Studies of EHEC and the complement system in renal diseases

Research output: ThesisDoctoral Thesis (compilation)

Abstract

This thesis addressed the diagnosis, pathogenesis and clinical course of specific renal diseases hemolytic uremic syndrome (HUS) and dense deposit disease (DDD). HUS may be associated with infection caused by Enterohemorrhagic Escherichia coli (EHEC) or with complement dysfunction due to complement mutations or auto-antibodies (atypical HUS, aHUS).

EHEC is a non-invasive highly virulent bacterium. In order to gain access to the circulation it first damages the intestinal mucosa. The mechanism of damage and the bacterial factors involved were addressed. Abundant cell death by apoptosis was demonstrated in HUS patients. EHEC virulence factors were correlated to the intestinal damage and symptoms in a mouse model using mutant strains. Intimin and the presence of the type III secretion system effectors were necessary for intestinal colonization and virulence in mice. The presence of Shiga toxin induced intestinal mucosal cell death by apoptosis, which could thus allow EHEC virulence factors to gain access to the circulation and reach target organs. A serotype-independent serodiagnostic assay for detection of EHEC was developed. Patients developed an antibody response to intimin, E. coli secreted protein A (EspA) and EspB. Antibodies to EspB were the most specific for detection of recent EHEC infection.

The second part of the thesis addressed complement-mediated kidney disease. We found that renin, a kidney-specific enzyme, activated the alternative pathway of complement by cleaving C3 into C3a and C3b in a manner identical to the C3 convertase. Cleavage was inhibited by the renin inhibitor aliskiren. Aliskiren treatment reduced complement activation and stabilized the clinical course in two DDD patients. Renin cleavage of C3 is a novel kidney-specific mechanism of complement activation, which may explain the renal specificity of complement-mediated renal diseases.

Patients with aHUS develop recurrences as long as there is viable renal tissue that triggers disease activity. We described a patient with multiple complement mutations who developed severe systemic vascular complications in the absence of kidneys and aHUS recurrences. To our knowledge this is the first patient treated with eculizumab, an anti-C5 antibody blocking the terminal complement cascade, in the absence of kidney tissue.

In summary this thesis defined novel mechanisms of pathogenesis and treatment of severe renal conditions.

Details

Authors
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pediatrics

Keywords

  • EHEC, hemolytic uremic syndrome, thrombotic microangiopathy, atypical hemolytic uremic syndrome, alternative pathway of complement, dense deposit disease, eculizumab
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2013 Dec 11
Publisher
  • Lund University, Paediatrics
Print ISBNs978-91-87651-09-0
Publication statusPublished - 2013
Publication categoryResearch

Bibliographic note

Defence details Date: 2013-12-11 Time: 09:00 Place: Belfragesalen, D15, Biomedicinskt centrum (BMC), Lund External reviewer(s) Name: Loirat, Chantal Title: professor Affiliation: Department of Pediatric Nephrology, University Hospital Robert Debré, Paris, France ---

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Research output: Contribution to journalArticle

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Research output: Contribution to journalArticle

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