Proteinuria reduction remains a major treatment target in IgA nephropathy (IgAN) due to its association with risk of progression to end-stage kidney disease (ESKD) and failure. Several researchers at Kidney Week 2024 presented data from clinical trials of US Food and Drug Administration (FDA)–approved and investigational agents impacting proteinuria in IgAN.

Following these presentations, featured expert Samir V. Parikh, MD, FASN, was interviewed by Conference Reporter Associate Editor-in-Chief Rick Davis. Dr Parikh’s clinical perspectives on these findings are presented here.

Proteinuria is the strongest clinical predictor of patient outcome and guides treatment decisions in IgAN. The goal of treatment is to reduce the proteinuria levels as much as possible to help preserve long-term kidney outcomes. A large UK registry study looked at long-term outcomes in patients with IgAN and found that even with low proteinuria levels, 20% to 30% of patients still progressed to ESKD over their lifetime. Previously, it was thought that if patients with IgAN had proteinuria levels of less than 1 g/d, then they would be at low risk for progression to ESKD and would only require supportive therapy with RAS blockers. But now, given the recent findings from the UK registry study and the availability of new, effective therapies that have been shown to slow the decline in glomerular filtration rate (GFR), we need to reconsider our approach to IgAN treatment for patients even with low levels of proteinuria. This may require using both supportive therapy and disease-modifying therapies.

We could not do this 5 years ago because there were no therapies available for IgAN other than RAAS blockade and systemic corticosteroids, which produced a lot of side effects. Now we have 2 fully FDA-approved therapies (ie, budesonide and sparsentan) and 1 FDA–conditionally approved therapy (ie, iptacopan) for IgAN. The treatment landscape has evolved, and it seems like we are coming into this renaissance of treatment in IgAN with really one goal in mind, and that is the preservation of kidney function long-term. Proteinuria reduction is critical to achieving this long-term goal.

One therapy with full FDA approval for IgAN is targeted-release budesonide, which targets the Peyer’s patches of the terminal ileum, where a large reservoir of galactose-deficient IgA1 is produced. The idea is that the drug blocks the release of galactose-deficient IgA1. Targeted-release budesonide showed a 27% reduction in proteinuria compared with placebo at 9 months in the NeflgArd study. Two-year follow-up data showed preservation of estimated GFR (eGFR), with a 5.05 mL/min/1.73 m² difference relative to placebo.

Some patients who were enrolled in the NeflgArd trial and had persistent proteinuria after receiving either targeted-release budesonide or placebo were enrolled in an open-label extension study. All patients in this study were given 9 months of targeted-release budesonide, and the results were presented during an oral abstract session at Kidney Week 2024 by Richard A. Lafayette, MD (abstract FR-OR56). Patients who were previously treated with targeted-release budesonide tolerated retreatment well and had reductions in proteinuria that were similar to what was seen in the NefIgArd trial. Those who were treatment naive had a similar reduction in proteinuria, showing the disease modification benefit of a 9-month course of treatment with targeted-release budesonide.

Sparsentan, the other fully FDA-approved therapy for IgAN, blocks both endothelin type A receptors and angiotensin II type 1 receptors. During an oral abstract session at the Kidney Week 2024 meeting, a cohort analysis of the PROTECT study was presented by Laura Kooienga, MD, who reported that sparsentan seemed to provide equal benefit for patients with baseline proteinuria levels of less than or greater than 1 g vs irbesartan (abstract FR-OR57). In another presentation during this oral abstract session, Chee Kay Cheung, MBChB, PhD, reported on data from an interim analysis of the SPARTAN trial examining sparsentan in patients with newly diagnosed IgAN (abstract FR-OR63). Sparsentan was well tolerated and reduced proteinuria by 68.9% at 24 weeks. These results suggest that even patients who are treatment naive may benefit from sparsentan and that it is beneficial for all levels of proteinuria.

There were also data presented at Kidney Week 2024 on the investigational agent atrasentan, a SERA, from a subgroup analysis of the placebo-controlled phase 3 ALIGN study by Hiddo J. L. Heerspink, PhD, PharmD, during an oral abstract session (abstract FR-OR62). Atrasentan showed a 36.1% relative reduction in least square mean percentage of change from baseline in proteinuria vs placebo at week 36. These results provide further proof of the relevance of targeting the endothelin pathway in IgAN, with both sparsentan and atrasentan showing significant reductions in proteinuria relative to placebo.