The persistence of microhematuria with or without proteinuria after an infection is an indication of the potential onset of C3G; however, C3G can only be diagnosed by a kidney biopsy. The intensity of glomerular immunofluorescence staining for C3 is at least 2 orders of magnitude greater than that for other stained immune reactants (eg, immunoglobulin G). In this scenario, once you have dominant C3 staining, the differential diagnosis is essentially limited to the following 2 entities: C3G and IRGN. There is some confusion surrounding these entities, as both can present with GN, a low serum C3, and C3 deposition in the kidneys. 

After C3G is detected via a kidney biopsy, there needs to be a workup for infections. This includes looking for evidence of streptococcal throat or skin infections, systemic bacterial infections, abscesses, and the like. If an infection is found and the GN is stable, one might decide to treat the infection and then see if the GN resolves. If the patient does not improve over time and has signs and symptoms of GN that have not resolved within 3 to 6 months, that would be more indicative of the clinical diagnosis of C3G, and repeat biopsy may not be necessary. 

However, when a patient presents with an obvious infection and GN with a low serum C3, the chances are good that they have IRGN, and an initial kidney biopsy may not be needed. If, following treatment of the infection, there is a recurring or ongoing GN after the expected time (eg, 3-4 weeks), then a kidney biopsy would be required. A biopsy showing ongoing glomerular inflammation with C3 deposits suggests C3G. The idea is that a flare of C3G can be precipitated by an infection, and the GN with C3 deposition can remain after the infection has resolved. Conversely, in individuals with true IRGN, an infection can cause C3 deposition that eventually goes away after the infection has resolved. 

Due to spontaneous hydrolysis, low levels of C3b are being constantly generated from C3 (known as the “tickover” phenomenon). Certain bacterial infections accelerate this conversion, forming C3 convertase that attaches to the pathogen membrane, causing direct damage and activating distal parts of the complement cascade via C5 activation. You can take a step back and say something like, "We all have C3 and an occasional minor infection, but why do some people develop IRGN or C3G?” 

Many patients with C3G have an autoantibody called C3 nephritic factor, which is thought to stabilize C3 convertase so that it does not shut off properly, like a faucet that is left running. In IRGN, one theory is that some individuals with acute IRGN have high levels of autoantibodies to complement regulatory proteins. In fact, Chauvet et al published work correlating the presence of anti–factor B antibodies with acute postinfectious GN in children. Factor B is a component of the alternative C3 convertase. You can think of this as an acute-phase event, whereby the anti–CFB antibodies enhance alternative pathway convertase activity, preventing the pathway from shutting down. In IRGN, the acute-phase event eventually resolves, the antibody goes away, and the patient gets better. In C3G, the faucet seems to remain on over a longer term.