Clinical phenotype predicts anti-PLA2R serology in nephrotic range proteinuria

BACKGROUND: The 2021 KDIGO guidelines permit non-invasive diagnosis of membranous nephropathy using anti-PLA2R antibodies in patients with nephrotic syndrome. However, optimal patient selection for anti-PLA2R testing remains undefined, particularly in patients with nephrotic-range proteinuria without nephrotic syndrome. METHODS: We conducted a retrospective analysis of 156 consecutive patients with nephrotic-range proteinuria presenting to a tertiary nephrology center between November 2022 and July 2024. Patients were stratified by clinical phenotype: nephrotic syndrome versus nephrotic-range proteinuria without nephrotic syndrome. Primary outcomes were anti-PLA2R positivity rates and anti-PLA2R-positive membranous nephropathy frequency between groups. RESULTS: Anti-PLA2R positivity was significantly higher in nephrotic syndrome patients compared to those with nephrotic-range proteinuria without nephrotic syndrome (26.5% vs 9.6%, p=0.007). Membranous nephropathy diagnosis was more frequent in the nephrotic syndrome group (43.3% vs 23.2%, p=0.008). Among patients with confirmed anti-PLA2R-positive membranous nephropathy, anti-PLA2R antibody levels were significantly higher in nephrotic syndrome patients (p=0.008). CONCLUSIONS: Clinical phenotype strongly predicts anti-PLA2R diagnostic yield in nephrotic-range proteinuria. These findings support KDIGO guidelines emphasizing nephrotic syndrome presence for non-invasive anti-PLA2R-positive membranous nephropathy diagnosis and suggest prioritizing anti-PLA2R testing in nephrotic syndrome patients for optimal resource utilization in limited settings.