Background: The M-type phospholipase A2 receptor (PLA2R) antibody positivity is considered a specific serological marker for idiopathic membranous nephropath...

ALT: an elderly woman wearing glasses and a red shirt says let 's have a look

KEY POINTS A 28-year-old woman presented to the emergency department with a 4-day history of shortness of breath and fatigue. The patient had received a diagnosis of immunoglobulin A (IgA) nephropath...

BACKGROUND Anti-nephrin autoantibodies have emerged as a putative pathogenic driver in a subset of patients with podocytopathies, including those with posttransplant disease recurrence.METHODS We measured anti-nephrin autoantibodies in a cohort of 65 patients with podocytopathy associated with steroid-sensitive nephrotic syndrome (n = 39) and steroid-resistant nephrotic syndrome (n = 26) and in 34 patients with posttransplant podocytopathy recurrence. Fourteen patients with membranous nephropathy and 20 healthy volunteers served as controls. ELISA and immunoprecipitation assays were performed to detect anti-nephrin IgG using 2 different recombinant human nephrin proteins. Immunofluorescence analysis was performed to assess gG deposition and its colocalization with nephrin in renal biopsies.RESULTS When using an ELISA based on murine cell-derived human antigen, the highest positivity was found in healthy volunteers (55%), correlating with levels of circulating natural anti–α-galactose-α-1,3-galactose antibodies. This cross-reactivity was abrogated with recombinant human nephrin expressed in human cells. In this setting, very low prevalence (<5%) of anti-nephrin antibody-positive patients was found in steroid-sensitive and -resistant nephrotic syndrome cohorts and in patients with posttransplant disease recurrence. These frequencies were comparable to healthy volunteers. Using confocal and super-resolution microscopy, only trace amounts of IgM, but no IgG, were found in the glomeruli of analyzed biopsies, which did not colocalize with nephrin.CONCLUSION With the methodology presented here, anti-nephrin reactivity was extremely rare and occurred at comparably low frequencies in healthy controls, native-kidney podocytopathies, and posttransplant disease recurrence. This suggests that these autoantibodies are not inherently disease specific and may not serve as a broad biomarker across podocytopathies.TRIAL REGISTRATION ClinicalTrials.gov NCT06334692.FUNDING The Medici di Marignano family.