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Pathogenesis of the C3 glomerulopathies and reclassification of MPGN

Nature Reviews Nephrology volume 8, pages 634–642 (2012)Cite this article

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Abstract

Until recently, membranoproliferative glomerulonephritis (MPGN) was clinically classified as either primary, idiopathic MPGN or as secondary MPGN when an underlying aetiology was identifiable. Primary MPGN was further classified into three types—type I, type II, and type III—based principally on the ultrastructural appearance and location of electron-dense deposits. Both the clinical and histopathologic schemes presented problems, however, as neither was based on disease pathogenesis. An improved understanding of the role of complement in the pathogenesis of MPGN has led to a proposed reclassification into immunoglobulin-mediated disease (driven by the classical complement pathway) and non-immunoglobulin-mediated disease (driven by the alternative complement pathway). This reclassification has led to improved diagnostic clinical algorithms and the emergence of a new grouping of diseases known as the C3 glomerulopathies, best represented by dense deposit disease and C3 glomerulonephritis. In this Review, we re-examine the previous and current classification schemes of MPGN, focusing on the role of complement. We survey current data about the pathogenesis of the C3 glomerulopathies, including familial studies and patient cohorts from the USA and Europe. In addition, we discuss the diagnosis, treatment, and prognosis of the C3 glomerulopathies.

Key Points

  • A new classification scheme for MPGN, centred on whether or not immunoglobulin accompanies complement on immunofluorescence, aims to capture the pathogenesis behind the MPGN lesion

  • A C3 glomerulopathy is a proliferative glomerulonephritis, usually (but not exclusively) with a MPGN pattern on light microscopy, with C3 staining alone on immunofluorescence, implicating hyperactivity of the alternative complement pathway

  • Mutations in and/or autoantibodies directed at factors that activate or regulate the C3 convertase of the alternative complement pathway can lead to dysregulation of this pathway and subsequent glomerular injury

  • Atypical hemolytic uremic syndrome is distinct from the C3 glomerulopathies in both the pattern of glomerular injury (a thrombotic microangiopathy) and phase of complement dysregulation (solid versus fluid phase)

  • Targeted and effective treatment of the C3 glomerulopathies will likely require an a priori, individualized understanding of the defect in the alternative complement pathway for each affected individual

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Figure 1: The reclassification of MPGN has led to the emergence of a new spectrum of diseases called C3 glomerulopathies.
Figure 2: Activation of C3 convertase is involved in both complement-mediated and immune-complex-mediated MPGN.

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Acknowledgements

The authors of this manuscript are supported by the Center for Glomerular Diseases at Columbia University, New York, USA.

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  1. Department of Medicine, Division of Nephrology, Columbia University Medical Center, 622 West 168th Street, New York, 10032, NY, USA

    Andrew S. Bomback & Gerald B. Appel

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The authors contributed equally to all aspects of this manuscript.

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Correspondence to Gerald B. Appel.

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A. S. Bomback declares an association with the following company: Alexion Pharmaceuticals (grant/research support).

G. B. Appel declares an association with the following company: Alexion Pharmaceuticals (consultant; grant/research support).

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Bomback, A., Appel, G. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nat Rev Nephrol 8, 634–642 (2012). https://doi.org/10.1038/nrneph.2012.213

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