Transforming Growth Factor Beta Receptor 3 (TGFBR3)–Associated Membranous Nephropathy
Tiffany Caza, Samar Hassen, Daniel J. Kenan, Aaron J. Storey, John M. Arthur, Christian Herzog, Rick D. Edmondson, T. David Bourne, Laurence H. Beck, Christopher P. Larsen
Abstract
Abstract Key Points TGF- β receptor 3 (TGFBR3) staining identifies a novel type of membranous nephropathy (MN). TGFBR3-associated MN is enriched in patients with membranous lupus nephritis with similar characteristics as exostosin 1/2- and neural cell adhesion molecule 1–associated MN. Identification of TGFBR3-associated MN should alert the clinician to evaluate for underlying autoimmune disease. Background Membranous lupus nephritis (MLN) comprises 10%–15% of lupus nephritis and increases morbidity and mortality of patients with SLE through complications of nephrotic syndrome and chronic kidney failure. Identification of the target antigens in MLN may enable noninvasive 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 TGF- β receptor (TGFBR3) as a novel biomarker expressed in a subset of patients with MLN. Methods Mass spectrometry was used for protein discovery through enrichment of glomerular proteins by laser capture microdissection and through elution of immune complexes within MLN biopsy specimens. Colocalization 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 coimmunoprecipitated with IgG within a subset of MLN biopsy specimens by mass spectrometry. Staining of consecutive MN cases without clinical evidence of SLE did not show TGFBR3 expression (zero of 104), but showed a 6% prevalence in MLN (11 of 199 cases). TGFBR3 colocalized with IgG along the glomerular basement membranes in TGFBR3-associated MN, but not in controls. Conclusions Positive staining for TGFBR3 within glomerular immune deposits represents a distinct form of MN, substantially enriched in MLN. A diagnosis of TGFBR3-associated MN can alert the clinician to search for an underlying autoimmune disease.