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- Bekassy, Zivile, et al.
(author)
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Crosstalk between the renin–angiotensin, complement and kallikrein–kinin systems in inflammation
- 2022
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In: Nature Reviews Immunology. - : Springer Science and Business Media LLC. - 1474-1733 .- 1474-1741. ; 22:7, s. 411-428
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Research review (peer-reviewed)abstract
- During severe inflammatory and infectious diseases, various mediators modulate the equilibrium of vascular tone, inflammation, coagulation and thrombosis. This Review describes the interactive roles of the renin–angiotensin system, the complement system, and the closely linked kallikrein–kinin and contact systems in cell biological functions such as vascular tone and leakage, inflammation, chemotaxis, thrombosis and cell proliferation. Specific attention is given to the role of these systems in systemic inflammation in the vasculature and tissues during hereditary angioedema, cardiovascular and renal glomerular disease, vasculitides and COVID-19. Moreover, we discuss the therapeutic implications of these complex interactions, given that modulation of one system may affect the other systems, with beneficial or deleterious consequences.
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- Békássy, Zivile D., et al.
(author)
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Aliskiren inhibits renin-mediated complement activation
- 2018
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In: Kidney International. - : Elsevier BV. - 0085-2538. ; 94:4, s. 689-700
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Journal article (peer-reviewed)abstract
- Certain kidney diseases are associated with complement activation although a renal triggering factor has not been identified. Here we demonstrated that renin, a kidney-specific enzyme, cleaves C3 into C3b and C3a, in a manner identical to the C3 convertase. Cleavage was specifically blocked by the renin inhibitor aliskiren. Renin-mediated C3 cleavage and its inhibition by aliskiren also occurred in serum. Generation of C3 cleavage products was demonstrated by immunoblotting, detecting the cleavage product C3b, by N-terminal sequencing of the cleavage product, and by ELISA for C3a release. Functional assays showed mast cell chemotaxis towards the cleavage product C3a and release of factor Ba when the cleavage product C3b was combined with factor B and factor D. The renin-mediated C3 cleavage product bound to factor B. In the presence of aliskiren this did not occur, and less C3 deposited on renin-producing cells. The effect of aliskiren was studied in three patients with dense deposit disease and this demonstrated decreased systemic and renal complement activation (increased C3, decreased C3a and C5a, decreased renal C3 and C5b-9 deposition and/or decreased glomerular basement membrane thickness) over a follow-up period of four to seven years. Thus, renin can trigger complement activation, an effect inhibited by aliskiren. Since renin concentrations are higher in renal tissue than systemically, this may explain the renal propensity of complement-mediated disease in the presence of complement mutations or auto-antibodies.
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- Békassy, Zivile, et al.
(author)
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Eculizumab in an anephric patient with atypical haemolytic uraemic syndrome and advanced vascular lesions.
- 2013
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In: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 1460-2385 .- 0931-0509. ; 28:11, s. 2899-2907
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Journal article (peer-reviewed)abstract
- Atypical haemolytic uraemic syndrome (aHUS) is associated with dysfunction of the alternative pathway of complement. Disease activity subsides as renal failure progresses but recurs upon renal transplantation, indicating that viable renal tissue contributes to disease activity. We present evidence of cerebrovascular occlusive disease indicating that vascular injury may occur in the absence of kidneys.
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- Békassy, Zivile, et al.
(author)
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Intestinal damage in enterohemorrhagic Escherichia coli infection.
- 2011
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In: Pediatric Nephrology. - : Springer Science and Business Media LLC. - 1432-198X .- 0931-041X. ; oct, s. 2059-2071
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Journal article (peer-reviewed)abstract
- Enterohemorrhagic Escherichia coli (EHEC) infection leads to marked intestinal injury. Sigmoid colon obtained from two children during EHEC infection exhibited abundant TUNEL-positive cells. To define which bacterial virulence factors contribute to intestinal injury the presence of Shiga toxin-2 (Stx2), intimin and the type III secretion system were correlated with symptoms and intestinal damage. C3H/HeN mice were inoculated with Stx2-producing (86-24) and non-producing (87-23) E. coli O157:H7 strains and 86-24 mutants lacking eae, encoding intimin (strain UMD619) or escN regulating the expression of type III secretion effectors (strain CVD451). Severe symptoms developed in mice inoculated with 86-24 and 87-23. Few mice inoculated with the mutant strains developed severe symptoms. Strain 86-24 exhibited higher fecal bacterial counts, followed by 87-23, whereas strains UMD619 and CVD451 showed minimal fecal counts. More TUNEL-positive cells were found in proximal and distal colons of mice inoculated with strain 86-24 compared with strains 87-23 and CVD451 (p
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7. |
- Bekassy, Zivile, et al.
(author)
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Is kidney biopsy necessary in children with idiopathic nephrotic syndrome?
- 2023
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In: Acta Pædiatrica. - 0803-5253. ; 112:12, s. 2611-2618
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Journal article (peer-reviewed)abstract
- AIM: To investigate the need, in the Northern European setting, to perform kidney biopsy in children with steroid-sensitive nephrotic syndrome.METHODS: In this retrospective study 124 individuals aged 1-18 years with idiopathic nephrotic syndrome, followed in the paediatric hospitals in southern Sweden from 1999 to 2018, were included.RESULTS: There was a median follow-up time of 6.5 (0.2-16.8) years. The majority (92%) of children were steroid-sensitive and of them, 60.5% were frequently relapsing or steroid-dependent. Microscopic haematuria was found at onset in 81.1% and hypertension in 8.7%. At least one kidney biopsy was performed in 93 (75%). The most common indication was a steroid-dependent or relapsing course (58.4%). One of 79 steroid-sensitive children had another histological diagnosis than minimal change nephropathy 1.3%, 95% confidence interval (0.002, 0.068). Bleeding occurred after eight biopsies (6.6%). Twenty individuals (30.7%) were transferred to adult units, 18 still on immunosuppression.CONCLUSION: We have in our cohort of unselected children with idiopathic nephrotic syndrome confirmed that a kidney biopsy rarely gives important medical information in steroid-sensitive children without any other complicating factor and that the liberal policy of kidney biopsy in the Nordic countries safely can be changed.
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8. |
- Békassy, Zivile
(author)
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Studies of EHEC and the complement system in renal diseases
- 2013
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Doctoral thesis (other academic/artistic)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.
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