Determination of Primary versus Secondary Membranous Glomerulopathy Utilizing Phospholipase A2 Receptor Staining in Renal Biopsies

Christopher P Larsen; Nidia C Messias; Fred G Silva; Erick Messias; Patrick D Walker

Disclosures

Mod Pathol. 2013;26(5):709-715. 

In This Article

Abstract and Introduction

Abstract

Autoantibody formation directed against phospholipase A2 receptor (PLA2R)1 is the underlying etiology in most cases of primary membranous glomerulopathy. This new understanding of the pathogenesis of primary membranous is in the process of transforming the way the disease is diagnosed. We validated an indirect immunofluorescence assay to examine PLA2R1 in renal biopsies utilizing a commercially available antibody and standard indirect immunofluorescence. Using this assay, we examined a total of 165 cases of membranous glomerulopathy including 85 primary and 80 secondary. We found tissue staining for PLA2R1 to have a sensitivity of 75% (95% CI 65−84%) and a specificity of 83% (95% CI 72−90%) for primary membranous glomerulopathy. Hepatitis C virus was the secondary etiology with the most number of cases staining positive for PLA2R1 (7/11, 64%) followed by sarcoidosis (3/4, 75%) and neoplasm (3/12, 25%). Autoimmune etiologies showed rare PLA2R1-positive staining (1/46, 2%). All cases of secondary membranous glomerulopathy with positive PLA2R1 showed IgG4-predominant staining, which is typically associated with primary membranous glomerulopathy. This IgG4 predominance raises the possibility that these cases are more pathogenically related to primary membranous glomerulopathy than secondary. We present the largest case series to date examining PLA2R1 involvement in membranous glomerulopathy utilizing a technique that is readily adoptable by most renal pathology laboratories.

Introduction

Membranous glomerulopathy is a morphological pattern of glomerular immune complex deposition characterized by widespread subepithelial deposits. There are numerous etiologies for this deposition including autoimmune disease, infection, and cancer. When one of these known etiologies is present the disease is termed 'secondary'. Those cases in which none of these systemic diseases are present have traditionally been termed 'primary' or 'idiopathic' membranous glomerulopathy. It has long been suspected that the pathogenesis of primary membranous glomerulopathy is related to autoantibodies reacting with a podocyte antigen, resulting in in situ formation of immune complexes.[1] The recent work of Beck et al[2] confirmed this hypothesis by showing that most cases of primary membranous glomerulopathy are the result of an autoimmune disease targeting the podocyte antigen phospholipase A2 receptor (PLA2R1).

The recognition of PLA2R1 as the target antigen in patients with membranous glomerulopathy has made it possible to design serological assays that hold promise for the diagnosis and monitoring of membranous glomerulopathy. The presence of PLA2R1 antibodies in the serum has been shown in previous reports to have a sensitivity of 70−82% and a specificity of 89−100%, for the detection of primary membranous glomerulopathy.[2,3] Despite the fact that PLA2R1 serological tests have been described in multiple reports, there are limited data available on the sensitivity and specificity of PLA2R1 staining in the renal tissue. Further, most of the reports to date of immunofluorescence testing for PLA2R1 in tissue use confocal microscopy that is not readily available in most pathology laboratories. One of the largest case series to date detailed PLA2R1 staining in 42 cases of primary membranous glomerulopathy and showed that tissue staining was more sensitive for detection of PLA2R1-associated membranous glomerulopathy than serological testing with sensitivities of 74% and 57%, respectively. No data for specificity were available as only primary cases were included in this study.[4] Another recent report showed better correlation between tissue staining and the serological test, though no sensitivity or specificity data were reported.[5]

We determined the sensitivity and specificity of PLA2R1 tissue staining for detecting primary membranous glomerulopathy in a large renal biopsy series. This is the largest series to date examining PLA2R1 involvement in membranous glomerulopathy. To perform this study, we first validated an immunofluorescence assay for PLA2R1 testing in renal biopsies using a commercially available antibody and standard immunofluorescence.

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