Edward John Filippone ^* Rakesh Gulati John Farber

• Jefferson University Hospitals, Thomas Jefferson University, Philadelphia, United States

Primary IgA nephropathy (IgAN) is the most common form of primary glomerulopathy. A slowly progressive disease presenting in the young to middle-aged, most patients with reduced eGFR or proteinuria will progress to ESKD in their lifetimes. The pathogenesis involves increased production of galactose-deficient IgA1 (Gd-IgA1) that forms immune complexes that deposit in the glomerulus, eliciting mesangial cell proliferation, inflammation, and complement activation.The backbone of therapy is supportive, including lifestyle modifications, strict blood pressure control, and renin-angiotensin system inhibition targeting proteinuria < 300 mg/day. Sodiumglucose transporter 2 inhibitors are indicated for persisting proteinuria or declining eGFR.Sparsentan is indicated for persisting proteinuria. Immunosuppression should be considered for all patients at risk for progression (persisting proteinuria and/or declining eGFR). To reduce Gd-IgA1 production, targeted release budesonide is approved. Agents targeting B-cell survival factors APRIL or BAFF/APRIL significantly reduce Gd-IgA1 production and proteinuria in phase 2 trials but await phase 3 data for approval. To reduce inflammation, high-dose steroids are ineffective in Caucasians and toxic, although lower dose regimens may be effective in Chinese. Complement inhibition is being actively studied. The factor B inhibitor iptacopan has conditional approval.Terminal pathway inhibitors cemdisiran and ravulizumab show promise in phase 2 studies. Our current approach in those requiring immunosuppression involves combining reduction of Gd-IgA1 (nefecon) with suppressing the effects of inflammation (iptacopan). The optimal duration of such therapy is uncertain. Clearly, more needs to be learned with many trials underway.