Redefining Treatment Goals in IgA Nephropathy: Insights from the KDIGO 2025 Guideline Update

Brad Rovin, MD, chief of nephrology at Ohio State University Wexner Medical Center, discusses how the KDIGO 2025 guidelines mark a major shift in the management of IgA nephropathy, emphasizing earlier diagnosis, lower proteinuria targets, and integration of new therapies into a flexible treatment paradigm.

Brad Rovin, MD: Hello, everyone. I am Brad Rovin. I'm the chief of nephrology at Ohio State University Wexner Medical Center and the Lee Hebert professor of nephrology. I have been a nephrologist here for 35 years. We established a glomerular diseases program here, and I run a glomerular disease fellowship.

My interest has always been in the interaction of the immune system with the kidney, and especially the idea of how we can understand using biomarkers to look at the pathology of glomerular diseases. That's what my laboratory works on.

We are also heavily involved in looking at the molecular pathogenesis of glomerular diseases by using tissue proteomics and tissue transcriptomics. I'm also heavily involved with clinical trials and am working actively on many glomerular disease clinical trials, with a special interest in lupus nephritis and immunoglobulin A (IgA) nephropathy.

The KDIGO 2025 guideline is described as a fundamental shift in how clinicians approach IgA nephropathy. From your perspective, what are the most important changes clinicians should be aware of?

Dr Rovin: That's really the key question. We now have evidence to push us to biopsy and diagnose patients with IgA sooner, and to have a new goal of therapy. This evidence started with registry data from the UK suggesting that even patients who achieve levels of proteinuria less than 1 gram a day were still at considerable risk for progressing to end-stage kidney disease with IgA nephropathy.

Our goals of treatment in the past have been to get proteinuria to about 1 gram a day or less, if we could achieve it, but that's where we left it. We now realize, as we've advanced our knowledge of IgA nephropathy and its natural history, that this goal was too high, and we need to push for better control of proteinuria. This leads us to change how we evaluate our therapies and change when we actually start to intervene with patients.

The second big change in the IgA guidelines is that we've had several therapies approved between the last update and now. These therapies allow us to target different parts of the presumptive pathway of IgA nephropathy pathogenesis.

This has led us to try to sort this out for the nephrologists and the nephrology community, because these advances have come rapidly and can be overwhelming and somewhat confusing. We've tried to do that in an algorithmic way. I understand that algorithms are not perfect and very few people fit the algorithm directly, but it's a starting point to think about how you might approach a patient with IgA nephropathy.

It also is modular in the sense that as new therapies are approved, they can be easily fit into this conceptual paradigm of how to treat IgA nephropathy. I think it's quite useful.

How do you see these changes influencing day-to-day clinical practice and patient outcomes?

Dr Rovin: We're gradually making inroads in explaining and reinforcing the fact that IgA nephropathy is not as a benign a disease as we had thought in the past. It is progressive, it starts in folks who are younger, and over their lifetime their risk of developing kidney failure is a lot higher than I think we ever presumed.

This is pushing many of us to recommend earlier diagnosis and also to recommend therapies that we now have that interfere directly with disease pathogenesis. This is a readjustment because I've been doing this, as I indicated earlier, for a really long time. When I was in training, IgA nephropathy all those years ago was considered a pretty benign disease and it was not very risky for patients. We know that is not the case. We have to consider this similar to any of our other immune-mediated kidney diseases and start to be a little bit more proactive in getting the disease under control.

You mentioned that there are now multiple approved therapies such as targeted-release budesonide, sparsentan, and SGLT2 inhibitors. How do you recommend clinicians prioritize or integrate these options into individualized treatment plans for IgA nephropathy?

Dr Rovin: This is a key part of the guideline, and really important. The therapies that we have now encompass therapies that theoretically target the production of the antigen in IgA nephropathy, which is presumed to be galactose-deficient IgA1. The therapies also target kidney injury after IgA has been deposited and the consequences of these IgA immune complexes winding up in the mesangium, such as complement activation.

The way we have put together an approach to therapy is that we need to think about turning off the disease immunologically, if that's possible. We are recommending that drugs that actually target the production of galactose-deficient IgA or the production of autoantibodies against the galactose-deficient IgA be used early on in this disease, especially in patients who are likely to progress and have high levels of proteinuria, impaired kidney function, and maybe hypertension on top of that.

At the same time, we recognize that the diagnosis of IgA nephropathy is often made late because it tends to be a fairly silent disease. When we see patients, not everyone, but many already have chronic damage to the kidney because the IgA has been going on in the background for some period of time.

We suggest that, simultaneously with attacking the immune mechanism of the disease, we also treat patients to preserve kidney mass and decrease the tendency for progression from the chronic injury they've already sustained. It's really a 2-pronged approach. As I said, we have medications now that target the second part, which is kidney injury. We have complement inhibitors. We know that the complement system is involved in IgA nephropathy, and it may perpetuate damage to the kidney, so that's one possible therapeutic option.

We also know that in IgA nephropathy, the renal angiotensin aldosterone system is activated. We've been using RAS inhibitors or antagonists of that system for a long time in the management of IgA, but we now know that if we add an endothelial antagonist, a system that actually interacts with and can replace or extends some of the adverse events of the renal angiotensin system on the kidney, we actually get even more benefit. We have all 3 of those types of drugs to use right now that have been approved by the US Food and Drug Administration (FDA).

We have several other drugs and approaches in the pipeline that are in late-phase trials, and given the results of the phase 2 data that we've seen, we anticipate that some of these will also be approved for use. They add exciting new dimensions to the toolbox we will have for IgA nephropathy.

The guideline notes limited progress in special populations, such as children, pregnant patients, or those with rapidly progressive disease. Where do you see the most urgent need for future research, and what’s on the horizon in this field?

Dr Rovin: I do think that we really need to be able to start understanding how to apply our adult therapies to children and pediatric patients. That, to me, is a huge need. We think a lot of these drugs can be used in children. Maybe the doses will need to be adjusted, but the safety profile in adults has been quite good. I would like to see the trials extended down into the pediatric age group. I think this is really important and something that we can and should do now.

We tend to treat rapidly progressive IgA nephropathy pretty aggressively with older therapies that are immunosuppressive, but have sustained the test of time in terms of working well in rapidly progressive glomerular diseases. So, while not perfect, I think we can take care of rapidly progressive IgA nephropathy as long as it's recognized as such. My personal experience with this has been, we can get the disease under good control using some of our more traditional and very aggressive immunotherapies.

The problem of IgA in pregnancy is really interesting. I would venture to guess that some of the medications we have approved may actually be pregnancy compatible. At the very least, we do know that we can give glucocorticoids or steroids in pregnant patients safely. We do that in some glomerular diseases, if necessary. We do know that some of the more recent data using systemic glucocorticoids at reduced doses have suggested benefit in IgA nephropathy.

That's not a very good answer for you. It would be much better to understand and have particular IgA drugs that have been tested during pregnancy that we know to be safe and effective, but I think that's a particularly difficult study to do, as you can well imagine. From a patient perspective, my suspicion is that's going to take longer to address than the other two that you've brought up.

Is there anything else you’d like our audience to take away from this?

Dr Rovin: As I mentioned, we do have other therapies that are being developed for IgA nephropathy that are equally exciting and will likely, at least some of them, become approved. We do intend to try and be as current as possible with the KDIGO guidelines in terms of adding these to our recommendations after the data becomes public and our evidence team can evaluate the data, because everything we do, we try to do evidence-based and have a rigorous evaluation of the studies supplying the evidence.

I would say that one of the benefits of the paradigm we've created for managing IgA nephropathy will easily allow the new therapies, based on their mechanisms of action or presumptive mechanism of action, to be integrated into that paradigm and updated. I would tell the community that we will continue to be on top of all of the advances in IgA nephropathy, review the evidence as it becomes available, and then try to update the guidelines accordingly very quickly.

This is an unprecedented time for those of us taking care of patients with glomerular disease, and we've not had this sort of flurry of development in the past. This is a challenge for everyone, but KDIGO intends to meet that challenge.