C3 glomerulopathy

Published on November 30, 2017   33 min

Other Talks in the Series: The Complement System

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My name is Matthew Pickering and I am a Wellcome Trust Senior Fellow in Clinical Science based at the Centre for Complement and Inflammation Research at the Imperial College, London. And the subject of my talk is C3 glomerulopathy. C3 glomerulopathy is a term used to describe
a group of kidney diseases characterized by abnormal amounts of complement C3 within the kidney. It is a new disease classification first proposed in this paper in 2010 written by myself, Dr. Fakhouri, Professor of renal medicine in Nantes, two renal pathologists, Laure-Helene Noel and Terence Cook and a complement biologist, Veronique Fremeaux-Bacchi. The talk will cover the definition of C3 glomerulopathy, its pathogenesis, lessons from animal models and therapeutic considerations. When I refer to published data, you will see the relevant references at the bottom of the slides. So, let us start with what is C3 glomerulopathy.
Here is the formal definition of C3 glomerulopathy, and I will abbreviate that to C3G for the rest of the talk. It is a disease process due to abnormal control of complement activation, deposition, or degradation, and it is characterized by predominant glomerular C3 fragment deposition with electron-dense deposits on electron microscopy. This finding indicates that there is a problem with the control of complement C3 activation, and we will see that this problem, which we refer to as C3 dysregulation can be due to either genetic or acquired factors. You can also see that the diagnosis of C3 glomerulopathy is reached by analysis of glomerular pathology following a renal biopsy. In other words, it is a histological diagnosis and there are recommendations for renal pathologists. These were published by professor D'Agati in 2014 and this states that renal biopsies in which there is dominant staining for C3 are referred to as glomerulonephritis with dominant C3 and what do we mean by dominant? Well, this is defined as C3c staining intensity which is 2 orders of magnitude more than any other immune reactant. This finding does not always mean the patient has C3G. Glomerulonephritis with dominant C3 could represent post infectious glomerulonephritis and this appearance could be due to an inability to detect glomerular immunoglobulin. For example, monotypic immunoglobulin deposits may only be revealed after antigen retrieval using for example, pronase digestion. Inversely, if there is co-dominant staining for C3 and immunoglobulin, then provided known causes of immunoglobulin associated gene have been excluded, and an underlying problem with complement activation may still be present. This may become clearer in a given patient with serial renal biopsies. I and many other physicians have seen cases where the initial renal biopsy shows C3 deposition that is co-dominant with immunoglobulin but subsequent biopsies show C3 dominance.