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] Olufunmilola Olubukola M.D.[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. 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.

C3 Glomerulopathies include the Dense Deposit Disease (DDD) and C3 Glomerulonephritis (C3GN). These diseases are very rare, with the Dense deposit disease (DDD) affecting only about two to three people per one million . Clinical presentation of C3 Glomerulopathies varies but diagnosis is by electron microscopy of kidney biopsy specimen.

Historical Perspective

The association between GN and low serum levels of complement proteins was first recognized by the pathologist Gunn WC in the early 1900 (Gunn WC). In the 1960s, the several researchers were able to determine the role of complement activation in several glomerulopathies .

In the year 1962, renowned Nephrologists, Berger J, Galle P identified a rare glomerular lesion characterized by dense intramembranous deposits with transmission EM . These were later denoted as the Dense Deposit Disease (DDD) which was described as an entity of the Membranoproliferative Glomerulonephritis (MPGN) (Mathew TH, Kincaid-Smith P).

Until recently, C3 glomerulopathy was thought to be a variant of MPGN. In 2007, Servais A. et al described C3GN as an entity by itself. C3 glomerulopathy was described as glomerular deposits made up of only C3 without any immunoglobulin deposits, that may or may not have a membranoproliferative pattern, and without any electron-dense intramembranous deposits

Classification

• C3 Glomerulopathy may be classified according to [classification method] into 2 main subtypes/groups:

• Dense Deposit Disease (DDD)
• C3 Glomerulonephritis (C3GN)

• Other variants of [disease name] include CFHR5 nephropathy is a form of C3GN.

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).

Dense Deposit Disease (DDD) is commoner in children although it is not exclusively a childhood illness. Cases of Dense Deposit Disease had been reported in older adults > 60 years old but it is a primarily a disease of children.

Another type of C3 glomerulopathy is C3 Glomerulonephritis (C3GN). C3GN is a subtype of C3 glomerulopathy in which C3 deposits are found in the small blood vessels of the kidney's glomeruli. This differs from DDD in that there are no linear deposits of c3 on the glomerular basement membrane.

CFHR5 nephropathy is a form of C3GN that has been described as genetically transmitted in some races. In this subtype, blood C3 levels are almost normal, suggesting that excessive C3 activation occurs not in the blood stream (as in DDD) but within the kidney.

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 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

• 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].