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Care Gaps in IgA Nephropathy
Addressing Care Gaps in IgA Nephropathy: Expert Commentary on Optimizing Care

Released: May 31, 2024

Expiration: May 30, 2025

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Key Takeaways
  • Although IgA nephropathy is considered the most common type of primary glomerulonephritis, traditional treatment has offered limited disease-targeted options for healthcare professionals and patients.
  • Exciting advancements in the therapeutic armamentarium for IgA nephropathy bring hope for a paradigm shift from supportive care to disease modification.

Unmet Needs in IgA Nephropathy Care
IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide, but there are significant challenges in providing an early diagnosis and, historically, limitations in treatment options. Traditional management strategies focus on supportive care and preventing disease progression and complications via optimizing blood pressure control and minimizing proteinuria.

Treatments for IgAN long have been limited to renin–angiotensin–aldosterone system (RAAS) blockers and glucocorticoids; as such, opportunities to meaningfully halt disease progression and optimize patient outcomes have remained out of reach. The Kidney Disease: Improving Global Outcomes guidelines recommend use of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, regardless of the presence of hypertension, to minimize risk of progression. In patients with high risk for disease progression (proteinuria >0.75-1 g/day) after 3 months of optimal supportive therapy, the guidelines recommend a 6-month course of glucocorticoids, while cautioning about the increased risk of adverse events (AEs) in those with an estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2. Despite this recommendation, there is continued concern about the effectiveness vs toxicity of systemic glucocorticoid therapy in IgAN.

Fortunately, in the past few years, several new therapies have become available, with a robust pipeline of potential therapies around the corner.

Rising to the Challenge: Breakthroughs in IgAN Management
In the realm of additional options for supportive care strategies, the ongoing improvements in our knowledge about the benefits of sodium-glucose cotransporter 2 inhibitors in attenuating the progression of chronic kidney disease warrant consideration. A subanalysis of the DAPA-CKD trial evaluating the impact of dapagliflozin on renal outcomes analyzed the agent’s effects on patients with IgAN. Compared with placebo, dapagliflozin conferred a lower rate of eGFR decline and a relative 26% reduction in proteinuria in these patients. Overall AEs were similar in both groups, with lower rates of serious AEs for patients receiving dapagliflozin.

In addition, there are now 2 FDA-approved therapies indicated in the management of IgAN that show promise as disease-modifying treatments. These include Nefecon (a targeted-release, locally acting formulation of budesonide that has demonstrated an impact on production of galactose-deficient IgA1, a critical step in IgAN pathogenesis) and sparsentan (a first-in-class dual endothelin and angiotensin receptor antagonist that augments the antiproteinuric response of RAAS inhibition).

The benefits of Nefecon have been reported in the phase III NefIgArd trial, with recent release of 2-year results. Outcomes of this trial indicated that the use of Nefecon 16 mg orally once daily slowed the rate of eGFR decline compared with those receiving placebo and provided lasting reductions in proteinuria. Studies indicated that the therapy is generally well tolerated, with only 2% of patients in each arm experiencing serious AEs deemed to be related to the treatment. The most common AEs observed in the trial included peripheral edema, hypertension, muscle spasms, acne, and headaches. These findings hold promise for a safe, disease-modifying treatment for patients with IgAN.

Two-year results of the phase III PROTECT trial evaluating the use of sparsentan 400 mg compared with an active control of irbesartan 300 mg also were published. Sparsentan use resulted in a slower eGFR decline compared with irbesartan and a durable decrease in proteinuria that was approximately 40% below that obtained in the irbesartan group. Several AEs occurred in a greater proportion of patients receiving sparsentan, including peripheral edema, hypotension, and dizziness. In addition, this agent required monitoring for both risk of hepatotoxicity and prevention of embryo-fetal toxicity and thus is available only through a Risk Evaluation and Mitigation Strategy program.

Treatments on the Horizon
Several novel agents with various (and potentially complementary) mechanisms of action for treating IgAN are being investigated in phase II and/or III clinical trials. Atrasentan, an endothelin type A receptor antagonist, has demonstrated superiority vs placebo in reducing proteinuria, providing some insights that targeting this pathway may provide classwide reductions in proteinuria, fibrosis, and inflammation.

In addition, several agents are targeting B-cell activation via blockade of APRIL (a proliferation-inducing ligand), with or without blockade of B-cell activating factor in the pipeline. In particular, initial results from trials evaluating sibeprenlimab hold promise for significant proteinuria reductions.

Finally, multiple agents targeting the complement system are in active development and boast varying mechanisms of action. Iptacopan, a complement factor B inhibitor, demonstrated superiority vs placebo in proteinuria reduction and provided a clinically meaningful and statistically significant proteinuria reduction on top of supportive care in patients with IgAN.

The future of IgAN management is promising, offering patients and nephrology providers hope for strategies that will not only stave off disease progression, but also potentially reverse damage. Although these preliminary data look promising, close attention will need to be paid to their safety profiles (particularly infection risk) and treatment durability.

Your Thoughts?
As a nephrology healthcare professional, how often do you use targeted treatment strategies to improve long-term outcomes for patients with IgAN in your practice? You can get involved by answering the polling question and posting a comment below.

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As a nephrologist, how often do you use targeted treatment strategies to improve long-term outcomes for patients with IgAN in your practice?

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