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A Narrative Review on C3 Glomerulopathy: a Rare Renal Disease

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A Narrative Review on C3 Glomerulopathy: a Rare Renal Disease International Journal of Molecular Sciences Review A Narrative Review on C3 Glomerulopathy: A Rare Renal Disease Francesco Paolo Schena 1,2,*, Pasquale Esposito 3 and Michele Rossini 1 1 Department of Emergency and Organ Transplantation, Renal Unit, University of Bari, 70124 Bari, Italy; [email protected] 2 Schena Foundation, European Center for the Study of Renal Diseases, 70010 Valenzano, Italy 3 Department of Internal Medicine, Division of Nephrology, Dialysis and Transplantation, University of Genoa and IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; [email protected] * Correspondence: [email protected] Received: 5 December 2019; Accepted: 10 January 2020; Published: 14 January 2020 Abstract: In April 2012, a group of nephrologists organized a consensus conference in Cambridge (UK) on type II membranoproliferative glomerulonephritis and decided to use a new terminology, “C3 glomerulopathy” (C3 GP). Further knowledge on the complement system and on kidney biopsy contributed toward distinguishing this disease into three subgroups: dense deposit disease (DDD), C3 glomerulonephritis (C3 GN), and the CFHR5 nephropathy. The persistent presence of microhematuria with or without light or heavy proteinuria after an infection episode suggests the potential onset of C3 GP. These nephritides are characterized by abnormal activation of the complement alternative pathway, abnormal deposition of C3 in the glomeruli, and progression of renal damage to end-stage kidney disease. The diagnosis is based on studying the complement system, relative genetics, and kidney biopsies. The treatment gap derives from the absence of a robust understanding of their natural outcome. Therefore, a specific treatment for the different types of C3 GP has not been established. Recommendations have been obtained from case series and observational studies because no randomized clinical trials have been conducted. Current treatment is based on corticosteroids and antiproliferative drugs (cyclophosphamide, mycophenolate mofetil), monoclonal antibodies (rituximab) or complement inhibitors (eculizumab). In some cases, it is suggested to include sessions of plasma exchange. Keywords: C3 glomerulopathy; Dense deposits disease; C3 glomerulonephritis; CFHR5 nephropathy 1. Introduction Membranoproliferative or mesangiocapillary glomerulonephritis (MPGN) has been traditionally classified based on the light and electron microscopy (EM) findings; here, there are three categories: type I, characterized by the presence of immune deposits in the subendothelial space and mesangium of glomeruli; type II, characterized by C3 deposits within the mesangium and in the basement membranes highly osmiophilic on electron microscopy (dense deposits disease; DDD); and type III, which is a variant of type I [1]. In August 2012, a group of experts in renal pathology, nephrology, complementology, and complement therapeutics organized a consensus conference on the C3 glomerulopathy (C3 GP), meeting in Cambridge, UK [2]. Subsequently, new information on the complement system has increased our understanding of the MPGN, which has been divided into two groups: (i) MPGN caused by immune complexes (IC-MPGN) that can be caused by polyclonal or monoclonal IgG and (ii) complement-mediated glomerulonephritis (Figure1). Int. J. Mol. Sci. 2020, 21, 525; doi:10.3390/ijms21020525 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 525 2 of 19 Int. J. Mol. Sci. 2020, 21, 525 2 of 18 Figure 1. Classification of the membranoproliferative glomerulonephritis (MPGN). Abbreviations: Figure 1. Classification of the membranoproliferative glomerulonephritis (MPGN). Abbreviations: IC-MPGN (immune complex MPGN); Ig (immunoglobulin); C3 GP (C3 glomerulopathy); DDD (dense IC-MPGN (immune complex MPGN); Ig (immunoglobulin); C3 GP (C3 glomerulopathy); DDD deposits disease); C3 GN (C3 glomerulonephrits); CFHR5 GP (complement factor H-related protein 5 (dense deposits disease); C3 GN (C3 glomerulonephrits); CFHR5 GP (complement factor H-related glomerulopathy). protein 5 glomerulopathy). The term C3 GP includes a group of nephritides based on the abnormal control of the alternative pathwayThe ofterm the complementC3 GP includes system a thatgroup causes of anephritides dominant accumulationbased on the of C3abnormal fragments control in glomeruli, of the alternativeas evidenced pathway by an intense of the stainingcomplement of C3 withsystem absence that causes or low presencea dominant of immunoglobulinsaccumulation of andC3 fragmentscomponents in ofglomeruli, the classical as evidenced complement by an pathway intense instaining the immunofluorescence of C3 with absence patternor low presence of a kidney of immunoglobulinsbiopsy [3]. This form and of nephritiscomponents can beof detected the inclassical individuals complement with defects pathway in the complement in the immunofluorescenceactivation that is induced pattern by circulatingof a kidney factors biopsy or the[3]. presence This form of rareof nephritis gene variants can be in complementdetected in individualscomponents with of the defects alternative in the pathway. complement activation that is induced by circulating factors or the presenceIn a recentof rare classificationgene variants proposed in complement by Cook components and Pickering of the [4], alternative C3 GP was pathway. shown to be principally composedIn a recent of three classification major subgroups proposed (Figure by Cook1): (i) andDDD Pickeringis characterized [4], C3 GP by was intramembranous shown to be principallyglomerular depositscomposed of denseof three osmophilic major material;subgroups (ii) C3(Figure glomerulonephritis 1): (i) DDD(C3 is GN) characterized is based on theby intramembranouspresence of less dense glomerular deposits deposits of C3in of the dense mesangial, osmophilic subendothelial, material; (ii) and C3 glomerulonephritis subepithelial areas (C3 of GN)glomeruli; is based it alsoon the appears presence with of the less presence dense deposits of circulating of C3 auto-antibodies in the mesangial, against subendothelial, C3bBb, factor and B subepithelial(FB), and factor areas H (FH);of glomeruli; (iii) complement it also factorappears H-related with the 5 glomerulopathy presence of circulating(CFHR5 GP) auto is-antibodies caused by againstgenetic variantsC3bBb, factor of CFHR5. B (FB), Di ffanderences factor in H these (FH); three (iii) nephritides complement are factor based H-related on the interpretation5 glomerulopathy of (CFHR5data obtained GP) is by caused light microscopy, by genetic immunofluorescencevariants of CFHR5. /immunohistochemistryDifferences in these three and nephritides EM, laboratory are basedcomplement on findings,the andinterpretation clinical data. However,of data in someobtained cases, there by is an overlaplight ofmicroscopy, clinical data immunofluorescence/immunohistochemistryand laboratory findings, suggesting the possibility and EM, of a diseaselaboratory continuum complement based findings, on the dysregulation and clinical data.of the However, complement in alternativesome cases, pathway; there thisis an would overlap be caused of clinica by acquiredl data factorsand laboratory (autoantibodies) findings, or suggestinggenetic variants the possibility of some complement of a disease components continuum of based the alternative on the dysregulation pathway. of the complement alternative pathway; this would be caused by acquired factors (autoantibodies) or genetic variants of2. some Pathogenesis complement components of the alternative pathway. The complement system is the first cornerstone of innate immunity, and in the presence of various 2. Pathogenesis infections, it induces the lysis of agents through the generation of the membrane attack complex (MAC)The [5 complement]. Moreover, thesystem system is the modulates first cornerstone adaptive immunity.of innate immunity, and in the presence of variousThe infections, complement it induces system the can lysis be activated of agents through through three the digenerationfferent pathways, of the membrane as illustrated attack in complexFigure2. (MAC) [5]. Moreover, the system modulates adaptive immunity. The complement system can be activated through three different pathways, as illustrated in Figure 2. Int. J. Mol. Sci. 2020, 21, 525 3 of 19 Int. J. Mol. Sci. 2020, 21, 525 3 of 18 FigureFigure 2. 2. ComplementComplement system system pathways. pathways. TheThe classicalclassical pathway pathway isis activated activated by by circulating circulating immune immune complexes, complexes, whe whereasreas the the lectinlectin pathway pathway isis activated activated by by bacteria bacteria or or their their membrane membrane fragments. fragments. Both Both pathways pathways cleave cleave C3 C3 into into C3a C3a and and C3b. C3b. C3aC3a is is an an anaphylatoxin anaphylatoxin withwith aa proinflammatoryproinflammatory e ffeffect,ect, whereas whereas C3b C3b binds binds a fragment a fragment of factorof factor B (Bb), B (Bb),thus formingthus forming the C3 the convertase C3 convertase (C3bBb). (C3 AdditionalbBb). Additional production production of C3b promotes of C3b thepromotes formation the of formationthe complex of C3bBbC3bthe complex (C5 C3bBbC3b convertase), (C5 which convertase), cleaves C5which into cleaves C5a and C5 C5b into and C5a combines and C5b with and C6, combinesC7, C8, and with C9, C6, thus C7, forming C8, and theC9, membrane thus forming attack the complexmembrane (C5b-9) attack that complex induces (C5b the-9) lysis that of induces cellular themembranes
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