Ultrastructural characterization of proteinuric patients predicts clinical outcomes

Background: The analysis and reporting of glomerular features ascertained by electron microscopy are limited to fewparameterswith minimal predictive value, despite some contributions to disease diagnoses. Methods: We investigated the prognostic value of 12 electron microscopy histologic and ultrastructural changes (descriptors) fromthe Nephrotic Syndrome Study Network (NEPTUNE)Digital Pathology Scoring System. Study pathologists scored 12 descriptors in NEPTUNE renal biopsies from 242 patients with minimal change disease or FSGS, with duplicate readings to evaluate reproducibility. We performed consensus clustering of patients to identify unique electron microscopy profiles. For both individual descriptors and clusters, we used Cox regression models to assess associations with time from biopsy to proteinuria remission and time to a composite progression outcome (≥40% decline in eGFR, with eGFR<60 ml/min per 1.73 m2, or ESKD), and linear mixed models for longitudinal eGFR measures. Results: Intrarater and interrater reproducibility was ≥0.60 for 12 out of 12 and seven out of 12 descriptors, respectively. Individual podocyte descriptors such as effacement and microvillous transformation were associated with complete remission, whereas endothelial cell and glomerular basement membrane abnormalities were associated with progression. We identified six descriptor-based clusters with distinct electronmicroscopy profiles and clinical outcomes. Patients in a cluster with more prominent foot process effacement and microvillous transformation had the highest rates of complete proteinuria remission, whereas patients in clusters with extensive loss of primary processes and endothelial cell damage had the highest rates of the composite progression outcome. Conclusions: Systematic analysis of electron microscopic findings reveals clusters of findings associated with either proteinuria remission or disease progression.