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Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN) (ANCA GN) is characterized as a pauci-immune type of crescentic GN. However, several studies have demonstrated the presence of membranous nephropathy (MN) as a rare concomitant pattern of ANCA GN. A granular pattern of myeloperoxidase (MPO) and immunoglobulin G (IgG) deposition along the glomerular basement membrane (GBM) was also observed in patients with MPO-ANCA GN and MN. Furthermore, MPO can be detected within subepithelial electron-dense deposits (EDD) in patients with MPO-ANCA GN accompanied by MN lesions. Although MPO-ANCA GN and MN might be closely related, the clinicopathological characteristics and underlying MPO-ANCA GN with MN development are unknown.
We selected 18 patients with either MPO-ANCA GN with MN, MPO-ANCA GN, or primary MN in the Department of Nephrology and Endocrinology of the National Defense Medical College from January 2011 to January 2023. Among 49 cases of MPO-ANCA positive crescentic GN, 7 were MPO-ANCA GN with MN cases. There were 6 MPO-ANCA GN cases with sufficient glomeruli and without deposition of immune complexes, complement, or EDD. Here, 5 cases of primary MN, which was defined as MN with serological anti-phospholipase A2 receptor (PLA2R) positivity and glomerular PLA2R positivity along the GBM, were present; this also ruled out secondary MN due to malignancy, autoimmune diseases, infections, and medications. The clinical and laboratory information of all cases was obtained from digital medical records. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was performed on laser microdissected glomeruli in all cases. After that, immunohistochemistry (IHC) and immunofluorescence (IF) staining were performed to confirm the LC-MS/MS results. Moreover, we described the clinicopathological features of MPO-associated MN compared with those of MPO-ANCA GN and primary MN.
We detected proteomic MPO and granular capillary MPO deposits in all MPO-ANCA GN with MN cases. Confocal microscopy revealed MPO and IgG colocalization along the GBM. The clinical features of MPO-associated MN are massive proteinuria and severe kidney damage, whereas its pathological features include crescentic GN with subepithelial EDD. Patients with MPO-associated MN had more severe proteinuria, a higher fibrous crescent rate, and a lower MPO-ANCA titer than those with MPO-ANCA GN. Meanwhile, patients with MPO-associated MN had a lower eGFR and less severe proteinuria than those with primary MN.
We identified MPO as the target antigen in MPO-ANCA GN with MN using LC-MS/MS, IHC, IF, and confocal microscopy. MPO-associated MN, a unique type of secondary MN where MPO serves as the causal antigen, is a subset of MPO-ANCA GN with MN. Prolonged periods of MPO-ANCA GN and a low MPO-ANCA titer might be related to MPO-associated MN development.
