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New IgAN Paradigm
A New Paradigm In IgAN Management: How Diagnostics and Treatment Are Evolving

Released: November 06, 2025

Andrew S. Bomback
Andrew S. Bomback, MD, MPH
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Key Takeaways
  • The key outcomes for proving efficacy of an agent in treating IgAN are reduced proteinuria at 9 months and eGFR decline at 2 years.
  • Several therapies are in development for IgAN that target various points in the multi-hit model—from APRIL and/or BAFF blockade to inhibiting components of the complement pathway, renin-angiotensin-aldosterone system, and endothelin-1.
  • A reframing of IgAN management is necessary to ensure access to much-needed therapy for patients to improve outcomes.

There is a clearly defined pathway to establish efficacy and get FDA approval for new IgA nephropathy (IgAN) therapies. The first critical endpoint in any IgAN clinical trial is changes in proteinuria at 9 months. This is because there is a clear correlation between changes in proteinuria and eventual stabilization of estimated glomerular filtration rate (eGFR). The next key endpoint is 2-year eGFR data, including the comparison of that data with a control group. If you put these 2 endpoints together, 9-month proteinuria data gets the agent an accelerated approval, whereas 2-year GFR gets it a full, regular approval by the FDA.

This approach makes sense because long-term outcomes data have shown that reductions in proteinuria lead to stabilization of eGFR. For example, data from a retrospective cohort analysis of the UK National Registry of Rare Kidney Diseases, or RaDaR for short, determined that every 10% decline in time-average proteinuria was linked to 11% lower risk of progression to kidney failure or death.

Yet the biggest limitations seen with clinical trials for IgAN are their inclusion and exclusion criteria. These criteria do not automatically match the patients that healthcare professionals (HCPs) often see in real-world practice. And because IgAN clinical trials are heavily weighted toward showing proteinuria reduction as a primary endpoint, they generally enroll patients with 1 g/day or more of proteinuria. Of course, there are patients with IgAN and proteinuria less than 1 g/day who still are at high risk for disease progression. These patients will require IgAN-directed therapy as well, but they are not represented in clinical trials. That is a large gap that HCPs must fill in on their own by determining which patients are approaching or at the same level of risk as those included in clinical trials.

On the flip side, patients with advanced disease are often excluded from these clinical trials, too. This includes IgAN where patients’ eGFR is too low to meet the inclusion criteria, yet these patients could be potential candidates for targeted therapy. They are just not matched by the participants in the clinical trials. This requires HCPs to know how to translate clinical trial data into their practice.

IgAN Biomarkers Beyond Proteinuria and eGFR
As of today, microscopic hematuria is the only other biomarker that is ready for public use beyond proteinuria and eGFR. Microscopic hematuria is a feature typical of most IgAN cases, but it is not as easily quantifiable as proteinuria. That is why it has not been used as a reliable endpoint in clinical trials or as a biomarker to the same degree proteinuria has been used. However, there are data that show patients with IgAN who lose their microscopic hematuria have better outcomes compared with those who continue to have microscopic hematuria. Some of the newer trials, particularly the ones looking at agents that block APRIL and/or BAFF, have included microscopic hematuria endpoints as a biomarker for disease activity. Emerging data are also showing that these novel therapies can clear out the microscopic hematuria in most patients.

The other biomarkers that have people the most excited about stem from the pathogenesis of IgAN and the multi-hit model of immunologic pathophysiology. Researchers are looking at galactose-deficient IgA1 and antigliadin antibodies, which operate in hit 1 and hit 2, respectively. Although there are some data on these from clinical trials, the data are not yet robust enough to validate them as biomarkers.

New and Emerging IgAN Therapies
All new and emerging therapies for IgAN target specific “hits” in the multi-hit model, though it is too early to know how the targeting of each “hit” is expected to translate into outcomes. Still, this is where the idea of precision medicine in IgAN comes into play. The idea being that if you can predict or identify where in the multi-hit model the pathogenesis of each patients’ IgAN is most ramped up, you might be able to choose the therapy that is going to target that part of the model and give you the best outcomes.

What we know so far is that the FDA-approved agents target different parts of the multihit model. For example, targeted-release formulation (TRF) budesonide goes after hit 1—the production of galactose-deficient IgA-1. Several emerging agents that target APRIL and BAFF go after hits 1 and 2 and are expected to be approved by the FDA in the coming months. But we cannot make an apples-to-apples comparison yet between these agents based on the data we have seen so far. In addition, there are some signals from the clinical trials for APRIL- and BAFF-targeting agents that suggest they may reduce proteinuria more than TRF budesonide. As I mentioned previously, these agents also show promising data in clearing hematuria, but hematuria was not one of the reported outcomes for TRF budesonide. This does not mean that TRF budesonide cannot treat hematuria, but it does suggest that you might get better disease control with improved hematuria and proteinuria.

Then there is the FDA-approved, complement factor B inhibitor iptacopan that targets hit 4—the inflammatory response that immune complex deposition elicits in IgAN. Again, it is hard to say which agent is going to have the more pronounced effect. For iptacopan, we only have 9-month proteinuria data, and these are pretty similar to the data seen with the other agents I have discussed. Therefore, in terms of which one has the more pronounced long-term impact, that is going to come out when the 2-year eGFR data settles.

Finally, there are a couple of recently approved agents that could now be considered foundational therapies for IgAN. Sparsentan is an endothelin and angiotensin II receptor antagonist, and atrasentan is an endothelin receptor antagonist. Although both agents are nonimmunomodulators, their ability to reduce proteinuria is not as robust as the immunomodulatory agents. Furthermore, the sparsentan 2-year eGFR data was strong enough vs placebo to receive regular approval from the FDA, but it does not appear to be as strong as TRF budesonide, which is not surprising, given the different mechanisms of action (immune-modulating vs nonimmune-modulating) and different patient populations enrolled in these studies. The patients who were enrolled in the sparsentan and atrasentan studies had significantly longer disease duration of IgAN compared to those enrolled in the immunomodulatory studies. So although the proteinuria reduction in sparsentan led to GFR slowing, it is a prevalent population, so you are not going to see as profound of a GFR effect as when you are trying a drug in an incident population.

Discussing Treatment Options With Patients
Because the IgAN space is getting so crowded with new therapies, the time is ripe for using shared decision-making. This is where HCPs should discuss the available treatment options with patients, including what therapies are appropriate, their efficacy data, whether the agent has accelerated or regular approval, and their safety data. The nice thing about these emerging agents is that their targets are very specific; they do not have the same degree of nonspecific immunosuppression seen with therapies that have been used in the past for IgAN. For example, high doses of systemic corticosteroids would be accompanied by high rates of toxicities, and alkylating agents or antimetabolites, like mycophenolate mofetil, were nonspecific approaches to treating this disease.

Now that we have these agents that go after specific targets in the multi-hit model, we can offer a more “designer” approach to treating IgAN. And the more precise the target is, the fewer safety concerns you should have. But each agent carries its own set of toxicity risks. For example, sparsentan has a risk evaluation and mitigation strategies (REMS) requirement due to an increased risk for hepatoxicity. Iptacopan has a REMS requirement due to an increased risk for serious infection caused by encapsulated bacteria. Although TRF budesonide is not a systemic corticosteroid, there still is a slight risk for systemic corticosteroid effects associated with it, and the anti-APRIL agents will bring on a potentially increased risk for infection.

As a part of shared decision-making, HCPs must also consider the potential barriers patients may face in accessing the agreed upon treatment. The most obvious barrier is cost. These new agents are very expensive, and we must negotiate with health insurance companies to ensure our patients can access the best therapies for them.

The 2025 Kidney Disease: Improving Global Outcomes guidelines suggest HCPs follow a 2-armed approach to treating IgAN. There are foundational therapies that are nonimmunomodulatory, and there are IgAN-directed therapies that are immunomodulatory. Most patients with IgAN are at high risk for disease progression, so they will need to be treated with both therapy types. But some of these newer foundational therapies carry high price tags that are essentially the same cost to the health insurance company as immunomodulatory therapies. Therefore, HCPs might be asking patients’ health insurance provider to cover 2 high-cost agents. Because there has already been pushback from health insurance companies, coverage of IgAN therapy remains a huge barrier to care.

Another key barrier is clinical inertia. All treating HCPs must be aware that IgAN is not a mild disease for most patients. It comes with a high risk of progression, and the proteinuria levels that we used to consider low risk are now classified as high risk. These patients absolutely need therapy, and 2 of the biggest lessons I have learned are not just that lower levels of proteinuria confer risk, but early reduction of proteinuria is the key to slowing eGFR decline. Both are essential to achieving the best outcomes for our patients. That is why a reframing of IgAN management is necessary and ensuring the nephrology community in general understands this is crucial to get patients access to these much-needed therapies.

Your Thoughts
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