Autoantibodies reactive with glomerular endothelial cells and podocytes in patients with membranous nephropathy.

Rationale & objective: Membranous nephropathy (MN) is a glomerular disease caused by autoantibodies reactive with podocyte antigens. The most common antigen is the M-type phospholipase A2 receptor (PLA2R), but autoantibodies to other podocyte antigens have also been identified. Investigators have reported elevated levels of complement fragments in plasma. However, most complement fragments generated on podocytes are likely to pass into the urine and not enter the bloodstream. Further, anti-PLA2R antibodies are usually IgG4 subclass and do not activate the classical pathway of complement. To look for additional autoantibodies capable of generating endovascular complement fragments, we examined whether MN patients have antibodies reactive with endothelial cell antigens. Study design: Retrospective cohort study. Setting & participants: We analyzed plasma samples from 64 patients with MN, and results were compared to healthy controls and patients with chronic kidney disease. Exposure: Plasma and urine complement activation fragments, glomerular endothelial cell and podocyte antibody binding assays, anti-cardiolipin antibody enzyme linked immunosorbent assay. Outcome: Proteinuria, estimated glomerular filtration rate. Analytical approach: Groups were compared with Wilcoxon, Kruskal-Wallis or chi-square tests. Correlations were performed using Pearson's correlation. Results: Plasma C3a, C4a, C5a, and sC5b-9 levels were elevated in MN patients. Some patients had IgG reacted with glomerular endothelial cells or with podocytes. These antibodies were seen in distinct subsets of patients and did not correlate with the presence of anti-PLA2R antibodies. Higher titers of anti-glomerular endothelial cell antibodies correlated with systemic complement activation, seen by sC5b-9, and disease severity, determined by proteinuria. Anti-cardiolipin IgG levels associated with proteinuria. Limitations: Assays used immortalized cell lines, and target antigens have not yet been identified. Conclusions: MN is a disease of autoimmunity directed against podocyte antigens, but some patients may also produce autoantibodies that target antigens on glomerular endothelial cells. The level of these antibodies correlates with adverse clinical findings.