C3 Glomerulopathy

Clinical characteristics.

C3 glomerulopathy (C3G) is a complex ultra-rare complement-mediated renal disease caused by uncontrolled activation of the complement alternative pathway (AP) in the fluid phase (as opposed to cell surface) that is rarely inherited in a simple mendelian fashion. C3G affects individuals of all ages, with a median age at diagnosis of 23 years. Individuals with C3G typically present with hematuria, proteinuria, hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome, and low levels of the complement component C3. Spontaneous remission of C3G is uncommon, and about half of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis, occasionally developing the late comorbidity of impaired visual acuity.

Diagnosis/testing.

The definitive diagnosis of C3G requires a renal biopsy with specialized immunofluorescence and electron microscopy studies both for diagnosis and to distinguish between the two major subtypes of C3G: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes that have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH, CFHR1, CFHR5, CFI, and DGKE).

Management.

Treatment of manifestations: Nonspecific therapies used to treat numerous chronic glomerular diseases, including angiotensin-converting enzyme inhibitors, angiotensin II type-1 receptor blockers, and lipid-lowering agents (in particular hydroxymethylglutaryl coenzyme A reductase inhibitors). Complement inhibition with a terminal pathway blocker may alter disease course in some individuals. When ESRD develops, treatment options are limited to dialysis or transplantation. C3G recurs in nearly all grafts and is the predominant cause of graft failure in 50%-90% of transplant recipients.

Prevention of primary manifestations: Plasma replacement therapy in individuals with pathogenic variants in CFH may be effective in controlling complement activation and slowing progression of ESRD.

Surveillance: Close monitoring of renal function by a nephrologist with familiarity with the C3G disease spectrum, complete biannual assessment of the complement pathway, periodic eye examinations to evaluate the fundus.

Evaluation of relatives at risk: If the family history is positive for renal disease, evaluation of apparently asymptomatic at-risk relatives can include molecular genetic testing (if the pathogenic variants in the family are known), urinalysis, and comprehensive analysis of the complement system.

Genetic counseling.

C3G is a complex genetic disorder that is rarely inherited in a simple mendelian fashion. Multiple affected persons within a single nuclear family are reported only occasionally, with both dominant and recessive inheritance being described.

Suggestive Findings

C3G should be suspected in individuals of all ages who present with one of the following:

• Hematuria
• Proteinuria
• Hematuria and proteinuria
• Acute nephritic syndrome
• Nephrotic syndrome
• Persistent hypocomplementemia (low serum levels of complement component C3)

Establishing the Diagnosis

The diagnosis of C3G is established in a proband with typical findings on renal biopsy. Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes listed in Table 1.

Note: Identification of a pathogenic variant may help to direct treatment of the individual.

Renal biopsy. The definitive diagnosis of C3G requires a renal biopsy with specialized studies (see Figure 1) both for diagnosis and to distinguish between C3 glomerulonephritis (C3GN) and dense deposit disease (DDD).

Figure 1.

Disease-specific characteristic IF, EM, and LM biopsy images in C3 glomerulopathy (C3G) A. Immunofluoresence (IF) shows bright staining for C3, which must be at least two orders of magnitude greater than any other immune reactant. Note the diffuse glomerular (more...)

• Immunofluorescence (IF). The diagnosis of C3G can only be made with IF studies of a renal biopsy.
  • The predominant staining of C3 is key in delivering a C3G diagnosis.
  • IF should be predominantly positive for C3 with C3 intensity at least two orders of magnitude greater than any other immune reactant (i.e., IgA, IgG, IgM, and C1q) (Figure 1A).
• Electron microscopy (EM) is used to distinguish between C3GN and DDD, a clinically relevant distinction (Figure 1). EM should demonstrate dense transformation of the glomerulus.
  • In C3GN there are light, hump-like and clustered deposits, which are found in the mesangium or in the subendothelial and/or subepithelial spaces.
  • In DDD, the deposits are darker, denser, segmental, discontinuous, ribbon-like, or diffuse and are most frequently located in the lamina densa of the glomerular basement membrane (GBM) (Figure 1B-C).
• Light microscopy (LM) is necessary to quantitate changes associated with chronic kidney disease and risk for progression of ESRD.
  LM most commonly demonstrates mild mesangial cell hypercellularity (45% of cases), although membranoproliferative (25%), crescentic (18%), and acute proliferative and exudative (12%) patterns are also seen (Figure 1D).

Note: Timing of the biopsy is important. If the presentation suggests post-infectious glomerulonephritis (PIGN; see Figure 2), waiting for three months is typically recommended. During that interval, the hypocomplementemia, hematuria, and proteinuria that are characteristic of both PIGN and C3G should resolve in cases of PIGN [Walker et al 2007, Nester & Smith 2016, Goodship et al 2017].

Figure 2.

Schematic representation of disease types Post-infectious glomerulonephritis (PIGN), C3 glomerulopathy (C3G), and other disease types fall under the classification "glomerular diseases with dominant C3" immunofluorescence (IF) staining, with the term (more...)

Molecular genetic testing approaches can include a multigene panel, more comprehensive genomic testing, and serial single-gene testing:

• A multigene panel that includes C3, CD46, CFB, CFH, CFHR1, CFHR5, CFI, DGKE, and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  Note: Analysis of CFH-related genes is complicated by the high degree of sequence identity between CFH and the downstream CFH-related genes (CFHR1-CFHR5). This similarity results in susceptibility to nonallelic homologous recombination (NAHR) events, large-scale deletions or duplications (copy number variants), and generation of hybrid CFH genes. Molecular assays must be specifically designed to detect the spectrum of changes that can occur in this region.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• Serial single-gene testing. Sequence analysis can be performed on a gene-by-gene basis, although this approach is generally not recommended because there are no phenotypic clues to inform the order of genes to be tested and because rare/novel variants can be present in multiple genes [Bu et al 2016]. If single-gene testing is performed, gene-targeted deletion/duplication testing over the CFHR1-CFHR5 region should also be completed in all cases.

See Figure 3.

Figure 3.

Complement factor H-related hybrid proteins and C3G Adapted from Togarsimalemath et al [2017] and references therein

Clinical Description

Age of onset. C3 glomerulopathy (C3G) affects individuals of all ages. Lu et al [2012] report a 1:1 female:male distribution and a median age at diagnosis of 23 years.

In comparing the two major subtypes, the median age at time of diagnosis in C3 glomerulonephritis (C3GN) is higher than in dense deposit disease (DDD). In childhood, DDD is more frequently diagnosed than C3GN [Nester & Smith 2016, Riedl et al 2017].

Renal disease. Individuals with C3G typically present with one of the following findings:

• Hematuria
• Proteinuria
• Hematuria and proteinuria
• Acute nephritic syndrome
• Nephrotic syndrome

Hypocomplementemia. Individuals with C3G have low levels of complement component C3. Complement dysregulation can be mediated by autoantibodies (see Pathophysiology).

Autoantibodies that may be detected in individuals with C3G:

• Serum C3 nephritic factor (C3NeFs). C3NeFs are present in up to ~50% of individuals with C3GN and ~80% of individuals with DDD [Salvadori & Bertoni 2016].
• Factor H autoantibodies (FHAAs). Blanc et al [2015] reported the prevalence of FHAAs in C3G individuals to be 11%.
• Factor B autoantibodies (FBAAs). FBAAs have been linked to C3G; their role in disease remains unclear [Pickering et al 2013].

Course and progression

• Spontaneous remission of C3G is uncommon [Habib et al 1975, Cameron et al 1983, Marks & Rees 2000, Thomas et al 2014]. While the disease can remain stable for years despite persistent proteinuria, in some individuals rapid fluctuations in proteinuria occur, with episodes of acute renal deterioration in the absence of obvious triggering events. Efforts to move individuals to remission have not been successful [Daina et al 2012, McCaughan et al 2012]. Current data suggest that C3G remains a chronic disease subject to acute exacerbations, with constant activation of the complement alternative pathway (AP) [Goodship et al 2017].
• About half of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis [Lu et al 2007, Servais et al 2012, Nester & Smith 2016, Goodship et al 2017], occasionally developing the late comorbidity of impaired visual acuity [Recalde et al 2016].
  • Progression to ESRD can be rapid [Smith et al 2007, Nester & Smith 2013b, Servais et al 2013].
  • Age and sex of an individual are not significant predictors of disease course.
  • Native kidney survival is comparable in C3GN and DDD [Servais et al 2013, Nester & Smith 2016].

Acquired partial lipodystrophy (APL). APL may develop as a direct aftermath of complement activation in 5%-17% of persons with C3G [Barbour et al 2013b, Goodship et al 2017]. The association between APL and C3G is related to the effects of AP dysregulation on both kidneys and adipose tissue [Goodship et al 2017]. The deposition of activated complement components in adipose tissue destroys adipocytes in areas where factor D (fD, also known as adipsin) is high; loss of subcutaneous fat in the upper half of the body typically precedes the onset of kidney disease by several years.

Eye findings. Individuals with C3G develop drusen as a result of complement activation, often in early adulthood [Barbour et al 2013b, Thomas et al 2014, Goodship et al 2017]. The whitish-yellow deposits, which lie within Bruch's membrane beneath the retinal pigment epithelium of the retina, are similar in composition and structure to the deposits observed in the kidney [D'Souza et al 2009, Lu et al 2012, Barbour et al 2013b]. The retinal distribution of drusen is variable [Thomas et al 2014, Goodship et al 2017] and initially has little impact on visual acuity or visual fields. However, vision loss can occur later in life [Cebeci et al 2016].

Recent investigations convey the importance of the complications that result from drusen [Cebeci et al 2016, Dalvin et al 2016, Savige et al 2016]. Tests of retinal function such as dark adaptation, electroretinography, and electrooculography can gradually become abnormal, and vision can deteriorate as subretinal neovascular membranes, macular detachment, and central serous retinopathy develop [Cebeci et al 2016, Dalvin et al 2016, Savige et al 2016].

The long-term risk for visual problems in individuals with C3G is approximately 10%. No correlation exists between disease severity in the kidney and in the eye.

Pathophysiology

See Figure 4. Fluid-phase dysregulation of the alternate pathway (AP) of the complement cascade is the triggering pathophysiologic event in C3G, and dysregulation of the C3 convertase alone is necessary and sufficient to result in C3G [Martínez-Barricarte et al 2010, Paixão-Cavalcante et al 2012, Zhang et al 2012].

Figure 4.

Complement alternative pathway (AP) Left. Three phases of complement activity are illustrated:

During disease progression, activation of downstream complement proteins in the solid phase, in particular cleavage of C5 to C5a and C5b, can contribute to tissue injury in the micro-environment of the renal glomerulus [Appel et al 2005, Smith et al 2007]. Current consensus considers that in C3G, uncontrolled regulation of the AP may be due to both genetic and/or acquired drivers of disease [Servais et al 2012, Nester & Smith 2016, Goodship et al 2017].

Acquired drivers of disease include autoantibodies such as C3 nephritic factors (C3NeFs), C4 nephritic factors (C4NeFs), C5 nephritic factors (C5NeFs), factor H autoantibodies (FHAA), and factor B autoantibodies (FBAA).

C3NeFs and C5NeFs are most commonly detected and are autoantibodies that recognize neoantigenic epitopes on C3bBb, the C3 convertase of the AP, and on C3bBbC3b, the C5 convertase of the terminal pathway, respectively (see Figure 4) [Paixão-Cavalcante et al 2012, Zhang et al 2012, Nester & Smith 2013a, Nicolas et al 2014]. C3 convertases cleave C3 into C3b and C3a, while C5 convertases cleave C5 into C5a and C5b. In the presence of C3NeFs and C5NeFs, the half-lives of C3 convertase and C5 convertase are increased. Persistent cleavage of C3 drives down serum concentrations of C3 and increases serum concentrations of its cleavage products, C3c and C3d, while persistent cleavage of C5 increases serum concentrations of soluble C5b-9. C4NeFs are found in fewer than 5% of individuals with C3GN and stabilize the C3 convertase of the classic and lectin pathways (C4b2a) [Zhang et al 2017].

Nephritic factors may persist in serum throughout the disease course [Schwertz et al 2001, Paixão-Cavalcante et al 2012, Zhang et al 2012]. Serum concentrations of C3NeFs can vary over time [Appel et al 2005, Paixão-Cavalcante et al 2012, Zhang et al 2012, Servais et al 2013, Rabasco et al 2015]. Their presence is nearly always associated with evidence of complement activation such as decrease in serum concentration of C3 and increase in serum concentration of C3 cleavage products (e.g., C3c and C3d), but the relationship between nephritic factors, C3, and prognosis is not clear [Paixão-Cavalcante et al 2012, Zhang et al 2012, Rabasco et al 2015]. The observed differences may be reconciled by several observations relevant to C3NeFs, which have been most thoroughly studied. First, not all C3NeFs recognize the same epitope on C3bBb; second, the methods for their detection vary; third, many studies do not report titers; and fourth, there is good evidence that the triggering epitopes can change over time [Ohi et al 1992, Spitzer & Stitzel 1996, Paixão-Cavalcante et al 2012, Zhang et al 2012].

The consequence of AP dysregulation in C3G is kidney damage. As the degree of chronic damage increases, renal outcome ultimately becomes independent of the degree of complement dysregulation. With sufficient chronic damage, even if complement normalcy is restored, the likelihood of improving or stabilizing renal function becomes remote and ESRD ensues.

Factor H autoantibodies (FHAA) have been reported in individuals with C3G; epitope mapping shows that these autoantibodies bind the N-terminus of fH [Zhang et al 2012, Blanc et al 2015, Goodship et al 2017].

Factor B autoantibodies (FBAA) have been linked to C3G; however, their role in disease remains unclear [Pickering et al 2013]. FBAAs were identified in a person with DDD without serum C3NeFs. FBAAs bind to and stabilize C3 convertase, targeting both fB and C3b, enhancing the consumption of C3. C5 convertase formation from C3 convertase is prevented, thus interfering with activation of the terminal complement cascade [Strobel et al 2010]. Additional studies have identified FBAAs targeting fB and C3b in two individuals with DDD; C3 convertase activity was increased although no C3NeFs were identified [Chen et al 2011].

As a general rule, C3Nefs, FHAAs, and FBAAs extend the half-life and stabilize C3 convertase, which leads to persistent AP activation in the fluid phase [Noris & Remuzzi 2015].

Genotype-Phenotype Correlations

To date, the most striking genotype-phenotype correlation has been with CFHR fusion genes and the C3GN phenotype (as opposed to the DDD phenotype) (see Figure 3).

Nomenclature

C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Prior to adopting the C3G classification [Pickering et al 2013], dense deposit disease (DDD) was also described as membranoproliferative glomerulonephritis type 2 (MPGN2). C3 glomerulonephritis (C3GN) was recognized as atypical MPGN1 (Burkholder variant of MPGN1) and atypical MPGN3 (Strife and Anders variant of MPGN3) [D'Agati & Bomback 2012, Sethi et al 2016].

Prevalence

The rarity of C3G makes it difficult to estimate prevalence, although from epidemiologic studies, its prevalence in the USA is estimated at 2-3 per 1,000,000 [Smith et al 2007].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with C3G, the following evaluations are recommended if they have not already been completed:

• Evaluate the complement system by measuring serum/plasma concentrations of C3, C3c, C3d, C4, C5, fB, Ba, Bb, fH, fI, properdin, and s(C5b-9).
• Quantitate the degree of complement function by measuring CH50 and APH50.
• Measure autoantibodies including C3NeFs, C4NeFs, C5NeFs, FHAA, and FBAA.
• Establish the extent of renal disease by measuring serum creatinine concentration, and monitor creatinine clearance, proteinuria, and hematuria.
• Quantitate the degree of chronic renal damage by renal biopsy.
• Obtain a baseline ophthalmologic examination.
• Consult with a clinical geneticist and/or genetic counselor.

Treatment of Manifestations

Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G. Nonspecific therapies are most commonly used.

Nonspecific therapies have been shown to be effective in numerous chronic glomerular diseases. The judicious use of these agents along with optimal blood pressure control is of benefit in individuals with C3G.

• Angiotensin-converting enzyme inhibitors and angiotensin II type-1 receptor blockers decrease proteinuria in many glomerular diseases and slow the progression to renal failure [Licht et al 2006, Lu et al 2012, Nester & Smith 2016, Riedl et al 2017]. A retrospective study found that the combination of angiotensin blockers and immunosuppressants (steroids) is more effective than each therapy alone in preventing the development of renal failure [Nasr et al 2009, Nester & Smith 2013b, Thomas et al 2014, Cook 2017].
• Lipid-lowering agents, and in particular hydroxymethylglutaryl coenzyme A reductase inhibitors, may delay progression of renal disease as well as correct endothelial cell dysfunction and alter long-term atherosclerotic risks in the presence of hyperlipidemia [Nester & Smith 2013b, Thomas et al 2014]. These agents are not widely used in children.
• Complement inhibition with a terminal pathway blocker may alter disease course. Eculizumab is a recombinant humanized monoclonal antibody that targets C5. It blocks cleavage of C5 by C5 convertase, thereby having two effects: (1) an anti-inflammatory effect caused by preventing the release of C5a, a potent anaphylatoxin; and (2) an anticomplement effect caused by preventing formation of the terminal complement complex (see Figure 4). Reports of its use in individuals with C3G have demonstrated limited success [ClinicalTrials.gov NCT00838513, Bomback et al 2012].
  • Individuals with C3G treated with eculizumab have not produced a uniform response [Noris & Remuzzi 2015].
  • Early administration of eculizumab prior to sclerotic tissue formation provides better results, reduces proteinuria, and improves kidney health [Vivarelli & Emma 2014]; however, success of this therapeutic is limited in C3G because proximal complement control is not restored (see Figure 4).

Renal allografts. When end-stage renal disease (ESRD) develops, treatment options are limited to dialysis or transplantation. When an individual with C3G elects to undergo a renal transplant, it is important to recognize that C3G recurs in nearly all grafts and is the predominant cause of graft failure in 50%-90% of transplant recipients [Appel et al 2005, Angelo et al 2011, Lu et al 2012, Servais et al 2012, Zand et al