Introduction:In PROTECT, sparsentan, a non-immunosuppressive, dual endothelin angiotensin receptor antagonist (DEARA), resulted in significant reduction in proteinuria and preservation of kidney function when compared to irbesartan in adults with IgA nephropathy.Here we investigate the impact of biopsy histology of PROTECT participants on the clinical efficacy of sparsentan.Methods: Clinical sites provided biopsy slides or whole slide images from 107 patients for central review.Biopsy scoring was carried out on digital slides by a single pathologist who was blinded to clinical and treatment data.15 histological data items were included in the analysis (Oxford Classification MEST-C scores, podocytopathic changes, continuous MEST-C data, and vascular lesion scoring).Results: Of 107 biopsies, 18 contained <8 glomeruli and were inadequate for MEST-C scoring.Of the remaining biopsies (n=89), 12% were scored M1, 22% E1, 80% S1, 23% T1, 4% T2, and 21% C1.The median (Q1, Q3) time from adequate biopsy to enrolment was 40.2 (9.0-101.3)months and 30% of biopsies were performed within 12 months of study entry.Baseline eGFR was significantly lower in patients with T1/T2 vs T0.The percentage of tubular atrophy/interstitial fibrosis and percentage of glomeruli showing segmental sclerosis showed a significant negative correlation with baseline eGFR whilst percentage of glomeruli showing endocapillary hypercellularity positively correlated with baseline GFR.The reduction in proteinuria at 36 weeks in patients treated with sparsentan (n=47) was consistent across MEST-C scores or continuous histological data; patients showed treatment benefit in all groups (Fig 1 ). Conclusion:Whilst histological features are associated with baseline eGFR and proteinuria, the therapeutic efficacy of sparsentan is independent of biopsy findings, including the Oxford Classification MEST-C scores.
Kimura et al. (Wed,) studied this question.