IgA Nephropathy: Next-Step Treatment When RAS Inhibition and SGLT2 Inhibition Fail to Control Proteinuria

In patients with IgA nephropathy who have already received optimized first-line supportive therapy but have not achieved the target proteinuria level or adequate kidney function stabilisation, escalation to a disease-modifying protocol is indicated.

First-Line Failure — Escalation Trigger

The preceding treatment step involved maximally tolerated RAS inhibition — an ACE inhibitor or ARB, or alternatively sparsentan as a dual endothelin–angiotensin receptor antagonist — together with an SGLT2 inhibitor, and comprehensive lifestyle measures including dietary sodium restriction, smoking and vaping cessation, weight control, and endurance exercise, with blood pressure targeted at ≤120/70 mm Hg.

This protocol is indicated when that regimen does not achieve: urine protein excretion below 0.5 g/d (ideally below 0.3 g/d), rate of eGFR loss reduced to below 1 ml/min/yr, and sustained blood pressure at or below 120/70 mm Hg.

Disease-Modifying Approach

When optimized supportive care does not achieve adequate proteinuria control, a disease-modifying therapy specifically targeting the IgAN pathogenic cascade may be added — involving a defined 9-month treatment course. Where the primary option is not available, an alternative systemic approach combined with appropriate prophylaxis is described in the full protocol.

Treatment Targets

Urine protein excretion below 0.5 g/d (ideally below 0.3 g/d)
Stabilisation of eGFR

Instant Access to Structured Evidence-Based Regimens

References

We suggest treatment with a 9-month course of Nefecon for patients who are at risk of progressive loss of kidney function with IgAN (2B).
In the NefIgArd study, 364 adult patients with IgAN, eGFR 35–90 ml/min per 1.73 m², and persistent proteinuria (urine protein-to-creatinine ratio [PCR] ≥0.8 g/g [80 mg/mmol] or proteinuria ≥1 g/24 h), despite physician-attested, optimized RASi use, were randomized (1:1) to receive 16 mg/d of Nefecon or placebo for 9 months, followed by a 15-month observational follow-up period off study drug.
In settings where Nefecon is not available, we suggest that patients who are at risk of progressive loss of kidney function with IgAN be treated with a reduced-dose systemic glucocorticoid regimen combined with antimicrobial prophylaxis (2B).
Treatment with systemic glucocorticoids should incorporate antimicrobial prophylaxis against Pneumocystis jirovecii and antiviral prophylaxis in hepatitis B carriers, along with gastroprotection and bone protection according to national guidelines.
The only validated early biomarker to help guide clinical decision-making is urine protein excretion, which should be maintained at a minimum of <0.5 g/d (or equivalent), and ideally at <0.3 g/d (or equivalent), accepting that in some patients with extensive kidney scarring, this may not be possible and that multiple treatment strategies, including nonpharmacologic interventions, may be needed to achieve this.

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