C3 glomerulopathy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ali Poyan Mehr, M.D. [2];Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [3]
Synonyms and keywords: glomerulonephritis; C3 glomerulonephritis; dense deposit disease
Overview
C3 glomerulopathy is a disorder of complement system, and can be due to inherited or acquired complement dysregulation and activation of the "alternative pathway". The category of C3 glomerulopathy contains a diverse group of disorders, including those leading to the inflammatory forms of C3 glomerulopathy, namely C3 glomerulonephritis (C3GN), as wells as those presenting as dense deposit disease (DDD). Both, C3GN and dense deposit disease are marked by C3 deposition along the capillary loop, the basement membrane, and the mesangium. It is a requirement for the diagnosis of C3 glomerulopathy, that the presence of C3 deposits comes without any concomitant immunoglobulin deposition.
The activation of the alternative pathway of the complement system can be either due to inherited, or acquired defects of the complement system. The inherited forms of complement dysregulation are due to numerous identified (and potentially yet to be identified) mutations of genes involved in complement pathway (see causes). The acquired forms of complement dysregulation are mostly due to autoimmunity against complement regulatory proteins.
Historical Perspective
- In 1915 William C. Gunn reported on the finding of low circulating complement levels in patients with acute infection and nephritic presentation
- Later on, additional reports on the involvement of complement system in other forms of inflammatory glomerulonephritis were presented, and their role further established.[1][2]
- In the year 1962, two renowned Nephro-pathologists, Jean Berger and Pierre Galle identified a rare glomerular lesion characterized by dense intramembranous deposits on transmission EM [3].
- The term dense deposit disease (DDD) was coined and described to be a disease entity associated with under belonging to the category of membrano-proliferative type glomerulonephritides (MPGN) (Mathew TH, Kincaid-Smith P).
- It took almost 50 years, until C3 glomerulopathy was identified as an independent disease entity, leading to potentially new diagnostic, therapeutic and prognostic opportunities. [4]
Classification
- Until recently,C3 glomerulopathy (C3 glomerulonephritis and DDD) were categorized under as a variant of MPGN, namely MPGN type 2. [5]
- In 2007, Servais A. et al described C3GN as an entity by itself. C3 glomerulonephritis was described as glomerular disease with deposits made up of only C3 without the presence of any immunoglobulins, that may or may not have a membranoproliferative pattern [6].
- Dense deposit disease refers to one subcategory of C3 glomerulopathy which is characterized by GBM deposits of C3 with characteristic appearance on electron micro graphs. Isolated C3 deposit in the glomerulus is the defining characteristics of C3 glomerulopathy. When deposit is linear, ribbon like and concentrated on the glomerular basement membrane, it is referred to as the Dense Deposit Disease (DDD). Currently, it is unknown whether the distinction between C3 glomerulonephritis and DDD has any therapeutic or prognostic relevance.
- C3 Glomerulopathy may be classified into 2 main subtypes/groups:
- Dense deposit disease (DDD)- more common in children, and is frequently associated with lipodystrophy.
- C3 Glomerulonephritis (C3GN)
Pathophysiology
- C3 glomerulopathy results from the appropriate or inappropriate activation of the alternative pathway of the complement system.
- The appropriate activation of complement system is under general circumstances triggered by infection. The inappropriate activation can be due to inherited or acquired disorders of complement pathway. Either a gain of function of complement “activators”, or a loss of function of complement “inhibitors” can lead to an activation of complement alternative pathway.
- Possible physiological and pathological activation mechanisms of the complement pathways which can contribute or lead to complement mediated glomerulopathy:
| Activation of Classic Complement Pathway | Activation of the Mannose-Binding-Lectin Pathway | Activation of Alternative Complement Pathway | ||||
|---|---|---|---|---|---|---|
| Acquired | Acquired | Acquired | Inherited | |||
| Infection | Apoptosis and necrosis | Infection | Infection | Autoimmune disorder | Paraneoplastic | Genetic mutations |
Causes
- Several genetic or acquired causes have been described to date:
- C3 mutations
- Complement Factor H (CFH):
- Like the majority of complement factors, CFH is a small glycoprotein which is produced in the liver, and circulates freely in the blood plasma .
- Several mutations in the CFH gene have been identified. While in type 1 mutations in this gene lead to a decrease in the level of functional CFH, the majority of mutations (type 2) do not affect the level of CFH, but rather decrease or diminish the function activity of this glycoprotein.
- Autoantibodies against CFH have been identified . [7]
- Complement Factor I (CFI):
- 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, which otherwise may initiate the formation of membrane attack complex.
- Mutations in the MCP gene can, similar to mutations in CFH lead to both, either a decrease in synthesis and expression of this protein, or a decreased activity.
- C3 nephritic factor (C3bBb antibody)
- Factor H antibody
- Factor I antibody
- Factor H mutations
- Factor I mutations
- Factor B mutations
- CR1 mutations
- CFHRs mutations[8]
- Dense Deposit Disease
Differentiating C3 Glomerulopathy from other Diseases
| Medical condition | Differentiating features |
|---|---|
| C3 glomerulopathy |
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| Lupus nephritis |
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| Poststreptococcal glomerulonephritis |
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| Staphylococcal associated glomerulonephritis |
|
Epidemiology and Demographics
- The prevalence of C3 glomerulopathy is approximately 3 per 100,000 individuals worldwide.
Age
- Patients of all age groups may develop C3 glomerulopathy but it commonly affects young adults and children (Dense deposit disease)
Gender
- C3 glomerulopathy affects men and women equally.
Race
- There is no racial predilection for C3 glomerulopathy.
Risk Factors
- Risk factors in the development of C3 glomerulopathy:
- Family history
- Having family members with autoimmune disorders
Natural History, Complications and Prognosis
- Common complications of C3 glomerulopathy include renal failure, atherosclerosis, and vision loss
- Prognosis of C3 glomerulopathy is generally poor, and 10 year mortality of patients is approximately 36%.
Diagnosis
Diagnostic test of choice
Gold standard test of choice for C3 glomerulopathy is kidney biopsy.
Symptoms
- Symptoms of C3 glomerulopathy may include the following:
- Foamy urine due proteinuria ( excessive protein in urine)or hematuria (blood in the urine)[9]
- Signs of renal insufficiency like general fatigue or malaise
- Hypertension (especially in children is a red flag )[10]
- Low serum C3 level
- Acquired lipodystrophy (loss of subcutaneous fat in the upper half of the body) in DDD
- Macular (Drusen) deposits in the retina of the eye (also seen in DDD)
Physical Examination
Appearance of the Patient
- Patients with C3 glomerulopathy usually appear cachectic.
Vital Signs
- New onset hypertension
Skin
HEENT
- HEENT examination of patients with C3 glomerulopathy is usually normal.
Neck
- Neck examination of patients with C3 glomerulopathy is usually normal.
Lungs
- Rales may be heard
Heart
- Cardiovascular examination of patients with C3 glomerulopathy is usually normal.
Abdomen
Laboratory Findings
- The following blood tests need to be done in the evaluation of C3 glomerulopathy .
- CBC
- Blood glucose levels and Hemoglobin A1C
- BUN and Creatinine levels
- Blood levels of Complement C3, C3 Nef, Serum factor H, CFHR ( Complement factor H-related protein)
- 24-hr urine protein analysis
Imaging Findings
- There are no imaging findings specific to C3 glomerulopathy.
Other Diagnostic Studies
- C3 glomerulopathy may also be diagnosed using light microscopy, immunofluorescence microscopy and electron microscopy
- Findings on electron microscopy include mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis and crescentic glomerulonephritis[11]
- Immunofluorescence microscopy: C3 deposits along the Bowman's capsule, glomerular and tubular basement membranes
- Electron microscopy findings in Dense Deposit Disease: Electron dense material in the glomerular basement membrane, lamina densa widening. Electron dense material is absent in C3 glomerulopathy. Subepithelial "humps" are found in both C3GN and Dense deposit disease. [12]
Treatment
Medical Therapy
- Patients with C3 glomerulopathy presents with rare form of glomerulonephritis called dense deposit disease which might end up in membranoproliferative glomerulonephritis (MPGN) pattern of injury on renal biopsy.[13][14]
- Patients with C3GN and Dense Deposit Disease who have hypertension or proteinuria receive an ACE-Inhibitor or Angiotensin-11 receptor blocker
- Disease due to genetic deficiency: The missing mutant protein should be replaced by the periodic infusion of fresh frozen plasma
- Disease secondary to autoantibody: Immunosuppression with Eculizumab and rituximab or plasma exchange
- Genetic activating mutation in C3: Plasma exchange
- Patients with progressively worsening renal function: Glucocorticoids with either cyclophosphamide (or) mycophenolate mofetil
- Patients with DDD or C3GN may be treated with lipid-lowering medications to prevent cardiovascular events.
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.
- ↑ 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.
- ↑ 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.