C3 glomerulopathy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2] Aditya Ganti M.B.B.S. [3]
For more information of Complement mediated glomerular disorders, Click here
Synonyms and keywords: Glomerulonephritis; C3 glomerulonephritis; dense deposit disease
Overview
C3 glomerulopathy is a complement system dysregulatory disorder resulting in abnormal activation of the alternative pathway. C3 glomerulopathy includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Both, C3GN and dense deposit disease are characterized by marked by C3 deposition along the capillary loop, the basement membrane, and the mesangium. Identification of C3 deposits without any concomitant immunoglobulin deposition is characteristic for diagnosing C3 glomerulopathy. The activation of the alternative pathway of the complement system can be either due to inherited, or acquired defects of the complement system. Gene mutations are the most common inherited causes while autoimmune disorders are responsible for acquired glomerulopathy.
Historical Perspective
- In 1915, William C. Gunn was first to report an association of low circulating complement levels in patients with acute infection and nephritic presentation.
- Based on the William's observations, role of complement system in inflammatory glomerulonephritis was well described.[1][2]
- In 1962, Jean Berger and Pierre Galle, Nephro-pathologists, was the first to identify dense intramembranous deposits on transmission EM [3].
- Mathew TH, Kinaid Smith P coined the term dense deposit disease (DDD).[4]
Classification
- Initially, C3 glomerulopathy was categorized as a variant of MPGN, namely MPGN type 2. [5][6]
- However in 2007, Servais A. et al described C3GN as an separate entity.
- C3 Glomerulopathy may be classified into 2 main subtypes based on the appearance of complement deposition in the glomerular basement membrane on EM:
- Dense deposit disease (DDD)
- Dense deposition of compliment in linear pattern.
- C3 Glomerulonephritis (C3GN)
- Isolated deposition of C3.
- Dense deposit disease (DDD)
Pathophysiology
- Excessive activation of the alternative complement pathway is the inciting event in the pathogenesis of C3 glomerulopathy.[7]
- Activation of alternative pathway results in excessive deposition of complement along the glomerular basement membrane.
- Pattern of compliment deposition is regulated by:[8]
- Leukocytic chemotaxis
- Cytolytic effects of C5b-9
Physiology
- Spontaneous cleavage of C3 to C3b results in activation of C3 convertase.[9]
- C3 convertase along with factor B and properdin catalyses the cascade of producing C5 convertase.
- C5 convertse cleaves 5 to C5a initiating C5b-9 ( MAC complex)
- Physiologically activation of C5 convertase is directly related to C3 convertase.
- Factors that can influence and control C3 convertase activity include
- Serum protein
- Factor H (inhibits the C3 convertase)
Pathogenesis
- Any mechanism by which C3 activity is increased leads to activation of alternate pathway activation resulting in complement deposition.[10][11]
- C3 convertase autoantibody C3 nephritic factor
- Loss of factor H
Causes
Common causes of C3 glomerulopathy include:[12]
- C3 mutations
- Mutation of Factor H (CHF)[13]
- CFH is a small glycoprotein which is produced in the liver, and circulates freely in the blood plasma .
- Primary role of factor H is to inhibit C3 convertase and thus not activating alternative complement pathway.
- Two types of mutations are of important significance
- Type 1 mutations are associated with decreased levels of CFH.
- Type 2 mutations decrease or diminish the functional activity of CHF.
- Autoantibodies against CFH. [14]
- Mutation of membrane cofactor protein ( MCP)
- MCP is a transmembrane protein, expressed by all nucleated cells and located at the cell surfaces.
- Together with Complement Factor I (CFI), MCP is required for the inactivation of C3b,
Differentiating C3 Glomerulopathy from other Diseases
| Medical condition | Differentiating features |
|---|---|
| C3 glomerulopathy |
|
| Lupus nephritis |
|
| Poststreptococcal glomerulonephritis |
|
| Staphylococcal associated glomerulonephritis |
|
Epidemiology and Demographics
- The prevalence of C3 glomerulopathy is approximately 3 per 100,000 individuals worldwide.[16]
- Patients of all age groups may develop C3 glomerulopathy but it commonly affects young adults and children (Dense deposit disease)
- C3 glomerulopathy affects men and women equally.
- There is no racial predilection for C3 glomerulopathy.
Risk Factors
Common risk factors in the development of C3 glomerulopathy include:
- Family history of C3 glomerulopathy
- H/O autoimmune disorders
Screening
- There is insufficient evidence to recommend routine screening for C3 glomerulopathy. However, screening is indicated for family members of affected individuals using genetic testing.
Natural History, Complications and Prognosis
- Common complications of C3 glomerulopathy include renal failure, atherosclerosis, and vision loss.[17]
- Prognosis of C3 glomerulopathy is generally poor without proper treatment.
- 10 year mortality of patients with C3 glomerulopathy is approximately 36%.
Diagnosis
Diagnostic test of choice
Kidney biopsy is the gold standard test for the diagnosis of C3 glomerulopathy.
Symptoms
Common symptoms of C3 glomerulopathy may include:[18][19]
- Foamy urine due proteinuria
- Hematuria
- Signs of renal insufficiency like general fatigue or malaise
- Hypertension
- Hypocomplementimia
- Acquired lipodystrophy
- Macular (Drusen) deposits in the retina of the eye
| Characterstics | DDD | C3GN |
|---|---|---|
| Mean age | 14 | 24 |
| ESRD | 50% in 10 years | 10% in 2.5 years |
| Associated conditions |
|
- |
| C3 convertase dysregulation | ↑↑ | ↑ |
| C5 convertase dysregulation | ↑ | ↑↑ |
| C3NF | +++ | + |
| MAC | ↑ | ↑↑↑ |
Laboratory Findings
- C3 glomerulopathy is diagnosed using immunofluorescence microscopy and electron microscopy.
- There are no specific findings for C3 glomerulopathy on light microscopic.
- Findings on electron microscopy include[20][21]
- Sub-epithelial lumps
- Abnormal electron-dense material within the GBM
- Dense and linear in DDD
- Isolated in C3GN
- Findings on immunofluorescence microscopy include:
- C3 deposits along the Bowman's capsule of glomerular and tubular basement membranes.
Other Diagnostic tests
Other diagnostic tests that can help in diagnosing C3 glomerulopathy include:
- Measurement of complement C3, C3 Nef, serum factor H, CFHR ( Complement factor H-related protein)
- Serum protein electrophoresis, immunofixation and serum free light chains
- sMAC level activity
Physical Examination
Common physical examination findings of patients with C3 glomerulopathy include:
- High blood pressure
- Pallor skin
- Edema of extremities
- Periorbital Edema
- Lipodystrophy
Imaging Findings
- There are no specific imaging findings associated with C3 glomerulopathy.
Treatment
Medical Therapy
- The mainstay of treatment for C3 glomerulopathy is pharmacotherapy.[22][23]
- Pharmacotherpay can be catagorized into:
- Supportive therapy
- Specific therapy based on disease severity
Supportive Therapy
Supportive therapy include antihypertensive medications and lipid lowering
- Indicated in C3 glomerulopathy patients associated with HTN and proteinuria.
- Preferred regimen (1): ACE-inhibitors
- Preferred regimen (2): Angiotensin-11 receptor blockers
Specific therapy based on disease severity
- Mild disease
- Supportive therapy
- Regular follow up
- Moderate disease
- Disease due to auto-antibody
- Preferred regimen (1): Plasma exchange
- Alternative regimen (1): Rituximab
- Alternative regimen (2): Eculizumab 900 mg IV/week for 4-5 weeks followed by 1200 mg every 2 weeks for approximately one year.
- Disease due to factor H deficiency
- Preferred regimen (1): Fresh frozen plasma 10-15 mL/ kg body weight infused regularly x 14 days
- Disease due to C3 mutation
- Disease due to auto-antibody
- Severe disease with rapidly progressive worsening renal function:
- Preferred regimen (1): Cyclophosphamide
- Preferred regimen (2): Mycophenolate mofetil[27]
Surgery
- Surgical intervention is not recommended for the management of C3 glomerulopathy
Prevention
- There are no primary preventive measures available for C3 glomerulopathy.
References
- ↑ SELIGMANN M, HANAU C (1958). "[Immuno-electrophoretic study of the blood of disseminated lupus erythematosus patients]". Rev Hematol (in French). 13 (2): 239–48. PMID 13568372.
- ↑ WEST CD, NORTHWAY JD, DAVIS NC (August 1964). "SERUM LEVELS OF BETA-1C GLOBULIN, A COMPLEMENT COMPONENT, IN THE NEPHRITIDES, LIPOID NEPHROSIS, AND OTHER CONDITIONS". J. Clin. Invest. 43: 1507–17. doi:10.1172/JCI105027. PMC 441951. PMID 14201535.
- ↑ BERGER J, GALLE P (1962). "[Unusual change of the basal membranes of the kidney]". J Urol Nephrol (Paris). 68: 116–22. PMID 13867660.
- ↑ Fakhouri F, Frémeaux-Bacchi V, Noël LH, Cook HT, Pickering MC (August 2010). "C3 glomerulopathy: a new classification". Nat Rev Nephrol. 6 (8): 494–9. doi:10.1038/nrneph.2010.85. PMID 20606628.
- ↑ Appel GB, Cook HT, Hageman G, Jennette JC, Kashgarian M, Kirschfink M, Lambris JD, Lanning L, Lutz HU, Meri S, Rose NR, Salant DJ, Sethi S, Smith RJ, Smoyer W, Tully HF, Tully SP, Walker P, Welsh M, Würzner R, Zipfel PF (May 2005). "Membranoproliferative glomerulonephritis type II (dense deposit disease): an update". J. Am. Soc. Nephrol. 16 (5): 1392–403. doi:10.1681/ASN.2005010078. PMID 15800116.
- ↑ Servais A, Frémeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B; et al. (2007). "Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome". J Med Genet. 44 (3): 193–9. doi:10.1136/jmg.2006.045328. PMC 2598029. PMID 17018561.
- ↑ Schwertz R, de Jong R, Gretz N, Kirschfink M, Anders D, Schärer K (March 1996). "Outcome of idiopathic membranoproliferative glomerulonephritis in children. Arbeitsgemeinschaft Pädiatrische Nephrologie". Acta Paediatr. 85 (3): 308–12. PMID 8695987.
- ↑ Thomas S, Ranganathan D, Francis L, Madhan K, John GT (November 2014). "Current concepts in C3 glomerulopathy". Indian J Nephrol. 24 (6): 339–48. doi:10.4103/0971-4065.134089. PMC 4244712. PMID 25484526.
- ↑ Noris M, Remuzzi G (November 2013). "Overview of complement activation and regulation". Semin. Nephrol. 33 (6): 479–92. doi:10.1016/j.semnephrol.2013.08.001. PMC 3820029. PMID 24161035.
- ↑ Thomas S, Ranganathan D, Francis L, Madhan K, John GT (November 2014). "Current concepts in C3 glomerulopathy". Indian J Nephrol. 24 (6): 339–48. doi:10.4103/0971-4065.134089. PMC 4244712. PMID 25484526.
- ↑ Bomback AS, Appel GB (November 2012). "Pathogenesis of the C3 glomerulopathies and reclassification of MPGN". Nat Rev Nephrol. 8 (11): 634–42. doi:10.1038/nrneph.2012.213. PMID 23026947.
- ↑ Holers VM (June 2013). "Human C3 glomerulopathy provides unique insights into complement factor H-related protein function". J. Clin. Invest. 123 (6): 2357–60. doi:10.1172/JCI69684. PMC 3668810. PMID 23728171.
- ↑ Rodríguez de Córdoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sánchez-Corral P (June 2004). "The human complement factor H: functional roles, genetic variations and disease associations". Mol. Immunol. 41 (4): 355–67. doi:10.1016/j.molimm.2004.02.005. PMID 15163532.
- ↑ Noris M, Donadelli R, Remuzzi G (June 2018). "Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy". Pediatr. Nephrol. doi:10.1007/s00467-018-3989-0. PMID 29948306.
- ↑ Togarsimalemath SK, Sethi SK, Duggal R, Le Quintrec M, Jha P, Daniel R, Gonnet F, Bansal S, Roumenina LT, Fremeaux-Bacchi V, Kher V, Dragon-Durey MA (October 2017). "A novel CFHR1-CFHR5 hybrid leads to a familial dominant C3 glomerulopathy". Kidney Int. 92 (4): 876–887. doi:10.1016/j.kint.2017.04.025. PMID 28729035.
- ↑ Smith RJ, Alexander J, Barlow PN, Botto M, Cassavant TL, Cook HT; et al. (2007). "New approaches to the treatment of dense deposit disease". J Am Soc Nephrol. 18 (9): 2447–56. doi:10.1681/ASN.2007030356. PMC 4853920. PMID 17675665.
- ↑ Servais A, Noël LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grünfeld JP, Niaudet P, Lesavre P, Frémeaux-Bacchi V (August 2012). "Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies". Kidney Int. 82 (4): 454–64. doi:10.1038/ki.2012.63. PMID 22456601.
- ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean L, Stephens K, Amemiya A, Martín B, Smith R. PMID 20301598. Vancouver style error: initials (help); Missing or empty
|title=(help) - ↑ Ito N, Ohashi R, Nagata M (August 2017). "C3 glomerulopathy and current dilemmas". Clin. Exp. Nephrol. 21 (4): 541–551. doi:10.1007/s10157-016-1358-5. PMC 5721121. PMID 27878657.
- ↑ Thomas S, Ranganathan D, Francis L, Madhan K, John GT (November 2014). "Current concepts in C3 glomerulopathy". Indian J Nephrol. 24 (6): 339–48. doi:10.4103/0971-4065.134089. PMC 4244712. PMID 25484526.
- ↑ Habib R, Gubler MC, Loirat C, Mäiz HB, Levy M (April 1975). "Dense deposit disease: a variant of membranoproliferative glomerulonephritis". Kidney Int. 7 (4): 204–15. PMID 1095806.
- ↑ Sethi S, Fervenza FC, Zhang Y, Zand L, Vrana JA, Nasr SH, Theis JD, Dogan A, Smith RJ (August 2012). "C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up". Kidney Int. 82 (4): 465–73. doi:10.1038/ki.2012.212. PMC 4438675. PMID 22673887.
- ↑ Servais A, Frémeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B, Grünfeld JP, Lesavre P, Noël LH, Fakhouri F (March 2007). "Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome". J. Med. Genet. 44 (3): 193–9. doi:10.1136/jmg.2006.045328. PMC 2598029. PMID 17018561.
- ↑ McGinley E, Watkins R, McLay A, Boulton-Jones JM (1985). "Plasma exchange in the treatment of mesangiocapillary glomerulonephritis". Nephron. 40 (4): 385–90. doi:10.1159/000183504. PMID 4022205.
- ↑ Kurtz KA, Schlueter AJ (2002). "Management of membranoproliferative glomerulonephritis type II with plasmapheresis". J Clin Apher. 17 (3): 135–7. doi:10.1002/jca.10026. PMID 12378549.
- ↑ Krmar RT, Holtbäck U, Linné T, Berg UB, Celsi G, Söderberg MP, Wernerson A, Szakos A, Larsson S, Skattum L, Bárány P (February 2011). "Acute renal failure in dense deposit disease: complete recovery after combination therapy with immunosuppressant and plasma exchange". Clin. Nephrol. 75 Suppl 1: 4–10. PMID 21269585.
- ↑ Rabasco C, Cavero T, Román E, Rojas-Rivera J, Olea T, Espinosa M, Cabello V, Fernández-Juarez G, González F, Ávila A, Baltar JM, Díaz M, Alegre R, Elías S, Antón M, Frutos MA, Pobes A, Blasco M, Martín F, Bernis C, Macías M, Barroso S, de Lorenzo A, Ariceta G, López-Mendoza M, Rivas B, López-Revuelta K, Campistol JM, Mendizábal S, de Córdoba SR, Praga M (November 2015). "Effectiveness of mycophenolate mofetil in C3 glomerulonephritis". Kidney Int. 88 (5): 1153–60. doi:10.1038/ki.2015.227. PMID 26221755.