Membranous Nephropathy: A Journey From Bench to Bedside

Abstract

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 A2 receptor 1 (PLA2R) 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-PLA2R and kidney biopsy specimen staining for PLA2R 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-PLA2R titers are useful to monitor treatment response. A positive pretransplantation test result for anti-PLA2R is also helpful for predicting the risk for posttransplantation recurrence. Identification of target epitopes within PLA2R 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.

Keywords: M-type phospholipase A(2) receptor 1 (PLA(2)R); Membranous nephropathy (MN); PLA2R1; class II major histocompatibility; epitope; genetic polymorphisms; nephrotic syndrome; organ-specific autoimmunity; post-transplant recurrent disease; thrombospondin type 1 domain-containing 7A (THSD7A).

Figure 1

Immunofluorescence micrographs of kidney biopsy specimens from patients with (A, B) primary membranous nephropathy and (C) membranous lupus nephritis stained for (A) immunoglobulin (Ig) G and (B, C) phospholipase A2 receptor (PLA2R). Note the bright staining for PLA2R in the immune deposits in primary MN but not in lupus MN. Abbreviation: IMN, idiopathic membranous nephropathy.

Figure 2

Comparison of serologic tests for anti–phospholipase A2 receptor (PLA2R) in patients with primary and secondary membranous nephropathy (MN) and other forms of glomerulonephritis (GN). The numbers within the bars represent the number of cases in each group. Results based on data collected by 2 of the authors (LHB, DJS). Abbreviation: WB, western blot; IFA, indirect immunofluorescence assay performed using cells transfected with a recombinant PLA2R-expressing vector; ELISA, enzyme-linked immunosorbent assay.

Figure 3

Schematic representation of the temporal association of serologic tests for anti–phospholipase A2 receptor (PLA2R), tissue staining for PLA2R, and clinical disease activity as represented by proteinuria. The mass of PLA2R within the deposits is represented by the gold-colored trapezoid at the bottom of the graph. Note that tissue staining for PLA2R may precede the appearance of circulating anti-PLA2R antibodies, as the kidney likely acts as a “sink” for these autoantibodies early in the disease. At some point (denoted by an asterisk), the subepithelial PLA2R- and immunoglobulin (Ig) G–containing deposits will cause sufficient podocyte injury to lead to detectable proteinuria, which increases with disease progression. Once anti-PLA2R antibody (α-PLA2R) levels decline and disappear, immune deposits will slowly start to recede, allowing resolution of proteinuria (partial and complete remissions). Note that PLA2R will continue to be detected in tissue well after the circulating antibody disappears.

Figure 4

Schematic of PLA2R structure, showing the sites of polymorphisms associated with primary membranous nephropathy (represented by black dots) and the location of common epitopes identified in Coenen et al (single asterisk) and Svobodova et al (double asterisk). Abbreviations and definitions: CysR, cysteine-rich (ricin B) domain; FnII, fibronectin II-like domain; CTLD, C-type lectin-like domains 1–8; M292V, methionine to valine substitution at amino acid 292; H300D, histidine to aspartate substitution at amino acid 300; G1106S, glycine to serine substitution at amino acid 1,106.