title: Direct acute tubular damage contributes to Shigatoxin-mediated kidney failure.
abstract: The pathogenesis and therapy of Shigatoxin 2 (Stx2)-mediated kidney failure remain controversial. Our aim was to test whether, during an infection with Stx2-producing E. coli (STEC), 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-receptor Gb3 in the tubular epithelium but, in contrast to humans, not in glomerular endothelia, and are thus free of glomerular thrombotic microangiopathy (TMA). In wild-type mice, Stx2 caused acute tubular dysfunction with consequent electrolyte disturbance, which was most likely the cause of death. Tubule-specific depletion of Gb3 protected the mice from acute renal failure. In vitro, 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-associated kidney failure (n = 11, aged 22-44 years). The majority of kidney biopsies showed different stages of an ongoing TMA; however, no glomerular complement activation could be demonstrated. All biopsies, including those without TMA, showed severe acute tubular damage. Due to these findings, patients were treated with supportive therapy without complement-inhibiting antibodies (eculizumab) or immunoadsorption. Despite the severity of the initial disease [creatinine 6.34 (1.31-17.60) mg/dl, lactate dehydrogenase 1944 (753-2792) U/l, platelets 33 (19-124)/nl and haemoglobin 6.2 (5.2-7.8) g/dl; median (range)], all patients were discharged after 33 (range 19-43) days with no neurological symptoms and no dialysis requirement [creatinine 1.39 (range 0.84-2.86) mg/dl]. The creatinine decreased further to 0.90 (range 0.66-1.27) 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-mediated acute kidney failure. Specifically in young adults, an excellent outcome can be achieved by supportive therapy only.
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Centre, Heidelberg, Germany; Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Porubsky
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Federico
authors.forename: Johannes
authors.initials: J
authors.lastname: Müthing
authors.forename: Richard
authors.initials: R
authors.lastname: Jennemann
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.forename: Stefan
authors.initials: S
authors.lastname: Büttner
authors.forename: Nicholas
authors.initials: N
authors.lastname: Obermüller
authors.forename: Oliver
authors.initials: O
authors.lastname: Jung
authors.forename: Ingeborg A
authors.initials: IA
authors.lastname: Hauser
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gröne
authors.forename: Helmut
authors.initials: H
authors.lastname: Geiger
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Christoph
authors.initials: C
authors.lastname: Betz
mesh_terms: D058186:Acute Kidney Injury / Q000382:microbiology / Q000473:pathology* / Q000628:therapy; D000328:Adult; D000818:Animals; D001706:Biopsy; D002460:Cell Line; D015331:Cohort Studies; D003404:Creatinine / Q000378:metabolism; D004195:Disease Models, Animal; D004848:Epithelium / Q000382:microbiology / Q000473:pathology; D004927:Escherichia coli Infections / Q000382:microbiology / Q000473:pathology* / Q000628:therapy; D005260:Female; D005915:Globosides / Q000378:metabolism; D006801:Humans; D007684:Kidney Tubules / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022641:Shiga Toxin 2 / Q000235:genetics / Q000378:metabolism*; D054323:Shiga-Toxigenic Escherichia coli / Q000472:pathogenicity*; D057049:Thrombotic Microangiopathies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D005915:Globosides; D022641:Shiga Toxin 2; D003404:Creatinine
keywords: Shigatoxin; Shigatoxin-producing Escherichia coli (STEC); acute renal failure; acute tubular damage; electron microscopy; globoside (Gb3, CD77); thrombotic microangiopathy