IgA Nephropathy – The Hope of Tomorrow, Is Here

Dr. Yariana E. Rodriguez Ortiz is a PGY5 Nephrology Fellow at Houston Methodist Hospital. Her main interests are chronic kidney disease education and prevention, health disparities, and leadership. She is the active National Vice-President of the Committee of Interns and Residents (CIR) in which she advocates for resident and fellows’ well-being and patient safety through contract bargaining and community activities.

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Dr. Shane Bobart is a Nephrologist, Associate Program Director of the Nephrology Fellowship and is leading the Glomerular Disease Program at Houston Methodist Hospital. His research involves reducing morbidity, mortality, and health care disparities among patients with glomerulonephritis and chronic kidney disease. He is passionate about improving access to patient-centered, optimal care for patients with glomerular diseases to improve health outcomes.

In the words of Orison Swett Marden — ‘There is no medicine like hope, no incentive so great, and no tonic so powerful as expectation of something tomorrow.’ When it comes to the treatment of IgA Nephropathy, this expectation for new treatment arriving “tomorrow,” will soon become today.

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and a significant cause of end-stage kidney disease (ESKD). Therefore, the need to develop innovative approaches to its management is of timely importance. The Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases highlights the importance of non-immunosuppressive based therapies such as lifestyle modifications, blood pressure control, and renin-angiotensin system (RAAS) blockade as the cornerstone of all management strategies. However, as the understanding of the pathogenesis of IgAN has evolved, new non-immunosuppressive and immunosuppressive treatment options have been explored and shown to be successful in ameliorating proteinuria and slowing disease progression. Drs. Caster and Lafayette provide a great overview of these recent advances in their recent publication in AJKD: The Treatment of Primary IgA Nephropathy: Change,Change, Change.

The pathogenesis of IgAN provides the basis of several new medications that have been studied. The “four-hit hypothesis” is currently the best way to explain the pathogenesis of IgAN. This process begins with genetically predisposed patients in whom multiple progressive events or “hits” set the path for glomerular inflammation and scarring. Mucosal hyperactivity is increased through immune response to stress and infections, leading to B lymphocyte class switching by Toll-like receptor activation and cytokine release including Blys (BAFF) and APRIL. Increased circulating levels of plasma cells then provide the path for production of galactose deficient IgA (GD-IgA) which in combination with anti-glycan antibodies form circulating immune complexes that subsequently accumulate in the mesangium. These mesangial immune complex deposits generate cytokine-, chemokine-, and complement- mediated cellular inflammation and injury leading to hematuria, proteinuria, and tubulointerstitial sclerosis. As we deepened our understand of the pathogenesis of IgAN, the evaluation of immunosuppressive therapy such as steroids, B cell targeted therapy, and complement blockade that target pathogenic pathways in IgAN have become a reality.

In addition to these advances in pathogenesis understanding, clinicians benefit from The International IgAN Network risk score that was created as a powerful risk prediction tool. This score is validated for adults at the time of biopsy, and an updated version can be used up to 1-2 years post –biopsy. With this score, which utilizes both clinical and pathology parameters (MEST score), nephrologists can predict the risk of kidney disease progression. In general, patients classified as low risk can be managed with conservative and supportive measures while those classified as high-risk might benefit from immunosuppressive management and other novel IgAN therapies.

Over the past two decades, there have been many clinical trials that have aimed to identify new treatments for the management of IgAN. An example of this was the STOP-IgAN trial in 2015 which evaluated if systemic corticosteroid therapy plus supportive care would be superior to supportive care alone for the management of IgAN. With this study, the management of IgAN started to move towards supporting immunosuppressive management for high-risk patients with persistent proteinuria. However, there were significant infection-related adverse events identified in the trial complicating the decision to initiate steroids and prompting a consideration of the risk-to-benefit ratio. Additional studies assessing the role of corticosteroids in IgAN such as the TESTING trial demonstrated significant side effects at higher doses of steroids, such as sepsis, pneumonia, and other complications potentially outweighing the benefits of proteinuria reduction and slowing of kidney function decline in IgAN patients. However, when using a lower dose strategy, the benefits of systemic corticosteroids were retained albeit with less side effects.

As nephrologists, are corticosteroids all we have in our armamentarium against IgAN?

While RAAS blockade and corticosteroids remain a key part of the management of IgAN, we have seen a paradigm shift with modern advances bringing light to new therapies that are non-immunosuppressive such as Sodium-Glucose Cotransporter 2 (SGLT-2) inhibitors, Endothelin Receptor Antagonist (ERAs), and novel immunosuppressive agents, targeting the pathways implicated in the pathogenesis of IgAN.

Given, the significant side effects associated with systemic corticosteroids and the pathogenesis linked to the Peyer’s patches of the small intestine, targeted release budesonide, has been studied to good effect.  Budesonide is the first treatment to receive approval from the Food and Drug Administration (FDA) for reducing proteinuria in IgAN patients. , the was published in August 2023 and showed a time-weighted average eGFR change of –2.47 mL/min/1.73 m2 in the budesonide group vs –7.52 mL/min/1.73m2 in placebo. Commonly reported adverse events with budesonide included muscle spasms, acne, and hypertension.

The had an impressive representation of 270 patients with an IgAN diagnosis, providing early evidence that dapagliflozin should be added to the standard of care for these patients. In the sub-analysis, 5.2% in the dapagliflozin arm vs 9.2% in the placebo arm reached the primary outcome of 50% decline in eGFR. Hence, “flozination” has now become a pillar of therapy in patients with IgAN.

A novel dual endothelin – angiotensin receptor antagonist (DEARA), sparsentan, is the first and only FDA approved non-immunosuppressive therapy for IgAN. In the Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT) trial, patients were randomized to receive sparsentan or maximally titrated irbesartan, which showed significant reduction in proteinuria of 42% in the sparsentan group vs 4.4% in irbesartan group at 110 weeks. The composite kidney failure endpoint occurred in 9% in the sparsentan group vs. 13% for placebo and a significant attenuation in eGFR decline was also shown in the sparsentan group. It is important to note that sparsentan, is only approved through a Risk Evaluation and Mitigation Strategy (REMS) given concerns of elevated liver function testing and embryo-fetal toxicity.  To add to this, an open label study, combining Sparsentan with SGLT2 inhibition is underway, and so far, is showing promising results, highlighting the multi-targeted approach that will soon become essential in IgAN patients.

Caster and Lafayette synthesize all the recent advances in the treatment for IgAN with consideration of the risks and benefits of each treatment modality. In Figure 1, they provide a potential treatment algorithm for IgAN.

In Figure 1, we can observe that for all risk-stratified IgAN patients the first step in treatment is optimizing supportive care including maximizing RAAS blockade therapy. Low toxicity risk and active disease/inflammation are taken into consideration to include corticosteroid therapy in IgAN treatment. To aid in the search for active inflammation, we suggest that hematuria be taken into consideration as it is after all the hallmark of IgAN and proliferative lesions noted on kidney biopsy are associated with the presence of hematuria. However, additional studies are needed to confirm these findings, and remission of hematuria should be considered as an endpoint in future clinical trials.

Other potential treatment approaches include targeting the B-cell and complement pathway. Several studies are underway targeting BLys and APRIL.  An example is Telitacicept which is a fully soluble fusion protein that targets the interaction of BLyS and APRIL suppressing the B cell-mediated autoimmune response, leading to proteinuria reduction in IgAN patients.  After 24 weeks of administration of telitacicept, patients’ average 24-hour proteinuria levels decreased by 49% from baseline compared to the placebo group. Another powerful example is that of Sibeprenlimab, which is a humanized IgG2 monoclonal that binds to and neutralizes APRIL. , in the phase 2 Sibeprenlimab trial, it was demonstrated that 12 months of treatment with Sibeprenlimab resulted in the geometric mean ratio reduction in proteinuria of 47% (2mg group), 59% (4mg group) and 62% (8 mg group) vs 20% in the placebo group.

Taking a deep dive into the complement pathway, the Phase 2 Trial of Cemdisiran was recently published. Cemdisiran is an RNA interference therapeutic that suppresses C5 production in the liver. Results showed a reduction in the placebo-adjusted geometric mean change in 24-hour protein to creatinine ratio of –37.4% after 32 weeks of therapy. Additional studies are underway.

The discussion in this article demonstrates that for IgAN, we can take things one step further. In addition to prognostication for IgAN, appropriate emphasis is placed on supportive care, but also considering personalized and novel pharmacological interventions for our IgAN patients. The landscape of IgAN management continues to evolve. It is an exciting time to be a practicing nephrologist, now that we have many more options to offer patients, to halt the progression of IgAN.

– Post prepared by Yariana Rodriguez @yari_nephro and Shane Bobart @shanebobart

To view Caster et al, please visit AJKD.org.
Title: The Treatment of Primary IgA Nephropathy: Change, Change, Change
Authors: Dawn J. Caster and Richard A. Lafayette

DOI: 10.1053/j.ajkd.2023.08.007

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