ABSTRACTMembranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. MN is characterized by subepithelial accumulation of immune complexes along the glomerular basement membrane. The immune complexes are composed of immunoglobulin G and a target antigen. PLA2R is the target antigen in approximately 60% of MN cases, and MN is traditionally classified as PLA2R-positive or PLA2R-negative MN. Over the last 7 years, additional target antigens have been identified, which have specific disease associations, distinctive clinical and pathologic findings, and therapeutic implications. The newly discovered target antigens include NELL1, EXT1/EXT2, NCAM1, SEMA3B, PCDH7, FAT1, CNTN1, NTNG1, PCSK6 and NDNF. To group all these antigens into a generic ‘PLA2R-negative’ MN group is imprecise and un-informative. We propose a logical approach for detection of the target antigen which includes (i) currently available serology-based testing to detect anti-PLA2R and anti-THSD7A antibodies; and (ii) kidney biopsy testing to detect the target antigens. Determination of the antigen on kidney biopsy can be done by immunohistochemistry or immunofluorescence studies. Alternatively, laser capture microdissection (LCM) of glomeruli followed by mass spectrometry (MS) can be used to identify a target antigen. LCM/MS has the advantage of being a one-stop test and is particularly useful for detection of rare target antigens. At the current time, while it is possible to detect the newer antigens by immunohistochemistry/immunofluorescence/LCM/MS, serology-based tests to detect serum antibodies to the new antigens are not yet available. It is critical that serology-based tests should be developed not just for accurate diagnosis, but as a guide for treatment. We review the current methodology and propose an algorithm for diagnosis and detection of target antigens in MN that may shape the current practice in the future. Membranous nephropathy (MN) results from accumulation of subepithelial immune complexes along the glomerular basement membrane.PLA2R is the most common target antigen, but newly discovered target antigens have filled the void of PLA2R-negative MN.MN associated with the newly discovered target antigens have distinctive clinical and pathologic findings, treatment and prognostic implications. These include NELL1, EXT1/EXT2, NCAM1, PCDH7, SEMA3B, CNTN1, FAT1, NDNF and PCSK6.Immunohistochemistry/immunofluorescence methodology is currently in use for detecting target antigens in kidney biopsy tissue, although we anticipate laser capture microdissection of glomeruli followed by mass spectrometry will become available soon.Serologic testing is currently available for only detecting antibodies to PLA2R and THSD7A. It is critical that serologic tests become available for detecting antibodies to the newly discovered antigens.
