Transforming growth factor beta receptor 3 (TGFBR3)-associated membranous nephropathy

Background: Membranous lupus nephritis (MLN) comprises 10-15 percent of lupus nephritis and increases morbidity and mortality of patients with systemic lupus erythematosus (SLE) through complications of nephrotic syndrome and chronic kidney failure. Identification of the target antigens in MLN may enable non-invasive monitoring of disease activity, inform treatment decisions, and aid in prognostication, as is now possible for idiopathic MN caused by antibodies against the phospholipase A2 receptor. Here, we show evidence for type III transforming growth factor-beta receptor (TGFBR3) as a novel biomarker expressed in a subset of patients with membranous lupus nephritis. Methods: We utilized mass spectrometry for protein discovery through enrichment of glomerular proteins by laser capture microdissection and through elution of immune complexes within MLN biopsies. Co-localization with IgG within glomerular immune deposits from patients and disease controls was evaluated by confocal microscopy. Immunostaining of consecutive case series was used to determine the overall frequency in MN and MLN. Results: TGFBR3 was found to be enriched in glomeruli and co-immunoprecipitated with IgG within a subset of MLN biopsies by mass spectrometry. Staining of consecutive MN cases without clinical evidence of SLE did not show TGFBR3 expression (0/104), but showed a 5.5% prevalence in MLN (11/199 cases). TGFBR3 co-localized with IgG along the glomerular basement membranes in TGFBR3-associated MN, but not in control cases. Conclusions: Positive staining for TGFBR3 within glomerular immune deposits represents a distinct form of membranous nephropathy, substantially enriched in membranous lupus nephritis. A diagnosis of TGFBR3-associated MN can alert the clinician to search for an underlying autoimmune disease.