C3 Glomerulonephritis & IC-MPGN

General information about the kidneys

About the disease

• What is the glomerulus? What does glomerulonephritis mean?
• What is a C3G and IC-MPGN?
• How often do these diseases occur?
• What are the causes of those diseases?
  • What is an Autoimmune diseases?
  • What is the immune system?
  • What are immunoglobins and what is complement system?
  • What is the complement system?
  • Complement System Dysregulation in IC-MPGN and C3G
  • Why are the kidneys affected when the immune system is dysregulated?

Symptoms

• Urine abnormality
• How is chronic kidney failure manifested?
• Drusen
• Lipodystrophy

Diagnosis

• Kidney biopsy
• COMPLEMENT WORKUP INCLUDING GENETIC TESTING
• Assessment of kidney function
• Understanding your blood and urine tests 

Treatment

• Supportive Therapies
• What can I do myself to manage my disease? How to live with the disease?
• Immunosupression
• Complement System Inhibitions

Prognosis and Complications

• What will happen to me / my child in the future?
• Pregnancy
• When to worry / contact my doctors?
• How do I use the urine strip test correctly?
• How do I measure my blood pressure correctly?
• Psychological consequences – The disease as a challenge

The Compcure Registry & Network

App INSIGHT KIDNEY

References

Please read here: General information about the kidneys

Please read here: App INSIGHT KIDNEY

Each kidney consists of about one million functional units, the so-called nephrons. The number of nephrons is individual determined and depending on many factors. For the kidney to function properly, it is necessary to keep at least 30% of the nephrons in operation to work well. The nephron is made of two essential parts: the glomerulus and the tubule.

Glomerulonephritis (GN) refers to inflammation of the glomeruli, the tiny filtering units of the kidneys. 

Inflammation is the body's response to injury or infection. It refers to all activities of the immune system that occur where the body is trying to fight off potential or real infections, clear toxic molecules or recover from physical injury. When glomerulonephritis occurs, the inflammation can impair the kidneys' ability to perform their essential function, potentially leading to kidney damage and even failure if left untreated. Glomerulonephritis can vary in severity and may result from different causes. It can be due to a primary immune system disorder (immune-mediated disease), or it may be secondary to other conditions such as previous infections, medications, systemic diseases, or cancer. Additionally, the deposition of certain proteins in the glomeruli can trigger inflammation and affect kidney function.

What is an Immune-complex membranoproliferative glomerulonephritis (IC-MPGN)?
 

IC-MPGN is a type of kidney disease where the glomeruli (the tiny filters in the kidneys) become inflamed due to immune system problems. This happens when the immune system mistakenly attacks the kidneys, causing harmful substances to build up in the filters. This damage makes it harder for the kidneys to remove waste and extra fluid from the body. To diagnose IC-MPGN, doctors may need to take a small sample of the kidney (biopsy) and use special tests to look for immune deposits.

There are two types of IC-MPGN:

C3 glomerulopathy (C3G) is a rare and serious kidney disease caused by dysregulation of the complement system – a system which plays a key role in the body’s immune defense (the explanation of this term please also see below) – characterized by the abnormal accumulation of the complement protein called C3 in the glomeruli. This accumulation leads to inflammation and damage to the kidney tissue, impairing their ability to filter waste and fluids from the blood.

In C3G, the complement system doesn’t work properly, either because of genetic changes or other factors (for more details see below: What is the complement system? Pathophysiology in IC-MPGN and C3G). To diagnose C3G, doctors usually need to take a small sample of the kidney (called a biopsy) and use a special microscope (called immunofluorescence microscope) to look at it closely. This helps them see the specific changes in the kidneys. There are two types of C3G: Dense Deposit Disease (DDD) and C3 Glomerulonephritis (C3GN). The difference between them is determined by examining the kidney tissue under another special microscope called electron microscopy (EM), which allows doctors to see the detailed structure of the kidney at a very small scale.

How often do these diseases occur?
 

C3G is considered very rare, affecting 1-2 in a million people per year. It is more common in children, but it can also occur in adults.

IC-MPGN is also rare, though it is somewhat more common than C3G. It can occur at any age, but it is more frequently diagnosed in adults. The exact incidence is hard to determine, but it is still considered a rare condition.

We will focus on the primary idiopathic forms of IC-MPGN and C3G. Both are autoimmune diseases where the complement system, which helps protect the body, is not properly regulated. This leads to the immune system mistakenly attacking the kidneys and causing damage to the kidney tissue. It is important to note that secondary forms of these diseases must always be ruled out for an accurate diagnosis. These conditions (some of which are listed below in causes and triggers of secondary IC-MPGN and C3G) may trigger or contribute to the development of IC-MPGN and C3G, and their potential role must always be considered in the diagnostic process.

Autoimmune Disease
 

An autoimmune disease happens when the immune system, which normally defends the body against harmful invaders like viruses and bacteria, starts attacking healthy tissues by mistake. 

This happens because the immune system produces antibodies that target the body’s own cells, causing inflammation and damage. Over time, this damage can impair the function of organs, leading to problems like joint pain, skin rashes, or even organ failure, depending on which tissues are affected. While the exact cause isn't fully understood, it's thought that genetics, infections, medications, or even hormones might trigger the disease. 
The immune system protects the body from harmful invaders like bacteria and viruses, but it can be weakened by diseases or become overactive, leading to autoimmune conditions where it attacks the body’s own tissues.
 

Key components of the immune system:

Complement System
 

The complement system is a part of the immune system that helps protect the body from infections and remove damaged cells. 

It consists of proteins in the blood and tissues that work together to fight infections, promote inflammation, and clear dead cells. The system can be activated in three different ways, ultimately forming the membrane attack complex (MAC) that destroys harmful cells or pathogens. If any of these pathways are not properly controlled, they can contribute to diseases like C3G and IC-MPGN.
 

Complement System Dysregulation in IC-MPGN and C3G
Both diseases IC-MPGN and C3G share overlapping pathological features, with a central role of the complement system in the progression of both diseases. In these diseases, the complement system becomes dysregulated, mistakenly attacking the kidneys, leading to inflammation and damage to kidney tissues.
 

Complement System Overactivation in C3G
In C3G, the complement system is over-activated. This overactivation triggers the inappropriate activation of C3 protein, causing it to accumulate in the glomeruli. This accumulation results in kidney inflammation and damage, impairing the kidney's ability to filter waste from the blood.
 

Genetic and Acquired Factors Driving Complement Dysregulation
The overactivation in C3G can be driven by both genetic abnormalities and acquired autoantibodies:

⤷ Genetic Abnormalities
Genetic mutations in the complement pathway are commonly found in patients with C3G. These mutations can lead to a loss of regulation and cause persistent activation of the complement pathway, which results in kidney damage.

⤷ Acquired Autoantibodies
In addition to genetic factors, acquired autoantibodies against complement proteins, such as C3 nephritic factor (C3NeF) and C5 nephritic factor (C5NeF), are often present in C3G patients. These autoantibodies stabilize the complement system, prolonging his activity and causing ongoing complement activation. This prolonged activation exacerbates the inflammation and damage in the glomeruli.

Although IC-MPGN mainly happens when the immune system creates harmful proteins that build up in the kidneys. However, problems with the complement system can also make the disease worse. Like C3G, IC-MPGN can be influenced by changes in the complement system, especially if someone has certain genetic or health issues. This shows that both diseases are complex and can be caused by different factors.

 

The kidneys are highly vascular organs, receiving about 20-25% of the blood pumped by the heart with each beat—roughly 1-1.2 liters per minute, or 1,500 to 1,700 liters per day in adults. As the body's primary filtering system, the kidneys are constantly exposed to the extensive blood supply. 
When the immune system is dysregulated, the immune complexes (clusters of antibodies and antigens) or complement proteins can circulate throughout the body, including the kidneys. The glomerulus, which acts as a filter in the kidney, is particularly susceptible to these deposits. Due to the high blood flow, immune complexes can become trapped in glomerulus in the glomerular membrane, where they end up as deposits and lead to inflammation and damage. 

Some of the causes and triggers of secondary IC-MPGN and C3G:

The course of the diseases can vary widely among affected individuals.
The diseases are almost always painless. Due to the overlooked and non-specific symptoms, the diagnosis is often made accidentally, when the presence of blood and / or proteins is detected in the urine during routine check-ups. Symptoms can vary from patient to patient. In early stages of the disease, it is possible that some patients with IC-MPGN or C3G do not have any obvious complaints or symptoms yet. The kidney-related symptoms depend on the severity of the damage of the glomeruli. The symptoms may become worse as the disease progresses.
 

The urine abnormalities associated with those diseases are:

How is chronic kidney failure manifested?

Other symptoms of advanced kidney failure (i.e. GFR below 20-30 ml/min) may include:

In severe kidney disease, symptoms may be subtle and develop slowly, often becoming noticeable only in advanced stages or when kidney function suddenly declines.

Extrarenal abnormalities (issues affecting organs outside the kidneys)

The following extrarenal abnormalities could be observed in patients with C3 glomerulopathy:

⤷ Drusen
Small yellow deposits in the retina, called drusen, can cause vision problems but are not closely linked to kidney disease activity. C3G patients should have regular eye check-ups to monitor for drusen and other issues.

⤷ Acquired partial lipodystrophy (APL)
It means changes in fat distribution in the body, like loss of fat in some areas and buildup in others. 

The diagnosis of IC-MPGN and C3G requires a comprehensive approach utilizing 
⤷ KIDNEY BIOPSY, 
⤷ COMPLEMENT WORKUP,
⤷ GENETIC TESTING, AND
⤷ EVALUATION OF NONCOMPLEMENT ETIOLOGIES,
particularly in the context of IC-MPGN.

IC-MPGN and C3G have no specific symptoms, but signs of kidney damage can be seen through tests. A kidney biopsy, using special microscopy (immunofluorescence microscopy), is needed for a definitive diagnosis and to guide treatment. This is the only way to make a reliable and precise diagnosis. 

What should I do before and after biopsy?

Before a kidney biopsy, inform your healthcare team about your medications, allergies, and any blood-thinning drugs, and follow their advice on stopping these meds. You’ll need to fast for about 8 hours before the procedure, and after the biopsy, you’ll be monitored for complications, with most patients able to leave within 12-24 hours. Avoid strenuous activities for a week, and contact the hospital if you experience issues like bleeding, fever, or changes in urine.

Additional diagnostic tests include blood- and urine sample analysis:

What do the results mean?

Creatinine is a waste product from muscles that the kidneys filter out, so high levels in the blood can suggest kidney problems, but it doesn’t detect early damage well.

Cystatin C is a better marker for early kidney damage, as its levels aren’t affected by age, weight, or muscle, and it’s often used along with creatinine and eGFR (estimated Glomerular Filtration Rate - which measures how well the kidneys are filtering blood) to check kidney function more accurately.

How does a urine test work?

⚠️ Urine test is essential to assess for hematuria and proteinuria — the presence of blood and excess protein in the urine. These indicators can reveal important information about kidney function and potential damage, aiding in the diagnosis and monitoring of the disease.
 

A urine test can help check for kidney or urinary tract issues and provide information about other conditions like diabetes or liver disease by examining things like color, protein, glucose, and bacteria. Depending on the test, you may need a midstream urine sample, where you collect the middle part of your urine to avoid contamination, or a 24-hour urine collection, where you gather all your urine over a day to measure substances filtered by your kidneys.
 

What do the results mean?

A urine sample is first checked by eye for clarity and color, which can show if you're well-hydrated or if there might be an infection or other health issues. Then, it's examined under a microscope to look for things like blood or cells that can’t be seen by the eye. A test strip can also be dipped into the sample to check for substances like protein, which helps doctors assess kidney function, especially in conditions like IC-MPGN and C3G.

Treatment of Secondary IC-MPGN

In secondary IC-MPGN, the disease is triggered by an infection or underlying condition, and treatment focuses on targeting the infection with appropriate medications, while avoiding immunosuppressive drugs that could worsen the condition.

Treatment of Idiopathic or Primary IC-MPGN and C3G

Current treatments for C3G and IC-MPGN mainly focus on supportive care for mild cases and nonspecific immunosuppression (MMF plus glucocorticoids) for moderate to severe disease. However, these treatments have limited benefits, and alternative options may be needed for some patients.

The future of treating IC-MPGN and C3G looks promising, with trials focused on targeted therapies to regulate the complement system. 
C3G and IC-MPGN don't have a standard treatment because they are rare, require expensive tests, and can vary a lot from person to person. While no treatment can completely stop the disease, symptoms can be managed, and research is important for finding better treatments.

⚠️ Please consult your physician to discuss your individual treatment options.

Supportive Therapy 

Supportive therapy is not intended to cure the disease, but aims to improve the patient's overall condition, ease symptoms, and support the main treatment by managing factors like nutrition, mental health, and other health issues.

Antiproteinuric/renoprotective therapy

Additional kidney protective measures include a low-salt diet, treatment of dyslipidaemia and hypertension.

Blood pressure control is crucial in supportive therapy to protect kidney function and prevent further damage. A general healthy lifestyle including quitting smoking and drinking alcohol, maintaining a healthy low sodium diet, and exercising regularly improves overall health and helps to manage the condition. It is beneficial to keep the body weight in the normal range and avoid obesity.
 

What can I do myself to manage my disease? How to live with the disease? 
Living a healthy lifestyle can slow disease progression, so it’s important to stay informed, manage your symptoms, and work closely with your doctor to control blood pressure, check urine for protein, follow a kidney-friendly diet, avoid harmful substances, and get regular exercise and sleep. Focus on mental well-being and don't hesitate to ask for support or advice from healthcare professionals.

Vaccinations

Supportive therapy for C3G and IC-MPGN includes infection prevention through vaccinations (pneumococcus, meningococcus, influenza) and good hygiene practices to reduce exposure to germs.

Plasma exchange

Plasma exchange allows the elimination of potentially harmful substances form the body. This can be dysfunctional complement factors or harmful antibodies which circulate in the blood. In some cases, this therapeutic approach has result in a partial therapeutic response. 

Dialysis

Dialysis is a blood purification procedure which artificially cleanses the blood, mimicking the natural function of the kidneys. 

During this process, excess water and toxins are filtered out of the blood and removed from the patient’s body. While machines can do some of the filtering jobs that your body does, they cannot take over the important task of producing hormones and enzymes. Those functions are very specific to your body and cannot be replaced by machines. Generally, there are two forms of dialysis: hemodialysis and peritoneal dialysis. 

Kidney transplantation

Immunosuppressive Therapy

Immunosuppressive drugs help control the immune system when it mistakenly attacks the body’s tissues, preventing damage and organ rejection. 

However, they can make it harder for the body to fight infections and may cause other side effects.

Complement Inhibitors

Complement inhibitors are drugs designed to block the overactivation of the complement system, a part of the immune system that can mistakenly attack healthy kidney tissue in diseases such as C3G and IC-MPGN. 

By targeting specific components of this system, these drugs could help reduce inflammation and prevent further kidney damage. They represent a promising approach to treating C3G and IC-MPGN, particularly through targeted therapies that modulate directly the alternative complement pathway. 
 

CAVE: 

⚠️ Currently the drugs are not officially approved for the treatment of C3G and IC-MPGN. 

⚠️ These drugs can weaken the immune system, increasing the risk of serious infections from bacteria like Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B. Vaccinations against these bacteria should be completed at least 2 weeks before starting treatment, though vaccines do not prevent all infections. Early detection and treatment of infections are crucial to avoid life-threatening complications.

Ongoing research and clinical trials paving the way for potential targeted treatments that could revolutionize the management of these complex glomerular diseases. Clinical outlook and future perspectives in C3G treatment are promising, with ongoing research and advancements offering hope for improved management of this complex disease.

⚠️ EXPERTS RECOMMEND GIVING ALL PATIENTS A CHANCE TO PARTICIPATE IN NEW CLINICAL TRIALS, ESPECIALLY PATIENTS AT HIGH RISK OF PROGRESSION.

Managing conditions like IC-MPGN and C3G requires a team of expert physicians, including nephrologists, dietitians, psychologists, and social workers, to provide comprehensive care. For assistance in finding an expert center near you, you can visit the CompCure website (www.CompCure.org) or the ERKNet website (www.erknet.org). Alternatively, feel free to contact us via email for further guidance.

The prognosis of C3G and IC-MPGN is variable and depends on factors such as the type of genetic mutation and the presence of autoantibodies, the degree of kidney damage, and how well the disease responds to treatment. Early diagnosis, careful monitoring, and appropriate treatment may help slow disease progression and improve long-term outcomes.

For C3G and IC-MPGN receiving treatment as soon as possible can help preserve the kidney function.

The course of the disease and the prognosis must be assessed individually, considering concomitant risk factors, the results of laboratory tests, kidney biopsy, clinical parameters and response to treatment. Talk to your attending physician and discuss your condition.

In general, regular clinical check-ups are indicated throughout the whole life. They include:

⤷ Blood pressure assessment

⤷ Laboratory tests of blood and urine to assess kidney function as well as the amount and the course of proteinuria and hematuria

⤷ Measurements of height, body weight and the calculation of body mass index to monitor the body’s development.

The frequency of tests depends on the abnormalities found as well as the stage of development. These checks will be carried out more frequently during periods of intense growth, i.e., early childhood or adolescence, or in case of identified problems.

Will I / my child experience any improvement? Can I / my child recover?

Statistics show that within 10 years of diagnosis, half of patients with C3G or Ig-MPGN will progress to end-stage kidney disease, with recurrence in transplanted kidneys in over 50% of cases. However, new treatments targeting the immune system, including gene therapy and complement inhibitors, offer hope for improved outcomes and more effective management of these diseases.

Can I become pregnant and give birth to a child despite my illness?

Yes, it is possible to become pregnant with C3G or IC-MPGN, but it requires careful management. It is important to consult with your nephrologist and gynecologist before attempting pregnancy. Some medications, such as those for controlling blood pressure and renoprotection (ACE inhibitors and AT-R1 blockers) or some immunosuppressants and also RAAS inhibitions, should not be used in women of childbearing age unless there is good contraception. During pregnancy, these medications are strongly contraindicated. Exposure of babies to these drugs has been associated with a number of serious malformations, impaired kidney function, low birth weight, growth retardation, and premature delivery. 

Can I pass on my illness to my children?

C3G and IC-MPGN are generally not inherited in a simple way, but there may be a genetic component involved. While most cases are not directly passed from parent to child, certain genetic factors can increase the risk of developing these conditions. It's important to discuss your family’s medical history with your nephrologist or genetic counselor, as they can provide more personalized information about any potential genetic risks.

I am affected, should I also have my children and relatives tested?

If you are affected by C3G or IC-MPGN, it can be a good idea to discuss testing options with your healthcare provider, especially for close relatives. While these conditions are not always directly inherited, there may be genetic factors that increase the risk, and early detection can be important for managing the disease and preventing complications. Your nephrologist or genetic counselor can help guide you on whether your children or other family members should undergo testing based on their medical history and any potential symptoms.

When should I worry and contact my doctor?

If you notice any drastic changes in your condition or have concerns about your well-being, always contact your doctor. Inform your nephrologist if your blood pressure or proteinuria levels increase. High blood pressure can harm your kidneys, and elevated proteinuria may signal disease progression, possibly requiring treatment adjustments. Don’t hesitate to reach out to your doctor for any questions or concerns about your disease, and remember, it is okay to ask for help if you are feeling overwhelmed. For dietary concerns, you can also contact a nutritionist in addition to your doctor.

Important Notes

Home tests are for monitoring only and prone to error. Exact protein levels can only be confirmed by a lab test. If you notice higher-than-usual protein levels or unusual color changes, contact your nephrologist.
Always follow the instructions provided with your test strips and consult your doctor if you have any questions.

How do I measure my blood pressure correctly?

Psychological consequences – The disease as a challenge

Being diagnosed with a rare, chronic disease can be overwhelming and lead to feelings of isolation, loneliness, and depression, impacting both the patient and their loved ones. It’s important to talk to your doctor about your concerns, seek support from patient groups, and ask for help if you're struggling with mental health, as you're not alone in dealing with these challenges.

Social counseling 

A rare disease diagnosis can significantly affect a patient's life, but social counseling services are available to help with financial, personal, and emotional challenges. Ask your doctor for information about these support services, which can provide valuable guidance during difficult times.