What goes wrong in C3G?
C3G is caused by problems in the complement system, a part of the immune system, which is your body’s defense system that fights off germs. The complement system includes three different pathways. The pathway that doesn’t work right in C3G is the alternative pathway.
When the alternative pathway is over-active, a complement protein called C3 builds up in the kidney’s filtering units. The filtering units are called glomeruli; they filter (clean) the blood by removing wastes. The build-up of C3 proteins reduces the glomeruli’s ability to filter wastes. This can eventually lead to kidney failure.
How Is C3G Diagnosed?
The diagnosis of C3G can be made only when C3 is seen in the glomeruli. This can be done only with a microscope and special tests. For these tests, a piece of kidney tissue is needle. Getting this piece of kidney tissue is called a kidney biopsy.
Kidney Biopsy
A kidney biopsy involves taking one or more tiny pieces (samples) of your kidney to look at with special microscopes. The microscopes make it possible to see the samples in greater detail.
The biopsy sample may be taken in one of two ways:
•Percutaneous (through the skin) needle biopsy: This is the most common type of kidney biopsy.
A needle is placed through the skin that lies over the kidney and is guided to the right place in the kidney. Then, a tiny sample of kidney tissue is removed through the needle.
•Open biopsy: the kidney sample is taken directly from the kidney during surgery.
For both types of biopsies, the biopsy sample is then sent to a pathology lab where it’s studied with special microscopes.
A special stain is added to the biopsy pieces to make C3 proteins in the kidney’s glomeruli show up under the microscope lens. This process is called immunofluorescence or IF.
When the pathologist, a doctor who identifies diseases using microscopes, sees a lot of C3 proteins in the glomeruli, that means the alternative pathway of the complement system is over-active. This finding helps to confirm a diagnosis of C3G.
The different patterns by which C3 proteins build up in your kidneys help inform your healthcare team about your type of C3G: dense deposit disease (DDD) or C3 glomerulonephritis (C3GN). To know which type of C3G you have, your biopsy has to be looked at using an electron microscope.
In DDD, the electron microscope shows that C3 deposits build up in one part of the glomeruli and appear dense and thick. In C3GN, the C3 deposits are more spread out and less dense and thick. So, an electron microscope is needed to tell if the diagnosis is DDD or C3GN. It’s the only type of microscope that can identify the specific type of deposits that are present in C3G.
Blood Tests
In addition to a biopsy, blood tests can be used to help your healthcare team decide which treatments are best for you. Blood tests used for C3G diagnosis can include the following:
•Tests for the type of C3G: These tests check complement protein levels in your blood to help diagnose your type of C3G (DDD or C3GN). The levels of many different complement proteins can be determined; some of the more common ones are:
-C1, C2, C3 and C4 complement protein levels: C1, C2, and C4 protein levels are usually normal in DDD and C3GN, although a few patients may have a low C4 level at certain times during their disease. Most people with DDD have low C3 levels in their blood. With C3GN, C3 levels are also low, but only slightly.
-Soluble C5b-9 complement protein levels: Soluble C5b-9 protein levels are usually normal in DDD and elevated in C3GN.
•Tests for the cause of C3G: There are other markers in the blood to help know what the reason is for your CG3. The following is not a complete list, so you’ll need to discuss which tests are best for you with your healthcare team.
-C3 nephritic factor (C3NeF): This is an autoantibody, a protein made by your body’s defense system that attacks your own body instead of invading germs. In this case, C3NeF activates the alternative pathway of the complement system, which leads to C3G. The presence of C3NeF in the blood supports a diagnosis of C3GN or DDD. It’s found in about 80% of people with DDD and about 40% of people with C3GN. This means that you can have C3G without C3NeF.
-Complement factor H-related (CFHR) protein gene mutations: Parts of your genes (DNA) have certain codes or instructions for making proteins. Gene mutations are mistakes in the instructions of certain genes. These mistakes can lead to proteins that don’t work the way they should. If a protein cannot work properly, that can cause disease. Mutations in some of the genes that make CFHR proteins result in an over-active complement system, which leads to C3G. Other types of gene mutations have also been linked to C3G.
-Paraproteins: These are harmful proteins in the blood that can make the complement system over-active. They are most often found in people with C3G who are over 50 years old.
C3G can be confused with other kidney diseases, so if your doctor is not sure of the diagnosis, it’s important that they speak with a kidney doctor who knows how to diagnose this disease.
