Early observations and pilot data that first suggested a new direction
IgA nephropathy is the most common primary glomerulonephritis worldwide, but treatment remained controversial for decades. The STOP-IgAN trial randomized 162 patients with persistent proteinuria despite optimized supportive care to continued supportive care or added immunosuppression. At 3 years, immunosuppression achieved more complete remissions (17% vs 5%, p=0.01) but did not reduce the rate of eGFR decline ≥15 mL/min (26% vs 28%). The immunosuppression group had more infections, including one fatal pneumonia. This suggested that optimized supportive care with RAAS blockade was the primary foundation of treatment.
Landmark RCTs and pivotal trials that established the evidence base
The TESTING trial revisited corticosteroids with a modified protocol. Among 503 patients, reduced-dose oral methylprednisolone (with antibiotic prophylaxis after a safety signal with the original high-dose protocol) reduced the composite kidney endpoint by 63% (HR 0.37; 95% CI 0.17-0.85; p=0.02) at 5.9% versus 15.9%. However, serious adverse events were increased. This confirmed that corticosteroids had genuine kidney-protective effects in high-risk IgA nephropathy but required careful risk-benefit assessment and infection prophylaxis.
Follow-up studies, subgroup analyses, and real-world validation
The PROTECT trial introduced sparsentan, a dual endothelin and angiotensin receptor antagonist, as the first non-immunosuppressive targeted therapy for IgA nephropathy. Among 404 patients, sparsentan reduced proteinuria by 49.8% versus 15.1% with irbesartan at 36 weeks (p<0.0001) and showed slower eGFR decline over 2 years (-2.7 vs -3.8 mL/min/1.73m2/year). Sparsentan received accelerated FDA approval in 2023 specifically for IgA nephropathy, marking a new therapeutic era.
Integration into clinical practice guidelines and recommendations
KDIGO 2021 guidelines recommended maximized supportive care (RAAS blockade, blood pressure control, sodium restriction) as the foundation, with corticosteroids considered for patients at high risk of progression despite 90 days of optimized supportive care. Following PROTECT and DAPA-CKD (which included IgA nephropathy patients), guidelines incorporated SGLT2 inhibitors and sparsentan as additional options.
KDIGO
Maximized supportive care as foundation; corticosteroids for high-risk patients with persistent proteinuria; consider SGLT2 inhibitors
FDA
Sparsentan accelerated approval for IgA nephropathy to reduce proteinuria
Now
Current standard of care and ongoing research directions
IgA nephropathy treatment has expanded from supportive care alone to a multi-therapeutic approach. Optimized RAAS blockade remains the foundation, supplemented by SGLT2 inhibitors (based on DAPA-CKD subgroup data), sparsentan (PROTECT), and corticosteroids for high-risk patients (TESTING). Targeted therapies attacking the pathogenic IgA1 pathway, including APRIL inhibitors (sibeprenlimab, atacicept) and complement inhibitors (iptacopan), represent the next frontier with promising phase 2/3 results.
What is sparsentan and why is it significant for IgA nephropathy?+
Sparsentan is a dual endothelin and angiotensin receptor antagonist approved by the FDA in 2023 for IgA nephropathy. In the PROTECT trial (404 patients), it reduced proteinuria by 49.8% versus 15.1% with irbesartan (p<0.0001). It is the first non-immunosuppressive targeted therapy for IgA nephropathy and showed slower eGFR decline over 2 years.
Are corticosteroids effective in IgA nephropathy?+
The TESTING trial (503 patients, JAMA 2022) showed reduced-dose methylprednisolone reduced the composite kidney endpoint by 63% (HR 0.37; p=0.02) but increased serious adverse events. The STOP-IgAN trial found no GFR benefit from immunosuppression when supportive care was optimized. Corticosteroids are considered for high-risk patients with persistent proteinuria despite optimized supportive care, with infection prophylaxis.
