C3 Glomerulopathy

C3 glomerulopathy is a rare kidney disease caused by problems with the body’s immune system, specifically affecting tiny filtering structures in the kidneys that help clean the blood and make urine.

Table of contents

• What is C3 glomerulopathy?
• Types of C3 glomerulopathy
• How common is the condition?
• Signs and symptoms
• Causes and risk factors
• How is C3 glomerulopathy diagnosed?
• Treatment options
• What to expect: Outlook and progression
• Living with C3 glomerulopathy

C3G, Dense deposit disease, DDD, C3 glomerulonephritis, C3GN, Membranoproliferative glomerulonephritis type II, MPGN type II

• Kidneys
• Glomeruli
• Blood vessels
• Eyes (retina)

What is C3 glomerulopathy?

C3 glomerulopathy is a group of conditions that affect how well your kidneys work^[1]. Your kidneys filter your blood and remove waste products and extra water to make urine. The name comes from two important parts: “Complement 3” refers to a protein in your blood that helps your immune system work properly, while “glomerulopathy” means damage to the glomeruli — tiny clusters of blood vessels in your kidneys that filter your blood^[4].

This disease happens when your body’s complement system, which is part of your immune system, stops working the way it should^[1]. The complement system is a group of proteins in your blood that normally helps protect your body from infections by fighting off bacteria and viruses. In C3 glomerulopathy, this system becomes overactive and starts damaging your kidneys instead of protecting them.

When the complement system works too hard, it damages the complement 3 proteins. Broken pieces of these proteins get trapped in your glomeruli, making it harder for your kidneys to filter blood and create urine^[4]. Without treatment to help slow down this damage, C3 glomerulopathy continues to harm your kidneys and can lead to kidney failure.

Types of C3 glomerulopathy

There are two main types of C3 glomerulopathy. Doctors can tell them apart by looking at kidney tissue samples under a microscope and examining what kind of damage has occurred^[4].

Dense deposit disease (DDD), which doctors previously called membranoproliferative glomerulonephritis type II, is identified by dense deposits that look like ribbons in the structure of the glomerular basement membrane — the foundation that supports the filtering units in your kidneys^[4]. This type primarily affects children and young adults, with symptoms typically appearing in adolescence^[1]. DDD can also be associated with other health problems unrelated to kidney function, such as acquired partial lipodystrophy, a condition where fatty tissue under the skin in the upper part of the body is lost^[1].

C3 glomerulonephritis (C3GN), formerly known as MPGN type I or III, is defined by the absence of the dense ribbon-like deposits that characterize DDD^[4]. Instead, deposits appear in other parts of the kidney’s filtering structures. C3GN primarily affects people 30 years and older^[4]. The median age at diagnosis for all C3 glomerulopathy cases is 23 years^[3].

How common is the condition?

C3 glomerulopathy is very rare. It affects 1 to 2 people out of every one million people worldwide^[1]. Other estimates suggest the incidence (new cases) ranges between 0.5 and 3 cases per 1 million people per year in the United States^[7]. The condition affects both men and women equally^[1].

Signs and symptoms

People with C3 glomerulopathy typically present with several kidney-related symptoms. The most common signs include high levels of protein in the urine, called proteinuria, and blood in the urine, known as hematuria^[3]. Some people have both of these symptoms together. Other common problems include reduced amounts of urine, low levels of protein in the blood, and swelling in many areas of the body^[1].

Additional symptoms that people with C3 glomerulopathy may experience include high blood pressure, feeling extremely tired, infections that go away and come back again, and gout^[4]. Some people may notice their urine appears dark or foamy^[11]. The range of symptoms can vary from mild, with no obvious signs, to severe, with classic features of acute kidney inflammation including kidney dysfunction and high blood pressure^[7].

Affected individuals may have particularly low levels of complement component 3 in their blood^[1]. Children and young adults often present with urinary problems following an upper respiratory tract infection^[7].

In some cases, C3 glomerulopathy can cause symptoms unrelated to kidney function. People with dense deposit disease may develop vision problems from the buildup of yellowish deposits called drusen in the retina, the light-sensitive tissue at the back of the eye^[1]. These deposits usually appear in childhood or adolescence and can cause vision difficulties later in life. Some people may also develop lipodystrophy^[4].

Causes and risk factors

C3 glomerulopathy occurs when your complement system, an important part of your immune system, becomes overactive and damages your kidneys^[4]. The complement system must be carefully regulated so it targets only unwanted materials and does not damage the body’s healthy cells. In C3 glomerulopathy, this system is not properly controlled, leading to uncontrolled activation of what’s called the alternative pathway of the complement system^[7].

In most cases of C3 glomerulopathy, healthcare providers aren’t sure what exactly causes the complement system to stop working properly^[4]. C3 glomerulopathy is associated with changes in many genes, most of which provide instructions for making proteins that help regulate the complement system^[1]. The genetic changes can be caused by mutations in specific proteins or by the development of abnormal antibodies in your immune system^[11].

A specific mutation in the CFHR5 gene has been found to cause C3 glomerulopathy in people from the Mediterranean island of Cyprus. Mutations in the C3 and CFH genes, as well as other complement system-related genes such as C3, CD46, CFB, CFH, CFHR1, CFHR5, CFI, and DGKE, have been found to cause the condition in other populations^[1][3]. For example, autoantibodies against CFH, CFB, or C3bBb (called C3 nephritic factor) are commonly found in patients diagnosed with C3 glomerulopathy^[13].

However, the known mutations account for only a small percentage of all cases of C3 glomerulopathy — approximately 10 to 25% of people with C3 glomerulopathy have identifiable genetic changes^[11]. Several normal variants in complement system-related genes are associated with an increased likelihood of developing the condition. In some cases, the increased risk is related to a group of specific variants in several genes, a combination known as a C3 glomerulopathy at-risk haplotype^[1]. While these genetic changes increase the risk of C3 glomerulopathy, many people who inherit these changes will never develop the condition.

C3 glomerulopathy is a complex genetic disorder that is rarely inherited in a simple pattern from parent to child^[3]. The genetic changes related to C3 glomerulopathy increase the activation of the complement system. The overactive system damages the glomeruli in the kidneys, preventing them from filtering waste products normally and potentially leading to end-stage kidney disease^[1].

How is C3 glomerulopathy diagnosed?

The definitive diagnosis of C3 glomerulopathy requires a kidney biopsy with specialized testing^[3]. During a kidney biopsy, doctors remove a tiny portion of kidney tissue and examine it in the lab using special techniques called immunofluorescence and electron microscopy. These studies are necessary both for diagnosis and to distinguish between the two major types of C3 glomerulopathy: C3 glomerulonephritis and dense deposit disease.

To diagnose C3 glomerulopathy, doctors also perform blood tests. These tests can reveal the levels of albumin, cholesterol, creatinine, protein, and many other components in the blood^[11]. Doctors may also calculate your glomerular filtration rate (GFR), which estimates how well your kidneys are working. This calculation uses your blood creatinine and urine protein levels.

Other diagnostic tests may include ultrasound to provide a closer look at the kidneys^[11]. Some individuals will have genetic testing to identify changes in genes that have been implicated in C3 glomerulopathy^[3]. Before diagnosis, doctors may also perform urinalysis to check for protein and blood in the urine.

Treatment options

There is currently no cure for C3 glomerulopathy, but several treatment approaches exist to help manage the condition and slow its progression^[11]. Treatment focuses on minimizing or stopping protein in the urine, since the less protein in the urine, the better people with C3 glomerulopathy tend to do. Treatment also includes managing side effects of the disease, such as high blood pressure.

For people with mild disease — defined as less than 1.5 grams of protein in urine each day and normal kidney function — doctors usually recommend nonspecific therapies used to treat many chronic kidney diseases^[3][19]. These include diet changes such as a low-sodium, low-protein diet that puts less strain on your kidneys. Blood pressure-lowering medications called angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type-1 receptor blockers (ARBs) are commonly prescribed. Doctors may also prescribe cholesterol-lowering drugs called statins if cholesterol levels are elevated.

For people with moderate to severe disease — more than 1.5 grams of protein in urine every day or declined kidney function — more aggressive treatment is usually needed^[19]. Doctors typically recommend immunosuppressants, which are medicines that calm down your immune system so it won’t go into overdrive and attack your body. These drugs include azathioprine, cyclophosphamide, corticosteroids (steroids), mycophenolate mofetil (MMF), rituximab, sirolimus, and tacrolimus^[19].

Research suggests that a combination of mycophenolate mofetil and steroids may work best^[7]. In studies, people who took these two medications had better outcomes than those who took other immunosuppressant drugs or no immunosuppressants at all. However, these medicines have had mixed results overall, and traditional anti-cellular immune suppression has limited efficacy in C3 glomerulopathy^[9].

For people who don’t benefit from immunosuppressants, doctors may recommend a drug called eculizumab, which blocks the part of the immune system that harms people with C3 glomerulopathy^[19]. This is called complement inhibition with a terminal pathway blocker, and it may alter disease course in some individuals^[3]. Before starting this medication, doctors may check your blood levels of a substance called soluble C5b-9. If your levels are high, there’s a good chance you will respond well to this drug.

Recently, the FDA has approved Fabhalta — the first-ever treatment option specifically for adults with C3 glomerulopathy, offering new hope for better disease management and outcomes^[11].

Plasma replacement therapy in individuals with genetic changes in the CFH gene may be effective in controlling complement activation and slowing progression to end-stage kidney disease^[3]. Other treatments like plasma infusion or plasmapheresis have shown inconsistent results in small patient groups.

Clinical trials are another treatment option that may test more targeted treatments with potentially lower risks of side effects^[11]. Some clinical trials enroll patients based on their genetic testing results to test the effectiveness of precision-based therapies targeted to specific genetic changes. Your doctor can help you find the right clinical trial for you.

What to expect: Outlook and progression

The prognosis for C3 glomerulopathy is generally poor, and spontaneous remission is uncommon^[3][16]. C3 glomerulopathy is a chronic condition, which means it slowly gets worse over time^[4]. The kidney problems associated with C3 glomerulopathy tend to worsen over time. About half of affected individuals develop end-stage renal disease (ESRD) within 10 years after their diagnosis^[1][7]. End-stage renal disease is a life-threatening condition that prevents the kidneys from filtering fluids and waste products from the body effectively.

End-stage kidney disease happens when the glomerular filtration rate drops below 15 milliliters per minute^[16]. If it’s not addressed in time, kidney failure can be fatal. When end-stage renal disease develops, treatment options are limited to dialysis or transplantation^[3]. Unfortunately, C3 glomerulopathy recurs in nearly all transplanted kidneys and is the predominant cause of graft failure in 50% to 90% of transplant recipients, with poor survival rates for the transplanted kidney^[3][7].

Several factors can affect a person’s outlook with C3 glomerulopathy. Age greater than 16 years, dense deposit disease subtype, and crescentic glomerulonephritis have been identified as predictors for end-stage renal disease^[7]. Life expectancy with C3 glomerulopathy depends on factors including your age and overall health, the specific type of kidney disease you have, and what lab results tell doctors about your kidney health^[16].

However, not everyone develops long-term complications. Many people can be successfully treated and live for a long time after diagnosis^[16]. Children with C3 glomerulopathy tend to respond better to treatment than adults^[11]. Some individuals may occasionally develop the late comorbidity of impaired visual acuity^[3].

Living with C3 glomerulopathy

Living with C3 glomerulopathy requires ongoing care and attention to both physical and emotional health. Close monitoring of kidney function by a nephrologist with familiarity with the disease is essential^[3]. This includes complete biannual assessment of the complement pathway and periodic eye examinations to evaluate the back of the eye for any changes.

Following a kidney-friendly diet is very important to your long-term health. A low-sodium, low-protein diet can help improve your kidneys’ function and your symptoms^[17]. Working with a dietitian who specializes in kidney disease can help you create an eating plan that’s right for you.

Regular, moderate physical activity helps manage your blood pressure and weight and improves your overall well-being^[11]. It’s important to find an exercise you enjoy and can stick with over time. Always talk to your doctor before starting a new exercise routine.

Following your treatment plan is crucial. This means taking your medicines as prescribed and seeing your nephrologist routinely for tests^[11]. Your care team can help you manage your condition and answer questions about your health.

The emotional toll of living with a rare, chronic kidney disease can be significant^[14]. People with chronic kidney disease have a higher risk of depression and anxiety, and having a rare disease increases that risk even further. Common stressors include the challenge of staying healthy while living with illness, unexpected effects or events of the disease, changes in your body, worries about being a burden to others, food restrictions, and concerns about the disease’s impact on your family, work, social life, and relationships.

There are many resources available to help with mental and emotional health. You can talk with your doctor about mental health resources, work with a social worker, join a support group for people with kidney disease or rare diseases, or see a counselor or therapist regularly^[14]. Healthy lifestyle changes such as keeping a journal, exercising regularly, eating a kidney-healthy diet, connecting with a higher power if you’re religious or spiritual, focusing on good sleep, and reaching out to trusted family or friends can all help improve mental well-being.

Learning about your disease, treatment options, and clinical trials can help you better advocate for yourself^[17]. Patient organizations can help you connect with other patients and find support to manage your disease. If the family history is positive for kidney disease, evaluation of apparently healthy at-risk relatives can include genetic testing (if the pathogenic variants in the family are known), urinalysis, and comprehensive analysis of the complement system^[3].