What are the other Names for this Condition? (Also known as/Synonyms)

• C3GN (C3 Glomerulonephritis)
• Complement Component 3 Glomerulopathy (C3G)
• DDD (Dense Deposit Disease)

What is C3 Glomerulopathy? (Definition/Background Information)

• C3 Glomerulopathy refers to a group of rare kidney-related disorders that has 2 major subtypes:
  • C3 Glomerulonephritis (C3GN)
  • C3 Glomerulopathy-Dense Deposit Disease (C3G-DDD)
• Both are differentiated on the basis of electron microscopy. The mean age of onset for DDD is earlier than that of C3GN, despite the fact that both can occur at any age
• Most cases of C3 Glomerulopathy have no known cause and the risk factors for such cases are currently unknown. A major risk factor for the inherited version of C3 Glomerulopathy is a family history of the condition
• In addition, a general family history of autoimmune disorders predisposes an individual to C3G. Nonetheless, an exact correlation between the two conditions is still not clearly understood
• The causes for most of the cases of C3 Glomerulopathy are still unknown. Mutations in the C3, CFH, and CFHR5 genes of the C3 complement system are known to cause this kidney disorder in certain cases. The complement system is a component of a body’s immune response involved in responding to invading entities such as bacteria and viruses
• The mutations in the aforementioned genes are known to deregulate the C3 system, leading it to become overactive. This leads to depositions of C3 protein due to damage to the cluster of blood vessels within the kidneys known as the glomeruli, which filter waste from the bloodstream
• The damage to the glomeruli results in the major symptoms of C3 Glomerulopathy including blood and protein in urine, reduced urine output, decrease in general alertness, and high blood pressure. Those with DDD also may have acquired lipodystrophy (lack of fat deposits in the body’s upper region) and deposits of a yellowish substance in the retina
• Some of the complications of C3 Glomerulopathy include progressive kidney damage leading to kidney failure, end-stage renal disease, and vision abnormalities
• A diagnosis of C3G may require a physical examination, an assessment of symptoms, an evaluation of family history, urine analysis, kidney biopsy, testing for blood C3 levels, and genetic testing
• There is currently no cure available for C3 Glomerulopathy; however, steps can be taken to slow the progression of the disorder. Treatment options can include medication to control the high blood pressure, use of steroids and other immunosuppressants, as well as monoclonal antibody-based therapy. When kidney failure ensues, dialysis and kidney transplantation become available options for treatment
• Thus far, no preventive methods or guidelines have been described for this disease. If there is a known family history of either C3 Glomerulopathy or autoimmune disorders, then it may be necessary to proceed with genetic testing of the fetal cells. This may allow the expecting parents to understand the disorder and its risks better
• Since C3 Glomerulopathy is a progressive disease, the prognosis is guarded. The 10-year life expectancy after diagnosis is approximately 65%. Even with kidney transplantation, there remains a 70% probability of the disease recurring in the transplanted kidney

Who gets C3 Glomerulopathy? (Age and Sex Distribution)

• C3 Glomerulopathy is a rare genetic disorder that is reported to affect 1 in every 500,000 individuals globally
• Although C3 Glomerulopathy can occur in individuals of all ages, the mean age of onset depends on the subtype of the disorder
  • The Dense Deposit Disease (DDD) appears to affect at an earlier age (adolescence) than C3 Glomerulonephritis (C3GN)
  • The prevalence of C3GN is 3 times higher than DDD
• Both male and female genders are susceptible to the disorder. Although, DDD is reported to be slightly more prevalent in females than in males
• No specific racial or ethnic predilection is noted

What are the Risk Factors for C3 Glomerulopathy? (Predisposing Factors)

The risk factors for most cases of C3 Glomerulopathy are unknown, since they are said to occur without a family history of the disorder.

• In very few cases, having one or more family members with the disorder is an established risk factor for developing the condition
• Inheriting genetic polymorphisms of the complement system i.e., normal variants of a group of genes in the complement system (termed “at-risk haplotype”), may increase the risk for developing C3 Glomerulopathy
• Having family members with autoimmune disorders appears to increase one’s risk of developing C3G, although the association between the two disorders is not very clear

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of C3 Glomerulopathy? (Etiology)

In most of the cases, the exact cause of C3 Glomerulopathy is unknown. It may be caused by yet unidentified mutations.

• In some cases, it is caused by genetic mutations and a number of these genes have been identified. Some of these genes have been characterized
  • Mutation in the C3, CFH and CFHR5 genes are known to cause the disorder in some populations; however, genetic mutations account for only a fraction of the known cases of C3 Glomerulopathy
  • Many of the affected genes are known to code for proteins that regulate the “complement system.” The complement system is a component of a body’s immune response, which works to destroy invading entities such as bacteria and viruses
  • The complement system triggers inflammatory processes in response to such invasions. The mutations in the genes of the complement system “upregulate” the system, leading to an “overactive” status
  • Loss of complement system regulation damages the glomeruli of the kidneys. The glomeruli are groups of blood vessels that help filter waste from the blood. This form of C3G is known as the C3 Glomerulonephritis (or C3GN)
  • The increased activity of the complement system can also affect fat and eye tissues in the affected individual. This type of disease is known as the “Dense Deposit Disease” or DDD, thus named, because of changes in the deposit of “electron-dense” material in the middle layer of the glomerular basement membrane, giving it a compartmentalized appearance
• Autoantibodies are antibodies directed against one’s own cells. Some studies indicate that such autoantibodies can cause C3 Glomerulopathy; however, the exact association between the two conditions is still not clear

What are the Signs and Symptoms of C3 Glomerulopathy?

The symptoms of C3 Glomerulopathy may differ depending on the type of C3G an individual develops:

• C3 Glomerulonephritis signs and symptoms may include:
  • Blood in urine or hematuria
  • Clouded appearance of urine
  • Protein in urine (proteinuria), which leads to urine that appears dark and foamy
  • Decreased urine output
  • Swelling in the legs and other body parts (edema)
  • High blood pressure
  • Reduced alertness
• C3 Glomerulopathy-Dense Deposit Disease signs and symptoms may include:
  • All the symptoms of C3GN may also occur in C3G-DDD
  • Lack of subcutaneous (beneath the skin) fat in the upper part of the body, termed as acquired lipodystrophy
  • Deposit of a yellowish substance (drusen) in the retina of the eye, with a potential to cause vision defects. This condition is also termed as Bruch’s membrane

How is C3 Glomerulopathy Diagnosed?

The diagnosis of C3 Glomerulopathy may be undertaken through the following tests and exams:

• Complete physical examination with an assessment of the symptoms
• An evaluation of family medical history in order to check for members with C3G, or identify individuals with autoimmune disorders
• Blood tests such as the following:
  • Complete blood count (CBC)
  • Blood glucose levels and hemoglobin A1c
  • Creatinine clearance blood test
  • Blood urea nitrogen (BUN) and creatinine levels
• Special blood tests to detect abnormal immune functions such as autoantibodies
• Blood test to check for levels of complement C3 in serum, which is often found to be low in this disease
• 24-hour urine protein analysis to detect blood and/or protein in urine
• Checking for autoimmune disorders
• Tests for ruling out hepatitis or other viral infections
• Ultrasound scan of the kidneys
• CT and MRI scan of the abdomen
• Intravenous pyelogram (IVP): A series of X-rays using contrast dyes to detect abnormalities in the kidneys
• Kidney biopsy to check for C3 deposits via immunofluorescence
  • A biopsy is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis
  • Biopsy specimens are studied initially using Hematoxylin and Eosin staining. The pathologist then decides on additional studies depending on the clinical situation
  • Sometimes, the pathologist may perform additional studies, which may include immunohistochemical stains, electron microscopy, and molecular studies to assist in the diagnosis
• Genetic testing for known mutations that cause the disorder

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of C3 Glomerulopathy?

Some of the potential complications from C3 Glomerulopathy include:

• Kidney failure
• Atherosclerosis, owing to increased lipid in blood
• Vision loss and related defects

How is C3 Glomerulopathy Treated?

There are no specific treatments available to cure C3 Glomerulopathy. Treatments are aimed at treating the symptoms and slowing progression of the disorder:

• Blood pressure control through medications such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type-1 receptor blockers (ARBs)
• Immunosuppressants, such as steroids and mycophenolic acid, to delay progression to end-stage kidney failure. The effect of these medications are reported to be inconsistent
• Monoclonal antibody therapy medications to block the terminal pathway of the complement system; this can help control the damage caused by the deposits
• Plasmapheresis: Plasma, which contains antibodies that destroys red blood cells, is removed from blood and donor (normal) plasma added. This new blood is introduced into the body through a blood transfusion procedure
• Dialysis to treat kidney failure
• Kidney transplantation, in case of end-stage kidney disease

How can C3 Glomerulopathy be Prevented?

• Currently, there are no specific methods or guidelines to prevent C3 Glomerulopathy, since it is a genetic condition
• If there is a family history of this disease or autoimmune disorders, genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks before planning for a child
• Active research is currently being performed in order to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as C3 Glomerulopathy
• Regular medical screening at periodic intervals with tests, and physical examinations are strongly recommended

What is the Prognosis of C3 Glomerulopathy? (Outcomes/Resolutions)

The prognosis of C3 Glomerulopathy is reported to be:

• Fatal for those with progressive kidney damage; more than 35% of the individuals diagnosed with this condition are known to succumb to the condition within 10 years
• The chances of the disorder recurring in the transplanted kidney are about 70% (following kidney transplantation procedure)

Additional and Relevant Useful Information for C3 Glomerulopathy:

Membranoproliferative glomerulonephritis (MPGN) includes several heterogeneous types of glomerulonephritis characterized by deposits in the glomerular mesangium of the kidney and thickening of the basement membrane. MPGN was previously categorised as type I, II or III, depending on the location and type of electron dense deposits seen on histology. It is now broadly categorized into:

• Immunoglobulin-mediated MPGN (typically caused by circulating immune complexes secondary to infections such as hepatitis B or C, or autoimmune conditions such as systemic lupus erythematosus)
• Complement-mediated MPGN (in which deposits of complement protein C3 are caused by dysregulation of the alternative complement system pathway, part of the body's immune system)
• MPGN that is not immunoglobulin- or complement-mediated