Nephrology
IgAN & C3G
Novel Approaches to Complement-Driven Renal Disease
Overview
There is hope that advancements in the science of complement inhibition will allow clinicians to do more for their patients with complement-driven diseases. Novel approaches targeting complement are now being studied in immunoglobulin A nephropathy (IgAN) and complement 3 glomerulopathy (C3G).
How would you characterize complement-driven renal disease, and what types of targeted approaches make sense to pursue in clinical trials?
Carla M. Nester, MD, MSA, FASN
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“ . . . IgAN may be driven by complement to some extent, and the complement cascade is likely to be an important therapeutic target in IgAN, but it is probably not the primary, or disease-initiating, target. In other words, we will still want to address the other hits, or parts of the puzzle, in IgAN.”
When you have genetic mutations in complement genes that result in a very specific disease such as atypical hemolytic uremic syndrome, the disease is aptly termed complement driven in my view, and targeting complement will be effective in management. In IgAN, our knowledge is incomplete. Because we understand IgAN as a multihit disease, I think that it is safe to say that IgAN is probably not a primary complement-driven disease, for lack of a better term. That is, IgAN may be driven by complement to some extent, and the complement cascade is likely to be an important therapeutic target in IgAN, but it is probably not the primary, or disease-initiating, target. In other words, we will still want to address the other hits, or parts of the puzzle, in IgAN.
The alternative pathway is the amplification loop for all 3 complement pathways. Regardless of whether IgAN occurs due to a defect in the lectin pathway or a problem with the classical pathway, the alternative pathway would still be expected to come into play. This raises the possibility that blocking the alternative pathway could be beneficial in improving lectin or alternative pathway–driven disease.
It is a little less clear whether the terminal pathway is involved in IgAN, and the extent to which C5a and/or C5b (in combination with the membrane attack complex) may be playing a major role in its pathogenesis is also less clear. Again, our knowledge in this area is incomplete; it would be very useful to know in advance precisely where an abnormality exists in the complement cascade, but if a patient does not respond to a terminal pathway blockade, we can assume that their disease is not driven strictly by terminal pathway components. Blocking the alternative pathway has the ability to block the C3a and even the C5a nephrotoxins to a degree because you are targeting the cascade at a more proximal point. In the absence of more specific knowledge, an alternative pathway blockade might prevent a wider range of activity than a terminal pathway blockade.
Jai Radhakrishnan, MD, MS
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“In a patient with a primary complement-driven disease, the treatment is more likely to be effective if you hit the right target.”
The pathogeneses of renal diseases are not necessarily all the same and should be considered on a spectrum. On the one hand, we have C3G and the like, which are more purely complement-driven diseases, and, on the other hand, we have IgAN and other diseases in which we believe that complement is involved, but more as an add-on inflammatory mechanism.
This brings up the concept of personalized medicine. In a patient with a primary complement-driven disease, the treatment is more likely to be effective if you hit the right target. But, in a given patient with a secondary complement-driven disease, we cannot yet look at biomarkers and predict who will respond to a specific targeted therapy.
Complementopathy is another term that is used in reference to complement-driven diseases, and it should be noted that you can have extrarenal involvement in complementopathies. For example, some patients with complement-driven renal disease may also have drusen under the retina. In fact, the importance of a retinal examination in this context is recognized and noted in the nephrology literature.
Richard Lafayette, MD, FACP
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“ . . . if you control the alternative pathway, even if the classical and lectin pathways are the initiators of disease, you may have less disease activity.”
We are only starting to learn about the role of complement in kidney disease. C3G is a prime example of a complement-driven renal disease. In C3G, there is very heavy complement deposition in the kidney on biopsy. In contrast, the complement cascade may be less of a target in diseases such as focal segmental glomerulosclerosis, in which complement activation is unlikely to play an important role in pathogenesis.
The lesson we learned from antineutrophil cytoplasmic autoantibody–associated vasculitis is that, even though there is little evidence that complement drives the disease, a C5a blocker can provide significant clinical benefits in these patients. Similarly, thrombotic microangiopathy strongly impacts the kidney, typically without obvious systemic complement activation, yet complement inhibitors can help control the disease.
We are seeing that complement is an important mediator of chronic fibrosis as well, and there has been some evidence that complement activation is probably an important factor in not only glomerular disease but also chronic tubulointerstitial nephritis and scarring. There may be a role for the lectin pathway in these disorders, more specifically, perhaps, than other pathways. Once complement is activated, because of its role as the amplification loop for all 3 pathways, if you control the alternative pathway, even if the classical and lectin pathways are the initiators of disease, you may have less disease activity.
I think that we are going to have to work through these concepts very methodically and think about complement and the opportunity to control diseases because there may be very broad involvement of complement in many tissue injury systems, including kidney injury, and blocking complement may provide long-term benefits.
References
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