{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T15:21:44Z","timestamp":1771514504527,"version":"3.50.1"},"reference-count":57,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2014,7,25]],"date-time":"2014-07-25T00:00:00Z","timestamp":1406246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB 938"],"award-info":[{"award-number":["SFB 938"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2014,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The pathogenesis and therapy of Shigatoxin 2 (Stx2)\u2010mediated kidney failure remain controversial. Our aim was to test whether, during an infection with Stx2\u2010producing <jats:italic>E. coli<\/jats:italic> (<jats:styled-content style=\"fixed-case\">STEC<\/jats:styled-content>), Stx2 exerts direct effects on renal tubular epithelium and thereby possibly contributes to acute renal failure. Mice represent a suitable model because they, like humans, express the Stx2\u2010receptor Gb3 in the tubular epithelium but, in contrast to humans, not in glomerular endothelia, and are thus free of glomerular thrombotic microangiopathy (<jats:styled-content style=\"fixed-case\">TMA<\/jats:styled-content>). In wild\u2010type mice, Stx2 caused acute tubular dysfunction with consequent electrolyte disturbance, which was most likely the cause of death. Tubule\u2010specific depletion of Gb3 protected the mice from acute renal failure. <jats:italic>In vitro<\/jats:italic>, Stx2 induced secretion of proinflammatory cytokines and apoptosis in human tubular epithelial cells, thus implicating a direct effect of Stx2 on the tubular epithelium. To correlate these results to human disease, kidney biopsies and outcome were analysed in patients with Stx2\u2010associated kidney failure (<jats:italic>n =<\/jats:italic> 11, aged 22\u201344 years). The majority of kidney biopsies showed different stages of an ongoing <jats:styled-content style=\"fixed-case\">TMA<\/jats:styled-content>; however, no glomerular complement activation could be demonstrated. All biopsies, including those without <jats:styled-content style=\"fixed-case\">TMA<\/jats:styled-content>, showed severe acute tubular damage. Due to these findings, patients were treated with supportive therapy without complement\u2010inhibiting antibodies (eculizumab) or immunoadsorption. Despite the severity of the initial disease [creatinine 6.34 (1.31\u201317.60) mg\/dl, lactate dehydrogenase 1944 (753\u20132792) U\/l, platelets 33 (19\u2013124)\/nl and haemoglobin 6.2 (5.2\u20137.8) g\/dl; median (range)], all patients were discharged after 33 (range 19\u201343) days with no neurological symptoms and no dialysis requirement [creatinine 1.39 (range 0.84\u20132.86) mg\/dl]. The creatinine decreased further to 0.90 (range 0.66\u20131.27) mg\/dl after 24 months. Based on these data, one may surmise that acute tubular damage represents a separate pathophysiological mechanism, importantly contributing to Stx2\u2010mediated acute kidney failure. Specifically in young adults, an excellent outcome can be achieved by supportive therapy only. \u00a9 2014 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.4388","type":"journal-article","created":{"date-parts":[[2014,6,6]],"date-time":"2014-06-06T16:04:01Z","timestamp":1402070641000},"page":"120-133","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Direct acute tubular damage contributes to Shigatoxin\u2010mediated kidney failure"],"prefix":"10.1002","volume":"234","author":[{"given":"Stefan","family":"Porubsky","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Pathology German Cancer Research Centre  Heidelberg Germany"},{"name":"Institute of Pathology, University Medical Centre Mannheim University of Heidelberg  Mannheim Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppina","family":"Federico","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pathology German Cancer Research Centre  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"M\u00fcthing","sequence":"additional","affiliation":[{"name":"Institute for Hygiene University of M\u00fcnster  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Jennemann","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pathology German Cancer Research Centre  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norbert","family":"Gretz","sequence":"additional","affiliation":[{"name":"Medical Research Centre, University Medical Centre Mannheim University of Heidelberg  Mannheim Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"B\u00fcttner","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Hospital Frankfurt\u2010am\u2010Main University of Frankfurt  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Oberm\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Hospital Frankfurt\u2010am\u2010Main University of Frankfurt  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Hospital Frankfurt\u2010am\u2010Main University of Frankfurt  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingeborg A","family":"Hauser","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Hospital Frankfurt\u2010am\u2010Main University of Frankfurt  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"Gr\u00f6ne","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pathology German Cancer Research Centre  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helmut","family":"Geiger","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Hospital Frankfurt\u2010am\u2010Main University of Frankfurt  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hermann\u2010Josef","family":"Gr\u00f6ne","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pathology German Cancer Research Centre  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Betz","sequence":"additional","affiliation":[{"name":"Department of Nephrology, University Hospital Frankfurt\u2010am\u2010Main University of Frankfurt  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,7,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198303243081203"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/151.5.775"},{"key":"e_1_2_8_4_1","first-page":"258","article-title":"Update: multistate outbreak of Escherichia coli O157:H7 infections from hamburgers\u00a0\u2013\u00a0western United States, 1992\u20131993","volume":"42","author":"MMWR","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a010082"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1086\/383473"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2012.196"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/toxins2122769"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1106483"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(11)70165-7"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022751"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1106920"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1159\/000185286"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.05139-11"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.12.026"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.051331"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.08.007"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.290.10.1360"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)01267-7"},{"key":"e_1_2_8_20_1","first-page":"905","article-title":"Hemolytic\u2013uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia","volume":"85","author":"Gasser C","year":"1955","journal-title":"Schweiz Med Wochenschr"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)71144-2"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa061648"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0902814"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc0808527"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1100859"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfs394"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.e4565"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63775-3"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01486688"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M010819"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0500893102"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201483"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/gene.20008"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/gene.10117"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-04-020362"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1994.6"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH08-05-0317"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.66.9.4355-4366.1998"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M600057200"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1128\/iai.58.12.3959-3965.1990"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.61.8.3392-3402.1993"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(02)01618-1"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00679-08"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2002.00502.x"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwj015"},{"key":"e_1_2_8_46_1","article-title":"Depletion of globosides and isoglobosides fully reverts the morphologic phenotype of Fabry disease","author":"Porubsky S","journal-title":"Cell Tissue Res"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1217775110"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100491"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00592-08"},{"key":"e_1_2_8_50_1","first-page":"447","article-title":"The neurotoxin of Shigella shigae: morphological and functional lesions produced in the central nervous system of rabbits","volume":"36","author":"Bridgwater FA","year":"1955","journal-title":"Br J Exp Pathol"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2012101044"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.01246"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/12.7.1344"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61253-1"},{"key":"e_1_2_8_55_1","volume-title":"Role of early volume expansion in mitigating Shigatoxin\u2010associated hemolytic uremic syndrome","author":"Ardissino G","year":"2013"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2004-2236"},{"key":"e_1_2_8_57_1","first-page":"803","article-title":"Leibowitz CS, et al","volume":"122","author":"Lee BC","year":"2013","journal-title":"Quiescent complement in nonhuman primates during E. coli Shiga toxin\u2010induced hemolytic uremic syndrome and thrombotic microangiopathy. Blood"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1006\/mpat.2001.0447"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.4388","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.4388","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.4388","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.4388","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T10:26:01Z","timestamp":1760955961000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.4388"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,7,25]]},"references-count":57,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2014,9]]}},"alternative-id":["10.1002\/path.4388"],"URL":"https:\/\/doi.org\/10.1002\/path.4388","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,7,25]]},"assertion":[{"value":"2014-01-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-06-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-07-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}