Rare case of exostosin 1/exostosin 2-related membranous lupus nephritis concomitant with dual ANCA- and anti-GBM antibody-associated crescentic glomerulonephritis effectively diagnosed by mass spectrometry: a case report.

Recent developments in mass spectrometry (MS) have revealed target antigens for membranous nephropathy (MN), including phospholipase A2 receptor and exostosin 1/exostosin 2 (EXT1/2). EXT1/2 are known antigens of autoimmune disease-related MN, especially membranous lupus nephritis. We describe the case of an elderly man who developed nephrotic syndrome followed by progressive renal dysfunction. A 78-year-old man presented with rapidly progressive renal dysfunction with proteinuria and hematuria. Three years previously, he had developed leg edema but did not receive any treatment. Laboratory tests showed elevated anti-nuclear antibody (Ab), anti-dsDNA Ab titer, and hypocomplementemia, indicating systemic lupus erythematous. Myeloperoxidase anti-neutrophil cytoplasmic Ab (ANCA) and anti-glomerular basement membrane (GBM) Ab were also detected. The renal pathologic findings were compatible with crescentic glomerulonephritis (GN), whereas non-crescentic glomeruli exhibited MN without remarkable endocapillary or mesangial proliferative change. Immunofluorescence microscopy revealed glomerular IgG, C3, and C1q deposition. All IgG subclasses were positive in glomeruli. Anti-PLA2R Ab in serum was negative. MS analysis was performed to detect the antigens of MN, and EXT1/2 was detected in glomeruli. Therefore, we reached a diagnosis of membranous lupus nephritis concurrent with both ANCA-associated vasculitis and anti-GBM-GN. The simultaneous occurrence of these three diseases is extremely rare. This is the first report of EXT1/2-related membranous lupus nephritis concurrent with ANCA-associated vasculitis and anti-GBM-GN. This case demonstrates the usefulness of MS in diagnosing complicated cases of MN.

Yamazaki T ，Takahashi H ，Takeuchi K ，Sakamoto E ，Tominaga K ，Sakurabayashi S ，Abe T ，Sano T ，Wada Y ，Kuwahara N ，Shimizu A ，Takeuchi Y ... -  《BMC Nephrology》

Lupus-like membranous nephropathy during the postpartum period expressing glomerular antigens exostosin 1/exostosin 2 and phospholipase A2 receptor: a case report.

Recently, several target antigens of membranous nephropathy (MN), such as phospholipase A2 receptor (PLA2R) and exostosin 1/exostosin 2 (EXT1/2), have been discovered. A 30-year-old woman was referred to our hospital with nephrotic range proteinuria and microscopic hematuria. She was first noted to have proteinuria before pregnancy, and her proteinuria worsened in the postpartum period. A renal biopsy showed MN. Immunofluorescence microscopy showed IgG, IgA, IgM, C3, C4, and C1q depositions in the mesangial area and glomerular capillary walls (GCWs). Regarding the IgG subclass, IgG1 and IgG3 were detected on glomeruli. Electron microscopy showed subepithelial electron-dense deposits (EDDs). EDDs were also detected in paramesangial and subendothelial areas. The diagnosis of membranous lupus nephritis (MLN) was suspected, but she did not fulfill the criteria for systemic lupus erythematosus. Neither anti-nuclear antibody nor hypocomplementemia were detected. We further evaluated glomerular EXT1/2 expressions, which were evident on GCWs. In addition, PLA2R was also detected on GCWs, although serum antibody for PLA2R was negative. She responded to immunosuppressive therapy with decreased proteinuria. In the present case, glomerular PLA2R expression implied the possibility of primary MN. However, pathological findings with a full-house staining pattern and glomerular EXT1/2 expressions were very similar to those of lupus-associated MN. Glomerular PLA2R expression appeared not to reflect immunocomplexes of PLA2R and autoantibody when considering the results for glomerular IgG subclass and the absence of serum anti-PLA2R antibody. Collectively, it is plausible that this was a case of a relatively young postpartum female who developed latent MLN rather than primary MN.

Miyasaka R ，Wada Y ，Takeuchi K ，Abe T ，Uchitsubo R ，Kawamura S ，Sakurabayashi S ，Naito S ，Aoyama T ，Shimizu A ，Takeuchi Y ... -  《-》

Exostosin 1/Exostosin 2-Associated Membranous Nephropathy.

In membranous nephropathy (MN), which is characterized by deposition of immune complexes along the glomerular basement membrane (GBM), phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing 7A are target antigens in approximately 70% and 1%-5% of cases of primary MN, respectively. In other cases of primary MN and in secondary MN, the target antigens are unknown. We studied 224 cases of biopsy-proven PLA2R-negative MN and 102 controls (including 47 cases of PLA2R-associated MN) in pilot and discovery cohorts. We also evaluated 48 cases of PLA2R-negative presumed primary MN and lupus MN in a validation cohort. We used laser microdissection and mass spectrometry to identify new antigens, which were localized by immunohistochemistry. Mass spectrometry detected exostosin 1 (EXT1) and exostosin 2 (EXT2) in 21 cases of PLA2R-negative MN, but not in PLA2R-associated MN and control cases. Immunohistochemistry staining revealed bright granular GBM staining for EXT1 and EXT2. Clinical and biopsy findings showed features of autoimmune disease, including lupus, in 80.7% of the 26 EXT1/EXT2-associated MN cases we identified. In the validation cohort, we confirmed that EXT1/EXT2 staining was detected in pure class 5 lupus nephritis (eight of 18 patients) and in presumed primary MN associated with signs of autoimmunity (three of 16 patients); only one of the 14 cases of mixed class 5 and 3/4 lupus nephritis was positive for EXT1/EXT2. Tests in seven patients with EXT1/EXT2-associated MN found no circulating anti-exostosin antibodies. A subset of MN is associated with accumulation of EXT1 and EXT2 in the GBM. Autoimmune disease is common in this group of patients.

Sethi S ，Madden BJ ，Debiec H ，Charlesworth MC ，Gross L ，Ravindran A ，Hummel AM ，Specks U ，Fervenza FC ，Ronco P ... -  《-》

Membranous nephropathy with crescents: a series of 19 cases.

Membranous nephropathy (MN) with crescents is rare and, in the absence of lupus, usually is associated with anti-glomerular basement membrane (anti-GBM) nephritis or antineutrophil cytoplasmic antibody (ANCA)-positive glomerulonephritis. Only rare cases of crescentic MN without ANCA or anti-GBM have been reported. Case series. 19 patients with ANCA- and anti-GBM-negative crescentic MN and no clinical evidence of systemic lupus. Clinical features, kidney biopsy findings, laboratory results, treatment, and follow-up of patients with crescentic MN. Mean age was 55 (range, 5-86) years. All patients presented with proteinuria (mean protein excretion, 11.5 [range, 3.3-29] g/d) and nearly all had hematuria; 16 of 19 (84%) patients had decreased estimated glomerular filtration rates (eGFRs; mean serum creatinine, 2.9 [range, 0.4-10] mg/dL; mean eGFR, 39.7 [range, 4 to >100] mL/min/1.73 m2). Glomeruli showed on average 25% (range, 2%-73%) involvement by crescents. All showed a membranous pattern; 7 showed mesangial and 2 showed segmental endocapillary proliferation. By immunofluorescence, all cases showed granular subepithelial immunoglobulin G (IgG) and κ and λ light chains, and all but one showed C3; 5 showed C1q or IgA. Electron microscopy revealed stages I-III MN; 38% of cases were M-type phospholipase A2 receptor (PLA2R) associated, indicating that at least some were primary MN. Follow-up clinical data were available for all patients (mean, 22 [range, 1.5-138] months). 14 patients received immunosuppressive therapy, and 2, only angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy. 4 patients (21%) progressed to end-stage renal disease, at 0-9 months postbiopsy. Mean serum creatinine level of those without end-stage renal disease at follow-up was 1.7 (range, 0.5-4.1) mg/dL; mean eGFR was 53.3 (range, 16-103) mL/min/1.73 m2. 67% of patients had proteinuria with protein excretion≥1 (mean, 3.2) g/d at follow-up. Retrospective study. Crescentic MN is a rare variant of MN that usually presents with heavy proteinuria, hematuria, and decline in GFR. The prognosis is variable and the disease may respond to therapy, but most patients develop a long-term decline in GFR.

Rodriguez EF ，Nasr SH ，Larsen CP ，Sethi S ，Fidler ME ，Cornell LD ... -  《-》

Myeloperoxidase-antineutrophil cytoplasmic antibody causes different renal diseases by immune-complex formation and pauci-immune mechanism: A case report.

Antineutrophil cytoplasmic antibody (ANCA) has been known to cause pauci-immune crescentic glomerulonephritis. In addition, several reports described membranous glomerulonephritis (MN) concurrent with ANCA-associated glomerulonephritis. Because the two glomerular diseases simultaneously appear in an ANCA-positive patient, the mechanisms whereby ANCA causes the two different glomerular diseases remain ambiguous. Herein, we report a case of 19-year-old man who presented with hematuria, pre-nephrotic proteinuria, and high titer of myeloperoxidase (MPO)-ANCA. The first renal biopsy revealed MN with chronic glomerular scar lesions of unknown etiology. Predominant immunoglobulin (Ig) G1 subclass and negative phospholipase-A2 receptor staining, together with granular-positive glomerular capillary co-localization of MPO and IgG staining, suggested secondary MN due to MPO-MPO-ANCA immune-complex. Five years later, the patient presented with fever, severe renal dysfunction, and alveolar hemorrhage with high titer of MPO-ANCA that indicated pulmonary renal syndrome due to ANCA-associated vasculitis. The second renal biopsy revealed pauci-immune crescentic glomerulonephritis without either apparent MN-lesion or glomerular IgG staining. This is the first reported case showing that MPO-ANCA caused two different glomerular diseases, MN and pauci-immune crescentic glomerulonephritis, in the same patient at the different time points. Our case indicated that common MPO-ANCA might cause different glomerular diseases by different immune mechanisms.

Manabe S ，Hatano M ，Nakano M ，Fujii T ，Nitta K ，Nagata M ... -  《-》