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C3 Glomerulopathies

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Pediatric Kidney Disease

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Abstract

Whereas in the past diagnosis was based on histomorphological criteria (electron microscopy; EM), dynamic advancement in the understanding of the disease causing pathomechanisms, with the identification of a key pathogenetic role for the complement system has recently resulted in a consensus on reclassifying membranoproliferative glomerulonephritis (MPGN). In keeping with observations in naturally occurring and genetically engineered mutant animals and validated by observations in patients, MPGN is now reliably linked to defects in the regulation of the complement alternative pathway (CAP). Different from atypical hemolytic uremic syndrome (aHUS) which is caused by local CAP dysregulation on (glomerular) endothelial cells, MPGN is thought to result from CAP dysregulation in fluid phase with glomerular deposition of excessively generated C3 metabolites. The new nomenclature – C3 glomerulopathy (C3G) – reflects this predominant pathogenetic role of the CAP resulting in glomerular deposition of complement C3 (both in the mesangium and capillary walls). In its purest form, C3G presents as dense deposit disease (DDD) with the typical continuous electron-dense deposits within the lamina densa of the glomerular basement membrane (GBM). By contrast, C3 glomerulonephritis (C3GN) refers to a subform of C3G characterized by electron-dense deposits within the subendothelial and the mesangial space. Immunofluorescence predominantly identifies C3 but immune complexes (containing IgG and IgM) or C1q deposition are also observed, albeit in significantly smaller quantities. Different from these clearly complement driven forms, cases of MPGN occurring subsequent to underlying diseases such as infections or neoplasms are summarized as secondary MPGN. The new classification system not only marks significant advancement in the pathogenetic understanding of this rare but often aggressive group of diseases, but also opens doors towards more specific treatment of C3G, i.e. treatment of the underlying disease in secondary vs complement blockade in primary forms.

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Authors and Affiliations

  1. Department of Nephrology, The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Canada

    Christoph Licht

  2. Department of Nephrology and Dialysis, Ospedale Pediatrico Bambino Gesu, Pizza S.Onofrio 4, Rome, 00165, Italy

    Marina Vivarelli

  3. Laboratory Medicine and Pathology Department, Mayo Clinic, 200 1st Street SW, Rochester, MN, 55902, USA

    Sanjeev Sethi

Authors
  1. Christoph Licht
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  2. Marina Vivarelli
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  3. Sanjeev Sethi
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Corresponding author

Correspondence to Christoph Licht .

Editor information

Editors and Affiliations

  1. Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada

    Denis F. Geary

  2. Division of Pediatric Nephrology, University of Heidelberg, Heidelberg, Germany

    Franz Schaefer

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Licht, C., Vivarelli, M., Sethi, S. (2016). C3 Glomerulopathies. In: Geary, D., Schaefer, F. (eds) Pediatric Kidney Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-52972-0_25

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  • DOI: https://doi.org/10.1007/978-3-662-52972-0_25

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