Jonathan Hogan is Assistant Professor of Medicine and Clinical Director of the Glomerular Disease Center at the Perelman School of Medicine at the University of Pennsylvania. His clinical and research interests are in glomerular diseases, paraprotein-mediated kidney diseases, and onconephrology.
Competitors for the Complement Region
C3 glomerulopathy (C3G) comprises C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), disorders that are caused by dysregulation of the alternative complement pathway. These diseases can cause microscopic hematuria, proteinuria, progressive chronic kidney disease, end-stage kidney disease (ESKD), and frequently recur after kidney transplantation.
Significant advances have been made in the understanding of C3G in the last decade. Research has shed light on the underlying mechanism of disease in many patients with C3G through genetic testing of genes involved in complement, and functional testing of various components of the alternative complement pathway. These have led to the categorization of patients as having genetic versus acquired C3G.
A recent review summarized that genetic testing finds complement-related gene variant in approximately 25% of patients with C3G. The majority of these variants are in the genes C3, CFB, CFH, CFI, and CHFR5. Familial C3G is very rare, but a 2017 KDIGO Controversies Conference statement recommended that all patients with C3G and ESKD who are undergoing transplant evaluation also undergo genetic testing, and if a variant is found, that related potential living donors undergo testing to exclude the presence of such variants.
The majority of patients with C3G are designated as having acquired C3G. The most common identified factor in patients with C3G is the C3 nephritic factor, an autoantibody that stabilizes the C3 convertase and leads to excessive activation of the alternative complement pathway. There is also a subset of patients with so-called monoclonal gammopathy-associated C3G, which are hypothesized to be caused by activation of the alternative complement pathway by a monoclonal immunoglobulin.
In this first round matchup, genetic C3G keeps it close during the first half. The second half is a different story. Acquired C3GN asserts its dominance of the C3G landscape by hitting a barrage of (C)3’s (sorry, I couldn’t help myself), and wins by 10 points.
The treatment of C3G with complement inhibitors is a hot topic. The C5 inhibitor eculizumab has been used in one prospective open-label trial of 6 adult patients, and retrospective case series and case reports in adults and children. These have found mixed results. The largest case series comprises 26 patients with C3G in France who were treated with eculizumab, with evidence of response in about half of patients. Some experts contend that based on mechanism and animal models, eculizumab does not stop the disease process but may be acting directly on glomerular inflammation. Until recently, eculizumab has been the only available complement inhibitor that physicians could consider, and its lack of FDA approval for C3G, combined with the high cost of the drug, has limited its availability to be studied in larger groups of patients.
There are now multiple complement inhibitors being studied in clinical trials for the treatment of C3G. Two such compounds, AMY101 and APL2, target C3 directly, which theoretically provide a targeted therapy for one of the main drivers of the C3G disease process.
In this first-round matchup, the C3 inhibitors get out to an early lead against eculizumab’s starting 5. However, after eculizumab brings in some of their bench players, the C3 inhibitors seem lost. This exposes the complexity of C3G, and how a more specific therapeutic target is likely to miss many patients who have other pathways involved in their kidney disease. Eculizumab continues to mix up their line-up throughout the game and wins this one. The C3 inhibitors vow to aggressively recruit the multiple other types of complement inhibitors that are currently being studied and make a stronger showing at next year’s NephMadness.
As noted previously, eculizumab seems to have a beneficial effect in up to half of patients with C3G based on the largest case series. The challenge remains in determining which individual patients will most benefit from eculizumab, or, for that matter, any other anti-complement therapies. Given the complexity of the biology involved in acquired C3G, it’s unlikely that a “one size fits all” approach will be effective. In this second round matchup, Acquired C3GN overwhelms eculizumab with complex offensive schemes and a 1990s-UNLV-style amoeba defense, and easily moves on to the Saturated Sixteen.
– Guest Post written by Jonathan Hogan
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