CureGN Pathology Classification and Core Scoring Criteria, Reproducibility, and Clinicopathologic Correlations

Abstract

Introduction: CureGN is an observational cohort study of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), or IgA nephropathy (IgAN). We developed a conventional, consensus-based scoring system to document pathologic features for application across multiple pathologists and herein describe the protocol, reproducibility and correlation with clinical parameters at biopsy. Methods: Definitions were established for glomerular, tubular, interstitial and vascular lesions evaluated semi-quantitatively using digitized light microscopy slides and electron micrographs, and reported immunofluorescence. Cases with curated pathology materials as of April 2019 were scored by a randomly assigned pathologist, with at least 10% of cases scored by a second pathologist. Scoring reproducibility was assessed using Gwet’s AC1 statistic and correlations with clinical variables were performed. Results: Of 800 scored biopsies (143 MCD, 185 FSGS, 206 MN, 266 IgA), 94 were scored twice (11.8%). Of 60 pathology features, 46 (76.7%) demonstrated excellent (AC1>0.8), and 12 (20.0%) had good (AC1 0.6-0.8) reproducibility. Mesangial hypercellularity scored as absent, focal or diffuse had moderate reproducibility (AC1=0.58), but good reproducibility (ACI=0.71) when scored as absent or focal vs diffuse. The percent glomeruli scored as no lesions had fair reproducibility (AC1=0.34). Strongest correlations between pathologic features and clinical characteristics at biopsy included interstitial inflammation, interstitial fibrosis and tubular atrophy with eGFR, foot process effacement with UPCR, and active crescents with hematuria. Conclusions: Most scored pathology features showed excellent reproducibility, demonstrating consistency for these features across multiple pathologists. Correlations between certain pathologic features and expected clinical characteristics show the value of this approach for future studies on clinicopathologic correlations and biomarker discovery.