C3 Glomerulopathy: Dense Deposit Disease And C3 Glomerulonephritis

C3 Glomerulopathy

Complement 3 Glomerulopathy (C3G) is a rare kidney disease characterised by abnormal deposits of the complement protein C3 within glomeruli. It is caused by dysregulation of the alternative complement system pathway, which is part of the body’s immune system. It has two forms: dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The incidence of C3 Glomerulopathy is 1-2 per million population per year. It affects people of all ages. 50% of patients with C3G will progress to end-stage renal disease within 5 years of diagnosis, with DDD patients progressing at twice the rate of CG3N patients.¹

Dense deposit disease (DDD)

Dense deposit disease (DDD) is characterised by dense sausage-like deposits that can be seen in the glomerular basement membrane (GBM) using an electron microscope when looking at a renal biopsy. It is associated with deposits of C3 in the glomeruli with little or no staining for immunoglobulin. DDD primarily affects children and young adults. DDD patients also develop drusen, which has a risk of vision problems. DDD progresses to end-stage renal failure and with transplantation, the graft fails within 5 years in 50% of cases.²

C3 Glomerulonephritis (C3GN)

C3 Glomerulonephritis (C3GN) is characterised by the presence of less dense deposits of C3 in the mesangial, subendothelial, and subepithelial areas of glomeruli.³ C3GN tends to affect slightly older people than DDD.⁴

Role of the complement system

The complement system is part of the immune system and plays a critical role in inflammation and in helping to fight off bacterial infections. The complement system can also be activated due to autoimmune diseases. It consists of about 50 proteins circulating in the blood and tissue fluids. Most of the proteins are inactive until they are triggered. Triggers can include an injury or bacteria that enter the body. The proteins then become activated in a chain reaction known as an enzyme cascade, where one protein activates the next one. 

The complement system can be activated by three different pathways: the classical pathway, the alternative pathway and the mannose-binding lectin (MBL) pathway. All three pathways lead to the activation of C3, which is split into a large fragment C3b, which acts as an opsonin, and a small fragment C3a, which acts as an anaphylatoxin and promotes inflammation. The alternative pathway can lead to the activation of more C3, known as an “amplification loop”.

What causes C3 Glomerulopathy?

When the complement system stops working as it should, the C3 proteins get trapped in the glomeruli, which makes it harder for the kidneys to filter the blood or create urine. Over time, this can damage the kidneys. Some patients with C3G have defects of regulatory proteins, inhibitors or accelerators of the alternative complement pathway.⁵ Some are caused by genetic mutations in the C3, CFH and other complement system genes. It may also be caused by monoclonal gammopathy, which causes a buildup of faulty antibodies (M proteins) in the kidneys, which can lead to kidney damage. This kidney damage then disrupts the alternative pathway of the complement system.

Symptoms

Symptoms of both types of C3G include:

• Blood in the urine (hematuria)
• High levels of protein in the urine (proteinuria)
• Urinating less than usual (oliguria)
• Low levels of protein in the blood (hypoalbuminemia)
• Oedema, usually of ankles, feet and hands
• High blood pressure (hypertension)
• Recurrent infections
• Fatigue
• Gout

Both types of C3G can also lead to kidney failure. Symptoms of kidney failure can include:

• Producing little or no urine 
• Pain, stiffness or fluid in your joints
• Confusion or trouble concentrating
• Nausea or vomiting

C3G can also cause other symptoms not relating to the kidneys, such as:

• Vision problems (drusen), due to the accumulation of protein and calcium deposits in the macula.
• Lipodystrophy is caused by a problem with, which the body stores and uses fats.

Diagnosis 

Various tests to evaluate the kidneys’ health and function may be used in order to diagnose C3G. These include:

• Blood tests examine the complement proteins in the blood to determine whether they are normal or if there is an excessive buildup.
• estimated glomerular filtration rate (eGFR) which shows how well the kidneys are filtering the blood. This is done using a blood test, which measures how well your kidneys are filtering the creatinine (a waste product from the normal wear and tear on muscles) or cystatin C (a protein that slows down the breakdown of other protein cells) in the blood.
• Urinalysis (urine test) to check the urine for microscopic amounts of protein or blood.
• A kidney biopsy can be used to determine which of the two types of C3G the patient has. A specialist will take a small tissue sample to look at the C3 proteins in your glomeruli. This can also be used to look for the presence of dense deposits.

Management and treatment

There is no cure for C3G, however, there are treatments available that can provide relief from symptoms and slow down the progression. These include:

• Blood pressure medications such as angiotensin-converting enzyme (ACE) Inhibitors and angiotensin II receptor blockers have been shown to be effective in other glomerular diseases in slowing the progression to renal failure, as they reduce the pressure inside the glomeruli.⁶
• Immunosuppressive therapies, such as a combination of corticosteroids and mycophenolate mofetil (MMF), are used to inhibit the immune response and prevent the immune system from attacking the glomeruli.
• Eculizumab is a monoclonal antibody that attaches to the C5 complement protein and inhibits complement activation, which stops complement proteins from damaging cells.
• Cholesterol-lowering drugs such as statins and changes in a patient’s diet may be recommended to reduce sodium, saturated fat and cholesterol and, therefore, help to reduce kidney damage.  

As approximately 50% of patients with C3G develop kidney failure dialysis or a kidney transplant may be needed.¹

FAQs

How common is C3 Glomerulopathy?

C3 Glomerulopathy is a very rare condition. It only affects 1-2 out of a million people a year.

Is there a cure for C3 Glomerulopathy?

Unfortunately, there is no cure for C3 glomerulopathy at the moment, but new medications are constantly being trialled.

What is C3 Glomerulopathy?

C3 Glomerulopathy is a rare kidney disease characterised by abnormal deposits of the C3 protein in the glomeruli. There are two forms of C3 glomerulopathy.

What causes C3 Glomerulopathy?

C3 Glomerulopathy is caused by a dysregulation of the alternative pathway of the complement system, which causes a buildup of C3 proteins in the glomeruli. This may be due to genetic or other factors.

Summary

C3G Glomerulopathy (C3G) is a rare kidney disease characterised by activation of the alternative pathway of the complement system, leading to abnormal deposits of the complement protein C3 in the glomeruli. This prevents your kidneys from filtering blood as efficiently as they should. There are two forms of C3G, which can be classified depending on the absence of dense deposits under the microscope: dense deposit disease (DDD) and C3 Glomerulonephritis (C3GN).

At the moment, there is no cure for C3G, and 50% of patients with C3G go on to develop kidney failure within 10 years of diagnosis. However, with proper diagnosis and treatment, such as medication, supportive therapies and lifestyle changes, patients can still live a long, fulfilled life.