C3 Glomerulopathy[Version 1; Peer Review: 4 Approved]

F1000Research 2017, 6(F1000 Faculty Rev):248 Last updated: 17 JUL 2019 REVIEW C3 glomerulopathy [version 1; peer review: 4 approved] H. Terence Cook Department of Medicine, Imperial College London, Hammersmith, London, UK First published: 10 Mar 2017, 6(F1000 Faculty Rev):248 ( Open Peer Review v1 https://doi.org/10.12688/f1000research.10364.1) Latest published: 10 Mar 2017, 6(F1000 Faculty Rev):248 ( https://doi.org/10.12688/f1000research.10364.1) Reviewer Status Abstract Invited Reviewers C3 glomerulopathy is a recently defined entity that encompasses a group of 1 2 3 4 kidney diseases caused by abnormal control of complement activation with deposition of complement component C3 in glomeruli leading to variable version 1 glomerular inflammation. Before the recognition of the unique pathogenesis published of these cases, they were variably classified according to their 10 Mar 2017 morphological features. C3 glomerulopathy accounts for roughly 1% of all renal biopsies. Clear definition of this entity has allowed a better understanding of its pathogenesis and clinical course and is likely to lead to F1000 Faculty Reviews are written by members of the design of rational therapies over the next few years. the prestigious F1000 Faculty. They are Keywords commissioned and are peer reviewed before C3 complement , glomerular inflammation , renal pathology publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. 1 Arvind Bagga, All India Institute of Medical Sciences, New Delhi, India 2 Francesco Emma, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy Marina Vivarelli, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy 3 Minghui Zhao, Peking University First Hospital, Beijing, China Peking-Tsinghua Center for Life Sciences, Beijing, China 4 John D. Lambris, University of Pennsylvania, Philadelphia, USA Any comments on the article can be found at the end of the article. Page 1 of 10 F1000Research 2017, 6(F1000 Faculty Rev):248 Last updated: 17 JUL 2019 Corresponding author: H. Terence Cook ([email protected]) Competing interests: The author declares that he has consulting agreements with Alexion Pharmaceuticals and Achillion Pharmaceuticals. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2017 Cook HT. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication). How to cite this article: Cook HT. C3 glomerulopathy [version 1; peer review: 4 approved] F1000Research 2017, 6(F1000 Faculty Rev):248 (https://doi.org/10.12688/f1000research.10364.1) First published: 10 Mar 2017, 6(F1000 Faculty Rev):248 (https://doi.org/10.12688/f1000research.10364.1) Page 2 of 10 F1000Research 2017, 6(F1000 Faculty Rev):248 Last updated: 17 JUL 2019 Introduction capillary wall3. The pathological significance of inhibition of the Classification of kidney pathology has traditionally relied on alternative pathway in the fluid phase compared with inhibition on separating diseases into categories depending on their light cell surfaces was elegantly demonstrated by taking the factor H- microscopic appearances. However, it is much more useful to deficient mice and making them transgenic for a form of factor H classify on the basis of pathogenesis. An excellent example of the lacking the last five SCRs of factor H4. These mice were able to change from morphology-based to pathogenesis-based classifica- regulate the alternative pathway in the circulation and had normal tion is the recent description of the entity of C3 glomerulopathy1 levels of C3 but were unable to control activation on the endothe- caused by uncontrolled activation of the alternative pathway of lium, leading to a renal thrombotic microangiopathy as seen in complement. In this review, I will describe the complement system human atypical haemolytic uremic syndrome. and the ways in which defects in control can lead to C3 glomerulopathy. I will outline what is known of the pathological and clinical In humans, the presence of isolated C3 deposits in glomeruli, detect- features and describe the outstanding questions in this disease. able by immunofluorescence and seen as deposits on EM, which are due to abnormal control of complement activation, has been given The complement system and the glomerulus the name of C3 glomerulopathy1. Before the recognition of this as a The complement system comprises over 30 proteins in circula- distinct pathological process, most of these cases would have been tion or on cell membranes. It has a central role in defence against classified on the basis of their morphological appearance and many micro-organisms and in clearance of apoptotic cells and debris. The of them would have been labelled as MPGN. It is important to be complement cascade may be activated in several ways but central aware that C3 in renal biopsies is usually detected with an antibody to all of them is the formation of an enzyme that cleaves C3, gener- to C3c which reflects recent C3 activation5. ating fragments C3a and C3b. Rapid amplification of the pathway is then achieved through a feedback loop that generates more C3b. Pathology of C3 glomerulopathy The classic pathway is activated by antigen-antibody complexes Glomerulonephritis due solely to alternative pathway activation and proceeds via C1, C2 and C4. The lectin pathway is activated would be expected to show C3 in glomeruli on immunofluores- by carbohydrate groups on micro-organisms and also involves cence with no immunoglobulins, C1q or C4 (Figure 1). This is the cleavage of C2 and C4. The alternative pathway, which is the finding in many cases, but (as discussed below) some cases that most primitive in evolutionary terms, is unique in that it is con- are almost certainly due to defects in alternative pathway activation tinually active in the circulation as a consequence of the spontane- may have small amounts of immunoglobulin, possibly because they ous hydrolysis of C3, allowing the formation of a C3 convertase. are triggered by immune complex deposition. With stringent cri- This ensures that the system is ready to respond rapidly to foreign teria requiring the presence of C3 and electron-dense deposits but surfaces such as micro-organisms. Because of this spontaneous no IgA or IgG deposition, C3 glomerulopathy was found in 1.34% activity of the alternative pathway and the rapid amplification of biopsies in a single centre with an estimated incidence of 2 per loop, the activity of the pathway needs to be tightly controlled. million population per year6. The major inhibitor of the alternative pathway in the circulation is factor H which acts to block the formation of alternative pathway Cases of C3 glomerulopathy show variable appearances on light convertases, promotes their spontaneous dissociation and also microscopy and EM. On EM, some biopsies show dense osmi- acts as a co-factor for the cleavage of C3b to its inactive form iC3b ophilic transformation of the glomerular basement membrane with by factor I. Factor H is composed of 20 protein subunits (each approximately 60 amino acids), known as short consensus repeat (SCR) domains. The complement-inhibiting activity of factor H resides within the first four N-terminal SCRs. The two C-terminal SCRs (SCR 19 and 20) are responsible for the ability of factor H to bind to self cell surfaces such as endothelium and locally inhibit the alternative pathway. The complement activation cascade and the role of factor H and its related proteins were recently reviewed2. The importance of factor H in inhibiting the alternative pathway is demonstrated by mice with a targeted deletion of factor H3. These mice have uncontrolled activation of the alternative pathway in the circulation and thus have very low circulating levels of C3. From 4 days of age (the earliest time point examined), they have deposition of C3 on the glomerular basement membrane with subsequent development of electron-dense deposits seen on electron microscopy (EM) by 2 months of age. This leads to glomerular inflammation and structural changes with the pattern of a membranoproliferative glomerulonephritis (MPGN)—that Figure 1. C3 staining in C3 glomerulopathy. Glomerulus showing is, glomerular architectural changes characterised by mesangial staining for C3 in a case of C3 glomerulopathy. The kidney is stained expansion and hypercellularity and by thickening of the glomerular with a fluorescently labelled antibody to C3. Page 3 of 10 F1000Research 2017, 6(F1000 Faculty Rev):248 Last updated: 17 JUL 2019 similar dense deposits in the glomerular mesangium and sometimes on Bowman’s capsule and in tubular basement membranes. This is referred to as a dense deposit disease (DDD) (Figure 2) and has been recognised as a distinct morphological appearance for over 50 years7. In most cases, the deposits do not have this dense appearance but may form ill-defined electron densities within the basement membrane or mesangium or may resemble the deposits typically seen in immune complex glomerulonephritis with deposits in sub-endothelial or sub-epithelial locations (Figure 3); this group is by convention referred to as C3 glomerulonephritis (C3GN). It is important to understand that, in this potentially con- fusing terminology, C3 glomerulonephritis is thus a subset of C3 glomerulopathy that does not show the morphological features of DDD. It is not known why, in some cases, the deposits of C3 lead to the typical appearances of DDD. It is important to realise that the assessment of the density of the deposits is subjective and there will be some cases where pathologists would disagree about whether to classify them as DDD or C3GN8,9.

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