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C3 Glomerulopathy

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Abstract

Recent advances in our understanding of the disease pathology of membranoproliferative glomerulonephritis has resulted in its re-classification as complement C3 glomerulopathy (C3G) and immune complex-mediated glomerulonephritis (IC-GN). The new consensus is based on its underlying pathomechanism, with a key pathogenetic role for the complement alternative pathway (AP), rather than on histomorphological characteristics. In C3G, loss of AP regulation leads to predominant glomerular C3 deposition, which distinguishes C3G from IC-GN with predominant immunoglobulin G staining. Electron microscopy further subdivides C3G into C3 glomerulonephritis and dense deposit disease depending on the presence and distribution pattern of electron-dense deposits within the glomerular filter. Mutations or autoantibodies affecting the function of AP activators or regulators, in particular the decay of the C3 convertase (C3 nephritic factor), have been detected in up to 80 % of C3G patients. The natural outcome of C3G is heterogeneous, but 50 % of patients progress slowly and reach end-stage renal disease within 10–15 years. The new classification not only marks significant advancement in the pathogenic understanding of this rare disease, but also opens doors towards more specific treatment with the potential for improved outcomes.

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Abbreviations

aHUS:

Atypical haemolytic uremic syndrome

AP:

Alternative pathway (of complement)

C3:

Complement component 3

C3G:

C3 Glomerulopathy

C3GN:

C3 Glomerulonephritis

C3NeF:

C3 Nephritic factor

CFH:

Complement factor H

CFHR1–5:

Complement factor H-related proteins 1–5

CP:

Classical pathway (of complement)

DDD:

Dense deposit disease

ESRD:

End-stage renal disease

GN:

Glomerulonephritis

IC:

Immune complex

MCP:

Membrane-cofactor protein/CD46

MPGN:

Membranoproliferative glomerulonephritis

PIGN:

Post-infectious glomerulonephritis

TMA:

Thrombotic microangiopathy

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Authors and Affiliations

  1. Cell Biology Program of the Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Magdalena Riedl & Christoph Licht

  2. Department of Paediatrics, Innsbruck Medical University, Innsbruck, Austria

    Magdalena Riedl

  3. Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada

    Paul Thorner

  4. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Paul Thorner

  5. Division of Nephrology, The Hospital for Sick Children, Toronto, ON, Canada

    Christoph Licht

  6. Department of Paediatrics, University of Toronto, Toronto, ON, Canada

    Christoph Licht

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  1. Magdalena Riedl
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Correspondence to Christoph Licht.

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C. Licht and M. Riedl have served on Advisory Boards and/or teaching courses for Alexion Pharmaceuticals, Inc. C. Licht and M. Riedl have received travel stipends. C. Licht has received research grants from Alexion Pharmaceuticals, Inc. and is member of the Scientific Advisory Board of the Alexion sponsored International aHUS Registry.

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4: c

5: b

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Riedl, M., Thorner, P. & Licht, C. C3 Glomerulopathy. Pediatr Nephrol 32, 43–57 (2017). https://doi.org/10.1007/s00467-015-3310-4

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