Emerging Therapies for Nephrotic and Nephritic Syndromes

The glomerular diseases have moved, in just a few years, from a field with almost no disease-specific drugs to one of the most active areas in all of nephrology — nowhere more dramatically than in IgA nephropathy.

Minimal change disease and FSGS

In minimal change disease, the discovery of circulating antinephrin autoantibodies — present in a substantial proportion of adults with minimal change disease and children with idiopathic nephrotic syndrome, and tracking with disease activity — has provided both a biomarker and a rational therapeutic target. In focal segmental glomerulosclerosis (FSGS), sparsentan, a dual endothelin-and-angiotensin receptor antagonist, produced greater proteinuria remission than irbesartan in the DUPLEX trial and was approved for FSGS in 2025. For the APOL1-driven form of FSGS specifically, the oral APOL1 inhibitor inaxaplin represents a precision approach (covered in the toxic-nephropathy section).

Membranous nephropathy

Rituximab achieved superior remission rates and more durable responses than cyclosporine in the MENTOR trial and, guided by anti-PLA2R antibody status, is now favored first-line over calcineurin inhibitors for most patients. Newer B-cell and plasma-cell-directed agents, including the anti-CD38 antibody felzartamab, have shown promise in early trials.

IgA nephropathy: from no therapies to five

The transformation here is the headline of modern glomerular medicine. As recently as 2021, IgA nephropathy had no disease-specific approved therapy — management meant RAAS blockade and, increasingly, SGLT2 inhibition. There are now five approved agents, each targeting a different point in the disease:

• Targeted-release budesonide (Tarpeyo), which acts on gut mucosal immunity where galactose-deficient IgA1 is produced (NefIgArd trial).
• Sparsentan (Filspari), the dual endothelin/angiotensin blocker, the first non-immunosuppressant option (PROTECT trial, ~50% proteinuria reduction).
• Iptacopan (Fabhalta), an oral factor B inhibitor of the alternative complement pathway (APPLAUSE-IgAN).
• Atrasentan (Vanrafia), the first selective endothelin A receptor antagonist for IgAN (ALIGN trial).
• Sibeprenlimab (Voyxact), an APRIL inhibitor that reduces production of the pathogenic antibody, which showed a 54.3% placebo-adjusted proteinuria reduction in VISIONARY — the largest Phase 3 trial ever conducted in IgAN — and was approved in late 2025.

The 2025 KDIGO guidelines were updated to reflect this shift toward early, mechanism-driven treatment on top of a foundation of RAAS and SGLT2 inhibition. Further B-cell and complement agents (telitacicept, povetacicept, zigakibart, atacicept) are in late-stage trials. A practical caveat: several of these carry REMS requirements or boxed warnings (liver monitoring for sparsentan; encapsulated-organism infection risk for complement inhibitors), and real-world uptake so far remains modest.

Nephritic syndromes and complement glomerulopathies

For C3 glomerulopathy and immune-complex MPGN, complement-targeted therapy has arrived: iptacopan (factor B inhibitor) and pegcetacoplan (a C3 inhibitor) both gained approval in 2025, replacing the previously off-label and inconsistent use of terminal complement blockade. In anti-GBM (Goodpasture) disease, rituximab combined with plasmapheresis and corticosteroids can induce remission and reverse dialysis dependence in selected cases. In crescentic glomerulonephritis, neutrophil- and NETosis-targeted strategies are under investigation as steroid-sparing options. Precision-medicine efforts such as the NEPTUNE Match program aim to match glomerular-disease patients to mechanism-based trials.

Further reading: antinephrin autoantibodies (Hengel et al., NEJM 2024); DUPLEX sparsentan in FSGS (Rheault et al., NEJM 2023); MENTOR rituximab (Fervenza et al., NEJM 2019); VISIONARY sibeprenlimab and the IgAN approvals (2024–2025); 2025 KDIGO IgAN guideline.