Alternative-pathway complement inhibitors have now succeeded in trials across C3 glomerulopathy, primary immune-complex membranoproliferative glomerulonephritis and IgA nephropathy. The 2025 International Society of Nephrology Forum convened a global panel to work out what that means for practice, and the honest answer it reports is that the selection question is open.
The pathophysiology differs across the three. In C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis, complement overactivation is the primary driver — these are prototypical complement disorders and inhibiting the pathway addresses the cause. In IgA nephropathy, complement is not the primary cause; the evidence implicates it as a secondary contributor to kidney damage within a more complex, multifactorial disease. That distinction should shape expectations: the same drug class is doing different work in the two settings.
The forum's list of unresolved areas is the useful part for a clinician. How complement biomarkers should guide therapy, what weight to give complement autoantibodies, what role genetics should play, and how the kidney biopsy should feed the decision are all named as uncertain rather than settled. A nephrologist reading this should take it as permission to say that the sequencing is not yet established — and as a reason to ensure that biopsy material and complement studies are obtained before treatment is started, because a retrospective answer will not be available.
- Secure adequate biopsy material and complement studies before starting an inhibitor
- Send complement biomarkers and autoantibodies where available, even without a validated threshold
- Distinguish primary complement disease from IgA nephropathy when setting expectations
- Discuss the unsettled selection criteria openly rather than implying a protocol exists
Why it matters
The drugs have arrived ahead of the rules for deciding who benefits from them.
Don't overread it
This is an expert forum report, not a guideline — it names uncertainties rather than resolving them.
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