-04-07T09:55:55Z", "subject": "[\"General Medicine\"]", "references-count": "18", "is-referenced-by-count": "0", "ISSN": "[\"2044-6055\", \"2044-6055\"]", "container-title": "BMJ Open", "abstract": "<jats:sec><jats:title>Introduction</jats:title><jats:p>Acute kidney injury (AKI) is a frequent complication after cardiac surgery with adverse short-term and long-term outcomes. Although prevention of AKI (PrevAKI) is strongly recommended, the optimal strategy is uncertain. The Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommended a bundle of supportive measures in high-risk patients. In a single-centre trial, we recently demonstrated that the strict implementation of the KDIGO bundle significantly reduced the occurrence of AKI after cardiac surgery. In this feasibility study, we aim to evaluate whether the study protocol can be implemented in a multicentre setting in preparation for a large multicentre trial.</jats:p></jats:sec><jats:sec><jats:title>Methods and analysis</jats:title><jats:p>We plan to conduct a prospective, observational survey followed by a randomised controlled, multicentre, multinational clinical trial including 280 patients undergoing cardiac surgery with cardiopulmonary bypass. The purpose of the observational survey is to explore the adherence to the KDIGO recommendations in routine clinical practice. The second phase is a randomised controlled trial. The objective is to investigate whether the trial protocol is implementable in a large multicentre, multinational setting. The primary endpoint of the interventional part is the compliance rate with the protocol. Secondary endpoints include the occurrence of any AKI and moderate/severe AKI as defined by the KDIGO criteria within 72 hours after surgery, renal recovery at day 90, use of renal replacement therapy (RRT) and mortality at days 30, 60 and 90, the combined endpoint major adverse kidney events consisting of persistent renal dysfunction, RRT and mortality at day 90 and safety outcomes.</jats:p></jats:sec><jats:sec><jats:title>Ethics and dissemination</jats:title><jats:p>The PrevAKI multicentre study has been approved by the leading Research Ethics Committee of the University of M\u00fcnster and the respective Research Ethics Committee at each participating site. The results will be used to design a large, definitive trial.</jats:p></jats:sec><jats:sec><jats:title>Trial registration number</jats:title><jats:p><jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" specific-use=\"clinicaltrial pre-results\" xlink:href=\"NCT03244514\">NCT03244514</jats:ext-link>.</jats:p></jats:sec>", "author_number": "29", "orcids": "[\"http://orcid.org/0000-0002-2124-1714\"]", "names": "[\"Mira K\\u00fcllmar\", \"Christina Massoth\", \"Marlies Ostermann\", \"Sara Campos\", \"Neus Grau Novellas\", \"Gary Thomson\", \"Michael Haffner\", \"Christian Arndt\", \"Hinnerk Wulf\", \"Marc Irqsusi\", \"Fabrizio Monaco\", \"Ambra Di Prima\", \"Mercedes Garcia Alvarez\", \"Stefano Italiano\", \"Virginia Cegarra SanMartin\", \"Gudrun Kunst\", \"Shrijit Nair\", \"Camilla L'Acqua\", \"Eric A J Hoste\", \"Wim Vandenberghe\", \"Patrick Honore\", \"John Kellum\", \"Lui Forni\", \"Philippe Grieshaber\", \"Raphael Weiss\", \"Joachim Gerss\", \"Carola Wempe\", \"Melanie Meersch\", \"Alexander Zarbock\"]", "award_numbers": "[]", "funder_names": "[\"European Society of Intensive Care Medicine\"]", "funder_dois": "[\"10.13039/501100013347\"]"}
{"rowid": 70, "title": "[\"TGF-\\u03b22 silencing to target biliary-derived liver diseases\"]", "DOI": "10.1136/gutjnl-2019-319091", "URL": "http://dx.doi.org/10.1136/gutjnl-2019-319091", "created": "2020-01-28T21:17:00Z", "subject": "[\"Gastroenterology\"]", "references-count": "0", "is-referenced-by-count": "0", "ISSN": "[\"0017-5749\", \"1468-3288\"]", "container-title": "Gut", "abstract": "<jats:sec><jats:title>Objective</jats:title><jats:p>TGF-\u03b22 (TGF-\u03b2, transforming growth factor beta), the less-investigated sibling of TGF-\u03b21, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-\u03b22 in biliary-derived liver diseases.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>As we also found upregulated <jats:italic>TGFB2</jats:italic> in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-\u03b22 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of <jats:italic>TgfB2</jats:italic> silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p><jats:italic>TgfB2</jats:italic>-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. <jats:italic>TgfB2</jats:italic> expression in MDR2-KO mice was blunted using <jats:italic>TgfB2</jats:italic>-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and \u03b1SMA expression as well as induced <jats:italic>PparG</jats:italic> expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on <jats:italic>Ccl3</jats:italic>, <jats:italic>Ccl4</jats:italic>, <jats:italic>Ccl5</jats:italic>, <jats:italic>Mki67</jats:italic> and <jats:italic>Notch3</jats:italic> expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, <jats:italic>TGFB2</jats:italic> and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Taken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-\u03b22 silencing and provide a direct rationale for TGF-\u03b22-directed drug development.</jats:p></jats:sec>", "author_number": "29", "orcids": "[\"http://orcid.org/0000-0002-4840-6240\", \"http://orcid.org/0000-0001-7953-8927\", \"http://orcid.org/0000-0003-3135-1359\", \"http://orcid.org/0000-0002-6022-073X\", \"http://orcid.org/0000-0003-0336-0581\", \"http://orcid.org/0000-0003-0211-352X\"]", "names": "[\"Anne Dropmann\", \"Steven Dooley\", \"Bedair Dewidar\", \"Seddik Hammad\", \"Tatjana Dediulia\", \"Julia Werle\", \"Vanessa Hartwig\", \"Shahrouz Ghafoory\", \"Stefan Woelfl\", \"Hanna Korhonen\", \"Michel Janicot\", \"Katja Wosikowski\", \"Timo Itzel\", \"Andreas Teufel\", \"Detlef Schuppan\", \"Ana Stojanovic\", \"Adelheid Cerwenka\", \"Stefanie Nittka\", \"Albrecht Piiper\", \"Timo Gaiser\", \"Naiara Beraza\", \"Malgorzata Milkiewicz\", \"Piotr Milkiewicz\", \"John G Brain\", \"David E J Jones\", \"Thomas S Weiss\", \"Ulrich M Zanger\", \"Matthias Ebert\", \"Nadja M Meindl-Beinker\"]", "award_numbers": "[\"non\"]", "funder_names": "[\"Robert Bosch Stiftung\", \"Bundesministerium f\\u00fcr Bildung und Forschung\", \"Deutsche Forschungsgemeinschaft\", \"ESF Baden W\\u00fcrttemberg (www.esf-bw.de) and the Ministerium f\\u00fcr Wissenschaft, Forschung und Kunst, Baden W\\u00fcrttemberg\", \"EU\", \"Isarna Therapeutics GmbH\", \"SPP 1937\"]", "funder_dois": "[\"10.13039/501100001646\", \"10.13039/501100002347\", \"10.13039/501100001659\", [\"\"], [\"\"], [\"\"], [\"\"]]"}