C3 glomerulopathy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ali Poyan Mehr, M.D. [2]

Synonyms and keywords: Synonym 1; Synonym 2; Synonym 3

Overview

C3 glomerulopathy is a disorder of complement system, and can be due to inherited or acquired complement dysregulation. It contains a diverse group of disorders including the inflammatory forms of C3 glomerulopathy, namely C3 glomerulonephritis, as wells as dense deposit disease, which is marked by C3 deposition at the basement membrane. Their common hallmark is C3 deposition within the structures of the glomerulus due to an overactive complement system.

This complement dysregulation can be either inherited, or acquired. 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). A well known disorder of complement pathway for example is the atypical hemolytic uremic syndrome.

Historical Perspective

• [Disease name] was first discovered by [scientist name], a [nationality + occupation], in [year] during/following [event].
• In [year], [gene] mutations were first identified in the pathogenesis of [disease name].
• In [year], the first [discovery] was developed by [scientist] to treat/diagnose [disease name].

Classification

• [Disease name] may be classified according to [classification method] into [number] subtypes/groups:

• [group1]
• [group2]
• [group3]

• Other variants of [disease name] include [disease subtype 1], [disease subtype 2], and [disease subtype 3].

Pathophysiology

• The pathogenesis of [disease name] is characterized by [feature1], [feature2], and [feature3].
• The [gene name] gene/Mutation in [gene name] has been associated with the development of [disease name], involving the [molecular pathway] pathway.
• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Causes

• C3 glomerulopathy includes several distinct disorders, each with their on underlying etiology and pathomechanism. The common denominator is glomerular injury due to complement activation and glomerular C3 deposition. This 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 overactive alternative pathway,

• C3 mutations:

Mutations in C3 have been described, whereby the mutant protein is resistant to the inhibitory effects of Membrane Cofactor Protein:

• C3 glomerulonephritis:

• 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
• Membrane cofactor protein mutations
• CR1 mutations
• CFHRs mutations

• Dense Deposit Disease

Dense Deposit Disease (DDD) is a variant form of C3 glomerulopathy and is marked by C3 deposition along the glomerular basement membrane. Under the electron microscope, these deposits appear as electron dense material along the lamina densa of the GBM. Hence being called dense deposit disease. Dense deposit disease (associated with lipodystrophy) Dense deposit disease (associated with other; specify) Dense deposit disease (no association)

Differentiating [disease name] from other Diseases

• [Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as:

• [Differential dx1]
• [Differential dx2]
• [Differential dx3]

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 [disease name] is made when at least [number] of the following [number] diagnostic criteria are met:

• [criterion 1]
• [criterion 2]
• [criterion 3]
• [criterion 4]

Symptoms

• [Disease name] is usually asymptomatic.
• Symptoms of [disease name] may include the following:

• [symptom 1]
• [symptom 2]
• [symptom 3]
• [symptom 4]
• [symptom 5]
• [symptom 6]

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

• There is no treatment for [disease name]; the mainstay of therapy is supportive care.

• The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
• [Medical therapy 1] acts by [mechanism of action 1].
• Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

Surgery

• Surgery is the mainstay of therapy for [disease name].
• [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
• [Surgical procedure] can only be performed for patients with [disease stage] [disease name].

Prevention

• There are no primary preventive measures available for [disease name].

• 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].