Treatments for renal IgA vasculitis are beginning to flow

By Warren R. Heymann, MD, FAAD
Feb. 19, 2025
Vol. 7, No. 7

The alliterative phrase “palpable purpura” will instantly conjure the diagnosis of leukocytoclastic vasculitis (LCV) for dermatologists. IgA vasculitis (IgAV, aka Henoch-Schönlein purpura [HSP]) is the most common vasculitis in children but is much less frequent in adults. Aside from nonthrombocytopenic palpable purpura, the clinical characteristics of HSP include abdominal pain, gastrointestinal bleeding, purpura, arthritis, and renal involvement. (1) IgA nephropathy (IgAN) presents a variant of IgAV restricted to the kidneys. (2) While IgAV with nephritis and IgAN share a common pathological feature of significant mesangial IgA deposition, whether they are clinical manifestations of the same disease occurring on a spectrum but varying in symptomatic presentations and prognosis remains controversial. (3)

Quoting myself from a commentary I previously wrote on HSP, “There are differences in HSP between children and adults. In children, HSP is usually postinfectious (notably β-hemolytic Streptococcus); in adult HSP, triggers are infections, medications, or malignancies. Solid tumors, especially lung cancer, are more commonly associated with HSP than hematologic malignancies. Anemia, diarrhea, and severe renal insufficiency are more frequently observed in adults. The prognosis of HSP in children is excellent, but the risk of persistent renal disease is increased in adults. HSP shares renal pathologic features with IgA nephropathy [IgAN]. The prevalence of progression to chronic kidney disease or end-stage renal disease in patients with HSP nephritis ranges from approximately 5% to 20% in children and 35% to 69% in adults.” (1)

According to Roache-Robinson et al., IgAV with nephritis shares many overlapping features with IgAN, the most common glomerulonephritis in the world. The main differences are that IgAV with nephritis is more likely to first occur in children younger than 15, while IgAN usually has an onset in patients older than 15. IgAV with nephritis is more likely to present with extrarenal symptoms; IgA nephropathy presents more often with gross hematuria. Histology in IgAV with nephritis shows more capillary staining and glomerular injury than in IgA nephropathy. IgAV with nephritis has a 98% clinical remission compared to patients with IgA nephropathy who progress to end-stage renal disease within 20 years of diagnosis in 30% to 50% of cases. (4)

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The pathogenesis of IgAV is obscure. Pathomechanisms involve various factors, including the interplay of aberrantly glycosylated IgA, anti-endothelial cell antibodies, and neutrophils following infectious triggers. (5) The activation of complement is involved in tissue injuries in patients with IgAV. The absence of C1q in most IgAN kidney biopsies suggests that the classical pathway is not significantly involved in the pathogenesis of IgAV. The activation of the alternative pathway is evident by the presence of elevated C3a, C5a, C4, and C5-9 deposits. Deposits of C4d and C5b-9 are associated with poor renal outcomes. (3)

As of 2021, clinical guidelines for IgAN were symptomatic care, lifestyle measures, control of cardiovascular risk, and use of a renin-angiotensin system blocker. (6) Early oral prednisone treatment is useful in managing renal, joint, and gastrointestinal manifestations. Prednisone does not prevent renal disease but reduces the risk of developing persistent renal complications in children. Although the benefit of immunosuppressive agents is questionable, cyclophosphamide, rituximab, azathioprine, mycophenolate mofetil, IVIG, and dapsone have been utilized for IgAV. (4)

New approaches may change the trajectory of IgAN.

Iptacopan inhibits the alternative complement pathway by specifically binding to factor B. Perkovic et al. performed a phase 3, double-blind, randomized, placebo-controlled trial of adults with biopsy-confirmed IgAN and proteinuria with a 24-hour urinary protein-to-creatinine ratio of 1 or higher (with protein and creatinine both measured in grams) despite optimized supportive therapy. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg, n=222) or placebo (n=221) twice daily for 24 months while continuing to receive supportive therapy. The primary objective of this prespecified interim analysis was to assess the efficacy of iptacopan as compared with that of placebo in reducing proteinuria at month 9. At month 9, the adjusted geometric mean 24-hour urinary protein-to-creatinine ratio was 38.3% (P<0.001) lower with iptacopan than with placebo. The incidence of adverse events during the treatment period was similar in the two groups; most events (upper respiratory infection, headache) were mild to moderate in severity and reversible. No increased risk of infection was observed. The authors concluded, “Among patients with IgA nephropathy, treatment with iptacopan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo.” (7) On August 8, 2024, the FDA granted accelerated approval for iptacopan (Fabhalta) in adults with IgAN who are at risk for rapid disease progression. (8)

According to Heerspink et al., “Endothelin-1 is a vasoactive peptide implicated in the pathophysiology of IgA nephropathy. Binding of endothelin-1 to the endothelin type A receptor in the kidney causes endothelial and podocyte damage, mesangial expansion, and tubular inflammation in experimental models of IgA nephropathy. Atrasentan, a selective inhibitor of the endothelin type A receptor, exerts antiproliferative, antifibrotic, and antiinflammatory effects in experimental models of IgA nephropathy.” In a phase 3, double-blind, randomized, controlled trial involving adults with biopsy-proven IgA nephropathy, the authors concluded that atrasentan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo in patients with IgAN. (9)

In his editorial discussing the burgeoning treatments for IgAN, Inglefinger notes that several other drugs have been approved for IgAN, including sodium–glucose cotransporter 2 inhibitors, a budesonide formulation designed to precisely deliver the drug within the intestine to immune cells producing IgA (Nefecon), and the dual endothelin–angiotensin receptor antagonist sparsentan (Filspari). He encourages practitioners to analyze data carefully and await head-to-head trials of these new agents to give perspective on their proper use. (6)

As dermatologists, we will defer the management of IgAV and IgAN to our nephrologist colleagues. Regardless, it will be interesting to learn how these new agents affect vasculitis in other organs, including the skin. Perhaps new therapeutic, steroid-free vistas are on the horizon that may benefit all manifestations of IgAV.

Point to Remember: Renal disease is the most severe complication of IgA vasculitis. New treatments such as iptacopan (an alternative complement inhibitor) and atrasentan (an endothelin type A receptor inhibitor) are promising novel therapies for this challenging disease.

Our expert’s viewpoint

Christopher B. McFadden, MD
Associate Professor of Medicine
Cooper Medical School of Rowan University
Division Chief, Nephrology
Cooper University Health Care

The treatment of IgA nephropathy is undergoing a revolution. Over the last several years researchers have identified several agents which can modify the frustratingly consistent decline in kidney function nearly 30% of individuals with the disease undergo. These newer treatment options provide important alternatives to the high-dose steroid regimen, and various options allowing oral-only steroid therapy, which were standard of care for the last 25 years. (10) Due to steroid-related side effects, clinicians have been hesitant to treat patients with “milder disease” with the steroid protocols derived from the previous study despite the recognition that kidney inflammation, and potential damage, is present and ongoing. Newer therapies provide an important role in filling this therapeutic gap. Concurrently, the field is rethinking the 1.0 gram per day of proteinuria, after maximal tolerated therapy with an ACE inhibitor or angiotensin receptor blocker, which has traditionally identified those at higher risk. We recognize that individuals with proteinuria levels less than this may have active inflammation and irreversible kidney damage leading to the potential for a beneficial response particularly if therapeutic options are more tolerable.

The assessment of an individual with IgA nephropathy involves a number of important steps as noted below:

• Identify the degree of kidney involvement through a kidney biopsy

• Quantify levels or proteinuria

• Estimate the risk of progressive kidney disease through online risk calculators

• Initiate and maximize renin-angiotensin based therapy side to the extent tolerable; SGLT2 therapy has an evolving role in the regimen

• Assess the impact of therapy on proteinuria levels

• Consider additional agents

For example, a 32-year-old female with a serum creatinine of 1.2 mg/dl (eGFR 62 ml/min) and 1.1 grams of proteinuria despite maximal ACE or ARB therapy, a biopsy showing IgA nephropathy with a moderate degree of activity based on the Oxford classification/ MEST score of (M1, E1, S0, T1) has a 21% five-year risk of 50% loss of kidney function. (11)

While traditional glucocorticoids are a valid treatment the side effect profile is often unacceptable to both patients and their doctors. Recent Kidney Disease Improving Global Outcomes (KDIGO) guidelines regarding the use of steroids note indications to avoid their use in the following situations: an eGFR < 30 ml/min, the presence of diabetes or severe osteoporosis, obesity, infections, uncontrolled psychiatric illness, and peptic ulceration. (12) Despite these guidelines being published in 2021, an updated set of guidelines is already in preparation in response to new treatment options. The new KDIGO guidelines (preliminary) recognize the value of treatment directed at “managing nephron loss” through lifestyle modifications, use of ACE/ARBs (or sparsentan in place if proteinuria is persistent) and the use of SGL2 inhibitors. Sparsentan, a dual endothelin angiotensin receptor antagonist, therapy reduced proteinuria and preserved GFR more than the ARB irbesartan in a Phase 3 trial leading to its approval for proteinuria despite maximal ACE or ARB therapy. (13)

In addition to the management of nephron loss, therapy directed at reducing pathogenic forms of IgA and associated immune complex inflammation through the use of steroids or several new agents should be considered in at-risk individuals. One such agent is a targeted release formulation of the steroid budesonide which targets the gut mucosa (a pathogenic component in IgA nephropathy) and improves proteinuria levels with limited systemic effects. (14) Additionally, as noted by Dr. Heymann, the alternative complement pathway inhibitor Iptacopan reduced proteinuria in individuals with > 1.0 gram proteinuria despite maximal supportive care (RAS active agents) in a Phase 3 trial. (7)

Taken together, multiple new agents are available for the treatment of IgA nephropathy. Individuals should absolutely benefit as the traditional struggle of tolerating steroids or watching the course of a slowly progressive disease will improve with these new therapeutic options. Active areas of pursuit include how to combine the multitude of agents and how to expand these newer agents to the worldwide IgA nephropathy population. Research trials are ongoing and should be one consideration for individuals noted to be high risk for progressive kidney disease.

1. Heymann WR. The renal reality of adult Henoch-Schönlein purpura. J Am Acad Dermatol. 2020 Jun;82(6):1303-1304. doi: 10.1016/j.jaad.2020.03.104. Epub 2020 Apr 9. PMID: 32278803.

2. Pillebout E, Sunderkötter C. IgA vasculitis. Semin Immunopathol. 2021 Oct;43(5):729-738. doi: 10.1007/s00281-021-00874-9. Epub 2021 Jun 25. PMID: 34170395.

3. Gan MY, Chua FZY, Chang ZY, Chua YT, Chan GC. Navigating Adult-Onset IgA Vasculitis-Associated Nephritis. Life (Basel). 2024 Jul 25;14(8):930. doi: 10.3390/life14080930. PMID: 39202674; PMCID: PMC11355272.

4. Roache-Robinson P, Killeen RB, Hotwagner DT. IgA Vasculitis (Henoch-Schönlein Purpura). 2023 Sep 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 30725937.

5. Hu YC, Yang YH, Chiang BL. Immunoglobulin A vasculitis: The clinical features and pathophysiology. Kaohsiung J Med Sci. 2024 Jul;40(7):612-620. doi: 10.1002/kjm2.12852. Epub 2024 Jun 3. PMID: 38828518.

6. Ingelfinger JR. Way Stations in Progress - Burgeoning Treatment Options for IgA Nephropathy. N Engl J Med. 2025 Feb 6;392(6):608-609. doi: 10.1056/NEJMe2413288. Epub 2024 Oct 25. PMID: 39453757.

7. Perkovic V, Barratt J, Rovin B, Kashihara N, Maes B, Zhang H, Trimarchi H, Kollins D, Papachristofi O, Jacinto-Sanders S, Merkel T, Guerard N, Renfurm R, Hach T, Rizk DV; APPLAUSE-IgAN Investigators. Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy. N Engl J Med. 2025 Feb 6;392(6):531-543. doi: 10.1056/NEJMoa2410316. Epub 2024 Oct 25. PMID: 39453772.

8. https://www.novartis.com/news/media-releases/novartis-receives-fda-accelerated-approval-fabhalta-iptacopan-first-and-only-complement-inhibitor-reduction-proteinuria-primary-iga-nephropathy-igan

9. Heerspink HJL, Jardine M, Kohan DE, Lafayette RA, Levin A, Liew A, Zhang H, Lodha A, Gray T, Wang Y, Renfurm R, Barratt J; ALIGN Study Investigators. Atrasentan in Patients with IgA Nephropathy. N Engl J Med. 2025 Feb 6;392(6):544-554. doi: 10.1056/NEJMoa2409415. Epub 2024 Oct 25. PMID: 39460694.

10. Pozzi C, Bolasco PG, Fogazzi GB, et al., Corticosteroids in IgA nephropathy: a randomized controlled trial, Lancet, 1999, Mar 13; 353 (9156): 883-887

11. Barbour S.J., Coppo R, Zhang H, et al., Evaluating a New International Risk-Prediction Tool in IgA Nephropathy, JAMA Internal Medicine, 2019, July1; 179(7): 942-952

12. KDIGO 2021 Clinical Practice Guidelines for the Management of Glomerular Diseases, Kidney International, vol 100, issue 45, Oct 2021

13. Rovin BH, Barratt J, Heerspink HJL, et al., Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT), Lancet, 2023, Dec 2; 402(10417): 2077-2090

14. Lafayette R, Kirstense J, Stone A, et al., Efficacy and safety of a targeted – release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd), Lancet, 2023, Sept 3, 402(10405): 859-870

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