Recent phase 3 trials suggest that complement inhibition and B-cell–directed therapies can preserve kidney function in high-risk IgA nephropathy. The challenge now is deciding how these treatments fit alongside established supportive care.
Evidence reviewed to 2 November 2026.
Why this matters now
IgA nephropathy is no longer managed simply by controlling blood pressure and waiting to see whether kidney function declines. The 2025 KDIGO guideline lowered the practical threshold for concern, strengthened proteinuria targets and incorporated several disease-modifying options.
Since the guideline evidence review closed, phase 3 trials of complement inhibitors and B-cell–pathway therapies have reported substantial preservation of estimated glomerular filtration rate (eGFR). These results mark an important change: several agents initially approved because they reduced proteinuria now have evidence suggesting a clinically meaningful effect on kidney function.
However, the trials do not establish a universal treatment sequence. They enrolled selected, generally high-risk populations, and direct comparisons or robust combination studies remain unavailable.
What has changed in clinical practice?
Persistent proteinuria above 0.5 g/day is clinically important
IgA nephropathy can only be definitively diagnosed by kidney biopsy. KDIGO now regards persistent proteinuria of at least 0.5 g/day as indicating a meaningful lifetime risk of progressive kidney disease.
For most adults, treatment should aim for:
- Proteinuria below 0.5 g/day, and ideally below 0.3 g/day.
- An annual eGFR decline approaching the physiological rate, generally less than 1 mL/min/1.73 m² per year.
- Sustained blood-pressure control and reduction of cardiovascular risk.
Patients should therefore not be reassured solely because proteinuria remains below the traditional 1 g/day threshold.
Management now addresses two processes simultaneously
The emerging approach has two complementary components:
1. Treat the generic consequences of chronic kidney disease: blood-pressure control, renin–angiotensin system blockade, lifestyle measures and, where appropriate, an SGLT2 inhibitor. 2. Treat IgA nephropathy-specific disease activity: reducing pathogenic IgA production, intestinal immune activation, immune-complex formation or complement-mediated glomerular injury.
This is not necessarily a rigid “supportive care first, specific treatment later” sequence. Patients with substantial proteinuria or declining kidney function may need both components addressed in parallel.
What remains the foundation of treatment?
A maximally tolerated angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker remains standard care for patients with proteinuria, unless contraindicated. Sodium restriction, smoking cessation, weight management, exercise and careful blood-pressure control remain essential.
KDIGO also suggests an SGLT2 inhibitor for patients at risk of progression. However, much of the evidence is extrapolated from broader chronic kidney disease populations. SGLT2 inhibition should not be regarded as a substitute for IgA nephropathy-specific therapy in a patient with active, progressive disease.
Sparsentan provides combined endothelin-A and angiotensin-II receptor blockade. In the PROTECT trial, it reduced proteinuria more effectively than irbesartan and produced a modest improvement in the chronic eGFR slope. Because sparsentan already blocks the angiotensin receptor, it must not be combined with an ACE inhibitor or ARB. Hypotension, dizziness, fluid retention, hepatic monitoring and pregnancy-related precautions require attention. Read the PROTECT trial .
Where does targeted-release budesonide fit?
Targeted-release budesonide, designed to act on mucosal immune tissue in the distal ileum, is supported by the NefIgArd trial.
Compared with placebo, nine months of treatment produced:
- A 27% reduction in proteinuria at nine months.
- A 5.05 mL/min/1.73 m² advantage in time-weighted eGFR over two years.
- Fewer events involving a sustained 30% eGFR decline or kidney failure: 12% versus 21%.
Despite its targeted formulation, budesonide still produces systemic glucocorticoid effects, including hypertension, oedema, acne, muscle spasms and deterioration in glycaemic control. The benefit may also diminish after treatment stops, while evidence supporting repeated or maintenance courses remains limited.
When targeted-release budesonide is unavailable, KDIGO permits consideration of a reduced-dose systemic glucocorticoid regimen with appropriate infection prophylaxis. Systemic steroids should be used very cautiously in people with diabetes, obesity, latent infection, osteoporosis, active peptic ulcer disease, psychiatric illness or markedly reduced eGFR.
What have the recent phase 3 trials shown?
| Treatment and mechanism | Trial population | Principal finding | Interpretation in 2026 |
|---|---|---|---|
| Iptacopan — oral alternative complement pathway factor B inhibitor | 477 adults with UPCR ≥1 g/g and eGFR ≥30 despite supportive care | Annual eGFR slope was −3.10 versus −6.12 mL/min/1.73 m²; the kidney failure composite occurred in 21.4% versus 33.5% | Strong evidence that complement inhibition can preserve kidney function. Serious infections were numerically more frequent, making vaccination and infection precautions important. APPLAUSE-IgAN |
| Sibeprenlimab — monoclonal antibody inhibiting APRIL | 510 adults with high-risk IgA nephropathy | At 24 months, eGFR slope was 0.3 versus −4.2 mL/min/1.73 m²/year. The kidney composite occurred in 0.4% versus 11.2% | Supports APRIL inhibition as a disease-modifying strategy. The unusually large composite effect was based on relatively few events and needs longer follow-up. VISIONARY |
| Atacicept — blocks APRIL and BAFF signalling | 431 randomised adults | Annualised eGFR slope through 104 weeks was −0.60 versus −5.60 mL/min/1.73 m²/year; progression events occurred in 5.1% versus 17.8% | Provides strong phase 3 support for targeting B-cell and plasma-cell survival pathways. Longer-term immunological safety remains important. ORIGIN 3 |
| Atrasentan — selective endothelin-A receptor antagonist | Adults with proteinuria ≥1 g/day and eGFR ≥30 | At week 36, proteinuria fell by 38.1%, compared with 3.1% on placebo | A meaningful antiproteinuric effect, but definitive long-term eGFR evidence was not available from the interim report. Monitor for fluid retention. ALIGN |
| Telitacicept — dual APRIL/BAFF inhibition | 318 adults, predominantly from China | At week 39, UPCR fell by 58.9%, compared with 8.8% on placebo | Promising proteinuria and early eGFR findings, but broader generalisability and longer-term kidney outcomes remain uncertain. Phase 3 trial |
| Ravulizumab — terminal complement C5 inhibitor | 485 randomised adults; interim analysis of 352 | Proteinuria at week 34 was 43.4% lower than with placebo | Supports complement as a therapeutic target, but long-term eGFR results and infection safety remain necessary before defining its place in practice. Phase 3 interim report |
These effect sizes should not be compared across rows as though the trials were head-to-head. Eligibility criteria, background treatment, proteinuria definitions, follow-up duration and statistical methods differed.
A practical approach to the patient with IgA nephropathy
Confirm the diagnosis and establish the trajectory
Document the kidney-biopsy findings, assess whether a secondary cause is plausible, and measure proteinuria, eGFR and blood pressure consistently over time. Review diabetes, obesity, infection risk, liver disease and pregnancy potential. The direction and rate of change are more informative than a single laboratory result.
The International IgA Nephropathy Prediction Tool can support risk discussions, but it does not replace clinical assessment or determine treatment by itself.
Optimise foundational kidney protection
Use a maximally tolerated ACE inhibitor or ARB, unless sparsentan is selected instead. Address sodium intake, smoking, body weight and blood pressure. Consider an SGLT2 inhibitor when the patient remains at risk of progression.
Decide whether disease-specific therapy is needed
Disease-specific treatment should be considered when proteinuria remains at least 0.5 g/day, eGFR is declining, or the overall clinical trajectory suggests meaningful lifetime risk.
Choice of therapy should consider:
- Proteinuria and eGFR trajectory.
- Blood pressure and susceptibility to hypotension.
- Diabetes, obesity and glucocorticoid toxicity.
- Infection history and vaccination status.
- Liver function and fluid-retention risk.
- Pregnancy potential.
- Regulatory approval, affordability and local availability.
- Patient preference regarding oral treatment, injections and monitoring.
There is currently insufficient evidence to prescribe a single preferred sequence for all patients.
Measure whether treatment is working
Proteinuria, eGFR, blood pressure and treatment-specific adverse effects should be reassessed regularly, commonly within three to six months after treatment initiation or modification.
Failure of proteinuria to fall towards below 0.5 g/day, or continued eGFR decline, should prompt review of adherence, blood pressure, alternative causes of deterioration and the need to modify treatment or seek a clinical trial.
Regulatory approval does not establish treatment superiority
Several treatments received US accelerated approval based initially on proteinuria reduction: iptacopan in August 2024, atrasentan in April 2025, sibeprenlimab in November 2025 and atacicept in July 2026.
The later eGFR results for iptacopan, sibeprenlimab and atacicept materially strengthen the evidence supporting their disease-modifying potential. They do not establish superiority over targeted-release budesonide, sparsentan or one another.
Approval status, indication wording and availability vary between countries. Clinicians should check the current local product label, vaccination requirements, safety monitoring and reimbursement rules before prescribing.
What remains uncertain?
- Which treatment should be used first in a particular patient?
- Should complement and B-cell–directed treatments be combined?
- Can a successful treatment be stopped without losing kidney protection?
- How should patients with proteinuria between 0.5 and 1 g/day be treated?
- How well do the results generalise to advanced chronic kidney disease, lower-risk disease, children or older adults?
- What are the long-term infection and immune consequences of sustained pathway inhibition?
- Are the large eGFR effects maintained beyond two years?
- Will these treatments be accessible outside high-income health systems?
Clinical takeaway
IgA nephropathy has entered an era of mechanism-based treatment. Persistent proteinuria of at least 0.5 g/day should trigger active risk assessment, while the treatment target is now below 0.5 g/day and ideally below 0.3 g/day.
ACE inhibitor or ARB therapy, lifestyle measures and selective use of an SGLT2 inhibitor remain foundational. Targeted-release budesonide and sparsentan are established disease-modifying options, while recent phase 3 data provide compelling evidence for complement inhibition and APRIL or BAFF pathway blockade in high-risk disease.
The evidence supports earlier and more active treatment, but not yet a universal drug sequence. Until direct comparative and combination trials become available, therapy should be individualised around the patient’s disease trajectory, comorbidities, safety profile, preferences and access to treatment.
Key sources
- Kidney Disease: Improving Global Outcomes. KDIGO 2025 Clinical Practice Guideline for the Management of IgA Nephropathy and IgA Vasculitis . Kidney International. 2025;108(Suppl 4S):S1–S71.
- Iptacopan in IgA nephropathy: final APPLAUSE-IgAN results . New England Journal of Medicine. 2026.
- Sibeprenlimab in IgA nephropathy: final VISIONARY results . New England Journal of Medicine. 2026.
- Atacicept in IgA nephropathy: ORIGIN 3 . New England Journal of Medicine. 2026.