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Objective: To describe the clinical and pathological phenotype of membranous nephropathy (MN) associated with M-type-phospholipaseeA 2 -receptor (PLA 2 R), thrombospondin-type-1-domain-containing-7A (THSD7A), semaphorin 3B (SEMA3B), neural-epidermal-growth-factor-like-1-protein (NELL-1), protocadherin 7 (PCDH7), exostosin 1/exostosin 2 (EXT1/EXT2) and neural cell adhesion molecule 1 (NCAM-1) as target antigens. Methods: A retrospective cohort of 270 adult patients with biopsy-proven MN diagnosed between January 2015 and April 2020 was classified as PLA 2 R-, THSD7A-, SEMA3B-, NELL-1e, PCDH7-, EXT1/EXT2-, NCAM-1eassociated or septuple-negative MN using serologic tests, immunostaining, and/or mass spectrometry. Clinical, biochemical, pathologic, and follow-up data were systematically abstracted from the medical records, including disease activity of conditions traditionally associated with MN and occurring within 5 years of MN diagnosis. Results: Patients with PLA 2 R-associated MN were predominantly middle-aged white men without associated disease. The presence of associated disease did not affect the clinical and pathologic characteristics of PLA 2 R-associated MN, suggesting that they were coincidental rather than causally linked. THSD7A-, NELL-1e, PCDH7-, and NCAM-1eassociated MN were rare and SEMA3Bassociated MN was not discovered in our cohort. EXT1/EXT2-associated MN was primarily diagnosed in younger women with active systemic autoimmunity. A significant proportion of septuple-negative patients had associated malignancy or systemic autoimmunity. Conclusion:The widely used distinction between primary and secondary MN has limitations. We propose a refined terminology that combines the target antigen and associated disease to better classify MN and guide clinical decision making.

Background and objectivesKidney biopsy is the current gold standard to diagnose membranous nephropathy. Approximately 70%–80% of patients with primary membranous nephropathy have circulating anti-phospholipase A2 receptor antibodies. We previously demonstrated that in proteinuric patients with preserved eGFR and absence of associated conditions (e.g., autoimmunity, malignancy, infection, drugs, and paraproteinemia), a positive anti-phospholipase A2 receptor antibody test by ELISA and immunofluorescence assay confirms the diagnosis of membranous nephropathy noninvasively. These data have not been externally validated.Design, setting, participants, & measurementsThe clinical and pathologic characteristics of patients with a positive anti-phospholipase A2 receptor antibody test at the Mayo Clinic, the University Hospital Vall D’Hebron (Barcelona), and the Columbia University Medical Center (New York) were retrospectively reviewed. Biopsy findings and presence or absence of a potential associated condition were assessed.ResultsFrom a total of 276 patients with positive anti-phospholipase A2 receptor serology, previously reported patients (n=33), kidney transplant recipients (n=9), pediatric patients (n=2), and patients without kidney biopsy (n=69) were excluded. Among the 163 remaining patients, associated conditions were identified in 47 patients, and 15 patients had diabetes mellitus. All 101 patients of the final cohort had a primary diagnosis of membranous nephropathy on kidney biopsy. In the 79 patients with eGFR≥60 ml/min per 1.73 m2, none of the biopsy findings altered diagnosis or management. Among the 22 patients with decreased eGFR, additional findings included superimposed acute interstitial nephritis (n=1).ConclusionsIn patients with preserved eGFR and absence of associated conditions or diabetes, a positive anti-phospholipase A2 receptor test by either ELISA >20 RU/ml or a positive immunofluorescence assay confirms the diagnosis of membranous nephropathy, precluding the requirement for a kidney biopsy.

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Fibrillary glomerulonephritis (FGN) is a rare glomerular disease. Kidney biopsy is required to establish the diagnosis. Recent studies have identified abundant glomerular deposition of DNAJB9 as a unique histological marker of FGN. We developed an immunoprecipitation-based multiple reaction monitoring method to measure serum levels of DNAJB9. We detected a 4-fold higher abundance of serum DNAJB9 in FGN patients when compared to controls, including patients with other glomerular diseases. Serum DNAJB9 levels were also negatively associated with estimated glomerular filtration rate in patients with FGN. Serum DNAJB9 levels accurately predicted FGN with moderate sensitivity (67%) and with high specificity (98%) and positive and negative predictive value (89% and 95%, respectively). A receiver operating curve analysis demonstrated an AUC of 0.958. These results suggest that serum levels of DNAJB9 could be a valuable marker to predict FGN, with the potential to complement kidney biopsy for the diagnosis of FGN.Kidney International (2019) 95, 1269-1272; https://doi.F ibrillary glomerulonephritis (FGN) is a glomerular disease observed in z1% of native renal biopsies. 1,2 Patients present with proteinuria, hematuria, and impaired renal function. A renal biopsy is required to diagnose FGN. [1][2][3][4] Traditional diagnostic criteria for FGN include the finding, by electron microscopy, of randomly oriented fibrils measuring 10-30 nm in diameter in the mesangium and/or along the glomerular basement membranes. On immunofluorescence, the deposits most commonly stain for IgG, both k and l light chains, and C3. Light microscopy usually reveals mesangial expansion/hypercellularity, with or without duplication of the glomerular basement membranes microscopy. 3 Recently, we 5,6 and others 7 have identified DNAJB9 as a biomarker protein in FGN. Normally, DNAJB9 is localized to endoplasmic reticulum and protects the cells from stress-mediated apoptosis. However, this protein was overly abundant in the extracellular space of FGN glomeruli and absent from glomeruli of healthy controls and a wide variety of non-FGN glomerular diseases (NFGNGDs). 5 Given that FGN is characterized by increased glomerular deposition of DNAJB9, in this study, we measured serum DNAJB9 concentrations in patients with renal disease to assess its potential for distinguishing FGN patients from NFGNGD controls. RESULTSWe wanted to assess whether DNAJB9 has potential as a serum biomarker for FGN. To accomplish this, we developed an immuno-MRM method for measuring serum levels of DNAJB9 in FGN patients and negative controls. FGN patients had significantly higher levels of serum DNAJB9. Multivariate and univariate analyses have suggested that serum DNAJB9 has significant predictive power for FGN. FGN patients have higher serum DNAJB9 levelsFigure 1a 8,9 presents the serum concentrations (expressed in nM) of DNAJB9 in FGN patients and negative controls (normal controls, multiple myeloma patients, NFGNGD patients, and AL patients). FGN patients had significantly hig...