Dr. Bomback, MD, MPH, is Associate Professor of Medicine at Columbia University Medical Center, where he is Director of Clinical Research for the Division of Nephrology. He has published >100 peer-reviewed articles on kidney disease, with a focus on novel therapies for glomerular diseases.
Competitors for the Complement Region
The best part of March Madness, especially its first weekend, is how Hope (with a capital H) is omnipresent. By the second and third weekend of the tournament, it’s usually the same teams (Duke, Kansas, North Carolina, Villanova, Michigan State, Oregon) from the same powerhouse conferences that emerge as the only ones with a chance to win. But on that first Thursday and Friday, every team seems like it could go all the way.
Hope (again, with a capital H) is the pervading spirit of the Complement Region of this year’s NephMadness. We’ve come a long way in just a short period of time delineating some of the intricacies behind the C3 glomerulopathies, and we’ve even had some successes in treating the disease with drugs other than corticosteroids and non-specific immunosuppression. Still, in my opinion, we’re just scratching the surface of what we know about the disease’s pathogenesis, course, and management. Those of us who see patients with these diseases are filled with hope that we’ll be doing a much better job caring for them in the not-too-distant future as the gaps in our knowledge continue to be filled.
Take, for example, the matchup between genetic variants that modify alternative complement activity versus acquired variants. Many of the so-called “mutations” in complement factor proteins that have been identified are, by strict nomenclature, labelled variants of uncertain significance. Likewise, auto-antibodies such as C3Nef and anti-factor B have (a) not always been linked to detectable complement abnormalities, (b) spontaneously disappeared and reappeared without any intervention, and (c) been detected with near similar frequency in patients with immune complex forms of MPGN. If it’s possible to label an autoantibody as a variant of uncertain significance, we may have a similar story in the “acquired” forms of C3G.
The subgroup of acquired cases that appear linked to monoclonal gammopathies poses some uncertainty, even though we have excellent case series of these patients (typically in their 50s and 60s, an unusual age for C3G) and their response to clone-directed therapy. We presume the monoclonal protein interferes with alternative pathway regulation, possibly via an anti-Factor H effect, but we don’t know how this occurs. I’m going to show my bias here, as I work at a center renowned for its research in the genetics of kidney disease, and my colleagues tell me (and have recently shown in the NEJM) that whole exome or whole genome sequencing can unlock many of the mysteries of kidney disease. This should particularly apply to C3G, so I am going to pick the “genetic” category in this part of the bracket.
In terms of therapy, the eculizumab story is complicated. As opposed to complement-mediated TMAs, where eculizumab has emerged as the clear choice in treating these disorders, in C3G the data has not been as robust or convincing. In large part, this is because C3G possesses a much greater heterogeneity in disease phenotype than complement-mediated TMAs. The 2018 paper by Le Quintrec et al published in AJKD currently stands as some of the best information we have on this drug for this condition. The paper shows that some respond and some don’t, without any obvious explanation for this differential. In fact, the report’s finding that eculizumab appeared to work “best” for the more aggressive forms of C3G (those resembling rapidly progressive GNs) raises questions as to whether this efficacy was from the drug’s effect on C5a, a potent anaphylatoxin, rather than on assembly of C5b-9, the membrane attack complex.
And here is where the Hope story comes into play again. Fortunately, a slew of new complement-targeting drugs are in development and, more importantly, in trials for patients with C3G. So we’ll have a study directly looking at whether blocking solely at the level of C5a can help this disease. And we’ll also have a study that tells us if targeting complement higher up in the cascade, at the level of C3, is effective and safe. Since March Madness is all about Hope, how could I not cast my vote here for “C3 inhibition (and beyond).”
Continuing that theme, I’ll stick with “C3 Inhibition and Beyond” as my ultimate winner of this part of the bracket. Although it’s only been 12 years since Servais et al first proposed a “new entity” for glomerulonephritis with isolated C3 deposits, C3G is now a well-known disease state to all nephrologists, many of whom are referring their patients into clinical trials of new complement-targeting drugs. As I said earlier, we’ve come a long way in a short period of time. There’s reason to hope (and Hope).
As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.