1. Disease Review: C3 Glomerulopathy
신장내과 R3 박세정/prof 정경환

2. Classification
Pathology
Pathogenesis
Clinical presentation
Diagnosis
Treatment
Prognosis

3. Classification
C3 glomerulopathy (C3G): glomerulopathy with isolated C3 deposition
Dense deposit diesease (DDD) C3 glomerulonephritis (C3GN)
Membranoproliferative glomerulonephritis (MPGN) - Type I: subendothelial deposits of IgG and C3 or isolated C3 - Type II: elctron dense deposits within the lamina densa of GBM. (C3+, Ig-) - Type III: both subendothelial and subepithelial
C3 glomerulopathy: a new classification. Nat. Rev. Nephrol. 6, (2010)
C3 glomerulopathy: glomerulopathy with isolated C3 deposition (glomerular disorders in which dysregulation of the complement system is either the key pathophysiological factor or the major mediator of glomerular damage)
KI (2012) 82, C3GN is a recently described entity that shows a GN on LM; bright C3 staining and the absence of C1q, C4 and Igs on IF microscopy; and mesangial and/or subendothelial electron-dense deposits on EM. Occasional intramembranous and subepithelial deposits are also frequently present.
KI (2012) 81,
MPGN denotes a general pattern of glomerular injury characterized by an increase in mesangial cellularity and matrix with thickening of glomerular capillary walls secondary to subendothelial deposition of immune complexes and/or complement factors, cellular entrapment, and new basement membrane formation. This pattern of injury is easily recognized by LM, making the diagnosis of MPGN relatively straightforward; however, IF and EM resolve differences among MPGN that have led to the adoption of classification systems to subgroup MPGN types. Subgrouping is driven by an effort to better understand this histologically driven subclassification is reflective of pathogenic similarities, which may have bearing on directing clinical care.
IF studies to detect proteinaceous deposits in MPGN will typically reveal Igs (usually IgG or IgM) in MPGN I and MPGN III, whereas MPGN II is noteworthy because of their absence. Although the three MPGN types stain positive for complement component 3 (C3) consistent with complement activation, as early as the 1970s it was observed that C3-positive but immunoglobulin-negative examples of MPGN I and MPGN III exist. (Levy M, Gubler M-C, Sich M et al. Immunopathology of MPGN with subendothelial deposits (Type I MPGN). Clin Immunol Immunopathol 1978;10: ) Together with MPGN II, which is appropriately called DDD, this grouop of C3-positive Ig-negative glomerular diseases has been labeled as C3 glomerulopathies. (Fakhouri F, Fremeaux-Bacchi V, Noel L-H et al. C3 glomerulopathy: a new classification. Nat Rev Nephrol 2010;6: ) (Sethi S, Fervenza F, Zhang Y et al. Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement. Clin J Am Soc Nephrol 2011;6: )
Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney International (2012) 82, 454–464
Dense deposit disease and glomerulonephritis with isolated C3 deposits are glomerulopathies characterized by deposits of C3 within or along the glomerular basement membrane. Previous studies found a link between dysregulation of the complement alternative pathway and the pathogenesis of these diseases.
Dense deposit disease (DDD) and glomerulonephritis with isolated C3 deposits (GNC3) are characterized by glomerular deposition of C3 and are associated with dysregulation of the complement alternative pathway (AP).1–3 The essential feature of DDD is the presence of electron-dense transformation of the glomerular basement membrane (GBM), and not the membranoproliferative pattern.4 These dense deposits contain components of the alternative pathway including C3b and its breakdown products iC3b, C3dg, or C3c, and terminal complement complex.5 Conversely, GNC3 are characterized by subendothelial deposits containing exclusively C3 products, without immunoglobulins and without dense intramembranous deposits within the glomerular and the tubular basement membranes.2,6–8 The AP dysregulation in DDD and GNC3 is usually induced by C3 nephritic factor (C3NeF), an autoantibody that stabilizes the AP C3 convertase.1 Only few patients with homozygous or heterozygous mutations in the regulatory complement proteins factor H (CFH), factor I (CFI), or C3 have been identified.2,7,9,10 Particular variants of CFH (H402Y) and of CFH-related 5 (CFHR5) may preferentially be associated with DDD.11–13 On the basis of etiology, DDD and GNC3 are classified as complement-mediated disease. However, few clinical series with complement analysis have been reported, and in particular no frequencies of acquired or genetic abnormalities are available.13,14 If the uncontrolled activation
of the AP in fluid phase seems a common feature between the two diseases, no biological or genetic markers influencing the
location of the dense deposits have been identified.
1. Appel GB, Cook HT, Hageman G et al. Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J Am Soc Nephrol 2005; 16: 1392–1403.
2. Servais A, Fremeaux-Bacchi V, Lequintrec M et al. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. J Med Genet 2007; 44: 193–199.
3. Fakhouri F, Fremeaux-Bacchi V, Noel LH et al. C3 glomerulopathy: a new classification. Nat Rev Nephrol 6: 494–499.
4. Walker PD, Ferrario F, Joh K et al. Dense deposit disease is not a membranoproliferative glomerulonephritis. Mod Pathol 2007; 20: 605–616.
5. Sethi S, Gamez JD, Vrana JA et al. Glomeruli of Dense Deposit Disease contain components of the alternative and terminal complement pathway. Kidney Int 2009; 75: 952–960.
6. Berger J, Noel LH, Yaneva H. Complement deposition in the kidney. In: Hamburger J (ed). Advances in Nephrology, vol 4, Year Book Medical Publishers: Chicago, 1974, pp 37–48.
7. Boyer O, Noel LH, Balzamo E et al. Complement factor H deficiency and posttransplantation glomerulonephritis with isolated C3 deposits. Am J Kidney Dis 2008; 51: 671–677.
8. Sethi S, Fervenza FC, Zhang Y et al. Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement. Clin J Am Soc Nephrol 2011; 6: 1009–1017.
9. Servais A, Noel LH, Dragon-Durey MA et al. Heterogeneous pattern of renal disease associated with homozygous Factor H deficiency. Hum Pathol 2011; 42: 1305–1311.
10. Martinez-Barricarte R, Heurich M, Valdes-Canedo F et al. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J Clin Invest 2010; 120: 3702–3712.
11. Licht C, Schlotzer-Schrehardt U, Kirschfink M et al. MPGN II–genetically determined by defective complement regulation? Pediatr Nephrol 2007; 22: 2–9.
12. Pickering MC, de Jorge EG, Martinez-Barricarte R et al. Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. J Exp Med 2007; 204: 1249–1256.
13. Abrera-Abeleda MA, Nishimura C, Smith JL et al. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). J Med Genet 2006; 43: 582–589.
14. Nasr SH, Valeri AM, Appel GB et al. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol 2008; 4: 22–32.
C3 Glomerulopathy: Clinicopathologic Features and Predictors of Outcome Clin J Am Soc Nephrol 9: 46–53, 2014
The term C3 glomerulopathy was recently coined to describe renal biopsy appearances characterized by the presence of glomerular deposits composed predominantly of C3 in the absence of significant amounts of Ig (5). The presence of C3 in the absence of Ig suggests activation of complement by antibody-independent pathways, typically the alternative pathway, and many patients with this type of renal lesion have evidence of genetic or acquired alternative pathway dysregulation (6). C3 glomerulopathy has been further divided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) based on electron microscopy (EM) appearances.

4. MPGN and C3G: resolving the confusion. KI (2012) 81, 434-441

5. PIGN (with C3 alone on IF)
MPGN type I
MPGN type II  DDD
C3 alone on IF
MPGN type III
C3 with IgG, IgM or C1q
C3 with IgG, IgM or C1q
C3 alone on IF
C3 alone on IF
C3 Glomerulopathy
PIGN (with C3 alone on IF)
Previous MPGN type I
Previous MPGN type III
Glomerulonephritis with dominant C3

6. 2007년 Servais 등은 용혈성 요독 증후군(hemolytic uremic syndrome, HUS)과 같은 유전적 소인을 갖는 사구체 신염 중, 일반적인 HUS와는 달리, 대체보체경로(alternative complement pathyway)가 활성화되고, 사구체에 보체3 (C3)이 침착되는 새로운 사구체 신염을 수집 정리하였다. 광학현미경적 변화보다는, 면역형광현미경 상 C3의 침착이 특징임으로, C3 사구체신염(C3 glomerulonephritis, C3GN)으로 명명하였다. 그러나 기존 사구체 질환에서도, C3만 침착되는 비전형적인 예들이 있어서, 이들을 C3GN과 감별하여 재분류하고 있다.
Fig 3 Schematic representation of the expanding spectrum of renal diseases a/w an abnormal control of the complement AP. The two types of GN reported in this study are defined by the presence of isolated C3 deposits (and no Ig), either GN with isolated C3 deposits w/ MPGN (GN C3 w/ MPGN) or GN C3 w/o GMPN. Pts with HUS and DDD were excluded from this study. GN C3 w/o MPGN shares risk factor with HUS, namely mutation; GN C3 with MPGN, although different from DDD by the absence of dense deposits, was often a/w C3NeF.

7. Pathology
Some formerly classified as persistent or resolving PIGN and even some with a documented infection history, the differentiation of true PIGN from C3GN often cannot be made on the basis of morphology and clinical and laboratory data available at the time of biopsy.
the term “C3 glomerulopathy” (C3G) : to designate a disease process due to abnormal control of complement activation, deposition, or degradation and characterized by predominant glomerular C3 fragment deposition with electron-dense deposits on EM
“glomerulonephritis with dominant C3” is useful to indicate the likelihood that the case represents the disease process of C3 glomerulopathy
Some cases of typical PIGN may show C3 dominance on IF

8. C3 glomerulonephritis (C3GN)
LM - variable - membranoproliferative pattern, mesangial proliferative pattern - variable endocapillary proliferation and crescent formation - rarely normal on LM
IF - C3 in GM (mesangial and/or capillary wall) - immunoglobulins: C3 intensity >=2 orders of magnitude more than any other immune reactant on a scale of 0 to 3(0, trace, 1-3)
C3 glomerulopathy: a new classification Fakhouri, F. et al. Nat. Rev. Nephrol. 6, 494–499 (2010);
Figure 3. C3G are caused by dysregulation of the AP and TCC. The prototypic example is DDD, in which there must be fluid-phase dysregulation of the C3 convertase, often with dysregulation of the C5 convertase. Dysregulation of the C3 convertase results in increased serum levels of CFI-generated iC3b, which accumulates in the GBM as the characteristic sausage-shaped dense deposits. C3b breakdown products are also detectable in plasma as C3c and C3d. Some pts w/ C3G also have elevated serum levels of sMAC. Why dysregulation of the AP and TCC leads to DDD in some pts and to C3GN in others is not understood at this time. However, genetic evidence suggests that a contributing factor may be the relative degree of dysregulation of the C3 and C5 convertases. For example, in the family described by Martinez-barricarte et al., there is dysregulation of C3 convertase but not of C5 convertase. Clarifying the differences btw DDD and C3GN is likely to be germane to the tx of these dzs as the availability of anti-complement therapies is currently limited to eculizumab, an anti-C5 monoclonal antibody that prevents cleavage of C5 to C5a and C5b, thereby preventing propagation of the TCC.
8. Montes, T., Tortajada, A., Morgan, B. p., rodriguez de Cordoba, S. & Harris, C. L. Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B. Proc. Natl Acad. Sci. USA 106, 4366–4371 (2009).
9. Tortajada, A. et al. The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity. Hum. Mol. Genet. 18, 3452–3461 (2009).
10. pickering, M. C. & Cook, H. T. Translational minireview series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals. Clin. Exp. Immunol. 151, 210–230 (2008).
11. Jokiranta, T. S. et al. Where next with atypical hemolytic uremic syndrome? Mol. Immunol. 44, 3889–3900 (2007).
12. Kavanagh, D., richards, A. & Atkinson, J. Complement regulatory genes and hemolytic uremic syndromes. Annu. Rev. Med. 59, 293–309 (2008).
13. Loirat, C., Noris, M. & Fremeaux-Bacchi, v. Complement and the atypical hemolytic uremic syndrome in children. Pediatr. Nephrol. 23, 1957–1972 (2008).
acquired causes include antibodies that either block the action of natural regulators of the alternative pathway (for example, anticomplement factor H antibodies) or directly stimulate activation of the alternative pathway (for example, C3 nephritic factor [C3NeF]). C3NeF is an IgG autoantibody that directly stabilizes the C3activating complex of the alternative pathway and thereby prevents the normal inhibitory action of complement factor H. C3NeF causes activation of plasma C3 despite normal levels of complement factor H.
Examples of genetic causes include lossoffunction mutations in genes that encode regulators of the alternative pathway, and gainoffunction mutations in genes that encode proteins that activate the alternative pathway. Interestingly, polymorphic protein variants of complement factor B8 and complement factor H9 have been associated with reduced activation of the alternative pathway and reduced susceptibility to complementmediated diseases. Therefore, within the family of alternative pathway proteins, important functional differences exist that may influence disease penetrance or disease severity. some or all of these abnormalities have been associated with the renal diseases aHUS and DDD.10
Although aHUs is strongly associated with a dysregulation of the alternative pathway, this condition is not consistently associated with detectable levels of C3 by immunohistochemistry, and electrondense deposits are not seen by electron microscopy. Therefore, aHUS is not included in our proposed classification, and we do not discuss it further since there are a number of excellent reviews of the role of the complement system in aHUs.11–13 C3
IgG

9. The deposits fulfill the criteria for DDD ?
C3GN vs DDD
Complex pattern of mesangial increase & GBM thickening with variable combinations of subendothelial, intramembranous and subepithelial deposits a/w fraying of the lamina densa
Less electron dense than those seen in classic DDD
Tend to be less discrete, more ill-defined, more confluent, more likely to blend with the extracellular matrix than those in DDD.
More discrete subendothelial deposits resembling MPGN type I
Mesangial deposits tend to by rounded in appearance
May exhibit large subepithelial hump-like deposits
C3 Glomerulopathy
The deposits fulfill the criteria for DDD ?
EM 소견으로 구분 no
yes
C3 glomerulopathy: a new classification Fakhouri, F. et al. Nat. Rev. Nephrol. 6, 494–499 (2010);
Figure 3. C3G are caused by dysregulation of the AP and TCC. The prototypic example is DDD, in which there must be fluid-phase dysregulation of the C3 convertase, often with dysregulation of the C5 convertase. Dysregulation of the C3 convertase results in increased serum levels of CFI-generated iC3b, which accumulates in the GBM as the characteristic sausage-shaped dense deposits. C3b breakdown products are also detectable in plasma as C3c and C3d. Some pts w/ C3G also have elevated serum levels of sMAC. Why dysregulation of the AP and TCC leads to DDD in some pts and to C3GN in others is not understood at this time. However, genetic evidence suggests that a contributing factor may be the relative degree of dysregulation of the C3 and C5 convertases. For example, in the family described by Martinez-barricarte et al., there is dysregulation of C3 convertase but not of C5 convertase. Clarifying the differences btw DDD and C3GN is likely to be germane to the tx of these dzs as the availability of anti-complement therapies is currently limited to eculizumab, an anti-C5 monoclonal antibody that prevents cleavage of C5 to C5a and C5b, thereby preventing propagation of the TCC.
8. Montes, T., Tortajada, A., Morgan, B. p., rodriguez de Cordoba, S. & Harris, C. L. Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B. Proc. Natl Acad. Sci. USA 106, 4366–4371 (2009).
9. Tortajada, A. et al. The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity. Hum. Mol. Genet. 18, 3452–3461 (2009).
10. pickering, M. C. & Cook, H. T. Translational minireview series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals. Clin. Exp. Immunol. 151, 210–230 (2008).
11. Jokiranta, T. S. et al. Where next with atypical hemolytic uremic syndrome? Mol. Immunol. 44, 3889–3900 (2007).
12. Kavanagh, D., richards, A. & Atkinson, J. Complement regulatory genes and hemolytic uremic syndromes. Annu. Rev. Med. 59, 293–309 (2008).
13. Loirat, C., Noris, M. & Fremeaux-Bacchi, v. Complement and the atypical hemolytic uremic syndrome in children. Pediatr. Nephrol. 23, 1957–1972 (2008).
acquired causes include antibodies that either block the action of natural regulators of the alternative pathway (for example, anticomplement factor H antibodies) or directly stimulate activation of the alternative pathway (for example, C3 nephritic factor [C3NeF]). C3NeF is an IgG autoantibody that directly stabilizes the C3activating complex of the alternative pathway and thereby prevents the normal inhibitory action of complement factor H. C3NeF causes activation of plasma C3 despite normal levels of complement factor H.
Examples of genetic causes include lossoffunction mutations in genes that encode regulators of the alternative pathway, and gainoffunction mutations in genes that encode proteins that activate the alternative pathway. Interestingly, polymorphic protein variants of complement factor B8 and complement factor H9 have been associated with reduced activation of the alternative pathway and reduced susceptibility to complementmediated diseases. Therefore, within the family of alternative pathway proteins, important functional differences exist that may influence disease penetrance or disease severity. some or all of these abnormalities have been associated with the renal diseases aHUS and DDD.10
Although aHUs is strongly associated with a dysregulation of the alternative pathway, this condition is not consistently associated with detectable levels of C3 by immunohistochemistry, and electrondense deposits are not seen by electron microscopy. Therefore, aHUS is not included in our proposed classification, and we do not discuss it further since there are a number of excellent reviews of the role of the complement system in aHUs.11–13
DDD
C3GN
Highly dense intramembranous,
as rounded deposits in mesangium, in many cases in TBM & BWC
may present in some segments only

10. Dense Deposit Disease (DDD)

11. C3GN

12. PIGN C3GN LM Diffuse proliferative
(Exudative with endocapillary proliferation)
Mesangial proliferative or crescentic (less common)
Rare double contour (membranoproliferative pattern)
Membranoproliferative pattern (sometimes, mesangial proliferative, or sclerosing pattern) IF
Bright C3 with IgG, Kappa and lambda light chains
(but frequently Ig negative)
Bright C3, with almost complete absence of Immunoglobulins and light chains EM
Many subepithelial humps
Few mesangial & subendothelial deposits
± Few subepithelial humps
Many mesangial & suendothelial deposits
± Few intramembranous deposits
Absence of atypical features on LM and EM, & typical clinical course with resolution  PIGN
Glomerulonephritis with dominant C3 (infection-associated)
Require following the pt clinically and serologically over several months to determine the course of urinary abnormalities and serum C3 levels.
The presence of any atypical clinical or histological features in a case of apparent PIGN should raise suspicion of C3G

13. Glomerulonephritis with dominant C3
C3 intensity >=2 orders of magnitude more than any other immune reactant
PIGN
Other
C3 Glomerulopathy
Dense osmophilic intramembranous ribbon-like electron dense deposits no
yes
DDD
C3GN

14. Pathogenesis
Figure 2. The complement cascade is initiated by the CP, AP, or LP. The principle trigger of the CP, Ig-complexed Ag, is the driving force for C3 deposition in Ig-positive MPGN. Two or more adjacent IgG Abs provide the structural framework for activation of C1, which cleaves C2 and C4 to generate C2a and C4b, respectively. These two proteins form the CP C3 convertase. The AP is constitutively active, a process that is referred to as ‘tick over’. Binding of CFB, CFD, and properdin to hydrolzed C3 or to C3b leads to formation of the AP C3 convertase C3bBb. This process also generates C3a, a potent anaphylatoxin. When an additional C3b molecule a/w C3 convertase, C5 convertase is formed, initiating the TCC and leading to the generation of MAC. Fluid-phase regulators of the CP include C4BP and C1INH, and of the AP, C5H and C5b.
MPGN and C3G: resolving the confusion. KI (2012) 81,

15. Figure 2. DDx of glomerular dz based on complement system pathway activation.
American Society of Nephrology Clinical Pathological Conference. Clin J Am Soc Nephrol 9: , 2014

16. abnormal control of the alternative pathway (AP)
acquired causes: Abs that either block the action of natural regulators of the AP (eg, anti-CFH or anti-CFI Abs) or directly stimulate activation of the aAP (eg, C3NeF)
genetic causes: - loss-of-function mutations in genes that encode regulators of the AP - gain-of-function mutations in genes that encode proteins that activate the AP
C3 glomerulopathy: a new classification Fakhouri, F. et al. Nat. Rev. Nephrol. 6, 494–499 (2010);
Figure 3. C3G are caused by dysregulation of the AP and TCC. The prototypic example is DDD, in which there must be fluid-phase dysregulation of the C3 convertase, often with dysregulation of the C5 convertase. Dysregulation of the C3 convertase results in increased serum levels of CFI-generated iC3b, which accumulates in the GBM as the characteristic sausage-shaped dense deposits. C3b breakdown products are also detectable in plasma as C3c and C3d. Some pts w/ C3G also have elevated serum levels of sMAC. Why dysregulation of the AP and TCC leads to DDD in some pts and to C3GN in others is not understood at this time. However, genetic evidence suggests that a contributing factor may be the relative degree of dysregulation of the C3 and C5 convertases. For example, in the family described by Martinez-barricarte et al., there is dysregulation of C3 convertase but not of C5 convertase. Clarifying the differences btw DDD and C3GN is likely to be germane to the tx of these dzs as the availability of anti-complement therapies is currently limited to eculizumab, an anti-C5 monoclonal antibody that prevents cleavage of C5 to C5a and C5b, thereby preventing propagation of the TCC.
8. Montes, T., Tortajada, A., Morgan, B. p., rodriguez de Cordoba, S. & Harris, C. L. Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B. Proc. Natl Acad. Sci. USA 106, 4366–4371 (2009).
9. Tortajada, A. et al. The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity. Hum. Mol. Genet. 18, 3452–3461 (2009).
10. pickering, M. C. & Cook, H. T. Translational minireview series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals. Clin. Exp. Immunol. 151, 210–230 (2008).
11. Jokiranta, T. S. et al. Where next with atypical hemolytic uremic syndrome? Mol. Immunol. 44, 3889–3900 (2007).
12. Kavanagh, D., richards, A. & Atkinson, J. Complement regulatory genes and hemolytic uremic syndromes. Annu. Rev. Med. 59, 293–309 (2008).
13. Loirat, C., Noris, M. & Fremeaux-Bacchi, v. Complement and the atypical hemolytic uremic syndrome in children. Pediatr. Nephrol. 23, 1957–1972 (2008).
acquired causes include antibodies that either block the action of natural regulators of the alternative pathway (for example, anticomplement factor H antibodies) or directly stimulate activation of the alternative pathway (for example, C3 nephritic factor [C3NeF]). C3NeF is an IgG autoantibody that directly stabilizes the C3activating complex of the alternative pathway and thereby prevents the normal inhibitory action of complement factor H. C3NeF causes activation of plasma C3 despite normal levels of complement factor H.
Examples of genetic causes include lossoffunction mutations in genes that encode regulators of the alternative pathway, and gainoffunction mutations in genes that encode proteins that activate the alternative pathway. Interestingly, polymorphic protein variants of complement factor B8 and complement factor H9 have been associated with reduced activation of the alternative pathway and reduced susceptibility to complementmediated diseases. Therefore, within the family of alternative pathway proteins, important functional differences exist that may influence disease penetrance or disease severity. some or all of these abnormalities have been associated with the renal diseases aHUS and DDD.10
Although aHUs is strongly associated with a dysregulation of the alternative pathway, this condition is not consistently associated with detectable levels of C3 by immunohistochemistry, and electrondense deposits are not seen by electron microscopy. Therefore, aHUS is not included in our proposed classification, and we do not discuss it further since there are a number of excellent reviews of the role of the complement system in aHUs.11–13
MPGN and C3G: resolving the confusion.
KI (2012) 81,

17. Clinical Presentation
proteinuria/hematuria
renal insufficiency, HTN
decreased serum C3 level
extrarenal: - drusen (macular deposit) - acquired partial lipodystrophy
Drusen are characteristically seen in age-related macular degeneration but have also been reported in individuals with DDD suggesting a common underlying etiology for deposits in the GBM and retina. A shows preTx drusen deposition in DDD3. B shows pretreatment drusen deposition in C3GN2.
(loss of subcutaneous fat layer in upper half of the body)
MPGN and C3G: resolving the confusion. KI (2012) 81,

18. Diagnosis renal biopsy complement investigation in C3G
Recommended all patients
Serum C3 and C4
C3 nephritic factor
Serum factor H
Serum paraprotein detection
Screening for CFHR5 mutation
Considered on a case-by-case
Serum factor B
Serum C3
Markers of C3 activation(C3d, C3c, C3adesArg)
Markers of C3 activation(C3adesArg, soluble C5b-9)
Anti-factor H autoantibodies
●C3 nephritic factor (C3NeF) – C3NeF is an autoantibody that stabilizes the C3 convertase (C3bBb). Determination of C3NeF in the serum supports the diagnosis of C3GN or DDD.
●Serum factor H – As noted above, factor H promotes the decay of the C3 and C5 convertases (C3bBb and [C3b]2Bb). If factor H activity is diminished or if factor H is deficient, evaluation of possible mutations in the factor H gene and autoantibodies to factor H should be performed.
●Complement factor H-related (CFHR) protein gene mutations – The CFHR proteins CFHR1, CFHR2, and CFHR5 are able to compete with factor H for binding to tissue-bound complement fragments, thereby deregulating the control of the alternative pathway by factor H [69]. This balance can be disturbed by CFHR mutations. As examples, mutations in the CFHR5 gene that produce an internal duplication are responsible for C3GN of Cypriot origin [70], and a hybrid CFHR3-1 gene mutation resulted in familial C3GN in an Irish family [71]. Thus, mutations in CFHR5 and in other complement factor H-related proteins (ie, CFHR1-4), as well as in complement factor 3 (C3), should be assessed.
●Serum protein electrophoresis (SPEP) and serum-free light chains – A paraprotein may be responsible for activation of the alternative complement cascade. If a monoclonal gammopathy is discovered, specialized tests are required to determine whether or not the protein could be responsible for the C3 glomerulopathy. (See "Recognition of monoclonal proteins".)
●Serum factor B, serum factor I, and membrane cofactor protein (MCP, or CD46) – Deficiency of serum factors B or I or MCP can be associated with activation of the alternative complement cascade. If low, mutations in these genes or autoantibodies against these proteins should be investigated.
●Soluble C5b-9 (soluble membrane attack complex, or sMAC) – Elevated levels of sMAC may indicate increased activity of the alternative pathway.
A presumed cause of DDD and C3GN can be identified in many patients. As examples:
●One or more of these alternative pathway abnormalities were identified in 28 of 32 patients (88 percent) with biopsy-proven DDD, most of whom had a positive C3NeF [13]
●Abnormalities such as C3NeF, factor H mutations, and CFHR5 mutations were found in all 12 patients in a series with biopsy-proven C3GN [68]

19. Treatment symptomatic Tx
no randomized controlled trial
symptomatic Tx
immune suppression targeting T cells and/or B cells (glucocorticoids, cyclophosphamide, MMF, rituximab)
plama therapy
plasmapheresis
eculizumab: monoclonal Ab, binds to C5 to prevent formation of MAC
Previous treatment of DDD has traditionally included immune suppression targeting T cells and/or B cells (glucocorticoids, cyclophosphamide, mycophenolate mofetil, rituximab) and plama therapy or plasmapheresis. (Nester DM, Smith RJ: Treatment options for C glomerulopathy. Curr Opin Nephrol Hypertens 22: , 2013) There is no good evidence that any of these therapies reliably alters renal survival in most patients with DDD, even when used for prolonged periods (American Society of Nephrology Clinical Pathological Conference. Clin J Am Soc Nephrol 9: , 2014)
26. Servais A, et al: Acquired and genetic complement abnormalities play a critical role in DDD and other C3Gs. KI 82: , 2012
43. Appel GB, Sethi S, et al: MPGN type II (DDD): An update. J Am Soc Nephrol 16: , 2005
44. Daina E, et al: Eculizumab in a patient with DDD. NEJM 366: , 2012
The KDIGO clinical guidelinees to treat children and adults with idiopathic MPGN accompanied by nephritis and progression of disease with “oral cyclophosphamide or MMF plus low dose daily or alternate day corticosteroids with initial therapy limited to less than 6 months” is based on insubstantial evidence and is not supported by recent experience.
45. Chapter 8: Idiopathic MPGN. KI Suppl 2: , 2012
46. Bomback AS, et al: Eculizumab for DDD and c3GN. Clin J Am Soc Nephrol 7: , 2012
Bomback et al. perfomed a trial of eculizumab in C3 glomerulopathy. This open-label, proof-of-concept, efficacy, and safety study evaluated three patients with DDD (one with a renal transplant) and tree patients with C3GN (two with a renal transplant). The patients received eculizumab every other week for 1 year. Genetic testing revealed a mutation in CFH and CD46 in one patient each. Complement function testing revealed C3NeF in three patients. There was a mixed response after 12 months of therapy: Two patinets (one with DDD and one with C3GN) showed significantly reduced serum creatinine, one patient (with DDD) and marked reduction in proteinuria, and one (with C3GN) had only histologic improvement without biochemical change. The response to eculizumab varied. The authors suggested that an elevation of sC5b-9 was potentially a marker of responsiveness to eculizumab.
Soliris has been made famous by Forbes as the world’s single most expensive drug, coming in at $409,500 a year.

20. Prognosis
DDD < C3GN
progression to ESRD: 23 % of C3GN vs. 47 % of DDD (median f/u 28 m) (Medjeral-Thomas NR, et al. Clin J Am Soc Nephrol 2014; 9:46)
63.5% 10-year survival rate in patients with DDD (Servais A, et al. Kidney Int 82: , 2012)
Factors predictive of progression to renal failure: (DDD) - younger age at dx, - increased sCr, - proteinuria at the time of dx, - initial presentation with nerphrotic and nephritis syndromes, - >20% chronic renal damage - crescents
Some patients have persistently low-grade proteinuria but maintain kidney function for a long time, while other patients have severe nephrotic syndrome, and some can present with rapidly progressive glomerulonephritis and have a poor prognosis.
(American Society of Nephrology Clinical Pathological Conference. Clin J Am Soc Nephrol 9: , 2014)
uptodate
The prognosis of dense deposit disease (DDD) is generally poor. Most studies reporting renal prognosis are several years old and do not differentiate between immune complex-mediated versus complement-mediated membranoproliferative glomerulonephritis, nor between end-stage renal disease (ESRD) and mortality [10,42,43,45,85]. When reported, rates of progression of MPGN to ESRD vary widely from 19 to 76 percent over a period of three months to 16 years [1,9,11,40,44,47,82]. In one prospective study in children, ESRD developed in over 70 percent of affected individuals with a median onset of nine years after diagnosis of DDD [9]. A similar percentage of patients who progressed to ESRD was reported in a review of data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS), although the rate of progression was not reported in this study [1].
The following observations were made in a review of native kidney biopsies from patients with DDD that included 13 children and 14 adults [40] 40Nasr SH, Valeri AM, Appel GB, et al. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol 2009; 4:22. :
●Over a mean follow-up of 79 months, six children (46 percent) had normal renal function and less than 500 mg/day of proteinuria. One child progressed to ESRD, and the remainder had persistent renal dysfunction.
●Over a mean follow-up of 49 months, one adult had normal renal function and less than 500 mg/day of proteinuria. Six adults developed ESRD, and seven had persistent renal dysfunction.
●Older age and serum creatinine at biopsy were independent predictors of progression to ESRD.
C3GN : variable but tends to be better than DDD

21. Reference
Fakhouri F, Fremeaux-Bacchi V, Noel L-H et al. C3 glomerulopathy: a new classification. Nat Rev Nephrol 2010;6:
Servais A, et al: Acquired and genetic complement abnormalities play a critical role in DDD and other C3Gs. KI 82: , 2012
MPGN and C3G: resolving the confusion KI (2012) 81,
American Society of Nephrology Clinical Pathological Conference. Clin J Am Soc Nephrol 9: , 2014
Walker PD, Ferrario F, Joh K et al. Dense deposit disease is not a membranoproliferative glomerulonephritis. Mod Pathol 2007; 20: 605–616.
J Korean Soc Pediatr Nephrol 2013;17:1-5
Servais A, Fremeaux-Bacchi V, Lequintrec M et al. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. J Med Genet 2007; 44: 193–199.
KI (2012) 82,
Nester DM, Smith RJ: Treatment options for C glomerulopathy. Curr Opin Nephrol Hypertens 22: , 2013
43. Appel GB, Sethi S, et al: MPGN type II (DDD): An update. J Am Soc Nephrol 16: , 2005
44. Daina E, et al: Eculizumab in a patient with DDD. NEJM 366: , 2012
46. Bomback AS, et al: Eculizumab for DDD and c3GN. Clin J Am Soc Nephrol 7: , 2012
48. Medjeral-Thomas NR, O'Shaughnessy MM, O'Regan JA, et al. C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol 2014; 9:46.
14. Nasr SH, Valeri AM, Appel GB et al. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol 2008; 4: 22–32.