The algorithm that is used most often in discussing the treatment of IgAN is from the KDIGO guidelines. The most recent guidelines were published in 2021, and since that time, at least 2 other drugs in the United States have achieved FDA approval for the treatment of IgAN. This is a useful algorithm that was published by colleagues in the United Kingdom that integrates some of the newer data and mimics or uses some of the same approaches as the KDIGO guidelines, and so I prefer to use it in practice.

The algorithm starts with supportive care at the top: lifestyle interventions and various types of interventions that will be useful to any patient with proteinuric kidney disease.

Listen to this brief audio clip to hear a patient’s experience with implementing lifestyle changes as part of her IgAN treatment plan.

The KDIGO approach to supportive care, which is the first recommendation in the KDIGO guidelines, includes similar considerations as those listed previously such as blood pressure management, maximal dose of either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), lifestyle modifications, and the assessment of cardiovascular risk.¹⁰

We know that angiotensin is important in proteinuric kidney disease. It has a variety of effects on glomerular hyperfiltration, oxidative stress, and profibrotic effects. We know that blockade of angiotensin has been broadly useful in various forms of proteinuric kidney disease. Unsurprisingly, in studies of IgAN, we find also that renin–angiotensin inhibition will decrease proteinuria and decrease the slope of GFR over time to prevent or delay kidney failure. It may not be sufficient to stop the disease entirely, but it is certainly an important part of the treatment toolkit.^20-23

When considering more aggressive treatments, traditionally what was used and what has been studied is oral glucocorticoids, and oral glucocorticoids continue to have a role for preventing or delaying progression to kidney failure in IgAN. This was best demonstrated by a study called the TESTING study, which is shown here. This was a randomized controlled trial of oral methylprednisolone on top of supportive care in patients with IgAN. The use of oral methylprednisolone in this trial was associated with improved kidney outcomes, both the composite kidney failure outcome, the progression to the need for dialysis or treatment were reduced with the use of oral methylprednisolone. Oral methylprednisolone was also associated with a decrease in proteinuria.

That came, however, at the cost of increased risk of adverse events including serious infections. Some of that risk was abrogated by modifications of the protocol and the use of lower doses of methylprednisolone in the second half of the study compared with the first half of the study. The protocol was reconfigured to reduce the dose and to add antibiotic prophylaxis to try to prevent some of those serious infections and seemed to help limit some of the risks. Although, of course, with systemic corticosteroids, one cannot eliminate the risk of infection altogether.²⁴

In the subgroup analysis of this study, it was not clear if there was any particular group that clearly benefited more than others. So claims have been made about whether the high dose or the lower dose might be better, but in the subgroup analysis, the lower dose had a greater indication of benefit. There certainly did not seem to be any harm that came from the reduced dose. The biopsies were not done immediately before enrollment, and it is difficult to interpret a biopsy that may be a few years old compared with the time of therapy, but they did not see strong associations with biopsy findings.

There have been theories about ancestry that perhaps glucocorticoids are more useful in patients of Chinese descent. This study did have a majority of patients who were of East Asian and Chinese ancestry, but perhaps even more so in patients of non-Chinese ancestry, methylprednisolone appears to have benefit.²⁴

In the KDIGO guidelines, after corticosteroids, there is not really much else that is recommended. The guidelines list several therapies that are not recommended.

Listen to this brief audio clip to hear about a patient’s experience with using corticosteroid therapy as part of her IgAN treatment plan.

An important agent to discuss is budesonide and in particular, the targeted-release formulation (TRF) of budesonide that now has FDA approval for the treatment of IgAN. Budesonide is a corticosteroid and has its main action at the level of the gastrointestinal mucosa. In our pathophysiologic model, we think that this would work at Hit 1 to reduce inflammation locally in the mucosa where the disease is beginning and where the early galactose-sufficient IgA1 molecules are being produced.¹⁴

The TRF of budesonide is designed to have its maximal effect in the distal small intestine and proximal large intestine, the areas of the gut where the highest density of Peyer patches are found and where we think that much of the pathogenic galactose-deficient IgA1 is produced. The TRF-budesonide provides anti-inflammatory effects and then undergoes 90% first-pass metabolism resulting in low systemic exposure to glucocorticoids, which has been estimated to be the equivalence of 5-10 mg of prednisone/day. It is the first drug approved for IgAN in the United States, which is great news for patients with the disease to see that drug development is progressing.²⁵

Here, you can see results from a phase III study that demonstrated that patients who were treated with TRF-budesonide had a marked reduction in the risk of the composite endpoint, which was a validated composite kidney failure endpoint, either kidney failure or a GFR reduction of 30%. The HR was 0.45 for those treated with TRF-budesonide compared with placebo. This seemed to be sustained at different levels of proteinuria, both above and below 1.5 g/g. The benefit, therefore, seems to be independent—or at least not strongly dependent on this binary cutoff of proteinuria. Therefore, the drug is approved for IgAN with risk of progression.²⁶

Here are the 2-year data on the use of TRF-budesonide in blue, and the data on proteinuria where treatment led to a decrease in proteinuria over 9 months. That decrease in proteinuria seemed to continue through 12 months and then perhaps from 12 months to 2 years. There is some regression to the mean, but the overall difference compared with placebo remains a 30% reduction in proteinuria.²⁶

This illustrates the GFR changes with TRF-budesonide, again in blue. During the treatment period, the GFR remained at or above baseline for patients treated with TRF budesonide, whereas a steady decline in GFR was observed in the placebo group. Of interest, the GFR does seem to decline after cessation of the drug. It is not entirely clear if these curves are statistically parallel, but the final GFR at 2 years is substantially better in the TRF-budesonide group compared with the placebo group.²⁶

TRF-budesonide seems to be fairly well tolerated, which addresses some of the concerns about systemic glucocorticoids like those that were observed in the TESTING study.

That is not to say that there are not adverse events, as you can see here in the table, documenting the adverse events with TRF-budesonide compared with placebo. Overall, the drug seems to be well tolerated, particularly in the 15-month observational follow-up. The differences in adverse events are minimal, but there is more discontinuation because of any treatment -related adverse event seen at 9 months with TRF-budesonide. Serious adverse events, although slightly higher in the treatment group, were low overall rate.²⁶

In TRF-budesonide, unsurprisingly, many of the adverse effects are in line with glucocorticoid effects and Cushing effects, including peripheral edema, hypertension, muscle spasms, acne, and facial edema, as would be expected to be seen with exposure to glucocorticoids. These are not being statistically compared, as they are from the supplementary data of the phase III study, but numerically, there are higher rates of these effects.²⁶

Next we address the pathogenic pathway related to Hit 4, which is the final common pathway of glomerulosclerosis. There are important classes of agents that focus on this part of the pathogenic pathway that have supportive data published in the past few years for their use.¹⁴

Endothelial activation is an important part of CKD. We think endothelial expression is associated with proteinuria and progression of CKD in general, and also specifically in IgAN where higher endothelin-1 levels seem to be associated with disease progression. There are drugs that can block endothelium and have a variety of effects including increasing vasodilation and ameliorating fibrosis.

There are 2 drugs that have been developed or are in development for IgAN: sparsentan and atrasentan. Sparsentan is a combined endothelial and ARB, and atrasentan is a pure endothelial blocker. Sparsentan has an accelerated FDA approval and can be prescribed to reduce proteinuria in adults with IgAN at risk of rapid disease progression, or a urine protein-to-creatinine ratio ≥1.5 g/g. Its continued approval will be contingent on the results of ongoing studies, and atrasentan is currently being studied in a phase III study.^27-29

These are data from the phase III PROTECT study on the efficacy of sparsentan for patients with IgAN, published in 2023. Results showed that treatment with sparsentan at 36 weeks compared with irbesartan, an ARB, led to a much greater decrease in proteinuria, 50% vs 15%, respectively.³⁰

The reduction in proteinuria seemed to be sustained over longer-term follow-up, through 110 weeks. And in sparsentan, the change in proteinuria happens fairly early in Week 4-6 and is sustained with ongoing treatment through the approximately 2 years patients were followed in this study. With irbesartan, there is a much smaller decrease in proteinuria.³¹

But what about GFR? Does this proteinuria reduction translate into improvements in GFR? This is a bit trickier to parse. In the phase II study, there were 2 slopes of GFR that were evaluated. The total slope is the change in GFR from the beginning of the study to the end of the study, and the chronic slope eliminates the first period of treatment where you see these hemodynamic changes in GFR. Of interest, the changes in the slope were fairly similar between the total slope and the chronic slope, but although the chronic slope just barely met statistical significance, the total slope did not meet statistical significance, with P values of .04 vs 0.06, respectively. Perhaps because of this, the drug does not yet have full FDA approval.³¹

Sparsentan is overall well tolerated. This chart demonstrates the treatment-emergent adverse events, and serious adverse events were thankfully rare and not too different between the sparsentan and irbesartan groups. Those are listed on the right side of the slide. On the left side, in those that occurred in more than 5% of patients, we see that the numbers seem to be fairly similar. There was slightly more peripheral edema but not dramatically more. This is important because of concerns about peripheral edema from earlier studies of endothelial antagonism in CKD, and in particular in diabetic kidney disease. There was slightly more dizziness and hypotension in the group being treated with sparsentan.³¹

Although sparsentan currently can be prescribed for IgAN under the accelerated approval, it comes with a boxed warning and a risk mitigation program. The Risk Evaluation and Mitigation Strategy (REMS) is based on a couple of points. One is that other endothelial antagonists in the past have demonstrated hepatic toxicity. It is not clear that this is a class effect. In fact, it is thought that this has to do with the pharmacology of the specific drugs. Thankfully, no significant hepatic toxicity with sparsentan has been demonstrated, and it is hoped that it will not share that pharmacologic risk. Regardless, there is a boxed warning to monitor for hepatic toxicity, and the REMS program requires monthly liver function test monitoring to screen for hepatotoxicity.³²

Second, there is a concern about embryo fetal toxicity, and so the REMS program requires pregnancy testing during treatment as well. Of importance, if you consider an endothelial antagonist like sparsentan as a replacement for an ARB, one would never use an ARB or an ACE inhibitor in pregnancy or in a patient who is trying to become pregnant because the ARBs and ACE inhibitors are also teratogenic. I think that this is not  dissimilar in concept and not unfamiliar to nephrologists who counsel patients, especially patients who are of childbearing capability, and who might take these medications.

SGLT2 inhibitors are an important addition to the armamentarium of nephrologists for all proteinuric kidney disease, and they have been studied now specifically in subgroups of patients with IgAN, in 2 very large studies on the use of this class of drugs in CKD. Dapagliflozin in the DAPA-CKD study and empagliflozin in the EMPA-KIDNEY study included subgroup analyses of more than 200 and 800 patients in those studies, respectively, who had CKD because of IgAN. The results mimic the results of the larger trials with substantial reductions in risk of progression to end-stage kidney disease with the use of the SGLT2 inhibitors in the subgroups with IgAN. Therefore, I do not think this is a function of these drugs that is specific to IgAN, but we know that these drugs have very important and beneficial local hemodynamic effects on the glomerulus and that they ameliorate protein or kidney disease, and we can confidently say that that effect is valid in the protein or kidney disease related to IgAN.

One important caveat is that patients who are enrolled in DAPA-CKD and EMPA-KIDNEY were patients who were not being treated with immunosuppression. In fact, the inclusion criteria for those studies excluded people who were thought to need immunosuppression. Therefore, these may not be fully indicative of the general IgAN population because patients with more aggressive disease requiring corticosteroids were not enrolled in these trials. For the more smoldering, chronic type of patients, these agents are an important addition to the supportive care algorithm and the type of treatments that focus on that Hit for that final common pathway of glomerulosclerosis and CKD.^33,34

There are various other therapies that are in active development and under active study for IgAN, which is very exciting for practitioners in the field. There are at least 4 agents targeting APRIL and BAFF B-cell activation in phase III studies and with phase II data that have been published and are generally supportive. There are also agents targeting the complement pathway in various ways that are also under advanced study.

This summarizes the key therapeutic agents that are currently under study. Sparsentan, an endothelin antagonist, has accelerated FDA approval, but is still awaiting additional data to see if it will get a full approval, and atrasentan, another endothelin antagonist, is being studied in the phase III ALIGN trial. Many complement inhibitors are being studied. We have positive phase II data for iptacopan, which is currently being studied in the phase III APPLAUSE trial. For drugs targeting either APRIL or APRIL and BAFF combined, sibeprenlimab, zigakibart, atacicept, and povetacicept are all in advanced phases of study and have given either peer-reviewed or topline positive data for proteinuria reduction in patients with IgAN.

There are many questions that remain in the treatment of IgAN—questions that we hope to address in the years to come, such as which agent to choose first. Currently, the KDIGO guidelines and most of the treatment algorithms focus on supportive care, but if some of these emerging agents are shown to have deep and lasting benefits at preventing disease progression, might we consider a future where some of those agents can actually be used earlier on? This is a type of debate that we have had in other areas of medicine with immune-mediated diseases, for example, rheumatoid arthritis or inflammatory bowel disease. At what point do you introduce, for example, biologic agents to try to prevent scarring and chronic damage? How long should the agents be used? The FDA-approved TRF-budesonide was studied for 9 months, which is where we have the benefits and safety data. But this is a chronic disease, and so the question is, could potentially longer courses or repeat courses of systemic glucocorticoids be useful? I generally try to avoid repeat courses of systemic glucocorticoids. The doses are high, the adverse events are substantial, and patients do not usually tolerate repeat courses. But if there are safer and better tolerated drugs, should we think more in the lines of other chronic diseases and maintenance types of therapies? How should we combine different therapies, including different immunologic therapies? How should we combine therapies that might be approved by the FDA? Should they be used in a stepwise fashion one after the other, or can we use our knowledge of the pathophysiology to integrate different agents depending on where they are on the therapeutic pathway and in the pathogenic pathway?

And then, of importance, is there a way to personalize the medicine? Can we use patient characteristics to choose drugs that are going to work best for a certain patient or have the lowest risk for a certain patient? The subgroup analyses thus far in some of the studies that have been presented have been a little disappointing in allowing us to select drugs that are best for certain groups of patients in a sophisticated way besides proteinuria, which is perhaps the most important exclusion criteria for many of these clinical trials. We are looking for ways to identify patients who might have a particular benefit or a particular risk and match drugs to patients to get the best outcomes with the least risk.

Returning to this algorithm, I think we are still in an era where we should focus our treatments to start with supportive care, and good clinical medicine including lifestyle interventions, maximizing blood pressure control, maximizing RAS inhibition, and increasingly adding an SGLT2 inhibitor because of their clear benefits for chronic disease. But think about trying to get patients into clinical trials: Many of these patients will be motivated to do so and think about these additional options we have. As KDIGO mentions, perhaps consider hydroxychloroquine or mycophenolate in Chinese patients. We now have the ability to consider replacing an ACE inhibitor or an ARB with sparsentan in the United States for greater proteinuria reduction and still not entirely clear effects on long-term GFR. Consider the use of TRF-budesonide, as well as the use of systemic corticosteroids, which have clear benefits on kidney outcomes, but come with fairly clear risks.¹⁴

Listen to this brief audio clip to hear a patient’s suggestions on the most important considerations for healthcare professionals caring for patients with IgAN.