Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy

Background and objectives The discovery of different podocyte autoantibodies in membranous nephropathy (MN) raises questions about their pathogenetic and clinical meaning. This study sought to define antibody isotypes and correlations; to compare levels in MN, other glomerulonephritides, and controls; and to determine their association with clinical outcomes. Design, setting, participants, & measurements Serum IgG₁, IgG₃, and IgG₄ against aldose reductase (AR), SOD2, and α-enolase (αENO) were measured at diagnosis in 186 consecutiveMN patients, in 96 proteinuric controls (36 with FSGS, and 60 with IgA nephropathy), and in 92 healthy people recruited in four Italian nephrology units. Anti-phospholipase A2 receptor (PLA2r) and anti-neutral endopeptidase (NEP) IgG₄ were titrated in the same specimens. Association with 1-year follow-up clinical parameters was studied in 120 patients. Results IgG₄ was the most common isotype for all antibodies; IgG₁ and IgG₃ were nearly negligible. IgG₄ levels were positive in a significant proportion ofMNpatients (AR, 34%; SOD2, 28%; aENO, 43%).Antibody titerswere higher in MN than in healthy and pathologic controls (P<0.005). Anti-NEP IgG₄ did not differ from normal controls (P=0.12). Anti-PLA2r IgG₄ was detected in 60% of patients and correlated with anti-AR, anti-SOD2, and anti-αENO IgG₄ (P<0.001). In MN patients negative for the whole antibody panel (20%), 1-year proteinuria was lower compared with patients with at least one antibody positivity (P<0.05). Conclusions Our data suggest that IgG₄ is the prevalent isotype for antibodies against cytoplasmic antigens of podocytes (AR, SOD2, αENO). Their levels were higher than in other proteinuric glomerulonephritides and in normal controls and were correlated with anti-PLA2r. Only baseline negativity for all known antibodies predicted lower 1-year proteinuria.