Diffuse foot process effacement in IgA nephropathy: MCD-Like versus non-MCD-like phenotypes and response to corticosteroid-based immunosuppression.

BACKGROUND AND HYPOTHESIS: Diffuse foot process effacement (FPE) is an ultrastructural associated with severe proteinuria and adverse renal outcomes in IgA nephropathy (IgAN). Among IgAN patients with diffuse FPE, light-microscopic patterns delineate two distinct clinicopathologic entities-MCD-like (MCD-IgAN) and non-MCD-like IgAN (DFPE-IgAN), yet their clinical features, histologic characteristics and prognosis remain incompletely characterized. METHODS: In this multicenter retrospective cohort study, 1 528 biopsy-proven primary IgAN cases (2021-2024 2023) were screened, and 358 patients with diffuse FPE (≥ 80% of glomerular capillary loops) were identified and classified as MCD-IgAN (n = 112) or DFPE-IgAN (n = 246) using predefined histologic criteria. Two-stage propensity score matching balanced baseline characteristics between phenotypes and, within each phenotype, between initial strategies: corticosteroid monotherapy (CS) versus corticosteroids plus additional immunosuppressants (CS + IS). Primary outcomes were time from treatment initiation to first complete remission (CR) and overall remission (OR) of proteinuria within 12 months, adverse events were recorded. RESULTS: After matching, patients with MCD-IgAN exhibited more nephrotic features but better preserved eGFR, whereas those with DFPE-IgAN had heavier IgA/C3 deposition and higher Oxford activity and chronicity scores. Over 12 months of follow-up, complete and overall remission were achieved more frequently in MCD-IgAN than in DFPE-IgAN (72% vs 28% and 96% vs 87%, respectively), with parallel advantages in eGFR, serum albumin and residual proteinuria. In DFPE-IgAN, CS + IS was associated with approximately two-fold higher cumulative probability of CR and OR compared with CS alone, whereas in MCD-IgAN, adding other immunosuppressants to CS conferred no clear additional benefit. Adverse events were infrequent and similar across groups-treatment strata, and subgroup analyses suggested a greater benefit of CS + IS in DFPE-IgAN with subnephrotic proteinuria or tubulitis. CONCLUSION: MCD-IgAN behaves as a steroid-sensitive podocytopathy in which CS monotherapy is generally sufficient, whereas DFPE-IgAN, embedded in a heavier immune complex and chronic lesion burden, appears to benefit from early combination immunosuppression.