The diagnosis of C3G is a histopathologic diagnosis. That said, there is a need for clinical correlation along with the biopsy findings. Years ago, we had more diagnostic certainty in that we recognized only dense deposit disease, and patients with this entity had abundant C3 deposition on biopsy and low serum C3 levels; they did very poorly. More recently, dense deposit disease was reclassified as 1 of 2 subgroups under the new heading C3G, with the second subgroup being C3 glomerulonephritis (C3GN). The inclusion of C3GN in C3G has opened the door to more cases of C3G and more heterogeneity in C3G. In C3GN, the C3 deposition may be a bit less dense, and the serum C3 levels may not necessarily be low.

Whenever we rely solely on a biopsy-based diagnosis, there are going to be confounders. For instance, C3G can look exactly like postinfectious GN on histologic analysis, and, in some patients, infectious GN might lead to C3G. It would be wonderful if we had a peripheral biomarker or even a definitive biopsy characteristic or marker that would seal the diagnosis, but we do not have these yet. A pathologist who reviews an individual biopsy may label it as C3 glomerulonephritis (the histologic term for C3G) because that is what they see. Clinically, however, we need to back up and determine whether the GN could be postinfectious or due to some other entity. So, while the biopsy report provides valuable information, a patient with C3 deposition could still have 1 of several different disorders that requires clinical correlation and, often, further investigation and workup.

We have been collecting C3G patient data for a long time, but we have not done well at connecting the dots between the clinical parameters and the basic science parameters of the disease, and our current overall understanding of C3G and its prognosis in an individual patient is somewhat limited. For instance, urine protein findings can offer important information, but, up to this point, the clinical parameters do not allow us to precisely predict how an individual patient will be doing in 5 years. Similarly, we do not know if a low serum C3 level predicts a worse prognosis for an individual patient versus someone with a normal C3 level. 

We are just beginning to learn more about the prognostic implications of the pathology of C3G. What we need are early biomarkers to help us identify and prognosticate earlier in the disease course and to help us follow the disease course more effectively. Because of the lack of validated biomarkers in this disease, we often have no recourse but to make therapeutic choices empirically; however, I am optimistic that we will have more information within the next few years, as people are now beginning to understand this disease a bit better.