Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies

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 À 84%) and a specificity of 83% (95% CI 72 À 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.

Membranous or membranous‐like GN: A case report of massive proteinuria, positive serum with negative PLA2R on biopsy

“…High titers are correlated to low risk of spontaneous remission and higher risk of the emergence of nephrotic syndrome in non‐nephrotic patients. Diagnostic sensitivity of anti‐PLA2R antibodies was found to be 70.6%, and diagnostic specificity of anti‐PLA2R antibody vs normal and pathological controls was 100% and 94.6%, respectively, as per Radice et al7 In 2013, examining 165 biopsies of primary and secondary membranous, Larsen et al8 reported sensitivity of 75% and a specificity of 83% for primary membranous glomerulopathy on PLA2R staining. Other causes of positive PLA2R biopsy staining were found to have hepatitis C, sarcoidosis (75%), and neoplasm (25%).…”

American Society of Nephrology Quiz and Questionnaire 2014

“…Furthermore, the sensitivity and specificity of this testing for primary MN remain to be defined across all populations. The original report by Beck et al (4) suggested a sensitivity of approximately 75% and a specificity of 100% using a serologic assay; however, subsequent reports have suggested a higher sensitivity combining serum and biopsy testing for anti-PLA 2 R antibodies (11), whereas other studies have reported a low rate of detection of anti-PLA 2 R antibodies in patients with MN with comorbidities typically associated with secondary forms of the disease, including hepatitis C, sarcoidosis, malignancy, and lupus (5,14). Therefore, the most conservative approach is to interpret a positive anti-PLA 2 R antibody test (whether by serum or biopsy staining) as highly consistent with primary MN; conversely, a negative anti-PLA 2 R antibody test denotes either a secondary form of MN or the roughly 20%-25% of primary patients who associate with a different autoantibody.…”

Immunology of membranous nephropathy: from animal models to humans

“…In addition, patients with MN related to sarcoidosis or active hepatitis B may show an increased prevalence of anti-PLA2R antibodies, which suggests that immunological disorders associated with these two diseases might induce or enhance immune response against PLA2R [48,49].…”