Association between anti-nephrin autoantibodies and disease activity in minimal change disease

BACKGROUND: Minimal change disease (MCD) is a podocytopathy linked to immune-mediated mechanisms, with emerging evidence suggesting the presence of anti-nephrin autoantibodies in a subset of patients. Given that Th2-type immune responses can promote IgG subclass switching to IgG4, this study aimed to characterize the distribution of these autoantibodies across disease stages, their correlation with clinical parameters, and to investigate their IgG subclass distribution and potential Th2 immune skewing. METHODS: This bi-centric study included 60 patients with MCD (including pediatric cases), 125 with other glomerular diseases, and 40 healthy controls. An affinity capture-elution ELISA was used to quantify serum anti-nephrin autoantibodies, evaluate their correlation with disease activity, and characterize their IgG subclass distribution. In addition, serum Th1/Th2 cytokine profiles were measured using Olink proteomics technology to assess Th2 immune skewing. RESULTS: Among 60 biopsy-confirmed MCD patients, circulating anti-nephrin autoantibodies were detected in 50% of cases. Notably, 70% of patients in the active phase tested positive for anti-nephrin autoantibodies, exhibiting significantly elevated antibody levels compared to those in partial or complete remission. Anti-nephrin levels positively correlated with proteinuria, and inversely with serum albumin and estimated glomerular filtration rate. Furthermore, patients positive for anti-nephrin autoantibodies had higher proteinuria, more severe dyslipidemia, and worse renal function compared to autoantibody-negative patients. Moreover, anti-nephrin antibody-positive MCD patients displayed a predominant IgG4 subclass alongside elevated serum IL-4 and IL-13 levels and an increased IL-4/IFN-γ ratio, supporting a Th2-skewed immune status. CONCLUSION: Anti-nephrin autoantibodies are associated with disease activity in MCD, exhibit an IgG4-predominant subclass, and are accompanied by a Th2-skewed cytokine profile. These findings suggest their potential as a noninvasive biomarker, warranting further prospective studies to validate their clinical utility.