UPDATE ON C3 glomerulopathy
Nephrol Dial Transplant (2014)0:1–9doi:10.1093/ndt/gfu317
Full Review
Update on C3glomerulopathy
Thomas D.Barbour,Marieta M.Ruseva and Matthew C.Pickering
Centre for Complement and In ?ammation Research (CCIR),Division of Immunology and In ?ammation,Department of Medicine,Imperial College London,London W120NN,UK
Correspondence and offprint requests to:Thomas D.Barbour;E-mail:t.barbour@https://www.wendangku.net/doc/3015130227.html,
A B S T R AC T
C3glomerulopathy refers to a disease process in which abnor-mal control of complement activation,degradation or depos-ition results in predominant C3fragment deposition within the glomerulus and glomerular damage.Recent studies have improved our understanding of its pathogenesis.The key ab-normality is uncontrolled C3b ampli ?cation in the circulation and/or along the glomerular basement membrane.Family studies in which disease segregates with structurally abnormal complement factor H-related (CFHR)proteins demonstrate that abnormal CFHR proteins are important in some types of C3glomerulopathy.This is currently thought to be due to the ability of these proteins to antagonize the major negative regu-lator of C3activation,complement factor H (CFH),a process termed ‘CFH de-regulation ’.Recent clinicopathological cohort studies have led to further re ?nements in case de ?nition,cul-minating in a 2013consensus report,which provides recom-mendations regarding investigation and treatment.Early clinical experience with complement-targeted therapeutics,notably C5inhibitors,has also now been published.Here,we summarize the latest developments in C3glomerulopathy.Keywords:C3glomerulopathy,complement,dense deposit,factor H
I N T RO D U C T I O N
C3glomerulopathy designates ‘a disease process due to abnor-mal control of complement activation,deposition,or degrad-ation and characterized by predominant glomerular C3fragment deposition with electron-dense deposits on electron
microscopy ’[1].It often progresses to end-stage kidney disease (ESKD)and recurs after renal transplantation.The prototypical form of C3glomerulopathy is dense deposit disease (DDD),which historically has been diagnosed based on linear,hyperosmiophilic electron-dense deposits occupying the middle layer of the glomerular basement membrane (GBM).‘C3glomerulonephritis ’(C3GN)refers to those cases of C3glomerulopathy in which the electron-dense deposits do not have this classic appearance.
One striking observation in patients with C3glomerulopa-thy is how commonly clinical presentation is preceded by an infectious episode.This suggests that infection may initiate or exacerbate the disease process,for example by acting as an ex-ogenous trigger of C3activation.Once C3is activated,abnor-mal glomerular accumulation of C3fragments occurs due to uncontrolled C3b ampli ?cation via the alternative pathway (AP).In the majority of patients with C3glomerulopathy,ac-quired or genetic defects in AP regulation can be demon-strated.In 2013,a consensus report in C3glomerulopathy was published with recommendations regarding case de ?nition,investigation and treatment [1].At present,all patients in whom C3glomerulopathy is diagnosed on either native or transplant kidney biopsy should be investigated for low plasma levels of C3,C4and complement factor H (CFH),and the presence of paraprotein (i.e.monoclonal gammopathy),C3nephritic factor and abnormal complement factor H-related protein 5(CFHR5).
CFH is the main plasma regulator of the AP and consists of 20protein subunits,termed short consensus repeat (SCR)domains,that are encoded within the regulators of comple-ment (RCA)gene cluster on chromosome 1q32.The CFH –CFHR protein family (Figure 1A)comprises CFH and ?ve structurally related CFHR proteins that are encoded down-stream of the CFH gene.Frequent interspersed repeat elements across the CFH –CFHR locus predispose to
genomic
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rearrangements,a number of which are associated with the renal pathologies atypical haemolytic uraemic syndrome (aHUS)and C3glomerulopathy.CFH surface recognition domains at the carboxy (C)-terminus contain ligand-binding sites for glycosaminoglycans and C3b and are highly con-served on CFHR proteins.In contrast,the ?rst four amino (N)-terminal SCR domains of CFH,which confer its comple-ment regulatory functions,are absent from the CFHR pro-teins.As a consequence,CFHR proteins do not possess the physiological CFH regulatory activity mediated by these SCR domains.Distinct N-terminal SCR domains 1and 2are highly conserved on CFHR1,CFHR2and CFHR5(Figure 1B),and these are important in dimerization.R E C E N T FA M I LY S T U D I E S
In 2010,Gale et al.demonstrated segregation of C3GN with a heterozygous mutation of CFHR5involving internal duplica-tion of exons 2and 3(which encode N-terminal SCR domains 1and 2,respectively)in a large Greek Cypriot cohort [2].Since the original description of Cypriot ‘CFHR5nephropa-thy ’,a number of families with autosomal dominant C3GN and distinct CFHR mutations have been reported .A striking common feature has been internal duplication of exons or for-mation of hybrid genes resulting in abnormal CFHR proteins with duplication of N-terminal SCR domains 1and 2(Figure 2).Recent family studies in C3glomerulopathy and membranoproliferative glomerulonephritis (MPGN)are brie ?y summarized below (see also Table 1),followed by a dis-cussion of the pathophysiological implications of abnormal CFHR proteins.
Medjeral-Thomas et al.demonstrated segregation of a het-erozygous mutation in CFHR5that results in duplication of SCR domains 1and 2with C3GN in a family without Cypriot ancestry [6].Although the abnormal protein,CFHR5121–9,is
identical to that reported in Cypriot CFHR5nephropathy,the respective genomic breakpoints within CFHR5intron 3are distinct.It is now recommended that assays to screen for the presence of CFHR5121–9are performed in patients with C3glomerulopathy irrespective of ancestry.
Malik et al.identi ?ed a novel heterozygous CFHR mutation in a large,Irish kindred in which C3GN had previously been linked to the RCA gene cluster [3].Deletion of a genomic segment comprising exons 4–6of CFHR3and exon 1of CFHR1produced a hybrid protein in which SCR domains 1and 2of CFHR3are linked to full-length CFHR1.The hybrid CFHR312–CFHR1gene was located on an allele also bearing intact CFHR1and CFHR3genes,suggesting disease causation due to a gain of function.
Tortajada et al.reported a Spanish family with C3glomeru-lopathy and a heterozygous mutation resulting in an abnormal CFHR1protein with duplication of SCR domains 1–4[5
].
F I
G U R E 1:The CF
H –CFHR protein family.(A )CFH consists of 20SCR domains.Those at the C-terminus (depicted in yellow)mediate
surface recognition and are common to the ?ve CFHR proteins (CFHR4has two isoforms,CFHR4A and CFHR4B).In contrast,N-terminal SCR domains mediating CFH complement regulatory function (red)are not found on CFHR proteins.The N-terminal SCR domains 1and 2are highly conserved on CFHR1,CFHR2and CFHR5(blue)but not CFHR3and CFHR4A/B,with very high sequence homology (B
).
F I
G U R E 2:Family studies have identi ?ed abnormal CFHR
proteins associated with C3glomerulopathy.These include duplica-tion of N-terminal SCR domains and formation of a hybrid CFHR protein containing two domains from CFHR3(depicted in purple)linked to the whole of CFHR1.
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Chen et al.reported a UK sibship with C3glomerulopathy associated with heterozygous deletion of exons 4–5of CFHR2[7].This produced a hybrid protein consisting of SCR domains 1and 2of CFHR2linked to full-length CFHR5(CFHR212–CFHR51–9).Due to the similarity between the initial two SCR domains of CFHR2and CFHR5,the hybrid CFHR212–CFHR51–9protein is structurally similar to CFHR5121–9.
A number of earlier family studies in which C3glomerulo-pathy was associated with mutations causing severe de ?ciency or dysfunction of CFH have been summarized previously [9].Recently,Wong et al.demonstrated association of a heterozy-gous CFH non-synonymous coding variant (c.249G>T)with MPGN in a UK family [8].This mutation resulted in a serine to arginine substitution (p.R83S)within SCR2.A recombinant mutant CFH protein fragment (SCR domains 1–4)displayed reduced C3b-binding and complement regulatory activity in vitro compared with a recombinant wild-type CFH protein.Ozaltin et al.identi ?ed a homozygous coding variant (c.127C>T)in the diacylglycerol kinase ε(DGK ε)gene in a consanguineous Turkish family (denoted in the manuscript as UT-062)with familial renal disease with features of MPGN and thrombotic microangiopathy [4].DGK εis an intracellular lipid kinase that is expressed in podocytes.The coding variant produces a premature stop codon (p.Q43X)leading to a trun-cated protein.How this results in renal disease remains unclear.However,the disease association was strengthened by the identi ?cation of other homozygous DGKE variants leading to protein truncation in two other consanguineous families.
R E C E N T I N S I G H T S I N TO C F H R B I O LO GY A key insight into the biology of CFHR1,CFHR2and CFHR5derived from the observation that a recombinant CFHR11–2protein formed obligatory head-to-tail dimers via a unique dimerization motif located within the highly conserved N-terminal SCR domains 1and 2of CFHR1,-2and -5[10].Recombinant CFHR5was shown to be an exclusively dimeric protein and,when key amino acids within the putative dimer-ization domains were mutated,the recombinant protein was monomeric.The identi ?cation of the dimerization motif within CFHR1,-2and -5leads to the prediction that both homo-and heterodimers could exist between these proteins (Figure 3).Fur-thermore,a common structural polymorphism that results in combined deletion of the CFHR1and CFHR3genes (ΔCFHR3/1)would result in de ?ciency of not only the CFHR1homodi-mer but also de ?ciency of heterodimers containing CHFR1(CFHR1–CFHR2and CFHR1–CFHR5heterodimers).
What is the relevance of these observations to patients with familial C3glomerulopathy associated with abnormal CFHR proteins?Duplication of the dimerization motif and the pres-ence or absence of the ΔCFHR3/1allele could theoretically lead to diverse species of CFHR homo-and heterodimers (Table 2).De ?ning the composition of these proteins in vivo is a prerequisite to understanding the association of abnormal CFHR proteins with C3glomerulopathy.In addition,it is im-portant for our understanding of why the ΔCFHR3/1allele
T a b l e 1.C o n t i n u e d
O r i g i n a l r e p o r t (y e a r )
R e p o r t e d d i a g n o s i s A f f e c t e d m e m b e r (C a s e n u m b e r )
G l o m e r u l a r I F /I H C E M d e p o s i t s
C 3l e v e l s
C 3N e F C F H l e v e l s
M o d i ?e d C F H R p r o t e i n s
M o l e c u l a r d e f e c t (s )
M e d j e r a l -T h o m a s e t a l .(2014)[6]
C 3G N
M a t e r n a l m a l e c o u s i n (I I I -2)
A l l o g r a f t C 3p o s
S u b e n d o t h e l i a l ,m e s a n g i a l (n a t i v e );s u b e n d o t h e l i a l ,I M (t r a n s p l a n t r e c u r r e n c e )—
——
C F H R 5121–9
H e t e r o z y g o u s i n t e r n a l
d u p l i c a t i o n o f
e x o n s 2–3(S C R s 1–2)i n C F H R 5
I n d e x m a l e (I I I -5)
C a p i l l a r y w a l l C 3;I g A /I g G /I g M n e g
S e g m e n t a l s u b e n d o t h e l i a l ,I M
N o r m a l N e g
N o r m a l
(w i t h a b s e n t C F H R 1,3)
(w i t h h o m o z y g o u s ΔC F H R 3/1)
C h e n e t a l .(2014)[7]
C 3g l o m e r u l o p a t h y w i t h s o m e E M f e a t u r e s o f
D D D
S i s t e r (635)
G B M >m e s a n g i a l C 3c ;I g n e g
R i b b o n -l i k e G B M >m e s a n g i a l (l i m i t e d q u a l i t y )V e r y l o w
N e g
N o r m a l H y b r i d C F H R 212–C F H R 5(w i t h l o w l e v e l s o f w i l d -t y p e C F H R 2,5)
H e t e r o z y g o u s h y b r i d C F H R g e n e w i t h d e l e t i o n o f C F H R 2e x o n s 4–5(S C R s 3–4)
B r o t h e r (638)
—
—W o n g e t a l .(2014)[8]/P o w e r (1990)
M P G N (a n d a c q u i r e d p a r t i a l l i p o d y s t r o p h y )M o t h e r (1.2)
C 3p o s ;I g M >I g G /I g A S u b e n d o t h e l i a l ,m e s a n g i a l
V e r y l o w P o s —
—
H e t e r o z y g o u s C F H c .249G >T (p .R 83S o n S C R 2)F i r s t s o n (2.1)
—
N o r m a l
N o r m a l
(a l s o C 3p o l y m o r p h i s m s p .R 102G /P 314L )(h e t e r o z y g o u s C F H H 3/H 5h a p l o t y p e s )
I F /I H C ,i m m u n o ?u o r e s c e n c e /i m m u n o h i s t o c h e m i s t r y ;E M ,e l e c t r o n m i c r o s c o p y ;C 3N e F ,C 3n e p h r i t i c f a c t o r ;I g ,i m m u n o g l o b u l i n .
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modi ?es disease susceptibility in age-related macular degener-ation [11],systemic lupus erythematosus [12]and IgA nephro-pathy [13].
At present,there is strong evidence to support the existence of all three homodimers [5,10]but only one heterodimer (CFHR1–CFHR2).The latter was readily identi ?ed because CFHR1but not CFHR2interacts with heparin.When serum or plasma is subjected to heparin chromatography,CFHR2is only retained (bound to heparin)in the presence of CFHR1[5,10].The CFHR1–CFHR5heterodimer has less clearly been identi ?ed [5,10]while CFHR2–CFHR5was not seen in one study [5]or was seen only in very low amounts in another [10].In addition to dimerization,there is evidence that these proteins can form larger complexes [5].Following heparin chromatography of CFHR1-containing plasma,protein complexes of various sizes were identi ?ed,consistent with for-mation of CFHR1homo-oligomers and a variety of CFHR1–CFHR2and CFHR1–CFHR5hetero-oligomers [5].What is the functional signi ?cance of dimerization and/or oligomerization?One obvious consequence would be an in-crease in https://www.wendangku.net/doc/3015130227.html,pared with monomeric recombinant CFHR5(lacking the dimerization motif),dimeric recombinant CFHR5displayed increased binding to GBM-bound mouse C3in vivo in the Cfh-de ?cient mouse model of C3glomerulopathy [10].Monomeric proteins also interacted less effectively than dimeric proteins with human C3b in vitro [5,10].The signi ?-cance of this increased avidity became clearer when it was pro-posed that following binding to C3b,unlike CFH,CFHR1,-2and -5do not inhibit C3b ampli ?cation but actually allow it to proceed [5,10].This led to the hypothesis that CFHR proteins,by competing with CFH for surface C3b,could in ?uence the degree to which C3b ampli ?cation is inhibited (predominant CFH binding)or allowed to proceed (predominant CFHR binding).The latter process was termed CFH de-regulation since these CFHR proteins were devoid of any intrinsic comple-ment regulatory
activity.
F I
G U R E 3:Schematic representation of potential homodimers and heterodimers within the CFHR1,CFHR2and CFHR5protein family.The
dimerization motif is located within N-terminal SCR domains 1and 2of CFHR1,-2and -5(depicted in blue)enabling head-to-tail dimer for-mation.Potential homo-and heterodimers are shown.The combined deletion of the CFHR1and CFHR3genes (ΔCFHR3/1)would,in homozy-gosity,result in a complete loss of CHFR1-containing species.In this setting,the potential species comprise:CFHR2and CFHR5homodimers and a CFHR2–CFHR5heterodimer (inset).
Table 2.Predicted homodimers and heterodimers associated with abnormal CFHR proteins in patients with C3glomerulopathy Modi ?ed CFHR protein
Abnormal homodimers
Abnormal heterodimers CFHR1,CFHR3present
Homozygous ΔCFHR3/1CFHR112341–5
(CFHR112341–5)×2
(CFHR112341–5)–CFHR1(CFHR112341–5)–CFHR2(CFHR112341–5)–CFHR5CFHR112341–5)–CFHR2(CFHR112341–5)–CFHR5CFHR5121–9(CFHR5121–9)×2
(CFHR5121–9)–CFHR1(CFHR5121–9)–CFHR2(CFHR5121–9)–CFHR5(CFHR5121–9)–CFHR2(CFHR5121–9)–CFHR5CFHR212–CFHR5(CFHR212–CFHR5)×2
(CFHR212–CFHR5)–CFHR1(CFHR212–CFHR5)–CFHR2(CFHR212–CFHR5)–CFHR5(CFHR212–CFHR5)–CFHR2(CFHR212–CFHR5)–CFHR5CFHR312–CFHR1(CFHR312–CFHR1)×2
(CFHR312–CFHR1)–CFHR1(CFHR312–CFHR1)–CFHR2(CFHR312–CFHR1)–CFHR5
(CFHR312–CFHR1)–CFHR2(CFHR312–CFHR1)–CFHR5
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CFH de-regulation has been shown in vitro .Normal CFHR proteins (CFHR1,-2and -5)can compete with CFH for binding to shared surface ligands in vitro using heterolo-gous erythrocytes (guinea-pig erythrocytes)as a complement-activating surface [5,10].By increasing the CFHR protein concentration,the interaction between CFH and surface ligands can be inhibited,resulting in lysis of the guinea pig er-ythrocytes.Notably,monomeric forms of these CFHR pro-teins were less ef ?cient at CFH de-regulation than dimeric forms,presumably due to differences in avidity [5,10].Abnor-mal CFHR proteins are even more ef ?cient de-regulators of CFH in this assay.Serum fractions,containing all CFHR1,-2and -5species from individuals with C3glomerulopathy asso-ciated with either the CFHR5121–9or CFHR312–CFHR1ab-normal protein,demonstrated enhanced red cell lysis (consistent with greater CFH de-regulation)[10].Similarly,a CFHR1-containing protein preparation from a family member with the CFHR112341–5protein (and accompanying homozy-gous ΔCFHR3/1)also mediated enhanced lysis of guinea-pig erythrocytes [5].This patient preparation was then enriched for large multimeric complexes,which could be visualized using electron microscopy as ‘bundle-like structures ’(whereas puri ?ed normal CFHR1and CFH could not be seen).However,antagonism of CFH by normal or abnormal CFHR proteins has not been demonstrated in vivo or on GBM pre-parations.In addition,the physiological relevance of CFH de-regulation by normal CFHR proteins remains unknown.An important and interesting observation indicating that our knowledge in this area remains incomplete is that the hybrid CFHR212–CFHR5protein [7],unlike the structurally very similar CFHR5121–9,protein [2],was associated with severe plasma C3depletion.Recombinant CFHR212–CFHR5protein enhanced the formation of the AP C3convertase in the absence of CFH and inhibited its dissociation in the presence of CFH.This activity is similar to C3nephritic factor and may be the reason that the phenotype was associated with very low plasma C3levels.
TOWA R D S A D I S E A S E M E C H A N I S M
A number of processes by which C3fragments accumulate along the GBM in C3glomerulopathy can now be proposed (Figure 4).Under physiological conditions,C3b ampli ?cation is limited by the actions of CFH.It has been dif ?cult to establish whether CFH prevents C3accumulation along the GBM pri-marily by regulating the AP in the circulation,or by ?rst attach-ing to the GBM in order to mediate its protective effects.Most likely,CFH performs both these actions in response to the various exogenous triggers of C3activation encountered by the innate immune system (e.g.infection).In patients with abnor-mal CFH,the physiological mechanism of ‘C3tickover ’,whereby spontaneous C3activation occurs via the AP in the cir-culation,proceeds without inhibition.This results in severe sec-ondary consumption of plasma C3and the AP activation protein,factor B,even in the absence of any exogenous trigger of C3activation.Experimentally,accumulation of C3fragments along the GBM has been demonstrated only in the setting of
uncontrolled C3activation due to complete CFH de ?ciency.In-dividuals with complete CFH de ?ciency and C3glomerulopa-thy typically have very low plasma C3levels in addition to abnormal glomerular C3accumulation.In contrast,patients with C3glomerulopathy associated with abnormal CFHR pro-teins but intact CFH often [2,6],but not invariably [7],have normal or only moderately reduced plasma C3levels.One ex-planation for the association between familial C3glomerulopa-thy and abnormal CFHR proteins is that these interfere with the CFH regulation of C3activation predominantly along the GBM.This would result in abnormal glomerular C3deposition with less marked or no effect on plasma C3regulation.Hence the CFHR212–CFHR5[7]protein may interfere with CFH regu-lation of C3both along the GBM (resulting in C3glomerulopa-thy)and in the circulation (resulting in plasma C3depletion).
T H E C U R R E N T H I S TO PAT H O LO G I CA L D E F I N I T I O N O F C 3G LO M E R U LO PAT H Y Hou et al.conducted a review of 319biopsies showing MPGN,in which different cut-off levels for glomerular immunoglobu-lin (Ig)deposition were evaluated as part of immuno ?uores-cence criteria for diagnosis of C3glomerulopathy [14].The results (published simultaneously with the consensus report)showed that strict de ?nition of C3glomerulopathy based on ‘C3only ’(i.e.total absence of glomerular Ig)was impractical,since it excluded half of the 42DDD cases identi ?ed on EM.Instead,a more inclusive criterion of predominant glomerular C3intensity of ≥2levels of magnitude greater than any com-bination of IgG,IgM,IgA and C1q increased the sensitivity for DDD to 88%.Applying this criterion to 200cases previously diagnosed as MPGN Type 1,and 77cases of MPGN Type 3,in which secondary causes including hepatitis C infection,cryoglobulinaemia and paraproteinaemia had been excluded,31%and 39%,respectively,could be classi ?ed as C3glomeru-lopathy.The authors concluded that this approach identi ?ed those patients who were most likely to bene ?t from evaluation of the AP.It is now recommended that in practice ‘glomerulo-nephritis with dominant C3’should be used as a morphologic-al term for those cases with dominant staining for C3c.Dominant is de ?ned as C3c intensity two orders of magnitude more than any other immune reactant on a scale of 0–3(com-prising 0,trace,1,2and 3).This approach will identify the ma-jority of cases of C3glomerulopathy and trgger (depending on the clinical scenario)investigations to identify known comple-ment abnormalities [1].
R E C E N T R E T RO S P E C T I V E CO H O R T S T U D I E S As C3glomerulopathy is extremely rare,patient cohort studies provide valuable information regarding clinical and patho-logical features and their correlation with disease outcomes [15].Medjeral-Thomas et al.conducted a retrospective cohort study in 80adults and children in the UK and Ireland with C3glomerulopathy [16].Based on a strict de ?nition of C3glo-merulopathy (in which cases were excluded if any amount of
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glomerular IgG/IgA or more than weak IgM was on immunostaining),they estimated an annual incidence one to two cases per million population.Electron was performed in all cases,enabling a number of clinicopathologic distinctions to be drawn between DDD patients)and C3GN (59patients).Age at diagnosis was signi cantly lower for DDD (median age 12versus 26for C3GN),low serum C3levels at diagnosis signi ?cantly more (79%versus 48%in C3GN among the 69patients MPGN was the most common lesion on light microscopy both groups (55%of all biopsies).Presence of >50%was more common in DDD (19%of biopsies versus 5%C3GN),whereas vascular disease and chronic changes glomerulosclerosis and interstitial ?brosis were more C3GN.At a median follow-up of 28months,29%of patients developed ESKD,with no difference in renal survival DDD and C3GN.However using multivariate analysis,emerged as a strong and independent predictor of ESKD,with age ≥16years at diagnosis and crescentic GN.Histo-recurrence following renal transplantation in all six DDD was associated with graft failure in three cases,while of seven C3GN recipients had histological recurrence,with failure in three cases.Zand et al.reported a US retrospective of 21adult and paediatric patients transplanted for ESKD to C3GN,of whom two-thirds had histological recurrence,half of these developing subsequent graft failure [17].Re-and graft failure rates have been similar in earlier cohort studies,although it is unclear whether
graft
F I
G U R E 4:Schematic representation of pathogenesis of C3glomerulopathy.Triggers of C3activation (depicted at the centre)may be exogen-
ous (e.g.infection)or endogenous (C3tickover).C3activation generates C3b molecules for attachment to surfaces including the GBM.In health (upper panel),C3b ampli ?cation is tightly controlled by factor H (CFH)in the circulation.Thus minimal C3b becomes available for attachment to surfaces,where ampli ?cation is further regulated by CFH on the GBM.In theory,any surface-attached C3b is then metabolised,leaving C3fragments (iC3b,C3d)attached to the GBM,and releasing CFH back into the circulation.In practice,neither C3nor CFH are detected along the GBM in normal glomeruli.In the setting of abnormal CFH (bottom left panel),uncontrolled C3activation leads to excessive C3fragments (iC3b,C3d)in the circulation,which later accumulate along the GBM.Some C3b ampli ?cation/metabolism may also occur on the GBM.Enhanced CFH de-regulation due to abnormal CFHR proteins (bottom right panel)has been proposed as one mechanism by which C3
accumulates along the GBM despite intact https://www.wendangku.net/doc/3015130227.html,petitive inhibition of CFH by abnormal CFHR proteins along the GBM would facilitate C3b surface ampli ?cation/metabolism.Increased C3b ampli ?cation in plasma due to an abnormal CFHR protein that stabilizes the C3convertase has also been demonstrated (see the text).
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survival is reduced in recipients with C3glomerulopathy com-pared with other types of glomerulonephritis.Nevertheless,development of effective therapies for use in native C3glomeru-lopathy may ultimately also be bene ?cial in the transplant setting.
R E C E N T T R E AT M E N T S T U D I E S
As no treatment is proven to be bene ?cial for C3glomerulopa-thy,research interest in therapeutic agents that modulate the complement pathways is high.Eculizumab is a humanized anti-complement C5monoclonal antibody approved for use in patients with paroxysmal nocturnal haemoglobinuria and aHUS.Off-label use of eculizumab for treatment of C3glo-merulopathy was initially reported in three cases of DDD [18,19](one with transplant recurrence [21])and an addition-al case of MPGN Type 1[20].In 2012,a prospective trial was reported by Bomback et al.in six patients with native or post-transplant recurrent DDD or C3GN [22].Since the trial,at least seven additional case reports of eculizumab use in C3glo-merulopathy have been published,most involving patients with persistent disease despite immunosuppressive therapy (Table 3).In the trial,eculizumab therapy was associated with a signi ?cant fall in serum creatinine or proteinuria in only 3out of 6patients,whereas 9out of the total 11case reports showed clinical improvement,raising the possibility of publi-cation bias.Nevertheless,further prospective evaluation of eculizumab in C3glomerulopathy appears warranted,with ju-dicious patient selection based on available prognostic data from retrospective cohort studies and the https://www.wendangku.net/doc/3015130227.html,rmation obtained from renal biopsy both before and after treatment,for example the degree of active in ?ammation,may ultimately also guide eculizumab use,although evidence for this approach from the existing studies is limited [19,23,29,30].It has not been established whether disease progression occurs in some cases despite therapeutic blockade of C5activation,as a result of ongoing upstream activation of C3.This concept was
highlighted by the family study involving CFHR212–CFHR5,in which eculizumab was associated in vitro with effective blockade of C5activation but not C3activation in patient serum [7].A Phase 1clinical trial in children and adults with DDD (NCT01791686)is currently evaluating recombinant soluble complement receptor 1(CR1),which was previously shown to restore plasma C3levels and reduce glomerular C3in Cfh ?/?mice [31],and inhibited C3activation in vitro in the CFHR212–CFHR5family study [7].Elsewhere rituximab has been reported with success in individual cases of C3glomerulo-pathy [17,32](as distinct from rituximab use in treatment of disease-associated paraproteinaemia).However treatment failure following sporadic use of rituximab,often in conjunction with immunosuppressive treatment (including in the renal transplant setting),has also been widely reported [17,18,21,23,26,28,29].CO N C L U S I O N
Enhanced CFH de-regulation has been proposed as a distinct pathophysiological mechanism in several families in which C3glomerulopathy segregates with mutations leading to abnor-mal CFHR proteins.These abnormal proteins display in-creased avidity for C3b and an enhanced ability to antagonize CFH in vitro.Hence,in patients with C3glomerulopathy,ab-normal CFHR proteins seem likely to prevent CFH-mediated inhibition of C3b ampli ?cation along the GBM.In patients with CFH de ?ciency/dysfunction,excessive production of C3fragments in the circulation,which then accumulate within the kidney,provides an additional disease mechanism for C3glomerulopathy.We now have an improved means of identify-ing patients with C3glomerulopathy through the introduction of a renal biopsy classi ?cation:glomerulonephritis with dom-inant C3.As C5inhibition is not effective in at least some pa-tients,we need to look for new approaches,the most obvious being to inhibit C3activation.How this is achieved will depend on how and where the defect in C3regulation has
Table 3.Published reports of eculizumab use in C3glomerulopathy and MPGN Report (year)
Study design
Reported diagnosis (age at treatment/sex)
C3NeF Treatment duration (months)Clinical response Daina et al .(2012)[18]Case report DDD (22F)+11Yes Vivarelli et al .(2012)[19]
Case report DDD (17M)
+18+9Yes Radhakrishnan et al .(2012)[20]Case report MPGN Type 1(16F)
+ 1.5Yes McCaughan et al .(2012)[21]Case report
Allograft recurrent DDD (29F)+ 2.5Yes Bomback et al .(2012)[22]
Prospective,open-label,uncontrolled trial
DDD (22M)?12Yes 50%82%DDD (42M)
+9No
Allograft recurrent DDD (32M)?12Yes C3GN (25M)
?12No Allograft recurrent C3GN (22M)+12No Allograft recurrent C3GN (20M)+12Yes Gurkan et al .(2013)[23]Case report Allograft recurrent C3GN (21M)+12Yes Besbas et al .(2013)[24]Case report C3glomerulopathy (16F)?10No Kerns et al .(2013)[25]
Case report C3glomerulopathy (16M)? 3.5Yes Rousset-Rouvière et al .(2014)[26]Case report DDD (10M)+ 6.5Yes Ozkaya (2014)et al .[27]
Case report DDD (14F)+7Yes Berthe-Aucejo et al .(2014)[28]Case report DDD (17M)
+ 3.5No Sánchez-Moreno et al .(2014)[29]Case report
Allograft recurrent DDD (14F)
+
30
Yes
F U L L R E V I E W
8T.D.Barbour et al.
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arisen.In addition,we need continued clinicopathological phenotyping,a prerequisite to the design of informative clinic-al trials.There are many ongoing innovative approaches to these challenges so the future for patients with C3glomerulo-pathy is bright.
AC K N OW L E D G E M E N T S
T.D.B.is a Kidney Research UK(KRUK)Clinical Research Fellow(TF/2011).M.C.P.is a Wellcome Trust Senior Fellow in Clinical Science(WT098476MA)and M.M.R.is funded by this fellowship.
CO N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declare that the results presented in this paper have not been published previously in whole or part.
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