Although treatment guidelines for chronic kidney disease were updated in 2024, rapid developments in the understanding of IgA nephropathy (IgAN) pathophysiology and related treatment options appear to be outpacing the recommendations in these treatment guidelines. Novel treatments and management approaches may need to be considered by practicing clinicians.

The field of IgAN therapeutics is rapidly changing, and, although the 2024 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines incorporate a lot more therapeutic options than were available in previous versions, they do not incorporate some therapies that many of us expect will be US Food and Drug Administration (FDA) approved over the next year or two. So, these guidelines will probably need to be modified again soon to incorporate newer therapies.

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One of the important strategies that the 2024 KDIGO guidelines stress is to use the treatments that we have available to target the pathogenesis of IgAN. When you think of the multi-hit model of IgAN, it all begins with the production of galactose-deficient IgA1 (Gd-IgA1) and the subsequent development of autoantibodies directed against Gd-IgA1, with subsequent immune complexes then mediating glomerular injury. The guidelines are telling practicing nephrologists that the key treatment strategies need to be focused on preventing that immune complex formation. Treatments that target these Gd-IgA1s, such as targeted budesonide, should be prioritized. However, if we are thinking about the production of the autoantibodies that target Gd-IgA1, then we start considering B-cell–targeted therapies, including investigational agents such as anti-APRIL and anti-BAFF agents. Moving down the pathway, another key treatment strategy emphasized in the KDIGO guidelines is to reduce immune complex–mediated injury. There, we start bringing in anticomplement therapies such as iptacopan because, when immune complexes form and deposit on the glomerulus, they activate complement.

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For years, prednisone was the only immunomodulatory therapy we had, but, of course, it comes with a lot of toxicity. However, prednisone also works at preventing immune complex formation and reducing immune complex–mediated injury. It is still a treatment option, especially if that is the only therapy that our patients have access to. Further, we now have data suggesting that we could use approximately half the amount of prednisone that we previously used thanks to the TESTING study of full- and reduced-dose methylprednisolone (what most of us now refer to as the “low-dose TESTING study”).

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The 2024 KDIGO guidelines also suggest that you can use multiple therapies alongside each other, which is a new challenge in IgAN, as there are 2 questions that need to be answered. First, can we combine them together mechanistically? Second, are payers going to cover the costs of those medicines at the same time? In theory, you should be able to combine a drug such as budesonide with a complement inhibitor. They have very different mechanisms of action and may work synergistically at different parts of the multi-hit model. Whether payers will cover the costs of this approach, though, is still unclear to me.

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What I like about the key treatment strategies from the KDIGO guidelines is this idea of managing nephron loss and the consequences of nephron loss. We have always known that controlling blood pressure by using RAAS-blocking drugs has been an important part of treating IgAN. But now, adding either an ERA or a DEARA may further enhance the response. In addition, adding an SGLT2 inhibitor on top of that may reduce negative outcomes, such as progression to end-stage kidney disease.

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The beauty of treating IgAN now is that you do not have to feel confined if you want to use immunomodulatory therapy. If you want to go after immune complex formation or immune complex–mediated injury, there are nonsteroid therapies that are already FDA approved. The drugs in the pipeline for FDA approval also suggest that there will be even more therapies that can be used in that setting in the future. This really gets us to the idea that, in the future, we will hopefully be able to use a more personalized or precision medicine approach in our treatment of IgAN.