C3 Glomerulopathy: The Genetic and ClinicalFindings in Dense Deposit Disease and C3GlomerulonephritisXue Xiao, BS, BA1,2 Matthew C. Pickering, MS, BS, PhD3 Richard J. H. Smith, MD1,2

1 Interdisciplinary PhD Program in Genetics, Carver College ofMedicine, University of Iowa, Iowa City, Iowa

2Molecular Otolaryngology and Renal Research Laboratories, CarverCollege of Medicine, University of Iowa, Iowa City, Iowa

3Centre for Complement and Inflammation Research, ImperialCollege, London, United Kingdom

Semin Thromb Hemost 2014;40:465–471.

Address for correspondence Richard J. H. Smith, MD, MolecularOtolaryngology and Renal Research Laboratories, Carver College ofMedicine, 21151 PFP, University of Iowa, 200 Hawkins Drive, Iowa City,IA 52242 (e-mail: richard-smith@uiowa.edu).

C3 glomerulopathy (C3G) describes a group of renal diseasescharacterized by complement C3 accumulation in renal glo-meruli. Traditionally, this was in the setting of the absence ornear absence of immunoglobulins. However, this criterionwas over-stringent and recently it has been suggested thatC3G is more appropriately identified by selecting glomerularchanges in which there is “C3 dominant” staining. C3 domi-nant is defined as C3 intensity at least two orders of magni-tude greater than anyother immune reactant.1 The twomajorsubgroups of C3G—dense deposit disease (DDD) and C3glomerulonephritis (C3GN)—are resolved by electronmicros-copy (EM). DDD is defined by the EM findings of intramem-branous glomerular basement membrane dense deposits,and C3GN encompasses the remainder of the C3Glesions and is defined by some combination of mesangial,

subepithelial, subendothelial, and/or less dense, discontinu-ous intramembranous deposits.2

Clinically, C3G presents with proteinuria, hematuria, andoften some degree of renal failure,3–6 although in DDD, acquiredpartial lipodystrophy and ocular drusen may be seen in addi-tion.3 The annual incidence of biopsy-provendisease is 1 to 2 permillion,4 with both sexes affected equally.4,7 Median age at C3Gdiagnosis as reported by Medjeral-Thomas et al is 21 years,4

although DDD typically presents earlier (mean age at diagnosis,14 years5; however, one-fifth of DDD patients are older than 60years7). Ten-year progression to end stage renal failure (ESRF) is�30–50%,4 although among DDD patients it appears higher(progression to ESRF in DDD, 36–50%4,5,7,8 vs. �25% inC3GN4). Recurrence of disease and allograft loss after transplan-tation is common (50–75%4,5,8).

Keywords

► C3 glomerulopathy► dense deposit disease► C3

glomerulonephritis

Abstract C3 glomerulopathy (C3G) defines a group of very rare renal diseases in whichdysregulation of the alternative and terminal complement pathways plays a pivotalpathogenic role. Dysregulation is driven by genetic and/or acquired defects, withinterindividual variability giving rise to two broad subtypes of C3G—dense depositdisease (DDD) and C3 glomerulonephritis (C3GN). Patient evaluation should includegenetic testing and biomarker profiling of complement activity. There is currently noeffective targeted treatment option for C3G and, as a consequence, a variety ofsupportive measures are used. C3G remains an ideal disease in which new complementtherapies can be tested as they become available. Trials must include a comprehensiveevaluation of each patient at the genetic and biomarker level so that individualresponses to therapy can be predicted and understood in light of the degree ofcomplement dysregulation and underlying pathology.

published onlineMay 5, 2014

Issue Theme An Update on theThrombotic MicroangiopathiesHemolytic Uremic Syndrome (HUS) andThrombotic Thrombocytopenic Purpura(TTP); Guest Editors, Magdalena Riedl,MD, Dorothea Orth-Höller, MD, andReinhard Würzner, MD, PhD.

Copyright © 2014 by Thieme MedicalPublishers, Inc., 333 Seventh Avenue,New York, NY 10001, USA.Tel: +1(212) 584-4662.

DOI http://dx.doi.org/10.1055/s-0034-1376334.ISSN 0094-6176.

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C3G is caused by genetic or acquired dysregulation of thealternative pathway (AP) of complement. Examples of theformer include the report by Gale et al9,10 of a genomicrearrangement in Cypriots in which exons 2 and 3 of thecomplement factor H-related 5 gene (CFHR5) are repeatedresulting in a longer translated protein (SCRs 1 and 2 areduplicated) (►Fig. 1). The phenotypic consequence is a vari-ably penetrant dominant disease. Eighty-two of 91 patients(90%) carrying the novel CFHR5 gene presented with micro-scopic hematuria, and of these patients, 31 of 82 (38%) also hadproteinuria. Twenty-eight proteinuric patients (90%) devel-oped chronic renal failure (CRF). Time with disease was asignificant contributor to ESRF—80% ofmen (16 of 20) and 21%of women (5 of 23) older than 50 years progressed to ESRF,with the reason for the male preponderance remaining un-clear. The biopsy in all cases was consistent with C3GN.

In a second noteworthy report, Martínez-Barricarte andcolleagues described a woman and her identical twin sonswho segregated a two amino-acid deletion in C3 (C3923ΔDG)that results in a DDD phenotype.11 The mutant proteinwas the predominant C3 plasma protein. It circulatedas non-activated C3 and C3Δ923DG convertase that wasresistant to regulation by complement factor H. The netconsequence was uncontrolled mutant fluid-phase C3 con-vertase (C3Δ923DG convertase) activity. However, the accel-erated decay of the C3Δ923DG convertase by decayaccelerating factor (DAF, CD55), and membrane cofactorprotein (MCP, CD46) cofactor activity for complementfactor I (CFI) were unaffected. As a result, cell-surfacecontrol of the AP was not impaired. The mother and oneson were dialysis dependent.

Studies using laser capture and mass spectrometry of theglomeruli in sporadic cases of DDD12 and C3GN13 are consis-tent with the insights the above families have provided to ourunderstanding of the disease process driving C3G. In bothdiseases, C3b, inactive C3b, and other alternative and termi-nal complement pathway proteins are found in glomerulifurther linking complement dysregulation to C3G. Sinceunderstanding complement biology is a prerequisite forunderstanding C3G pathophysiology, we will briefly over-view complement biology.

The Complement Cascade

The complement system is the cornerstone of innate immu-nity. It serves as the first line of defense against invadingmicroorganisms, which can be lysed through the generationof membrane attack complex (MAC) or opsonized by C3b andC4b and marked for phagocytosis. C3b and C4b also play animportant role in solubilizing and removing immune com-plexes from the circulation. Three components of comple-ment—C3a, C4a, and C5a—are inflammatory activators andinduce vascular permeability and the recruitment and acti-vation of phagocytes.

Complement activity in the initiation phase is triggeredthrough three pathways—the classic (CP), lectin (LP), andalternative (AP) (►Fig. 2). While the CP is activated byimmune complexes containing IgG or IgM as well as somemicroorganisms14 and the LP is activated by binding tocarbohydrates on the surface of a wide range of pathogens14

(viruses, bacteria, fungi, protozoa), the AP is constitutivelyactive through a process known as “tick-over.”15 “Tick-over”

Fig. 1 CFHR fusion genes that arise following nonallelic homologous recombination events that are common throughout the CFHR genomicregion and reflect the multiple areas of genomic duplication and consequent high sequence homology. Of the novel genes shown, the first threelead to a C3GN phenotype, while the last one leads to a DDD phenotype. Whether this difference in outcome reflects the inclusion of CFHR2 SCRsin the last novel gene is not known. (Each circle represents a short consensus repeat: maroon, CFHR3; blue, CFHR1; green, CFHR5; purple, CFHR2.)

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occurs because C3 has a reactive thiol ester which spontane-ously hydrolyzes to C3(H2O). The hydrolyzed C3(H2O) is ableto interact with factor B that is then cleaved by factor D togenerate a C3 convertase: C3(H2O)Bb. This enables directcleavage of C3 to C3b, which, unless regulated, can rapidlyamplify through a positive feedback loop. Binding of C3b to C3convertase produces C5 convertase (C3bBbC3b), which thentriggers the terminal complement pathway resulting in theformation of the terminal complement complex and theanaphylatoxin, C5a.

Close regulation of the complement cascade is important tohomeostasis and health, and is provided in the fluid-phase byproteins like complement factorH (CFH) andon cell surfaces byDAFandMCP.16An imbalance in activity versus control leads todisease. For example, the Cypriot CFHR5 nephropathy de-scribed earlier9,10 is the result of loss of complement regula-tory function in the glomerular microenvironment as opposed

to more global systemic activation of complement in the fluidphase since C3 serum levels are normal in these patients. TheC3923ΔDG mutation,11 in contrast, results in enhanced activityand uncontrolled fluid-phase activity of the mutant C3 con-vertase. In both cases, however, the consequence of comple-ment dysregulation is C3G.

Genetic and Acquired Factors in DDD andC3GN

Familial cases of DDD and C3GN have provided importantinsight into disease pathogenesis. In addition to the reportsbyGale et al9,10 andMartínez-Barricarte et al,11 familial C3GNhas been reported in association with a hybrid CFHR3–1protein,17 an internal duplication of CFHR1,18 and an internalduplication in CFHR5 in a family without Cypriot ancestry.19

DDD has recently been linked to a fusion protein consisting of

Fig. 2 The complement cascade. In the classical pathway, C1q in the immune complex activates proteases C1r and C1s. C1s cleaves C4 and C2 toform the C3 convertase of the classical pathway, C4b2a. In the lectin pathway, activated MBL-MAPS or ficolin-MAPS cleave C4 and C2 to formC4b2a. The alternative pathway is constitutively activated by tick-over, in which C3 is hydrolyzed to C3(H2O) (or C3i), which forms a C3(H2O)Bcomplex that cleaves more C3 to generate C3b and the C3 convertase of the AP, C3bBb, setting up an amplification loop. C3b also associates withC3bBb to produce the C5 convertase, C3bBbC3b. C5 convertase cleaves C5 into C5a and C5b, leading to the formation of membrane attackcomplex. (Biomarkers that have been studied in DDD and C3GN are denoted with an asterisk.)

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CFHR2 SCRs 1 and 2 coupled to CFHR5.20 These changes areshown schematically in ►Fig. 1.

The impact of these rearrangements is clearer, at least on astructural basis, now that it has been shown that CFHR1, 2, or5 interact with each other.21,22 The first two SCR domains ofthese three proteins are almost identical and form a tighthead-tail dimer.21 This association enables homodimers (R1-R1, R2-R2, R5-R5) and heterodimers (R1-R2, R1-R5, R2-R5) toform. As CFHR1 is the most abundant protein, the predomi-nant species are likely to be those that contain CFHR1 (R1-R1,R1-R5, R1-R2). Furthermore, in plasma these proteins formlarger oligomeric complexes.18 Although the structural basisof dimerization has been resolved using X-ray crystallogra-phy, the structural basis of the oligomeric species is notdefined. These findings suggest that the abnormal CFHRproteins associated with C3G may promote formation ofunusual dimers and/or multimers that impact control ofthe C3 and/or C5 convertases in the fluid phase or in themicroenvironment of the glomerulus (►Fig. 3).

Familial cases justify genetic testing in sporadic cases. Todate, 20 different mutations have been identified in 12 differ-ent genes, with the CFH-CFHR gene family and C3 implicated in50% and 15% of cases, respectively (►Table 1).6,8,11,17,18,23–30

What is more noteworthy, however, is the very strong associ-ation of C3G with specific alleles of several genes that definedisease haplotypes or complotypes. For example, in DDD theC3 at-risk haplotype is GGTA25 (haplotype 2, defined by p.R102GC > G [rs2230199], p.R304A > G [rs2230201], p.P314LC > T [rs1047286], and p.P518 C > A [rs1047286]) and the

CFH low-risk or protective haplotype is CATA25 (haplotype 2,defined by -331 T > C [rs3753394], p.V62I G > A [rs800292],p.Y402H T > C [rs1061170], and p.Q673 A > G [rs3753396]).In C3GN, the haplotype MCPaaggt (� 652 A > G [rs2796267],� 366 A > G [rs2796268], IVS9–78 G > A [rs1962149], IVS12þ 638 G > A [rs859705], c.4070 T > C [rs7144]) defines theat-risk allele (►Fig. 4).8

Most DDD patients (80–85%) and many C3GN patients(�50%)8 also develop autoantibodies to C3 convertase calledC3 nephritic factors (C3Nefs), which protect the convertaseagainst CFH-mediated decay, prolonging its half-life andleading to fluid-phase dysregulation of the AP. Autoanti-bodies against other proteins such as CFB31,32 and CFH33

are occasionally detected as well. Whether or how the C3Gcomplotypes shown in ►Fig. 4 contribute to or facilitate thedevelopment of autoantibodies is not known.

Understanding the Differences betweenDDD and C3GN

Although DDD and C3GN are both subtypes of C3G, they aredifferentiated histologically by their EM differences andclinically by the generally more aggressive course of DDD.Although there are no clear boundaries distinguishing thesetwo diseases, considerable research is being done to under-stand the pathophysiological reasons for the observed differ-ences. Using serological biomarkers of complementactivity,3,34 recent research has shown that in these twodiseases both the AP and terminal complement pathway

Fig. 3 CFHR1, 2, and 5 multimerize. CFHR1, CFHR2, and CFHR5 form homo- or heterodimers (all of which normally include CFHR1 if it is available)by interacting through their two similar N-terminal SCRs. The presence of novel fusion proteins alters the formation of these multimers and alterscontrol of the C3 and/or C5 convertases.18 (A–C) Homodimers formed by CFHR1, 2, and 5. (D–F) Heterodimers CFHR1–2, CFHR1–5, and CFHR2–5.Goicoechea de Jorge et al21 and Tortajada et al18 detected all three homodimers as well as CFHR1–2 and CFHR1–5 heterodimers in vivo. The CFHR2–5heterodimer has not been detected. (G-J) Tetramers formed by CFHR1 in G; CFHR1 and CFHR2 in H and I; and CFHR1 and CFHR5 in J that are described byTortajada et al.18 (SCRs are represented by red ovals.)

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are overactive as comparedwith controls (►Fig. 2). In general,biomarker profiling also shows that dysregulation of the AP isgreater in DDD than in C3GN, while for the terminal comple-ment pathway, the reverse is true. However, our currentcomposite understanding of C3G based on genetic studiesand biomarker profiling is incomplete. We do not know howthe unique microenvironment of the glomerulus contributesto disease outcome andneither doweknow the role played bythe kidney itself in either contributing to or protecting againstdisease.

Treatment

There is currently no broadly effective targeted treatmentoption for C3G and, as a consequence, a variety of supportivemeasures have been used. In a French cohort, treatment withangiotensin-converting enzyme inhibitors (ACEIs) or angio-tensin receptor blockers (ARBs) has shown to improve renalsurvival (p < 0.0001).8 Although plasma exchange shouldtheoretically be useful as it can remove autoantibodies and

mutated proteins, it has met with only limited success. In anearly report of a 15-year-old girl with C3Nefs, plasma ex-change was used to remove these autoantibodies from thecirculationwhen DDD recurred in her allograft. Unfortunate-ly, treatment was eventually discontinued as continual thriceweekly plasma exchange was required to keep C3Nefs levelsdown and that was not sustainable.35 In contrast, plasmaexchange has been used successfully to treat patients withmutations in CFH.36While anti-cellular immune suppressiontargeting T and/or B cells also should be beneficial by limitingthe effects of anaphylatoxins (C3a and C5a), inhibiting im-mune cell reaction and inflammation, and reducing antibodyproduction, several case reports suggest otherwise.37,38 Theuse of immune suppression in a French cohort also did notchange renal survival.8 In aggregate, these data support theuse of ACEIs and ARBs and the careful consideration ofplasma exchange in select patients with specific geneticcauses of C3G.

With the availability of eculizumab as an anticomplementtherapy for paroxysmal nocturnal hemoglobinuria and

Table 1 Gene variants reported to be associated with C3G

Genea HGMD aminoacid changeb

HGVS nucleotide HGVS protein Phenotypec References

ADAM19 Gly508Ser c.1522G > A p.G508S DDD Abrera-Abeleda et al25 (2011)

C3AR1 Leu84Phe c.250C > T p.L84F DDD Abrera-Abeleda et al25 (2011)

C3 Lys155Gln c.463A > C p.K155Q DDD Westra et al (2011)26

Lys1203Arg c.3608A > G p.K1203R DDD Abrera-Abeleda et al25 (2011)

c.2768_2773delACGGTG DDD Martínez-Barricarte et al11 (2010)

C8A Ala221Glu c.662C > A p.A221E DDD Westra et al26 (2011)

CFD Ala41Pro c.121G > C p.A41P DDD Westra et al26 (2011)

CFH Val143Ile c.427G > A p.V143I DDD Servais et al8 (2012)

Arg232Term c.694C > T p.R232 DDD Servais et al8 (2012)

Cys673Arg c.2017T > C p.C673R DDD Servais et al8 (2012)

Val837Ile c.2509G > A p.V837I DDD Zhang et al27 (2012)

Glu1145Asp c.3435G > C p.E1145D DDD Zhang et al27 (2012)

c.2171delC C3GN Sethi et al6 (2012)

CFHR3 incl. ex. 1–3 C3G Malik et al17 (2013)

CFHR1 ex. 2–5 C3G Tortajada et al18 (2013)

CFHR5 c.646_647delAAinsTT C3GN Sethi et al6 (2012)

ex. 2–3 C3GN Goicoechea de Jorge et al21 (2013)

CFI Gly261Asp c.782G > A p.G261D C3GN Servais et al29 (2007)

CR1 Val1222Leu c.3664G > T p.V1222L DDD Abrera-Abeleda et al25 (2011)

MCP Val215Met c.643G > A p.V215M C3GN Servais et al8 (2012)

aADAM19 (ADAM metallopeptidase domain 19 (meltrin-β) NM_033274.3); C3AR1 (complement component 3a receptor 1, NM_004054.2); C3(complement component 3 NM_000064.2); C8A (complement component 8, α-polypeptide NM_000562.2); CFD (complement factor D (adipsin),NM_001928.2); CFH (complement factor H (HF1), NM_000186.3); CFHR3 (complement factor H-related 3, NM_021023.5); CFHR1 (complementfactor H-related 1, NM_002113.2); CFHR5 (complement factor H-related 5, NM_030787.3); CFI (complement component I, NM_000204.3); CR1(complement component receptor 1 NM_000651.4); MCP (also known as CD46, membrane cofactor protein NM_002389.4). HGMD, Human GeneMutation Database.

bHGMD30 professional 2013 [accessed on December 9, 2013]; HGVS, nomenclature created by the Human Genome Variation Society to unequivocallydescribe sequence variants.

cC3G, C3 glomerulopathy; C3GN, C3 glomerulonephritis; DDD, dense deposit disease.

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atypical hemolytic uremic syndrome,39 attention has natu-rally focused on C3G. Eculizumab is a humanized monoclonalantibody against C5which prevents activation of the terminalcomplement pathway and formation of MAC. It has met withmixed results in its use in C3G. In the largest single study todate—an open-label, proof-of-concept, efficacy-and-safetystudy of three patients with DDD and three patients withC3GN40,41—improvements in either serum creatinine or his-tology were observed in four patients. In the remaining twopatients, renal function declined during treatment. Based onthe pathophysiology of C3G, this type of mixed responsewould be expected. In patients with significant complementdysregulation at the level of the C3 convertase, which isupstream of the point of action of eculizumab, althougheculizumab therapy might conceivably slow down diseaseprogression (by preventing C5a generation and/or MAC), itwould not be curative.

C3G will be an ideal disease in which new complementtherapies can be tested as they become available. However,because C3G is complicated, a comprehensive evaluation ofeach patient at the genetic and biomarker level must becompleted so that individual responses to therapy can bepredicted and understood in light of the degree of comple-ment dysregulation and underlying pathology.

Concluding Remarks

C3G describes a group of very rare renal diseases in whichdysregulation of the AP and terminal complement pathwayplays a pivotal pathogenic role. Dysregulation is driven by

genetic and/or acquired defects with a great deal of interin-dividual variability. Althoughwe nowunderstand a great dealof the overall disease process, more comprehensive geneticand biomarker studies are needed to refine our knowledgebase. These studies will allow us to offer patients well-planned and well-designed clinical studies as new anti-complement agents are developed.

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Fig. 4 Haplotypes associated with DDD and C3GN. Specific haplotypes of C3 and FH are associated with DDD. The DDD C3 risk haplotype is GGTAand is defined by p.R102G C > G (rs2230199), p.R304 A > G (rs2230201), p.P314L C > T (rs1047286), and p.P518 C > A (rs1047286). The DDDCFH protective haplotype is CATA and is defined by �331 T > C (rs3753394) in the promoter, p.V62I G > A (rs800292), p.Y402H T > C(rs1061170), and p.Q673 A > G (rs3753396). In C3GN, the MCP risk haplotype is aaggt and is defined by �652 A > G (rs2796267) and �366A > G (rs2796268) in the promoter, and IVS9–78 G > A (rs1962149), IVS12 þ 638 G > A (rs859705) in introns, and c.4070 T > C (rs7144) in the3′-UTR. HGMD, Human Gene Mutation Database30; HGVS, nomenclature created by the Human Genome Variation Society to unequivocallydescribe sequence variants.

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