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      Is Open Access

      Immunohistochemical Glomerular Expression of Phospholipase A2 Receptor in Primary and Secondary Membranous Nephropathy: A Retrospective Study in an Indian Cohort with Clinicopathological Correlations

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          Abstract

          Background

          Limited published literature exists on the utility and standardization of anti-phospholipase A2 receptor (anti-PLA2R) immunohistochemistry (IHC) for the diagnosis of primary membranous nephropathy (MN). The study aimed to validate anti-PLA2R IHC for the diagnosis of primary MN and clinicopathological correlations in an Indian cohort.

          Methods

          Subjects included patients with primary and secondary MN diagnosed between January 2012 and August 2014 with an adequate renal biopsy and at least 1 year of clinical follow-up. Anti-PLA2R IHC was performed in all cases with miscellaneous renal lesions as controls. Electron microscopy was performed in selected cases. Sensitivity and specificity of anti-PLA2R IHC to identify primary MN was evaluated. Histopathological analyses of primary and secondary MN were done with clinicopathological correlations including serum creatinine, eGFR, chronic kidney disease stage, 24-h urine protein, serum cholesterol, serum albumin, and hypertension at presentation and follow-up, using the Kruskal-Wallis test and Spearman rank correlation. A p value of ≤0.05 was considered statistically significant.

          Results

          In 153 MN patients (99 primary, 54 secondary) and 37 miscellaneous controls, anti-PLA2R IHC differentiated primary from secondary MN with a sensitivity of 70.2% and a specificity of 96.6%. Secondary MN had increased mesangial matrix expansion compared to primary MN ( p = 0.001). Severe nephrotic syndrome, impaired renal function, and hypertension were all more common in primary than in secondary MN.

          Conclusion

          Anti-PLA2R IHC is a specific marker to distinguish primary MN from secondary MN.

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          Most cited references 13

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          PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy.

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            Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy.

            The M-type phospholipase A2 receptor (PLA2R) is the major target antigen in idiopathic membranous nephropathy with detectable autoantibodies in the serum of up to 70% of patients. In retrospective studies, the PLA2R-autoantibody titer in the serum was sometimes negative indicating their measurement alone may be inconclusive. In order to better differentiate between primary and secondary membranous nephropathy, we conducted a prospective study that included 88 patients with a histologic diagnosis of membranous nephropathy. Immunohistochemical analysis for PLA2R was faintly positive in kidneys from normal individuals and patients with various other glomerular injuries. In 61 of the 88 patients, PLA2R expression was strongly positive in glomeruli, and in 60 of these patients PLA2R autoantibodies were also detected in the serum. The 27 patients negative for serum PLA2R autoantibodies were faintly positive for PLA2R staining in glomeruli and in 15 of these patients a secondary cause was found. The remaining 12 patients have a yet undetected secondary cause of membranous nephropathy or have different glomerular antigens other than PLA2R. Thus, increased staining for PLA2R in glomeruli of renal biopsies tightly correlates with the presence of PLA2R autoantibodies in the serum and this may help discriminate between primary and secondary membranous nephropathy.
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              Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy.

              Antibodies against M-type phospholipase A2 receptor (PLA2R) are serological markers of disease activity in patients with idiopathic membranous nephropathy (iMN). To determine the most sensitive test for the diagnosis of PLA2R-related membranous nephropathy (MN) irrespective of sampling time, we investigated the presence of PLA2R in glomerular immune deposits and assessed circulating anti-PLA2R antibodies in a retrospective cohort of Czech patients with idiopathic, lupus and other few secondary MN. We tested archival paraffin-embedded kidney biopsies of 84 consecutive patients with biopsy-proven MN, for the presence of PLA2R in glomerular immune deposits and we measured circulating anti-PLA2R antibodies using the indirect immunofluorescence test, all reagents being commercially available. In 45 of 65 (69%) patients with iMN, PLA2R was detected in a finely granular pattern in sub-epithelial deposits along glomerular capillary loops. Circulating anti-PLA2R antibodies were detected in 20 of 31 (65%) sera from patients sampled during active disease. Six patients with active disease were negative for circulating anti-PLA2R antibodies despite PLA2R antigen positivity in the kidney biopsies. Only 8 of 37 (22%) sera sampled at the time of remission were PLA2R positive while PLA2R antigen was found in 22 of the 37 (59%) corresponding biopsies. PLA2R was found in immune deposits in 3 patients with secondary MN (2 with hepatitis B, and 1 with sarcoidosis) but in none of the 16 patients with lupus. In case of delayed serum sampling, assessment of PLA2R antigen in biopsy specimens is more sensitive than the serological test for the diagnosis of PLA2R-related MN which can be established retrospectively.
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                Author and article information

                Journal
                Nephron Extra
                Nephron Extra
                NNE
                Nephron Extra
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch )
                1664-5529
                Jan-Apr 2017
                9 February 2017
                9 February 2017
                : 7
                : 1
                : 1-9
                Affiliations
                aDepartment of Pathology, Christian Medical College, Vellore, India
                bDepartment of Nephrology, Christian Medical College, Vellore, India
                Author notes
                *Dr. Sanjeet Roy, Department of General Pathology, Christian Medical Hospital, Asha Building, 4th floor, Vellore, Tamil Nadu 632004 (India) E-Mail sanjeetroy06@ 123456gmail.com
                Article
                nne-0007-0001
                10.1159/000453675
                5346929
                Copyright © 2017 by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

                Page count
                Figures: 2, Tables: 3, References: 20, Pages: 9
                Categories
                Original Paper

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