C3G and IC-MPGN
C3G and IC-MPGN represent a group of chronic kidney disorders characterized by abnormal activation of the alternative complement pathway and typically manifest with proteinuria, hypertension, and progressively impaired kidney function.
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The disease affects 1-2 per 10,000 individuals, and the annual incidence of newly diagnosed patients is 2 per million. The disease occurs in children and adults alike. The long-term prognosis of MPGN/C3G is poor, with a substantial fraction of patients progressing to end-stage kidney disease.
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The etiology of the disorder is complex and involves both genetic and immunological abnormalities. The disease group is classified according to histopathological, immunological and genetic criteria into individual disease entities, i.e. dense deposit disease (DDD), C3 glomerulonephritis (C3GN) and immune complex (IC)-MPGN.
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Therapeutic options for the disorder are largely limited to non-specific immunosuppressants, which are often ineffective and can have serious side effects. Even kidney transplantation may not provide an ultimate ‘cure’ for the disease since C3G tends to recur in the transplant kidney, leading to early graft loss
About the Kidneys
Mark Frankiw and
Dr. Giulia Bassanese
The kidneys are two bean-shaped organs, each about the size of a closed fist. They are located in the lower back, with one on each side of the spine. Their main function is to filter out waste, toxins, and extra fluid from the blood to produce urine. They also help control blood pressure and maintain the balance of important minerals and electrolytes, as well as producing hormones that support healthy blood and bones. Since the kidneys perform so many vital functions, maintaining their health is crucial for survival and overall wellbeing.
Giulia Bassanese
Clinician in training
E-Mail: giulia.bassanese@med.uni-heidelberg.de
About the Complement System
Alex Gibbs and
Dr. Jutta Schroeder-Braunstein
The complement system is an essential component of the innate immune system. It consists of more than 30 proteins that circulate in the blood. It protects the body against pathogens by directly killing them and by triggering a rapid inflammatory response that includes activation of immune cells. Furthermore, by supporting the removal of immune complexes as well as damaged or altered body cells, it helps maintain tissue integrity. Deficiencies in complement proteins can lead to increased risks of infections and chronic inflammatory and autoimmune diseases. Complement molecules are organized in three activation cascades which all meet at C3, which is the central component of the complement system: Alternative Pathway Classical Pathway Lectin Pathway These pathways are activated following detection of pathogens or cell damage by different sensor molecules. Complement activation means that complement molecules are split into smaller fragments (e.g., C3a, C3b, C5a) or form pore complexes (C5b-9). Some of these activation products then mediate the complement effector functions that is killing pathogens (e.g., C5b-9), removing irregular cells (e.g., C3b), and recruiting and activating immune cells (e.g., C3a, C5a). Complement activation is tightly controlled by regulator proteins, such as factor H and factor I, to prevent damage to healthy cells. Overactivation of the complement system due to complement dysregulation or other causes can lead to chronic inflammation. Sometimes this requires a triggering event, such as an infection. Eventually, chronic inflammation can destroy healthy tissues, affecting the kidneys and other organs.
In C3G, dysregulation of the alternative pathway is frequently observed. In IC-MPGN, both the alternative and the classical pathways can be overactivated. To optimally diagnose and treat complement-mediated diseases, such as C3G and IC-MPGN, it is important to understand complement dysregulations in individual patients. This requires advanced testing by a specialized laboratory.
Top-line overview of the complement system
C3 convertases cleave the central complement protein C3 into active C3a and C3b. This process is essential for amplifying the immune response and killing pathogens. C
5 convertases cleave the complement protein C5 into active C5a and C5b. They play a critical role in inflammation and killing pathogens.
Jutta Schroeder-Braunstein
About C3G and IC-MPGN
Ane Merino Guevara
and Prof. Dr. Gema Ariceta
Both C3G and IC-MPGN are rare, progressive kidney diseases caused by abnormal immune system activity. Both diseases can occur in children and in adults.
The diseases lead to inflammation and the accumulation of C3 deposits in the kidneys in C3G and immunoglobulins and/or other complement proteins in IC-MPGN. Over time, this process damages the kidneys and impairs their ability to filter waste and fluids from the blood in most patients. Fortunately, in some patients - more frequently children - the diseases may stay in remission with standard antiproteinuric treatment (ACEi/ARBs), and/or immunosuppression, and eventually even after pausing treatment. As the diseases can progress in silence, meaning that the patient does not feel any symptoms, it is important to be seen regularly by a nephrologist, or for children a pediatric nephrologist.
C3G
In most cases, C3G is idiopathic, meaning the cause is unclear. In other cases, it is caused by genetic variants. Although infections are a common trigger of C3G flare-ups, the exact cause of the disease is often unknown.
There are two types of C3G: dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The difference between the two types is determined by examining kidney tissue following a biopsy (see the biopsy section).
IC-MPGN
There are two types of IC-MPGN. Secondary IC-MPGN occurs when kidney disease is caused by other health conditions, such as infections (like hepatitis), autoimmune diseases (like lupus), or cancer. These conditions trigger the immune system to attack the kidneys, leading to inflammation and damage. This book focuses on primary IC-MPGN.
Idiopathic IC-MPGN means the cause is unknown. However, once secondary forms are excluded, highly specialized analyses often reveal the same complement system abnormalities that cause C3G, leading nephrologists to consider these two diseases to be part of one spectrum.
Both C3G and IC-MPGN are complex diseases that develop differently in each patient. In addition to the kidneys, there may be an impact on mental health and other organs. Historically around half of the affected patients progressed to end-stage kidney disease within a decade after they were diagnosed. Fortunately, the prognosis is improving. We are entering into a new era, where new targeted therapies are becoming available, and we are learning more about the diseases. Putting together the right team of healthcare professionals, nurses, nutritionists, psychologists, pediatricians (for children), etc. according to the individual needs of the patient will make a big difference.
Symptoms and Screening
Oksana Paulsen and
Prof. Dr. Yoshitaka Isaka
The symptoms of C3G and IC-MPGN tend to be unspecific and can vary widely. It may not be obvious that they are linked to kidney disease, which can delay diagnosis and the initiation of treatment.
In the initial phases, many patients do not feel any symptoms at all. When C3G and IC-MPGN are detected early, it is commonly in connection with screening or a health check where blood and/or proteins are detected in the urine. The insidious thing about this disease is that urine samples are sometimes normal during the initial phase. In this case, protein and/or blood are found in urine only when someone has an infection. As the diseases progress, many patients feel more tired, they might feel nausea and their blood pressure may increase. It is also common to notice puffiness around the eyes, swollen legs, and sudden weight gain. Recurring infections and other signs that the immune system is not functioning properly are other common symptoms of C3G and IC-MPGN.
It is important to act on these symptoms, as they indicate the severity of the diseases. The inflammation in the small filters in the kidneys, the glomeruli, is called glomerulonephritis. If left untreated, glomerulonephritis can lead to kidney failure and other serious complications.
Regular screening programs offer a meaningful approach to helping patients with all kidney diseases, including C3G and IC-MPGN, to get diagnosed early. Such programs successfully exist in Japan, where most of the population is screened for proteinuria annually. This enables patients to receive an early diagnosis and treatment, which is crucial given that loss of kidney function tends to be irreversible.
In countries where urine tests are not part of routine medical examinations, it is advisable for patients to check their or parents to check their children’s urine themselves for proteins and blood from time to time. This can be done at home at any time using an inexpensive urine test strip from a drugstore.
Diagnosis and Testing
Marianne Silkjaer Nielsen,
Prof. Dr. Carla Nester and
Dr. Jutta Schroeder-Braunstein
A kidney biopsy is required for diagnosing C3G and IC-MPGN, and a specialist experienced in these diseases must interpret the analysis. Before undergoing a biopsy, patients usually get several urine and blood tests. These are the same tests often used to monitor the disease after diagnosis. This section will cover the most common tests used for diagnosing and monitoring C3G and IC-MPGN.
Urine Tests
Hematuria is the presence of blood in the urine. There are two types: macrohematuria, which is visible and makes the urine appear red or brown, and microhematuria, which can only be seen under a microscope. Since hematuria can be harmless or a sign of serious kidney disease, such as C3G or IC-MPGN, determining the cause is important.
Proteinuria means protein in the urine. Normally, there is very little protein in the urine. Low levels of proteinuria usually do not result in symptoms. However, when there is a lot of protein in the urine, it may appear foamy. If patients have high levels of proteinuria for a long time, the level of an important protein called albumin in the blood will decrease because it is being lost in the urine. This causes fluid to leak from blood vessels into tissues, leading to swelling and weight gain. This condition is known as edema. Instead of testing for total proteinuria, some doctors will test only for the level of albumin in the urine (albuminuria), which is acceptable. The concentration of protein and other constituents in urine can vary throughout the day, which can affect lab results. Therefore, testing urine collected over an entire 24-hour period can be meaningful. Another common method for assessing the severity of proteinuria or albuminuria is considering the ratio of protein or albumin in the urine compared to the amount of creatinine in the urine, known as the protein-to-creatinine ratio (UPC). This method is particularly useful in children, as collecting a 24-hour urine sample can be difficult. The best time to test the UPC is in the first morning urine, collected immediately after the patient wakes up.
Illustration of urine with presence of macrohematuria, microhematuria, and proteinuria
Blood Tests
C3G and IC-MPGN are heterogeneous glomerular diseases, meaning they manifest differently from patient to patient. This makes them difficult to treat. This heterogeneity stems from the various causes of the diseases. Sometimes genetic abnormalities cause the disease. Other times, autoimmune reactions may underlie the disease. In many cases, the cause is unknown. To better understand potential causes, it can be helpful to periodically have a full blood panel done at a specialized lab, in addition to routine tests performed during doctor’s visits. These tests can help define the underlying features of the disease and are often useful in diagnosis, disease management, and important treatment decisions.
Genetic and Acquired Factors Driving Complement Dysregulation
These diseases are characterized by the overactivation of the complement system, which can be caused by genetic abnormalities or acquired autoantibodies. Genetic abnormalities in the complement pathway are occasionally found in patients with C3G. These variants often lead to a loss of regulation, causing persistent activation of the complement pathway and ultimately resulting in kidney damage. A genetic test involves sending a blood sample to a lab that specializes in complement genetics. However, finding a genetic variant does not necessarily mean that the patient will develop kidney disease. Often, genetic studies identify variants of uncertain significance. These are gene differences in the population whose function is unknown. They may have no function at all, including in relation to the disease.
Genetic and Acquired Factors Driving Complement Dysregulation These diseases are characterized by the overactivation of the complement system, which can be caused by genetic abnormalities or acquired autoantibodies. Genetic abnormalities in the complement pathway are occasionally found in patients with C3G. These variants often lead to a loss of regulation, causing persistent activation of the complement pathway and ultimately resulting in kidney damage. A genetic test involves sending a blood sample to a lab that specializes in complement genetics. However, finding a genetic variant does not necessarily mean that the patient will develop kidney disease. Often, genetic studies identify variants of uncertain significance. These are gene differences in the population whose function is unknown. They may have no function at all, including in relation to the disease. In addition to genetic factors, the body may produce proteins that act against complement proteins, known as acquired autoantibodies. The most common of these in C3G and IC-MPGN are nephritic factors C3, C4, and C5 (see the table of complement tests). These autoantibodies may cause excessive complement activation. Prolonged activation leads to inflammation and progressive damage to the glomeruli of patients with C3G or IC-MPGN.
Biopsy
A kidney biopsy is necessary for diagnosing C3G and IC-MPGN. During the procedure, a small sample of kidney tissue containing glomeruli is removed. The sample is then sent to a specialized laboratory, where a renal pathologist examines it. To make an exact diagnosis, the pathologist must have experience diagnosing C3G and IC-MPGN. The following techniques will be used:
Light microscopy (LM): This technique uses several different stains to evaluate the general appearance of various structures in the biopsy tissue.
Immunofluorescence (IF): This technique reveals the presence of C3 or immunoglobulin staining and the intensity of the staining.
Electron microscopy (EM): This technique is used to visualize structural changes and the location of complement proteins and/or immunoglobulin deposits. EM helps differentiate between C3G disease types. However, EM is not always performed and is not required for a C3G or IC-MPGN diagnosis.
If the biopsy shows C3 staining that is twice as strong as any other fluorescent stain, the pathologist will call it „C3-dominant glomerulonephritis,” which may suggest C3G. However, it is important to note that up to 30% of patients with postinfectious glomerulonephritis (PIGN) may also have „C3-dominant glomerulonephritis.” This can be confusing. The distinction between C3G and PIGN can only be made after infection has been ruled out as the cause of the biopsy results. A C3G diagnosis can be further classified by electron microscopy as dense deposit disease (DDD), which is characterized by sausage-shaped, thick intra-membranous deposits, or C3 glomerulopathy (C3GN), which involves mesangial and capillary wall deposits of lesser intensity. If a membranoproliferative pattern of injury is present along with immunoglobulin staining (instead of C3 dominant staining), immune-complex membranoproliferative glomerulonephritis (IC-MPGN) can be diagnosed. A biopsy is performed by a nephrologist or radiologist in a hospital while the patient is under general or local anaesthesia. It is important to avoid strenuous activities for one to two weeks after the biopsy and to contact the hospital if you experience bleeding, fever, or changes in your urine. Biopsies may be repeated to monitor progression and the effectiveness of treatment.
Overview of Diagnoses Based on Biopsy Results
Pediatrics, medicine, uiowa: Carla Nester
Uihc: Carla Nester
Researchgate: Scientific contributions; Carla Nester
Dr. Jutta Schroeder-Braunstein
Disease Management
Katrine Maiggard and
Prof. Dr. Marina Vivarelli
The management of C3G and IC-MPGN varies depending on each patient’s individual needs. These needs are defined by disease activity and progression, among other factors. It is important for everyone living with these diseases to undergo ongoing disease monitoring. This is because both C3G and IC-MPGN can flare up and become active without obvious symptoms. Therefore, when living with C3G or IC-MPGN, taking medication and monitoring disease progression becomes normal routines, as does planning and prioritizing interactions with nephrologists and other healthcare professionals. Additionally, lifestyle changes such as limiting sodium intake, managing protein consumption, and prioritizing rest may help maintain health and stability. C3G and IC-MPGN can progress silently, meaning patients do not experience symptoms. This is why monitoring key markers of progression in the blood and urine is important. Regular follow-up appointments with a medical professional can facilitate the early detection of flares and prevent the decline of kidney function and other possible complications. The frequency of these appointments depends on the severity of the disease. The level of proteinuria and the patient’s other laboratory values are decisive factors. If the patient is doing well, appointments may be scheduled twice a year. Otherwise, they should see a nephrologist more frequently. A full assessment is important during monitoring and includes blood tests to measure relevant markers, such as creatinine and eGFR levels, as well as complement activation. Regular urine tests are also important for measuring proteinuria and hematuria. Patients should undergo periodic eye examinations to rule out drusen, which is commonly associated with C3G and IC-MPGN. They should also be evaluated by a specialist who can recognize partial lipodystrophy, a rare disorder involving progressive subcutaneous fat loss. All patients are advised to check their proteinuria level every month, regardless of how well they are doing. This test is important for promptly detecting relapses, which can occur at any stage of the disease. Early detection often makes relapses much easier to manage.
Katrine Maigaard
Prof. Dr. Marina Vivarelli
Treatment
Hyo Jin Heinz and
Prof. Dr. Fadi Fakhouri
Treatment of C3G and IC-MPGN is rarely straightforward, and many patients undergo a period of trial and error. These diseases are rare and vary widely, so responses to therapy differ from person to person. Weighing potential benefits against side effects is important, so patients have the best possible opportunity to live healthy, fulfilling lives.
This makes shared decision-making between nephrologists and patients an important part of care.
Reducing and maintaining low proteinuria levels while stabilizing or improving estimated glomerular filtration rate is key.
The treatment has two main goals:
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Slow kidney damage
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Stabilize kidney function
Since there is no single cure for C3G or IC-MPGN, therapy must be customized to each patient’s needs. Most patients start with supportive care, which includes medications to control blood pressure and reduce protein loss in the urine. Lifestyle changes, such as following a low-sodium diet and avoiding kidney-toxic medications, become part of daily life.
Depending on the severity and activity of the disease, nephrologists may add immunosuppressive therapies. In the past, these therapies were limited to non-specific immunosuppressive medications without documented effect on complement dysregulation, with varying efficacy and side effects. However, new targeted complement therapies are becoming available that provide significantly improved opportunities to manage disease activity.
Reducing and maintaining low proteinuria levels while stabilizing or improving estimated glomerular filtration rate is key.
The side-effect profile of medications that have been on the market for a long time is well established. For the new products, the long-term efficacy and side-effects need to be established (see chapter on Networks and Evidence). Some medications are not safe during pregnancy and breastfeeding.
This is why dialogue and close collaboration with your doctor are always crucial.
When a patient reaches the end-stage of renal disease, they require dialysis or a transplant to survive.
Dialysis
Dialysis is a procedure that cleanses waste from blood. During this process, excess water and toxins are filtered out of the blood and removed from the body. While machines can perform some of the filtering functions of the body, they cannot replace the important tasks of producing hormones and enzymes. There are generally two forms of dialysis: hemodialysis (HD) and peritoneal dialysis (PD). With PD, the abdominal lining is used for daily filtering at home, while with HD, a machine is typically used three to five times weekly at a center.
Kidney Transplantation
Although dialysis is lifesaving, it can be hard on the body and is associated with risks and challenges. Therefore, kidney transplantation is the best option for most people with end-stage renal disease. For patients with C3G or IC-MPGN, there is a high risk of the disease recurring in the transplanted kidney. Thus, continued monitoring and specialized care are critical.
Beyond Medical Treatment
The emotional impact of living with a rare kidney disease extends beyond medical treatment. Uncertainty and isolation are common, especially when symptoms change or the future feels uncertain. Many patients find support through peer communities, advocacy groups, and education, which make them feel more informed and less alone. From the patient’s perspective, successful disease management is ultimately defined not only by lab results, but also by preserving quality of life, resilience, and hope while living with a lifelong condition.
Medications Commonly Used To Treat C3G and IC-MPGN
Medicines that Protect Kidney Function and Reduce Proteinuria
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Renin-angiotensin-aldosterone system inhibitors (RAAS inhibitors), Angiotensin-Converting Enzyme inhibitors (ACE inhibitors), Angiotensin II Receptor Blockers (ARBs).
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In patients at risk for progressive kidney disease these medications are used to lower blood pressure, reduce protein in the urine, and slow kidney damage, starting at diagnosis, based on protein levels and blood pressure.
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Inhibitors of sodium-glucose cotransporter 2 (SGLT2-inhibitors), like dapagliflozin and empagliflozin, helps protect the kidneys by blocking sugar from being absorbed in the kidneys.
Targeted Therapies with Complement Inhibitors
Two of these therapies, iptacopan and pegcetacoplan, are new and have recently been approved by the FDA and the EMA. They are designed to block the overactivation of the complement system by targeting specific complement proteins.
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Iptacopan/Fabhalta is an oral complement factor B inhibitor, approved by the EMA and the FDA to treat C3G. Clinical trials for IC-MPGN are ongoing.
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Pegcetacoplan/Empaveli/Aspaveli is a C3 complement inhibitor administered via subcutaneous infusion twice per week. It has been approved by the EMA and the FDA to treat C3G and IC-MPGN.
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Eculizumab/Soliris and ravulizumab/Ultomiris are administered as infusions given every second week (eculizumab) or every second month (ravulizumab) to block the terminal complement cascade. Eculizumab and ravulizumab can help some patients with C3G and IC-MPGN, though the products are approved for other conditions. Efficacy of eculizumab and Ravulizumab has not been shown in prospective randomized trials.
Unspecific Immunosuppressive Therapies
These help control the immune system when it mistakenly attacks the body’s tissues. Suppressing the immune system can make it harder for the body to fight infections.
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Corticosteroids, such as prednisone, dexamethasone and hydrocortisone, are strong anti-inflammatory drugs used to manage overactive immune conditions. They are typically prescribed for the shortest time needed, to avoid complications
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Mycophenolate mofetil/CellCept or mycophenolate sodium/Myfortic, helps control the immune system by preventing certain immune cells from growing and is used to treat autoimmune diseases.
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Cyclophosphamide is sometimes used when other treatments do not work, and there is a strong risk of rapid kidney damage. It helps reduce inflammation and can slow disease progression, but it requires careful administration and monitoring, due to increased risks of infections, infertility, malignancies, etc.
The side-effect profile of medications that have been on the market for a long time is well established. For the new products, the long-term efficacy and side-effects need to be established (see chapter on Networks and Evidence). Some medications are not safe during pregnancy and breastfeeding.
This is why dialogue and close collaboration with your doctor are always crucial.
Hyo Jin Heinz
