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IgA Nephropathy Management
Expert Commentary on Key Updates in Managing IgA Nephropathy

Released: August 26, 2024

Expiration: August 25, 2025

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Key Takeaways
  • The pathology for IgA nephropathy follows a multihit model of 4 key events, from increased galactose-deficient IgA1 production to kidney injury.
  • Recent advances in treating IgA nephropathy include use of targeted-release budesonide, endothelin receptor antagonists, sodium–glucose cotransporter 2 inhibitors, and iptacopan.

We have learned a lot about the pathogenesis of immunoglobulin A (IgA) nephropathy during the past 40 years—a great deal of which has been derived from studies on the genetics that influence disease risk. These studies highlight the importance of the mucosal-associated immune system in the pathogenesis of IgA nephropathy, which led to the development of the “multihit pathogenesis” model.

This model includes 4 pathologic areas. Starting with hit 1, patients experience an increase in a circulating form of IgA1 (also called galactose-deficient IgA1). This type of IgA1 is unique to humans and produced mostly in the mucosal-associated immune system, where it helps protect the moist surfaces of the body like the respiratory and gastrointestinal tract. Galactose-deficient IgA1 then acts as an antigen against which other antibodies form, leading to the production of antiglycan antibodies, which describes hit 2. When these antibodies stick together, they form immune complexes in the blood, which characterizes hit 3. Finally, hit 4 occurs when these immune complexes are deposited in or form locally in the kidney, particularly in the mesangium where the galactose-deficient IgA1 seems to deposit most readily. The IgA seen in the mesangium of the kidney is almost exclusively galactose-deficient IgA1. When immune complexes form and antibodies target galactose-deficient IgA1, immune complexes are activating the immune system and resulting in downstream pathways of injury. This leads to the activation of mesangial cells and the complement pathway, formation of fibrosis, recruitment of inflammatory cells, and finally, the resulting glomerular injury and glomerular sclerosis—leading to proteinuria and glomerular filtration rate (GFR) loss.

Updates in IgA Nephropathy Management
The latest guidelines on managing IgA nephropathy were published in 2021. Since then, there have been new agents approved by the FDA to treat this disease.

Targeted-Release Budesonide
One important new agent is the targeted-release formulation (TRF) of budesonide—a corticosteroid acting against mucosal B-cells in the gastrointestinal tract. Looking at the pathophysiologic model, this agent should work at hit 1 by reducing inflammation locally in the mucosa. TRF budesonide is designed to have its maximal effect in the distal small intestine and proximal large intestine, the areas of the gut where there are the highest density of Peyer’s patches and where it is thought that much of the galactose-deficient IgA1 are produced. The agent first acts there to induce its anti-inflammatory effects and then undergoes 90% first-pass metabolism such that the systemic exposure to glucocorticoids is low. It is estimated that the systemic exposure is approximately 5 mg/day or more of prednisone.

TRF budesonide was studied in the phase III NeflgArd trial, with published results in 2023 leading to an accelerated approval and subsequently a full approval from the FDA to treat adults with IgA nephropathy at risk of disease progression. In the study, TRF budesonide had a marked reduction in the composite endpoint of kidney failure or estimated GFR (eGFR) reduction of 30% vs placebo. And this seemed to be consistent at different levels of proteinuria both above and below 1.5 g/g. Additional outcomes demonstrated the therapy reduces proteinuria, which continues through 2 years (15 months after stopping therapy), compared with placebo. During the treatment period, patients’ eGFR remained at or minimally below baseline with TRF budesonide vs those in the placebo group who saw a steady decrease. Of interest, eGFR looks to decline after cessation of the agent. And TRF budesonide seems to be well tolerated, which addresses some concerns about systemic glucocorticoids like those evaluated in the TESTING study. This is not to say that there were no adverse events with TRF budesonide, but the difference in toxicities between both study groups were small, especially after the treatment period.

Endothelin Receptor Antagonists
Moving on to another mechanism to focus on the other end of the IgA nephropathy pathogenic pathway, a novel class of agents called endothelin receptor antagonists address components of hit 4 where glomerular damage is occurring. Endothelin activation is an important part of chronic kidney disease (CKD). It is thought that endothelial overexpression is associated with proteinuria and disease progression in IgA nephropathy and CKD.

The agents targeting this pathway (sparsentan and atrasentan) have a variety of positive effects, including increasing vasodilation and ameliorating fibrosis. Sparsentan, which has an accelerated approval by the FDA for the treatment of adults with IgA nephropathy, is a combined endothelin and angiotensin II receptor blocker (ARB). So this agent is a 2 for 1, whereas atrasentan is a pure endothelin receptor antagonist currently being studied in phase III trials.

The phase III PROTECT study evaluating sparsentan for IgA nephropathy demonstrated that sparsentan induced a significantly greater decrease in proteinuria vs the ARB irbesartan (50% vs 15% at 36 weeks, respectively). This reduction in proteinuria was sustained over longer-term follow-up: 43% with sparsentan vs 4% with irbesartan at 110 weeks. Furthermore, sparsentan was associated with a fairly early change in proteinuria at Week 4.

Although sparsentan can be prescribed for IgA nephropathy, it comes with a boxed warning as well as a Risk Evaluation and Mitigation Strategy (REMS) program. One reason for this warning is that other endothelial antagonists in the past have demonstrated hepatotoxicity, but it is not clear if this is a drug class effect. In fact, it is thought that risk for hepatotoxicity has to do with the pharmacology of specific agents. Thankfully, the PROTECT study did not demonstrate significant hepatotoxicity with sparsentan. Regardless, there is a boxed warning to monitor this, with the REMS program requiring monthly liver function testing for the first year before starting treatment and every 3 months during treatment.

Second, there is a concern about embryo-fetal toxicity, so the REMS program also requires pregnancy testing before, during, and after treatment. When considering an endothelial antagonist like sparsentan as a replacement for an ARB, one should never use an ARB or angiotensin-converting enzyme inhibitor during pregnancy or for patients who are trying to become pregnant. This is because these agents are also teratogenic. Therefore, I think that this is not dissimilar in concept and not unfamiliar to nephrologists, especially among those treating patients who are of childbearing capability.

Sodium–Glucose Cotransporter 2 Inhibitors
Another class of therapies showing promise in the treatment of IgA nephropathy are sodium–glucose cotransporter 2 inhibitors, which have become an important addition to nephrologists’ armamentarium for all proteinuric kidney diseases. These agents have now been evaluated in subgroups of patients with IgA nephropathy, and 2 large studies were conducted for patients with CKD. Dapagliflozin in the DAPA-CKD study and empagliflozin in the EMPA-KIDNEY study both included subgroup analyses of the patients with CKD caused by IgA nephropathy. The benefits seen among the overall treated population were also observed among the IgA nephropathy subgroups, which included well over 200 participants in the DAPA-CKD study and approximately 800 in the EMPA-KIDNEY study.

Iptacopan
Finally, it is worth briefly mentioning the most recently FDA-approved drug for IgA nephropathy. Iptacopan is a complement factor B inhibitor that likely works against hit 4 of IgA nephropathy’s pathophysiologic pathway to reduce complement-mediated inflammation in the kidney. In August 2024, it received accelerated approval to reduce proteinuria in adults with IgA nephropathy. In the phase III APPLAUSE trial, iptacopan significantly reduced proteinuria by 38% vs placebo at 9 months. This agent also includes a REMS program because of an increased risk of encapsulated bacterial infections. However, iptacopan represents yet another approach to disease treatment, targeting a unique aspect of the IgA nephropathy pathogenesis.

Your Thoughts? 
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Which of the following strategies do you use to meet clinical targets in your patients with IgA nephropathy? [select all that apply]

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