Transforming Growth Factor Beta Receptor 3 (TGFBR3)-Associated Membranous Nephropathy.

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.
Competing Interests: J. M. Arthur reports serving as a scientific advisor for, or member of, Kidney360; and receiving honoraria from Travere Pharmaceuticals. L. H. Beck reports serving on the advisory boards of Alexion, Genentech, Ionis, and Visterra; serving on the editorial boards of Kidney International Reports and Kidney Medicine; receiving research funding from Pfizer and Sanofi-Genzyme; receiving honoraria from UpToDate, Inc.; and being a coinventor on, and receive royalties related to, the US patent “Diagnostics for Membranous Nephropathy.” D. J. Kenan reports having patents and inventions with EMD Millipore. All remaining authors have nothing to disclose.
(Copyright © 2021 by the American Society of Nephrology.)