Prognostic role of glomerular electron microscopy lesions in IgA nephropathy: “the devil is in the details”

Introduction Transmission electron microscopy enables examination of ultrastructural glomerular changes; while this tool has already been applied in IgA nephropathy (IgAN), limited information exists on the prognostic value in this disease. We aimed to systematically investigate ultrastructural lesions and assess their role in predicting the evolution of IgA nephropathy to end-stage kidney disease. Methods A single-center retrospective study was performed on 107 consecutive IgAN patients (median age 42 years, 67% male, estimated glomerular filtration rate 46 mL/min, proteinuria 1.0 g/g) between 2010 and 2015, who were followed-up until end-stage kidney disease, death, or end of study (January 2021). A pathologist evaluated the Mesangial hypercellularity (M), Endocapillary hypercellularity (E), Segmental glomerulosclerosis (S), and Tubular atrophy/interstitial fibrosis—Crescents (C) (MEST-C) score and transmission electron microscopy lesions according to a comprehensive protocol that encompassed all glomerular structures. Results Patients were followed up for a median of 7.1 years; 32 (43%) reached end-stage kidney disease. Patients who reached kidney failure had higher comorbidity score, more frequent arterial hypertension, lower estimated glomerular filtration rate, and higher MEST-C score. In terms of transmission electron microscopy lesions, patients who progressed to end-stage kidney disease had more frequent podocyte activation, effacement, and presence of microvilli; more frequent signs of endothelial cell activation and fenestration; higher mesangial cell proliferation. In the univariate Cox proportional hazard regression, higher MEST-C score and lesions detected by transmission electron microscopy in podocytes, endothelial cells, and mesangial cell proliferation were associated with shorter kidney survival time. In the multivariate Cox proportional hazard regression, only higher MEST-C score, presence of podocytes with microvilli, and mesangial cell proliferation were associated with end-stage kidney disease. Conclusion This study shows that, besides the MEST-C score, the presence of podocytes with microvilli and mesangial cell proliferation are associated with poor kidney survival in IgAN patients, highlighting the prognostic value of lesions detected by transmission electron microscopy. Graphical abstract