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 DDD 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.
Classification
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-Lictin 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:
Mutations in C3 have been described, whereby the mutant protein is resistant to the inhibitory effects of Membrane Cofactor Protein (ref needed)
- 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 (ref). Several mutation in the CFH gene have been identified (ref OMIM). 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 in up to xx of cases (ref). Here, a binding of the antibody to the glycoproteins leads to functional inactivation and removal of CFH from the plasma.
- 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
- Dense Deposit Disease
Differentiating C3 glomerulopathy from other Diseases
C3 glomerulopathy is differentiated from other inflammatory glomerulopathies by the sole presence of C3 deposits without any immune-complex depositions.
Epidemiology and Demographics
C3 Glomerulopathies are rare, with the Dense deposit disease (DDD) affecting only about two to three people per one million [1] and C3. Clinical presentation of C3 Glomerulopathies varies but diagnosis is by electron microscopy of kidney biopsy specimen.
Risk factors
Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms | Physical Examination | Laboratory Findings | X ray | CT | MRI | Echocardiography or Ultrasound | Other Imaging Studies | Other Diagnostic Studies
Treatment
Surgery | Medical therapy | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies
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 DDD 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 (DOI: 10.1002/path.1700190202). Later on, additional reports on the involvement of complement system in other forms of inflammatory glomerulonephritis were presented, and their role further established (PMID:13568372) (PMID: 14201535) [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] (PMID: 20606628).
Classification
Until recently, C3 glomerulopathy (C3 glomerulonephritis and DDD) were categorized under as a variant of MPGN, namely MPGN type 2 (PMID: 15800116). 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 [5]. 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 according to [classification method] into 2 main subtypes/groups:
- Dense Deposit Disease (DDD)
- C3 Glomerulonephritis (C3GN)
Dense Deposit Disease (DDD) is more common in children, and is frequently associated with lipodystrophy.
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-Lictin Pathway | Activation of Alternative Complement Pathway | ||||
|---|---|---|---|---|---|---|
| Acquired | Acquired | Acquired | Inherited | |||
| Infection | Apoptosis and necrosis | Infection | Infection | Autoimmune disorder | Paraneoplastic | Genetic mutations |
Causes
Differentiating C3 Glomerulopathy from other Diseases
- C3 glomerulopathy must be differentiated from other diseases that cause inflammatory glomerulonephritis with glomerular complement deposition such as:
- Infection-related glomerulonephritis
- Lupus nephritis
- Paraprotein related glomerulonephritis.
Epidemiology and Demographics
- The prevalence of [disease name] is approximately [number or range] per 100,000 individuals worldwide.
- In [year], the incidence of [disease name] was estimated to be [number or range] cases per 100,000 individuals in [location].
Age
- Patients of all age groups may develop [disease name].
- [Disease name] is more commonly observed among patients aged [age range] years old.
- [Disease name] is more commonly observed among [elderly patients/young patients/children].
Gender
- [Disease name] affects men and women equally.
- [Gender 1] are more commonly affected with [disease name] than [gender 2].
- The [gender 1] to [Gender 2] ratio is approximately [number > 1] to 1.
Race
- There is no racial predilection for [disease name].
- [Disease name] usually affects individuals of the [race 1] race.
- [Race 2] individuals are less likely to develop [disease name].
Risk Factors
- Common risk factors in the development of [disease name] are [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].
Natural History, Complications and Prognosis
- The majority of patients with [disease name] remain asymptomatic for [duration/years].
- Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
- If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
- Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
- Prognosis is generally [excellent/good/poor], and the [1/5/10year mortality/survival rate] of patients with [disease name] is approximately [#%].
Diagnosis
Diagnostic Criteria
- The diagnosis of C3 glomerulopathy is made by one of the following techniques:
- C3 nephropathies are diagnosed by light and electron microscopy of kidney biopsy specimen. Electron microscopy can be used to differentiate DDD from other C3 Glomerulopathies.
- Other specialized diagnostic techniques include: Serum C3 and C4 levels, Serum Protein Electrophoresis studies, Genetic screening.
- The kidney biopsy and blood tests are currently done only in highly specialized laboratories.
Symptoms
- [Disease name] is usually asymptomatic.
- Symptoms of C3 glomerulopathy may include the following:
- Foamy urine due proteinuria ( excessive protein in urine)or hematuria (blood in the urine)
- Signs of renal insufficiency like general fatigue or malaise
- Hypertension (especially in children is a red flag )
- 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
- Patients with [disease name] usually appear [general appearance].
- Physical examination may be remarkable for:
- [finding 1]
- [finding 2]
- [finding 3]
- [finding 4]
- [finding 5]
- [finding 6]
Laboratory Findings
- There are no specific laboratory findings associated with [disease name].
- A [positive/negative] [test name] is diagnostic of [disease name].
- An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
- Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].
Imaging Findings
- There are no [imaging study] findings associated with [disease name].
- [Imaging study 1] is the imaging modality of choice for [disease name].
- On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
- [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].
Other Diagnostic Studies
- [Disease name] may also be diagnosed using [diagnostic study name].
- Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].
Treatment
Medical Therapy
- Treatment is based on type of C3 glomerulopathy, severity and available treatment modalities.
- Adequate control of proteinuria and hypertension is important. T.
- Patients with DDD or C3GN may be treated with lipid lowering medications to prevent cardiovascular events.
- All patients should be closely monitored with scheduled checkups and diagnostic laboratory workups.
- Genetic screening is also advised for family members of patients that have genetic mutations.
- Patients’ support groups can be found with groups like NEPHCURE Kidney International and other foundation that provide support for kidney patients and their families.
Prevention
- There are no primary preventive measures available for C3 glomerulopathy .
- Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].
- Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].
References
- ↑ 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.
- ↑ LACHMANN PJ, MULLER-EBERHARD HJ, KUNKEL HG, PARONETTO F (1962). "The localization of in vivo bound complement in tissue section". J Exp Med. 115: 63–82. PMC 2137475. PMID 14461382.
- ↑ BERGER J, GALLE P (1962). "[Unusual change of the basal membranes of the kidney]". J Urol Nephrol (Paris). 68: 116–22. PMID 13867660.
- ↑ 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.
- ↑ 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.