Membranous Nephropathy: A Journey From Bench to Bedside

Lessons from an animal model that faithfully resembles human membranous nephropathy (MN) have informed our understanding of the pathogenesis of this organ-specific autoimmune disease and common cause of nephrotic syndrome. After it was established that the subepithelial immune deposits that characterize experimental MN form in situ when circulating antibodies bind to an intrinsic podocyte antigen, it was merely a matter of time before the human antigen was identified. The M-type phospholipase A(2) receptor 1 (PLA(2)R) represents the major target antigen in primary MN, and thrombospondin type 1 domain-containing 7A (THSD7A) was more recently identified as a minor antigen. Serologic tests for anti-PLA(2)R and kidney biopsy specimen staining for PLA(2)R show >90% specificity and 70% to 80% sensitivity for the diagnosis of primary MN in most populations. The assays distinguish most cases of primary MN from MN associated with other systemic diseases, and sequential anti-PLA(2)R titers are useful to monitor treatment response. A positive pretransplantation test result for anti-PLA(2)R is also helpful for predicting the risk for posttransplantation recurrence. Identification of target epitopes within PLA(2)R and the genetic association of primary MN with class II major histocompatibility and PLA2R1 variants are 2 additional examples of our evolving understanding of this disease. (C) 2016 by the National Kidney Foundation, Inc.