<p>Unlike traditional immunosuppressants, targeted therapies for IgA nephropathy (IgAN) aim to minimize systemic side effects while improving outcomes. Ongoing clinical trials are evaluating agents such as complement, BAFF, and APRIL inhibitors, offering new hope for patients with IgAN.</p>

The story with targeted therapy is an evolving one. For the past 3 or 4 decades, all we had were RAAS inhibitors and corticosteroids. That led to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines stating that corticosteroids can be considered in carefully selected patients after discussing the risks from therapy with them. Most recently, we have a 2025 version of the KDIGO guidelines, coming after the recent explosion of newer therapies for IgAN.

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With targeted therapy, we are looking at pathogenesis-based treatments. The 4-hit model is now very well ensconced in our daily discussions of what is behind IgAN. An abnormal galactose-deficient IgA1 (Gd-IgA1) leads to immune complex formation, which then leads to deposition in the kidney, inciting inflammation involving the complement pathway and then, eventually, kidney fibrosis in the absence of inflammation control. Looking at this paradigm, we can consider therapies at various points in this 4-hit pathway.

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We do use targeted therapy as “foundational therapy.” RAAS inhibition is targeted therapy, and so are SGLT2 inhibitors and, of course, ERAs. All these targeted treatments are foundational therapies that the patient should be on for their lifetime, or for as long as we think that there is a risk for progression.

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When you look at the future of targeted therapies, they are really expanding from foundational therapies to therapies that can hit the proximal parts of the pathogenic cascade. There are 2 main drug classes in the pipeline: B-cell–targeting therapies and complement inhibitors. The B-cell–targeting therapies consist of anti-APRIL and -BAFF treatments. It has previously been shown that anti-CD20 drugs such as rituximab have not been effective, so targeting other aspects of the B-cell pathway, focusing on the proximal part of the 4-hit pathogenesis, is important. Regarding complement inhibitors, there are many in the pipeline.

Targeted therapy directed at hit 1 of the 4-hit model in the ileum, one of the sites where Gd-IgA1 is produced, is something that has been in use with targeted-release budesonide. And, of course, B-cell–modulating therapies, directed at hits 1, 2, and 3, are increasingly being looked at, as B cells produce the Gd-IgA1 and associated autoantibodies that lead to the formation of immune complexes, culminating in hit 4 with their deposition in the glomerular mesangium of the kidney. Clinical trials with inhibitors of APRIL and BAFF, which are key mediators of Gd-IgA1 production, are ongoing and are on our radar. Complement activation, which contributes to mesangial and podocyte injury, inflammatory mediator release, and glomerulosclerosis, is also really important in terms of its relationship with progressive disease in IgAN. Inhibitors of complement activation may mitigate IgAN progression. However, there have not been any head-to-head comparisons or additive clinical trials looking at these simultaneously.

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IgAN is a disease that lasts for multiple decades and has probably been ongoing in a patient by the time the diagnosis is made. Most patients are diagnosed at chronic kidney disease stage 3B. In my opinion, durable disease-modifying treatment for IgAN has not yet been identified, and we need to look at long-term effects and real-world evidence beyond what was seen in clinical trials. For a disease that may have been ongoing for decades, what do we do at the end of 9 or 12 months of these targeted therapeutic interventions? When do we stop treating? Do we recommend cyclical treatment? This is going to be an important part of the conversation about targeted therapies. How do we start re-treating patients who have not achieved remission?

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Regarding the heterogeneity of IgAN, it is not just a disease that involves hematuria, proteinuria, and progressive fibrosis. There are so many parts of IgAN progression, and it is interesting to consider the roles of combination and targeted therapies all along the continuum. In the future, it will be important to determine the patient’s phenotype, which can guide our decisions on the use of targeted therapy.

I start by putting every patient with IgAN on foundational therapy, which is nonimmunomodulatory therapy. Getting as many of these agents as I can on board to lower the proteinuria without any immunomodulation is the core concept of foundational therapy. I will treat with the highest-tolerated dose of an ACE inhibitor or an ARB, potentially followed by an MRA and an SGLT2 inhibitor, unless the patient does not have an indication (although most patients with IgAN will). Potentially, in the future, I may add a GLP-1 agonist on top of the SGLT2 inhibitor. Then, for maximum protein reduction, I may also add an ERA. Moreover, if there is activity on a biopsy, I will want to add something immunomodulatory.

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I really want to stress that this is a disease that is going to stay with the patient, even with the best of therapies. You may be using targeted therapies for several years, followed by foundational therapy alone. Then something unexpected could happen that triggers disease activity, and you may have to think about using something more targeted again.

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I think that we are in a really exciting era in that we have multiple therapeutic agents at our disposal—and more on the way. With regard to some of the emerging therapies, there are several APRIL- and BAFF-targeting drugs for which there are published data or data presented at meetings. What is so exciting about these data is that they are showing that these drugs are not only decreasing proteinuria but also leading to improvements in, and sometimes a resolution of, hematuria. To me, if the hematuria goes away when the proteinuria goes away, that would be a sign, without having to do a repeat biopsy, that the patient is in a true immunologic remission. Then I could follow that patient and use just the foundational therapies to keep their proteinuria levels low. If hematuria reemerges over time, then you might rebiopsy to see if there is more activity, or you might put the patient back on a targeted therapy.