Acknowledgement of Membranoproliferative Glomerulonephritis (aka Complement 3 Glomerulopathy C3G) has not been added yet.

C3G is a rare disease that affects people of all ages regardless of other factors. It has been estimated to occur in 2-3 people out of 1 million. In many cases, the average age of patients with the DDD type is lower than patients with C3GN. About 10-25% of C3G cases are linked to genetic mutations that affect the proteins that regulate the complement system.

 

Name	Abbreviation
Complement 3 Glomerulonephritis	C3GN
Dense Deposit Disease	DDD
Mesangioproliferative glomerulonephritis	MPGN

Complement 3 Glomerulopathy is caused by an abundance of C3 in the blood leading to blockage in the glomeruli of the kidney. In a normally functioning immune system, C3 proteins are activated by a protein called C3 convertase that cleaves the protein into its active form. The active C3 convertase is then deactivated by other proteins called complement factor H (fH) to stop cleaving C3 and effectively stop the immune response. However, individuals with C3G lack this system of regulation and C3 continues to circulate in the blood at increased levels. The body may lose these deactivating proteins in one of two ways. First, the deactivating fH proteins may not be produced in the body due to a genetic mutation that does not encode them. This is called genetic C3G. Second, the deactivating fH proteins may develop abnormally, sometimes as autoantibodies called C3 nephritic factors (C3Nefs). These C3Nefs stabilize the C3 convertase enzyme even in the presence of deactivation factors, causing acquired C3G. Cases of acquired C3G caused by C3Nefs have been more highly reported in children than adults. 

 

Individuals with the rare disease C3G experience many symptoms common to other kidney diseases. These include symptoms caused by the lack of filtration of toxins from the blood into the urine, such as:

• Hematuria - blood in the urine

• Proteinuria - protein in the urine, characterized by darker, cloudy urine

• Hypoalbuminemia - low levels of protein in the blood, which can lead to leakage of water into the surrounding areas of the body and cause swelling of the hands, feet, ankles, etc. 

• Reduced glomerular filtration rate (GFR) - reduced ability of the kidneys to filter toxins from the blood and release waste into the urine; can cause increased creatine levels

• Fatigue

There is a membrane found in the eyes called the choriocapillaris-Bruch’s membrane that resembles a membrane found in the kidneys, the capillary-GBM membrane. Since this is where filtration occurs in the kidneys, it is also where deposits of C3 are found in cases of C3G. Some individuals with C3G may also experience build-up of C3 in this similar eye membrane, which can impact the retina and cause vision problems. 

 

Name	Description
Hematuria	Blood in the urine
Proteinuria	Protein in the urine
Hyploalbuminemia	Leakage leading to swelling

As with most rare diseases and disorders affecting the kidney, a specific molecule must be detected in kidney deposits to classify it as C3G. In this case, C3 must be detected in the glomerular capillaries using a technique called immunofluorescence. This will also enable the physician to distinguish the deposits’ characteristics to determine which type of C3G – DDD or C3GN – is present. Therefore, a kidney biopsy removing part of the kidney and examining it using fluorescent light microscopy is necessary to diagnose an individual with C3G.

Although a kidney biopsy is necessary to ultimately determine a diagnosis of C3G, other tests can be administered by physicians to investigate the likelihood of diagnosis. 

1. Urine test - tests for high levels of protein or blood in the urine

2. Blood test - tests for levels of complement proteins (C3) or waste products in the blood that are not filtering out due to damaged kidneys

3. Glomerular filtration rate (GFR) - blood test that determines how well the kidneys filter waste out of the blood

4. Kidney biopsy – a piece of the kidney is removed and examined for signs of high levels of C3 products; uses electron microscope that can magnify the glomeruli of kidneys 1000 times; determines the location of C3 in the glomeruli and whether the diagnosis is DDD or C3GN

There are currently no FDA-approved drugs designed specifically to treat C3G in patients. However, there are treatments for the symptoms of kidney problems to prevent or slow further kidney damage.

1. Corticosteroids and immunosuppressants – Medications taken to calm the immune system and prevent it from overwhelming the glomeruli.

2. Angiotensin-converting enzyme (ACE) inhibitor and angiotensin II type-1 receptor blockers (ARBs) – Medications taken to control blood pressure and reduce protein loss from blood into urine; may also prevent white blood cells from entering the kidneys and delay progression of kidney damage; ex: lisinopril and ibesartan.

3. Diet changes – a low sodium and low protein diet can prevent build-up of these wastes in the blood and therefore prevent them from overwhelming the kidneys’ filtration system.

4. Mycophenolate mofetil immunosuppressant (MMF) – inhibits inosine monophosphate dehydrogenase enzyme, controls synthesis of guanine monophosphate and has been linked to better prognosis in individuals with C3GN (not DDD).

5. Complement inhibitors – currently in development to counteract the complement system.

6. Eculizumab – anti-complement drug that is an antibody (-mab suffix indicates an antibody therapeutic) that blocks C5 activity at the end of the complement protein pathway. This can decrease the amount of protein released into the urine and reduce the progression of kidney decline.

Patients with C3G will experience variances in the progression of the disease, and should consult with their doctor about a treatment plan to prevent or slow kidney damage. Some patients may respond well to treatments without the need for kidney transplants or dialysis, but still others may require these treatment options to prevent kidney failure. Consistent damage sustained to the glomeruli over a 10 year period can lead to kidney failure.

Antidote is conducting a new clinical trial and seeking individuals with C3G to participate: https://antidote.me/prescreener/s/complement_3_glomerulopathy-169?utm_source=RareShare&utm_medium=partner&utm_campaign=E169&utm_content=advocacy 

Clinical trials of complement protein inhibitors are being conducted by  ChemoCentryx and Achillion at the NIH Clinical Center in Bethesda, MD contact: prpl@cc.nih.gov

Visit https://kidneyhealthgateway.com/ for up-to-date clinical trials for any kidney diseases.

 

1. https://www.kidney.org/atoz/content/complement-3-glomerulopathy-c3g

2. https://rarediseases.org/rare-diseases/c3-glomerulopathy-dense-deposit-disease-and-c3-glomerulonephritis/

3. https://nephcure.org/livingwithkidneydisease/ns-and-other-glomerular-diseases/c3-glomerulopathy/

4. Law, S.A. (2002). C3 Complement Protein. In Wiley Encyclopedia of Molecular Medicine, (Ed.). https://doi.org/10.1002/0471203076.emm0310

5. Medjeral-Thomas, N. and Pickering, M.C. (2016), The complement factor H-related proteins. Immunol Rev, 274: 191-201. https://doi.org/10.1111/imr.12477