Research ArticlesCombined Plasmatic and Tissue Approach to Membranous Nephropathy—Proposal of a Diagnostic Algorithm Including Immunogold Labelling: Changing the Paradigm of a Serum-based ApproachL’Imperio, Vincenzo MD*; Pieruzzi, Federico G. MD†; Sinico, Renato A. MD†; Nebuloni, Manuela MD‡,§; Tosoni, Antonella BSc‡,§; Granata, Antonio MD∥; Santoro, Domenico MD¶; Capelli, Irene MD#; Garozzo, Maurizio MD**; Casano, Stefano BSc*; Smith, Andrew PhD††; Radice, Antonella MD‡‡; Pagni, Fabio MD*,§Author Information *Department of Medicine and Surgery, Pathology, San Gerardo Hospital †Department of Medicine and Surgery, Nephrology Unit ††Department of Medicine and Surgery, Proteomics and Metabolomics Unit, University of Milano-Bicocca, Monza ‡Department of Biomedical and Clinical Sciences L. Sacco §Research Center for Renal Immunopathology, University of Milan, Milan ‡‡Microbiology and Virology Department, San Carlo Borromeo Hospital, Milan, Italy ∥Department of Nephrology, San Giovanni Di Dio Hospital, Agrigento ¶Department of Clinical and Experimental Medicine, University of Messina, Messina #University of Bologna, Nephrology Unit, Sant’Orsola Malpighi Hospital, Bologna **Renal Unit, Santa Marta e Santa Venera Hospital, Acireale, Catania, Italy The study was conducted following the ethical standards stated in the Declaration of Helsinki. The authors declare no conflict of interest. Reprints: Fabio Pagni, MD, Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, Monza 20900, Italy (e-mail: [email protected]). Applied Immunohistochemistry & Molecular Morphology: May/June 2020 - Volume 28 - Issue 5 - p 376-383 doi: 10.1097/PAI.0000000000000753 Buy Metrics Abstract Membranous nephropathy represents the most frequent cause of nephrotic syndrome in the adult, leading to end-stage renal disease in one third of all the patients. In the last years, the discovery of circulating autoantibodies against phospholipase A2 receptor 1 (PLA2R) and thrombospondin type-1 containing 7A domain (THSD7A), shed light on the pathogenesis of idiopathic forms, being responsible for 70% and 3% of all the cases, respectively. These identifications allowed the development of serological and histologic tests to detect autoantibodies and relative targets for diagnostic and prognostic purposes. Rising evidences suggest that serum titer correlates with disease activity and response to therapy. For these reasons, for patients with nephrotic syndrome, a serum-based approach has been proposed, reserving renal biopsy only in cases with doubtful/negative serology. However, the recent introduction of useful criteria for the interpretation of PLA2R/THSD7A immunohistochemistry could lead to high values of sensitivity and specificity for the in situ detection of target antigens. The present multicentric study on a series of membranous nephropathy cases with available serum/histologic correlation will show the importance of the crosstalk among the different techniques, recovering the possible role of electron microscopy in challenging situations. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.