It seems likely that we are on the right track with our current model of IgAN, whereby genetically predetermined individuals have a multi hit experience that leads to an overly florid immune response to certain signals, boiling over into clinical disease. The immune insult (eg, bacterial or viral infection) triggers the mucosal immunity, resulting in the production of galactose-deficient immunoglobulin A1 (Gd-IgA1). Circulating Gd-IgA1 reacts with autoantibodies to form immune complexes in the blood. Immune complexes are recognized by cells in the mesangium, and there may be some nonspecific deposition as well. The recognition of immune complexes leads to the activation of complement system, cytokines, chemokines, and inflammation. This can progress to hematuria and proteinuria when there is downstream injury to the podocytes; additionally, tubular inflammation can cause injury, scarring, and loss of kidney structure and function. At each of these steps in the pathogenesis of IgAN—from mucosal inflammation to autoantibody production to localized tissue inflammation and complement activation—we can identify multiple targets to attack and thereby interrupt the development of the disease process. 

C3G involves both direct complement-mediated injury and glomerular inflammation. It is felt that the kidneys bear the excessive brunt of complement activation and may be especially vulnerable to systemic complement activation. As with IgAN, there may be a genetic predilection to C3G; predominant findings have been in gene coding for proteins related to the alternative pathway. In most cases of C3G, autoantibodies are involved. In thinking about IgAN and C3G side by side, immunosuppression may still be a goal in both diseases. But we have not observed consistent improvements with corticosteroids or mycophenolate mofetil in IgAN, and the story is not too dissimilar in C3G, so there is definitely interest in new targets. 

A novel, oral, targeted-release formulation of budesonide has become available for the treatment of IgAN, which reflects the growing understanding of the role of mucosal immunity. Anti-CD20 agents do not seem to be uniformly effective in IgAN and have had little success in modulating the culprit autoantibodies in C3G. But there is still a lot of enthusiasm in IgAN to look at other anti–B-cell agents. Clinical evidence strongly implicates the alternative pathway in much of the dysregulation in C3G. The complement system is clearly overactive in IgAN as well, so targeting the complement system makes sense. Early data on anti–factor B drugs and anti-C3 drugs are exciting, as are efforts to use anti-inflammatory agents such as avacopan.

As noted by Dr Lafayette, in IgAN, there is an increasing recognition of the role of mucosal immunity and the gut-associated lymphoid tissue in the generation of pathogenic IgA molecules, so perhaps the regulators of mucosal immunity may be an appropriate target. We also think about targeting B cells in patients with diseases that are associated with pathogenic autoantibodies. 

The role of complement inhibition has become a hot topic. Anticomplement agents are already available for other diseases, and several new agents are in development and emerging, and we need to determine whether they work for these particular diseases. Our understanding of the precise role of complement in IgAN and C3G is incomplete, but, in the absence of a complete understanding, we still have to make clinical decisions. If your patient does not respond to standard immune suppression or even terminal pathway blockade, such as with eculizumab, we must assume that we are failing to target the actual disease mechanism.  

Since we generally lack effective targeted therapies in C3G, clinical trials are very important. While the role of complement activation in IgAN is not as clear as it is in C3G, I consider it to be a rational target to study further in IgAN.

Sparsentan is an oral medication that has recently been approved by the US Food and Drug Administration for the treatment of IgAN in adults who are at risk for rapid disease progression. It is designed to specifically target the endothelin-1 and the angiotensin II pathways. Sparsentan may be considered purely as a supportive therapy, much like an angiotensin receptor blocker; however, it might also inhibit mesangial cell proliferation. If it does, that would give us an opportunity to target disease mechanism.  

Risk stratification will continue being important for these lifelong diseases, both of which are quite heterogeneous. I think that it is important to continue exploring both immune and nonimmune targets, and it is likely that we will be moving toward a model of combination therapy, which is analogous to what is done in heart failure and cancer. In addition to the renin-angiotensin-aldosterone system inhibitors, we now have sparsentan. These are nonimmunological therapies that are available for IgAN and have been found to be effective. 

As relates to new targets, I agree with my colleagues that you could overlay the "4-hit" model of IgAN and choose targets based on this model. On one level, IgAN is clearly an autoimmune disease. B cells have been implicated in the pathogenesis of IgAN by their role in the production of Gd-IgA1 and glycan-specific immunoglobulin G and IgA autoantibodies against Gd-IgA1. 

Additionally, as Dr Nester alluded to, there is inflammation and complement activation in hit 4 (ie, mesangial deposition and activation of mesangial cells, resulting in glomerular injury) because of the preceding events. We cannot yet predict whether a particular patient with IgAN will respond better if we target hit 2 or hit 4 of the model, for instance. But hopefully, with an increased understanding of the roles of complement and B cells in IgAN, as well as improvements in biomarkers, we will be able to target specific treatments to individual patients.