<p>At <strong>Kidney Week 2025</strong>, researchers presented positive data from phase 3 trials of novel B-cell–directed agents for IgA nephropathy (IgAN). Treatments targeting pathogenic IgA synthesis, inflammation, and optimized supportive kidney care are all part of a multipronged approach to protecting the kidneys.</p> <p><br></p> <p><em>Following these presentations, featured expert Myda Khalid, MD, was interviewed by </em>Conference Reporter<em> Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Khalid on these findings are presented here.</em></p>

When we consider the pillars of IgAN therapy, it is crucial to stop the immune-mediated process that causes the underlying condition. The 4-hit hypothesis refers to the pathogenesis of IgAN and is outlined as follows: Mature B cells (also known as plasma cells) produce abnormally glycosylated IgA (ie, galactose-deficient IgA1). This abnormal IgA is recognized as a foreign antigen, and antibodies (ie, IgG and IgA) form against the abnormal IgA. The antibodies bind to the abnormal IgA, forming circulating immune complexes that eventually get trapped in the kidney, triggering the proliferation and release of cytokines and chemokines in the kidney tissue. Over time, this leads to permanent kidney damage resulting in chronic kidney disease and, in some cases, end-stage kidney disease. Based on what we have been learning about the natural history of IgAN, it appears that both the development of chronic kidney injury and the progression to end-stage disease are more common than previously thought.

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Therapeutic agents can intervene at any stage of the 4-hit hypothesis, and we are fortunate to live in a time when treatments targeting each step are becoming available as potential options. Along those lines, it was so exciting to see data on BAFF and APRIL inhibitors at the recent Kidney Week 2025 meeting. These agents block B cells from maturing and surviving, thereby reducing the production of abnormally glycosylated IgA. During the opening plenary session, Richard A. Lafayette, MD, shared positive 9-month data from the phase 3 trial of atacicept, a dual BAFF and APRIL inhibitor. And, the following day, we saw positive phase 3 data for sibeprenlimab, which inhibits APRIL, presented by Vlado Perkovic, MBBS, PhD, FASN (abstract SA-OR086).

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Of course, we know that complement also plays a role in the pathogenesis of IgAN, given the deposition of complement in tissue biopsied from individuals with IgAN and the demonstration of complement inhibitors as effective agents in the reduction of proteinuria in the setting of IgAN. Additionally, budesonide, a synthetic corticosteroid, is now included in the most recent Kidney Disease: Improving Global Outcomes (KDIGO) guidelines and is probably working at the level of both the gut and the kidney (by limiting inflammation). A potential conceptual approach to the treatment of IgAN is to block the “bad” B cells from producing abnormal IgA and making antibodies to the abnormal IgA, and to deploy complement inhibitors to limit the extent of renal inflammation or the reaction within the kidney. It is likely that budesonide works along this entire spectrum.

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During our educational symposium titled “Expanding Therapeutic Horizons in IgAN,” Ali G. Gharavi, MD, illustrated how different mutational profiles might have therapeutic implications for both disease-modifying and supportive agents, spotlighting previous work by Kiryluk and colleagues on genome-wide risk loci in IgAN. Ana Malvar, MD, then outlined the case for targeting B cells, as framed by the 4-hit model, touching on emerging agents, including sibeprenlimab, atacicept, and povetacicept.

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Lastly, simultaneous nephroprotective strategies to preserve kidney architecture are paramount. We have been doing this effectively as nephrologists for years with ACE inhibitors and, more recently, with SGLT2 inhibitors and DEARAs. During the opening plenary session, Prabir Roy-Chaudhury, MD, PhD, FASN, current president of the American Society of Nephrology, highlighted the seminal work demonstrating that ACE inhibitors are effective in diabetic nephropathy. ACE inhibitors were the “big thing” for so long. We have been using ACE inhibitors for renal protection for many kidney conditions—even in children. So, the concept of having to preserve kidney tissue is not new, but the concept of being able to treat the underlying pathology of the disease in a targeted manner is newer and is very exciting.

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The emergence of amazing new therapies for the treatment of glomerular disease and for kidney preservation in recent years has been thrilling. Historically, the renal community had to focus on improving outcomes in dialysis and transplant, but, during the past few years, there has been a significant shift toward preventing affected individuals from progressing to the point of needing dialysis and transplant. Maybe very soon we will have a world in which IgAN and other glomerular diseases will become treatable conditions that do not progress to chronic kidney injury or end-stage kidney disease. This would mean so much to people living with IgAN or glomerular disease and their loved ones. It would be life-changing.