Gerald B. Appel, MD

How the 2025 KDIGO Guidelines Are Personalizing IgA Nephropathy Care, With Gerald Appel, MD

 and IgA vasculitis (IgAV), in tandem with the evolving therapeutic landscape, has introduced significant changes to clinical care, essentially individualizing treatment strategies.

These clinical shifts included a reassessment of treatment targets for key biomarkers and a greater emphasis on addressing the underlying mechanisms driving disease progression.

From a clinician's perspective, Gerald Appel, MD, professor of clinical medicine at Columbia University, IgAN has shifted management toward a more personalized approach, supported by a broader range of therapeutic options, combination strategies, and long-term patient-centered goals.

In practice, this personalization is increasingly guided by biopsy findings, baseline proteinuria, and patient-specific risk factors, allowing clinicians to tailor therapy based on dominant inflammatory or hemodynamic drivers of disease.

“Kidney biopsy can be very helpful in this regard. If a patient has significant scarring, therapy may focus more on ACE inhibitors, ARBs, endothelin receptor antagonists, and SGLT2 inhibitors,” said Appel.” If inflammation predominates, we may target that pathway more aggressively.”

Notably, the 2025 KDIGO IgAN guideline encourages kidney biopsy in adults with suspected IgAN and proteinuria ≥0.5 g/d. This represents a shift from the 2021 guideline, which emphasized reducing proteinuria to <1 g/d.

Additionally, the guideline authors underscore proteinuria as a validated surrogate marker for long-term renal outcomes, supporting both earlier diagnostic evaluation and more aggressive treatment targets. The updated guideline reduces the recommended target to <0.5 g/d, with an ideal goal of <0.3 g/d, regardless of treatment status, reflecting evidence linking persistent proteinuria to an increased lifetime risk of kidney failure.

A major new concept in the 2025 guideline is to initiate treatment with therapies to prevent or reduce pathogenic IgA production and IgA/IgA and IgA/IgG immune complex formation, along with therapies to manage the consequences of existing IgAN-induced nephron loss.

“For example, targeted-release budesonide (Tarpeyo) acts on the distal ileum, specifically the Peyer’s patches, where it reduces the production of galactose-deficient IgA1 and immune complexes. This, in turn, reduces proteinuria and kidney injury,” explained Appel. “Other emerging agents also block the production of galactose-deficient IgA1 and immune complexes, while some newer therapies primarily focus on reducing proteinuria and inflammation. We now have multiple points of intervention to alter the course of the disease, and KDIGO highlights this approach.”

The 2025 KDIGO recommendations emerge amid a rapidly evolving IgAN therapeutic landscape, with 10 agents in late-phase clinical development demonstrating comparable proteinuria reductions. These late-phase programs span multiple mechanistic classes, including endothelin pathway inhibition, complement modulation, and targeted immunosuppression, reinforcing the guideline’s emphasis on combination and mechanism-driven therapy.

Collectively, these advances have the potential to expand clinician choice and create new opportunities to individualize disease management.

As therapeutic options continue to expand, the 2025 KDIGO guideline provides a framework for integrating emerging agents into individualized treatment strategies aimed at delaying or preventing kidney failure.

Editor’s Note: Appel reports relevant disclosures with Novartis, Travere Therapeutics, and others. 

Floege J, Barratt J, Cook HT, et al. Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV). 

https://doi.org/10.1016/j.kint.2025.04.003

Jürgen Floege, MD. PREVAIL: Felzartamab’s Sustained Clinical Outcomes In IgAN, With Jurgen Floege, MD. HCPlive

 Published online November 20, 2025. doi:

https://doi.org/10.1016/S0140%E2%80%916736(23)02302%E2%80%914

Brooks A. KDIGO Releases Updated IgA Nephropathy, IgA Vasculitis Clinical Practice Guideline. HCPLive. Published September 18, 2025. Accessed February 5, 2026. 

https://www.hcplive.com/view/kdigo-releases-updated-iga-nephropathy-iga-vasculitis-clinical-practice-guideline

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2025 KDIGO guidelines reshape IgA nephropathy care with earlier biopsy, tighter proteinuria targets, and personalized treatment strategies.


I've said this many times, we're in the golden age of studies in glomerular disease. And we are making great strides in an ultra-rare disease like C3G. I know our center's certainly recruiting and there's a global network of GN centers now recruiting to these studies, which we'll hopefully deliver, but we are spoiled for choice Jerry, and we have lots of studies. I will you just first run us through your approach to managing patients in 2023 and the kind of opportunities that might be available with all the clinical trials that are happening at the moment?

I was hoping you'd come back to IgA nephropathy, because we've lacked a good biomarker. People have said, level of galactose deficient IgA or antibodies to galactose deficient IgA. But so far, we have not had a good biomarker. And the best correlation we've had is with proteinuria. Now, the good news is that the FDA realizes that some of these patients will only slowly progress. They're using the surrogate marker, which has been mentioned, a proteinuria reduction. The bad news is they're using a surrogate marker. We don't necessarily know what's going to happen to the GFR in all these cases. We've recently had 2 drugs approved in terms of treating patients with IgA nephropathy, first of all, without the final publication of the manuscript initially, and then without the final data in terms of what's happening to the GFR. And certainly, in terms of we've got the shorter terms data, not the longer term data that we might need. I'm not against the fact that the FDA is approving these, it's just making it more challenging in terms of following these patients without a good biomarker in terms of this. My view in terms of treating the patient is that given anybody with risk factors, I would put them on maximal supportive care. Now, if you look at KDIGO guidelines, they say that high risk is over 0.75 to one grams of proteinuria that persists for more than X amount of time. That which is 3 months is what they're talking about there. But in some of the studies, the stop trial that was done in Germany, they said you had to be on it 6 months. Before you had standard of care. The other thing is, none of the studies yet have included SGLT2 inhibitors, which are rapidly becoming standard of care. We already have data in IgA nephropathy that it makes a significant difference in terms of time and proteinuria and course of the patient too, in terms of GFR. Given that the standard of care has changed, we've upped the level blockade of the renal angiotensin system, strong consideration to SGLT2 inhibition, then the role of steroids, which we've certainly confused a lot of nephrologists by starting out by saying they worked because we had 3 or 4 trials, small, but they seem to work, then we all of a sudden have a big trial that looks like it's done very well, but it had unique features that made it a little different from some of the others. But the stop trial that said they didn't work long term, then we get to the testing trial that doesn't work at first, but then does work after they do it at a lower dose. Everybody has been changing what they're doing, and we're going back and forth. I feel sorry for a patient if they heard this, that the steroids you tried 3 years ago that we stopped, well now we're going to try them again. And whether those steroids or a non-absorbable steroid that works predominantly on the gut should be used, is just not clear. What we're left at least in IgA now in terms of standard of care. For anybody who's high risk, and I think high risk is probably going to be more than 0.5 grams not 0.75. It's very clear that there is data from Vega and other studies that show that, so at lower levels of proteinase should get standard of care. And then if they're not at the point that keeps them at high risk, and that's going to be different for different people, we should be doing something. And whether it's steroids, straightforward, old-fashioned steroids at a lower dose for still about a 6 month course, or whether you want to say, look a non-absorbable one because this person has high risk factors for steroids, they're they also have diabetes and where they don't want cosmetic changes that person might benefit from a non-absorbable steroid, which we don't have good proof that they're entirely non-absorbable but again, there's going to be individualization of therapy at the current time until we get more clear data or until we get a good biomarker. They are looking at new CD markers, CD8 I think it is, but they're looking at new markers trying to say that this is going to make a difference. And in some diseases it looks better than others in terms of lupus. Some people feel using urinary biomarkers is making a difference already now. But still for IgA we're left with getting what we wished for, we wished for the FDA to finally approve something, and now they're approving it faster than we know the data. And we can't make decisions based on it.

: It is a real challenge. You're right. I go to my therapeutic cupboard for my IgA patients and it's empty, and we're going to move from zero. We've had nothing for 50 years. Two new drugs in the last 18 months. Three phase 3 studies are likely to be reporting over the next 12 to 18 months. We are going to need to educate our nephrologists, our colleagues, how to use these with the right patients. What are the safety concerns? How might we potentially combine them?

Gerald B. Appel, MD, discusses the changing treatment landscape of IgAN.

Clinical trial data on IgAN for therapies

Anuja, you touched on something interesting in your context of post-transplant recurrent disease. Is transplant patients have a lot of immunosuppression on board. And it doesn't seem to impact greatly on recurrence of IgA, but also C3G in your, is that your experience?

And that shows a limitation really of conventional approaches.

Would you, in terms of your transplant practice, where would you see complement, therapies fitting in, in the context of patients already on often triple immunosuppression?

Following up on what Dr Nester mentioned, we are always worried about infections in these patients because as you said, as we know, these patients are on baseline immunosuppression to begin with. A few different things to keep in mind when we are using complement inhibition in transplant population or even in native kidneys, is that, as we've talked about, complement is part of innate immunity we are born with it, but as a person grows, your maturing adaptive immunity also starts playing a role in preventing infection. That's an important protective factor. The other thing depends on what inhibition you're using and which level that is. If you're using a C3 inhibitor, which is more central to the complement activation versus if you're using a more terminal inhibitor, you would worry that if you have a patient on a more C3 inhibitor, will that person be at a risk of broader infections. I would say that even though these drugs inhibit the complement system, they don't completely abolish the ac- abolish. There is even that little residual complement that you have is protective. And in our transplant population, my experience is that we've had a pretty good success with using these drugs, particularly patients that I take care of with atypical hemolytic UIC syndrome, where we use anti C5. And a very important factor is the vaccination. These patients are vaccinated, and the vaccination does bring down the risk of these infections, at least stand forward from what the literature shows. In addition, we keep our patients with prophylactic antibiotics. If you don't have enough time to vaccinate them and you must start the therapy, you could start them on antibiotics. And we keep our patients on antibiotics lifelong. There is a lot we can work with in using the inhibitors even in a more immunosuppressed population like the kidney transplant.

Anuja Java, MD, discusses the role of complement inhibitors in transplant patients with C3G.

Complement therapy in transplant patients in C3G

: If you take a step back and think about your pathophysiology if it's an autoimmune-driven process, you might want to target the B cells that are producing the autoantibody. If it's a complement-driven process, targeting the complement system is the direct route to take, isn't there?

That's correct. In fact, there have been, again, not any randomized controlled trials, but there have been attempts to block B-cells that have been almost flipping a coin, whether it's been successful or not. It works in some case reports. It doesn't work in other case reports. Routinely we can't depend on blocking B-cells to help us with this autoimmune disease. It sounds like a great idea, but it hasn't been clearly proven to be successful. But yes, you're right. If you believe that the disease is driven by alternative complement pathway dysregulation, then you need to block the complement system at the level that it needs to be blocked.

What clinic current clinical trials are you aware of attempting to do that?

You can go to clinicaltrials.gov and you can figure out, for instance, what trials are out there. But I would say that in thinking about where the disease is originating so if you think it's in the middle of the pathway at the level of the convertase, then there are at least three agents that are out there, or three ages that could target where we think. The first one would be that was trialed, was the factor D inhibitors. That trial is now closed. It wasn't as successful as we thought it would be, but it was probably because they didn't reach the appropriate PK studies. We can't say D is out, based on that. But then now there are also factor B inhibitors and factor - and C3 inhibitors. Both of those would be predicted to be a much better match to this disease or target the disease much more closely than we've been able to do, for instance, with terminal complement blockade.

: I believe some of that data has been presented at conferences.

Yes. The D inhibitor has been published, so that people can find that in the published literature. The factor B inhibitor and the C3 inhibitor both have been taken to multiple congresses. Any of the nephrologists or even hematologists can go to their congresses and actually see the fact that both of them have reported preliminary successes, actually.

That success has been reduction in proteinuria.

Reduction in proteinuria, improvement in GFR or at the very least stabilization in GFR and in some cases, even though it's a surrogate, improvement, or normalization of C3 as a surrogate of quieting the complement pathway. Those have shown up in our congresses and, I’m sure that both of those studies are in phase 3 right now. It's very important to be watching for the results because obviously as nephrologists, we want to know that they're effective, absolutely, but also that they're safe.

And that's important. And I think we do need to highlight the fact this is going to happen soon if these trials are positive, we are going to be faced with drugs hopefully that will be approved and will be coming into clinical practice for these patients with this devastating disease. But I'm just going to come back to safety, because that clearly is the critical other side of the coin, isn't it? We need to know these drugs are efficacious, but only in the context of them being safe. And what are your concerns if you were to use a complement inhibitor, what would be going through your mind in terms of things?

Again, if you think about it, again this is part of your innate immunity. This is part of your immune system that was meant to fight infections that you were not vaccinated against, for instance. You must think about those sorts of things. But the classic concerns are encapsulated organisms. Those are the organisms that you require your complement system to be functionally active to be able to defend against. Antibiotics work but you need your complement system to keep you safe while you're waiting for the antibiotics or wait to even be started or to even work. We think about encapsulated organisms, and that's meningococcus, streptococcus and hemophilus influenza are the 3. Fortunately, we have some data from the Eculizumab or the terminal complement blockade trials that we know that you can vaccinate for those three organisms and get some protection. So that's very important. And in fact, I believe that that's been carried forward in pretty much all the upcoming trials. You'll have to be vaccinated and be watching for those organisms.

: That's an important point to note. For those nephrologists who potentially may want to use these drugs in the future is that's really going to be critical in terms of managing the safety aspects of this drug.

I suspect that the regulatory agencies will require those vaccinations prior to the use just because they were part of the clinical trials.

Carla M. Nester, MD, MSA, FASN discusses recent clinical trials on complement inhibitors for C3G.

Gerald B. Appel, MD

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