Association between Complete Proteinuria Remission and Kidney Function in the Phase 3 PROTECT Trial of Sparsentan in IgA Nephropathy

Key Points This analysis explored the association between complete remission of proteinuria and kidney function decline during sparsentan or irbesartan treatment. Patients achieving complete remission of proteinuria experienced better eGFR preservation and fewer kidney failure events. These data support Kidney Disease Improving Global Outcomes guideline recommendations to maintain proteinuria levels in IgA nephropathy ideally below 0.3 g/d. Background In the phase 3, randomized, double-blind PROTECT (NCT03762850) trial, sparsentan, a single-molecule dual endothelin angiotensin receptor antagonist, reduced proteinuria and preserved kidney function compared with maximum labeled dose irbesartan in adults with IgA nephropathy. In this post hoc analysis of PROTECT, we assessed the association between complete remission of proteinuria (CR) and preservation of kidney function. Methods This analysis compared kidney function in patients who achieved CR (urine protein excretion <0.3 g/d) by week 36 (CR36) or at any time up to week 110 (CR110) versus those who did not (non-CR), regardless of original treatment allocation. End points assessed by CR status were change in proteinuria, eGFR, and BP, rate of eGFR decline, a composite kidney end point, and safety. Results Of 404 patients who were randomized and received study drug, 43 (11%) achieved CR36 and 85 (21%) achieved CR110. CR patients demonstrated greater and more rapid reductions in proteinuria compared with non-CR patients. CR110 patients had a smaller absolute change in eGFR versus non-CR patients (−4.0 versus −8.6 ml/min per 1.73 m 2 ) and a slower rate of eGFR decline (day 1–week 110; −0.7 versus −4.2 ml/min per 1.73 m 2 per year). Fewer CR110 patients (1%) reached the composite kidney end point versus non-CR patients (14%). CR110 patients were more likely to experience treatment-emergent adverse events associated with hypotension (hypotension, orthostatic hypotension, or BP systolic decreased) and less likely to experience treatment-emergent adverse events of hypertension than non-CR patients. More non-CR patients versus CR110 patients discontinued treatment due to AEs (11% versus 4%, respectively) or patient decision (8% versus 2%, respectively). Conclusions Participants in PROTECT who achieved CR36 or CR110 showed greater eGFR preservation, fewer kidney failure events, and similar safety profiles compared to non-CR participants. These data reinforce recommendations to maintain proteinuria levels ideally <0.3 g/d and underscore its relationship with kidney function preservation. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT03762850.