C3G is an ultra-rare kidney disease that most frequently affects children and young adults. It may present with few obvious symptoms. Many times, findings of blood and/or protein in the urine are identified during a routine doctor appointment or while being evaluated for high blood pressure. Others present with more aggressive symptoms such as swelling and acute kidney injury. Fatigue is a frequent patient complaint.

C3G is caused by excessive activity of the alternative pathway (AP) of complement, an important part of our immune system. This is why it frequently presents for the first time after an infection – after the immune system has been activated. Once activated, the immune system of the C3G patient fails to shut down properly, and the excess activity begins to create many byproducts of complement activity (protein complexes and breakdown products) that deposit on the kidney and produce disease. Excess complement activity is why many (but not all) patients with C3G present with a low complement C3 level in the blood; C3 is being consumed (“used up”) due to dysregulation of the alternative pathway of complement.

The driver or cause of C3G is most often autoimmune (~65%), and less frequently genetic (~20%). Autoimmune proteins known as nephritic factors (C3, C5 and/or C4) are most commonly identified. They bind to and disrupt the normal function of key enzymes in the complement system. Other complement protein autoantibodies may also be present. We do not know why these proteins are made.

The diagnosis of C3G is made by finding predominantly C3 deposits (at least 2 times more than any other protein) on the immunofluorescence (IF) part of the kidney biopsy. Other diseases (i.e., post infectious glomerulonephritis) may mimic this exact biopsy pattern therefore it may be difficult to diagnose C3G when the disease first presents itself. There are two types of C3G: C3 Glomerulonephritis (C3GN) and Dense Deposit Disease (DDD)