Eculizumab treatment for rescue of renal function in IgA nephropathy

Rosenblad, Therese; Rebetz, Johan; Johansson, Martin; Békássy, Zivile; Sartz, Lisa; Karpman, Diana

doi:10.1007/s00467-014-2863-y

Cited by 111 publications

(65 citation statements)

References 15 publications

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“…Mouse kidney was stained for C5b-9 as described for human kidney (36). Detection was performed using rabbit anti-rat C5b-9 (41) (a gift from Paul Morgan, Cardiff University, Cardiff, U.K.) that cross-reacts with mouse C9 (42) or, as a control, rabbit IgG (Dako), both at 5 mg/ml overnight at 4˚C.…”

Section: Blood Collectionmentioning

confidence: 99%

Early Terminal Complement Blockade and C6 Deficiency Are Protective in Enterohemorrhagic Escherichia coli–Infected Mice

Arvidsson

Rebetz

Loos

et al. 2016

The Journal of Immunology

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Complement activation occurs during enterohemorrhagic Escherichia coli (EHEC) infection and may exacerbate renal manifestations. In this study, we show glomerular C5b-9 deposits in the renal biopsy of a child with EHEC-associated hemolytic uremic syndrome. The role of the terminal complement complex, and its blockade as a therapeutic modality, was investigated in a mouse model of E. coli O157:H7 infection. BALB/c mice were treated with monoclonal anti-C5 i.p. on day 3 or 6 after intragastric inoculation and monitored for clinical signs of disease and weight loss for 14 d. All infected untreated mice (15 of 15) or those treated with an irrelevant Ab (8 of 8) developed severe illness. In contrast, only few infected mice treated with anti-C5 on day 3 developed symptoms (three of eight, p < 0.01 compared with mice treated with the irrelevant Ab on day 3) whereas most mice treated with anti-C5 on day 6 developed symptoms (six of eight). C6-deficient C57BL/6 mice were also inoculated with E. coli O157:H7 and only 1 of 14 developed disease, whereas 10 of 16 wild-type mice developed weight loss and severe disease (p < 0.01). Complement activation via the terminal pathway is thus involved in the development of disease in murine EHEC infection. Early blockade of the terminal complement pathway, before the development of symptoms, was largely protective, whereas late blockade was not. Likewise, lack of C6, and thereby deficient terminal complement complex, was protective in murine E. coli O157:H7 infection.

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Section: Blood Collectionmentioning

confidence: 99%

Early Terminal Complement Blockade and C6 Deficiency Are Protective in Enterohemorrhagic Escherichia coli–Infected Mice

Arvidsson

Rebetz

Loos

et al. 2016

The Journal of Immunology

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“…The first case of a child with rapidly progressive IgAN who benefitted from treatment with a monoclonal anti-C5 antibody, eculizumab, was recently published. 45 …”

Section: Terminal Pathway Complement Complexmentioning

confidence: 99%

Current Understanding of the Role of Complement in IgA Nephropathy

Maillard

Wyatt

Julian

et al. 2015

Journal of the American Society of Nephrology

274

231

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“…activators, galactose-deficient IgA1-containing immune complexes, or AMD risk polymorphisms will trigger C3G, IgA nephropathy, or AMD, 14,[27][28][29][30] respectively. Additional genetic and/or environmental factors altering host surfaces, depositing activating molecules (i.e., C-reactive protein, malondialdehyde), or removing FH ligands (i.e., heparan sulfate, sialic acid) might also influence the pathologic outcome in these individuals.…”

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confidence: 99%

Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases

Recalde

Tortajada

Subias

et al. 2015

JASN

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The complement factor H (FH) mutation R1210C, which was described in association with atypical hemolytic uremic syndrome (aHUS), also confers high risk of agerelated macular degeneration (AMD) and associates with C3 glomerulopathy (C3G). To reveal the molecular basis of these associations and to provide insight into what determines the disease phenotype in FH-R1210C carriers, we identified FH-R1210C carriers in our aHUS, C3G, and AMD cohorts. Disease status, determined in patients and relatives, revealed an absence of AMD phenotypes in the aHUS cohort and, vice versa, a lack of renal disease in the AMD cohort. These findings were consistent with differences in the R1210C-independent overall risk for aHUS and AMD between mutation carriers developing one pathology or the other. R1210C is an unusual mutation that generates covalent complexes between FH and HSA. Using purified FH proteins and surface plasmon resonance analyses, we demonstrated that formation of these FH-HSA complexes impairs accessibility to all FH functional domains. These data suggest that R1210C is a unique C-terminal FH mutation that behaves as a partial FH deficiency, predisposing individuals to diverse pathologies with distinct underlying pathogenic mechanisms; the final disease outcome is then determined by R1210C-independent genetic risk factors.

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Eculizumab treatment for rescue of renal function in IgA nephropathy

Abstract: Background

Cited by 111 publications

References 15 publications

Early Terminal Complement Blockade and C6 Deficiency Are Protective in Enterohemorrhagic Escherichia coli–Infected Mice

Early Terminal Complement Blockade and C6 Deficiency Are Protective in Enterohemorrhagic Escherichia coli–Infected Mice

Current Understanding of the Role of Complement in IgA Nephropathy

Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases

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