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Histopathology of MPGN and C3 glomerulopathies

Key Points

  • 'Membranoproliferative' is a descriptive term for a morphological pattern of glomerular injury characterized by an enlarged mesangium and capillary wall thickening with double contours

  • Membranoproliferative changes are usually caused by deposition of immunoglobulin and/or complement in glomeruli, in which case the disease is called membranoproliferative glomerulonephritis (MPGN)

  • Many cases of MPGN are caused by defective control of the alternative complement pathway, associated with dominant C3 deposition in glomeruli with little immunoglobulin, and are now classified as C3 glomerulopathies

  • C3 glomerulopathies can be divided into dense deposit disease and C3 glomerulonephritis, depending on the ultrastructural appearance by electron microscopy

  • Recognition of the underlying cause of MPGN is important to guide investigation and treatment

Abstract

'Membranoproliferative' describes glomerular injury characterized by capillary wall thickening and mesangial expansion owing to increased matrix deposition and hypercellularity. The presence of immune deposits is indicative of membranoproliferative glomerulonephritis (MPGN). Historically, MPGN was further classified into three types according to the appearance and site of the electron-dense deposits seen by electron microscopy, but it is now recognized that many cases show only deposition of the complement component C3, owing to abnormal control of the alternative pathway of complement activation—these cases are now classified as C3 glomerulopathies. Not all cases of C3 glomerulopathy, however, show an MPGN pattern. C3 glomerulopathies include dense deposit disease, which shows dense osmiophilic deposits, and C3 glomerulonephritis, which shows isolated deposits. In many cases, the genetic mutations or autoantibodies responsible for C3 deposition have been identified. Some patients in whom complement control is abnormal will accumulate small amounts of immunoglobulin in their glomeruli and so, in everyday practice, the morphological diagnosis of 'glomerulonephritis with dominant C3' is useful for identifying patients who require investigation of the complement pathway. The recognition that many cases of MPGN are C3 glomerulopathies and that the underlying cause can often be identified in immunoglobulin-associated cases means that the diagnosis of idiopathic MPGN is now very uncommon.

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Figure 1: Membranoproliferative glomerulonephritis.
Figure 2: Membranoproliferative morphology in thrombotic microangiopathy.
Figure 3: Histopathology of MPGN and C3 glomerulopathy.
Figure 4: The relationship between historical and modern classification of glomerulonephritis with membranoproliferative morphology.
Figure 5: Simplified schematic of the pathways of complement activation.
Figure 6: An approach to the classification of disease in a biopsy sample showing the morphological changes of a glomerulonephritis with dominant C3.

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Acknowledgements

The authors' research is supported by the NIHR Imperial Biomedical Research Centre and grants from the Wellcome Trust and Kidney Research UK. M.C.P. is a Wellcome Trust Senior Fellow in Clinical Science (WT098476MA).

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Cook, H., Pickering, M. Histopathology of MPGN and C3 glomerulopathies. Nat Rev Nephrol 11, 14–22 (2015). https://doi.org/10.1038/nrneph.2014.217

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