Editorial disclosure: This article is original educational commentary based on the cited literature. It summarizes and interprets published evidence rather than reproducing source text. Clinical decisions should be based on the full original publications, current guidelines, regulatory status, and individual patient factors.
Scope: This review addresses primary IgA nephropathy (IgAN) in adults. It is not a prescribing protocol. Drug availability, approved indications, reimbursement, and monitoring requirements differ by country and change quickly.
Why the treatment conversation has changed
IgA nephropathy is no longer framed only as a choice between supportive care and broad immunosuppression. The 2025 KDIGO guideline places the patient at the centre of a parallel strategy: reduce the generic consequences of nephron loss while also considering therapies directed at the disease-specific drivers of IgA-containing immune-complex injury. That reframing matters because the newer options work through distinct biological pathways and have materially different safety, monitoring, and access implications. [[inline_viewer url="https://kdigo.org/wp-content/uploads/2026/04/KDIGO-2025-IgAN-IgAV-Guideline.pdf"]]
The practical question is therefore not simply, “Which new drug should be used?” It is, “Does this patient have confirmed primary IgAN with a meaningful risk of progressive kidney-function loss, has foundational care been optimized, and which treatment mechanism best fits the patient’s risk, comorbidity profile, reproductive plans, infection risk, kidney function, and local label?”
Start with diagnosis, prognosis, and the foundation of care
KDIGO states that IgAN requires kidney-biopsy confirmation; there are no validated serum or urine biomarkers that can establish the diagnosis. Once primary IgAN is confirmed and secondary causes have been assessed, the most informative routinely available prognostic measures remain proteinuria and estimated glomerular filtration rate (eGFR). KDIGO advises considering treatment or additional treatment when proteinuria is at least 0.5 g/day (or equivalent), while recognizing that the trajectory, biopsy findings, clinical context, and the International IgAN Prediction Tool inform a more complete risk discussion. [[inline_viewer url="https://kdigo.org/wp-content/uploads/2026/04/KDIGO-2025-IgAN-IgAV-Guideline.pdf"]]
Foundational management is not a waiting room before “real” therapy. Blood-pressure management, reduction of intraglomerular pressure and proteinuria, cardiovascular-risk management, smoking cessation, dietary counselling where appropriate, and longitudinal assessment of eGFR and proteinuria remain central. KDIGO positions renin–angiotensin system (RAS) blockade or a dual endothelin–angiotensin receptor antagonist (DEARA), with or without an SGLT2 inhibitor where appropriate, as measures that address the generic pathways of nephron loss. [[inline_viewer url="https://kdigo.org/wp-content/uploads/2026/04/KDIGO-2025-IgAN-IgAV-Guideline.pdf"]]
A patient-selection framework for contemporary therapy
The table below is a structured review framework, not a substitute for a local label or multidisciplinary decision. Trial eligibility is useful for judging applicability, but it is not the same as universal clinical eligibility.
| Clinical question | Why it changes selection | Practical implication |
|---|---|---|
| Is the diagnosis biopsy-confirmed primary IgAN, and have secondary causes or a rapidly progressive variant been addressed? | New IgAN trials largely enrolled defined primary IgAN populations; alternative diagnoses and rapidly progressive disease may require a different pathway. | Confirm the disease phenotype before applying a trial-based treatment framework. |
| What is the current risk signal? | Proteinuria, eGFR, eGFR slope, blood pressure, biopsy context, and longitudinal trajectory carry more decision value than a single result. | Use serial measurements and validated prediction tools where applicable rather than a one-time UPCR threshold alone. [[inline_viewer url="https://kdigo.org/wp-content/uploads/2026/04/KDIGO-2025-IgAN-IgAV-Guideline.pdf"]] |
| Has foundational care been optimized and tolerated? | Recent pivotal trials commonly studied treatment on a background of stable supportive therapy, often including RAS inhibition; the exact background differed between trials. | Document current blood pressure, RAS/DEARA strategy, SGLT2 inhibitor status when relevant, and reasons for intolerance before escalating. |
| Which safety domain is dominant? | Infection and vaccine planning, liver function, edema/heart-failure risk, blood pressure, anemia, reproductive plans, and steroid toxicity are not interchangeable adverse-effect profiles. | Match monitoring capacity and patient circumstances to the mechanism before choosing a therapy. |
| What is available locally and what does the label actually say? | Approvals range from proteinuria-based accelerated pathways to approvals supported by kidney-function outcomes; availability differs across jurisdictions. | Check the current local prescribing information and avoid importing a US indication into another setting. [[inline_viewer url="https://kdigo.org/wp-content/uploads/2026/04/KDIGO-2025-IgAN-IgAV-Guideline.pdf"]] |
New and emerging medication classes: what they add
1. Targeted-release budesonide: mucosal immune modulation
Targeted-release budesonide is designed to act at the intestinal mucosal immune system implicated in pathogenic IgA production. KDIGO suggests a nine-month course for patients at risk of progressive kidney-function loss where the therapy is available. The same guideline cautions that a course may not produce a sustained response in every patient, that repeat-course data are awaited, and that approval and availability vary globally. [[inline_viewer url="https://kdigo.org/wp-content/uploads/2026/04/KDIGO-2025-IgAN-IgAV-Guideline.pdf"]]
Selection should still include a steroid-safety review. The original FDA accelerated-approval communication for delayed-release budesonide highlighted corticosteroid-related risks, infection considerations, and potentially greater exposure in moderate-to-severe liver impairment. It should not be presented as systemically inert simply because it is targeted-release. [2]
2. Hemodynamic and endothelin-pathway therapy: sparsentan and atrasentan
Sparsentan is a DEARA, while atrasentan is a selective endothelin A receptor antagonist. Both represent a move beyond conventional RAS-only hemodynamic management, but they should not be treated as interchangeable. KDIGO places RAS blockade or a DEARA within the strategy to reduce hyperfiltration and proteinuria, and highlights that sparsentan is the DEARA with evidence beyond in-trial RAS up-titration. [[inline_viewer url="https://kdigo.org/wp-content/uploads/2026/04/KDIGO-2025-IgAN-IgAV-Guideline.pdf"]]
For atrasentan, the interim ALIGN trial enrolled adults with biopsy-proven IgAN, proteinuria of at least 1 g/day, eGFR of at least 30 mL/min/1.73 m², and background RAS inhibition. At 36 weeks, the geometric mean reduction in proteinuria was greater with atrasentan than placebo. [3] The FDA’s US accelerated-approval snapshot describes an indication for adults at risk of rapid progression, generally UPCR at least 1.5 g/g, and explicitly identifies fetal harm, blood-pressure reduction, fluid retention, anemia, and liver-test monitoring as clinically relevant considerations. [4]
In practice, an endothelin-pathway option merits special caution when edema, heart failure, low blood pressure, anemia, liver disease, or pregnancy potential materially changes the risk–benefit balance. It also requires a deliberate decision about the background hemodynamic regimen rather than casual layering onto existing RAS therapy.
3. Complement-pathway inhibition: iptacopan
Iptacopan inhibits factor B in the alternative complement pathway. In the APPLAUSE-IgAN phase 3 interim analysis, adults with biopsy-confirmed IgAN and UPCR at least 1 despite optimized supportive therapy had a 38.3% lower adjusted geometric mean UPCR at nine months with iptacopan than with placebo. The report characterizes this as a proteinuria result; kidney-function effects require interpretation against the complete trial evidence and current local label. [5]
This mechanism is attractive when complement-pathway targeting is available and biologically plausible, but patient selection should still include infection history, immunization planning, concomitant therapies, and access to the monitoring specified in the current label. A favourable trial safety profile does not remove the need for mechanism-specific precautions in routine care.
4. APRIL inhibition: sibeprenlimab
Sibeprenlimab targets APRIL, a pathway relevant to IgA-producing B-cell biology. In November 2025, the FDA granted accelerated approval in the United States to reduce proteinuria in adults with primary IgAN at risk of progression. The FDA summary reports a 50% reduction in proteinuria at nine months with sibeprenlimab versus a 2% increase with placebo in the evaluated population, while stating that long-term slowing of kidney-function decline still requires confirmation. [6]
That distinction is important for consent and shared decision-making. For an immune-modifying agent, active infection assessment, vaccination status and timing, live-vaccine avoidance according to the label, and the patient’s ability to adhere to ongoing infection surveillance are part of selection—not an afterthought. [6]
How to translate evidence into a treatment review
A structured visit can prevent the common error of choosing a therapy from a drug list rather than from the patient’s disease state. First, reconfirm the risk phenotype and exclude a pattern that warrants urgent, variant-specific management. Second, show the longitudinal proteinuria and eGFR data, not only the latest value. Third, record the current foundational regimen and any constraints to its optimization. Finally, compare candidate therapies against the population studied, what the trial actually measured, label status, safety-monitoring burden, reproductive considerations, infection and vaccination plans, patient preferences, and affordability.
It is equally important to say what the evidence does not show. Not every positive proteinuria result has yet established a long-term eGFR benefit. Not every trial population mirrors an older patient, a person with advanced chronic scarring, a transplant recipient, a person with nephrotic syndrome, or someone with rapidly declining kidney function. And not every newly approved option is available, funded, or labelled the same way outside the United States. KDIGO explicitly advises attention to the representativeness of trial populations and to country-specific indication status. [[inline_viewer url="https://kdigo.org/wp-content/uploads/2026/04/KDIGO-2025-IgAN-IgAV-Guideline.pdf"]]
Key clinical takeaways
- Use kidney-biopsy confirmation, proteinuria, eGFR, trajectory, and validated prediction tools to frame risk; no single novel biomarker currently replaces this assessment. [[inline_viewer url="https://kdigo.org/wp-content/uploads/2026/04/KDIGO-2025-IgAN-IgAV-Guideline.pdf"]]
- Foundational CKD care and proteinuria reduction remain active treatment, not a prerequisite that becomes irrelevant once a targeted agent is considered.
- Targeted-release budesonide, endothelin-pathway agents, complement inhibition, and APRIL inhibition address different parts of IgAN biology or the kidney’s response to injury; their selection logic and safety profiles differ.
- For therapies with accelerated or conditional authorization, explain clearly whether the demonstrated endpoint was proteinuria reduction or confirmed slowing of kidney-function decline.
- Before initiating any option, align the treatment with local labeling, monitoring capacity, pregnancy and contraception requirements where relevant, infection and vaccination planning, comorbidities, and patient priorities.
References
- [inline_viewer url="https://kdigo.org/wp-content/uploads/2026/04/KDIGO-2025-IgAN-IgAV-Guideline.pdf"]
- U.S. Food and Drug Administration. FDA approves first drug to decrease urine protein in IgA nephropathy, a rare kidney disease.
- Heerspink HJL, et al. Atrasentan in Patients with IgA Nephropathy. New England Journal of Medicine. 2025;392:544–554.
- U.S. Food and Drug Administration. Drug Trials Snapshot: VANRAFIA (atrasentan).
- Perkovic V, et al. Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy. New England Journal of Medicine. 2025;392:531–543.
- U.S. Food and Drug Administration. FDA approves a new treatment for primary immunoglobulin A nephropathy: Voyxact (sibeprenlimab-szsi).