A 67-year-old woman with severe edema and anuria for 14 days was admitted to our hospital. On admission, she had pitting edema in her lower legs, shifting dullness in her abdomen, which is a sign of ascites, and body weight gained of 2–5 kg. She had an upper respiratory tract infection and hemoptysis at home. Her body temperature was 36.4 °C, her pulse was 80 breaths/minute, and her blood pressure was 164/87 mmHg. Urinalysis revealed 4 + protein with numerous red blood cells in the sediment. Her hemoglobin level was 89 g/L, and her white blood cell count was 15.89 × 109/L, with 87.7% neutrophils, 5.8% lymphocytes, 6.3% monocytes, 0% eosinophils, and 0.2% basophils. Her platelet count was 291 × 109/L. Serum albumin level was 25 g/L. Renal function deteriorated rapidly, and her serum creatinine level was 7.79 mg/dL (normal range 0.7–1.4 mg/dL). Anti-GBM was positive, and the titer was > 200 RU/ml (negative range, less than 9 units). Serum M-type phospholipase A2 receptor antibody (anti-PLA2R) was positive (1:10 positive, indirect immunofluorescence assay). Her C-reactive protein level was 265.02 µg/dl, and her anti-streptolysin-O and anti-streptokinase titers were within normal ranges. Her serum cholesterol was slightly elevated (5.96 mmol/L). Antineutrophil cytoplasmic antibodies (ANCAs) were negative. Tests for anti-nuclear antibody (ANA), double-strand DNA (ds-DNA), extractable nuclear antibody (ENA), anti-SSA, anti-SSB, hepatitis B or C and human immunodeficiency virus were negative. Immunoglobulins (IgG, IgA, and IgM) and C3 and C4 levels were normal. Computed tomography (CT) of the chest revealed lung congestion and exudation. Renal ultrasound revealed that the sizes of both kidneys were normal (right, 10.5 × 4.9 cm; left, 11.4 × 4.7 cm), and the thickness of the cortex in both kidneys was normal (0.8 cm).

Renal biopsy was performed for diagnosis. Light microscopy revealed crescentic glomerulonephritis with 15 of 17 glomeruli showing circumferential cellular crescent formation with fibrinoid necrosis. The glomerular capillary walls had spikes on PAM staining. Diffuse interstitial cell infiltration was observed with moderate tubular degeneration and interstitial fibrosis. Light microscopy pathology indicated the presence of crescentic glomerulonephritis (Fig. 1). Immunofluorescence demonstrated coexistent finely granular and linear depositions of IgG, IgG subclass except IgG4, C3 and κ and λ light chains along the glomerular capillary walls. However, PLA2R and IgG4 staining was granular along the glomerular capillary walls (Fig. 2). Electron microscopy revealed irregularly thickened glomerular basement membranes, rupture of the GBM and subepithelial electron-dense deposits. Podocytes revealed diffuse foot-process effacement and microvillous transformation (Fig. 1).

A Circumferential cellular crescent formation accompanying fibrin deposits (HE × 200). B Transmission electron microscopy image showing diffuse foot process effacement of the podocytes and subepithelial immunocomplex deposits (× 4000)

A Direct immunofluorescence reaction with FITC (fluorescein isothiocyanate)-labeled anti-IgG (note the simultaneous granular and linear staining). B Indirect immunofluorescence reaction with FITC-labeled anti-IgG3 (linear and granular staining). C Indirect immunofluorescence reaction with FITC-labeled anti-IgG4 (granular staining). D Indirect immunofluorescence reaction with FITC-labeled anti-PLA2R (granular staining)

Based on these histological findings, MN stage II with anti-GBM glomerulonephritis was diagnosed. The patient received 10 plasma exchange treatments and a pulse of 500 mg intravenous methylprednisolone for 3 days during the early phase of the disease, followed by an oral prednisolone taper regimen (60 mg/day). After this aggressive treatment, renal function never improved, and the serum creatinine decreased to 4.52 mg/dL. The patient received maintenance hemodialysis therapy during follow-up.

A 70-year-old woman had a high fever with nausea and vomiting for 2 days. She had no history of arthralgia or skin rashes. On admission, swelling of the lower extremities was noted. Her body temperature was 36.2 °C, her pulse was 85 breaths/minute, and her blood pressure was 160/80 mmHg. Urinalysis revealed 3 + for protein with gross hematuria in the sediment. Her hemoglobin level was 74 g/L, and her white blood cell count was 23.03 × 109/L, with 85.2% neutrophils, 8.3% lymphocytes, 6.3% monocytes, 0.1% eosinophils, and 0.1% basophils. Her platelet count was 75 × 109/L. Serum albumin level was 23 g/L. Serum creatinine level was 6.33 mg/dL (normal range 0.7–1.4 mg/dL). Anti-GBM was positive, and the titer was 165.2 RU/ml (negative range, less than 9 units). Anti-PLA2R was positive (1:32 positive, indirect immunofluorescence assay). Her C-reactive protein level was 44.59 µg/dl, and titers of anti-streptolysin-O and anti-streptokinase were within normal ranges. She had no underlying disease. Renal ultrasound revealed that the sizes of both kidneys were normal (right, 9.7 × 4.3 cm; left, 9.8 × 4.5 cm), and the thickness of the cortex in both kidneys was normal (0.8 cm).

Renal biopsy was performed for diagnosis. Light microscopy revealed exudative crescentic glomerulonephritis with cellular to fibro-cellular crescents involving 20 of 26 glomeruli, 6 of which exhibited fibrinoid necrosis. The glomerular capillary walls had spikes and bubbling on PAM staining. Light microscopy pathology indicated the presence of crescentic glomerulonephritis. The immunofluorescence portion of the specimen was near the obliteration of the glomerular tufts. The remnant glomerular basement membranes exhibited intense linear staining for IgG, IgG subclass excluded IgG4 and C3 along the glomerular capillary walls. The κ and λ light chains exhibited the same pattern. PLA2R and IgG4 staining was granular along the glomerular capillary walls. Electron microscopy revealed subepithelial electron-dense deposits with a distribution characteristic of membranous nephropathy involving all examined loops. Podocytes revealed diffuse foot-process effacement and microvillous transformation (Fig. 3). Electron microscopy revealed that the biopsy specimens were stage II MN.

A Circumferential cellular crescent (PASM + HE × 400). B Transmission electron microscopy image of subepithelial immunocomplex deposits (× 2500). C Immunofluorescence (IF) staining showing global linear and granular deposition of IgG on capillary loops. D-E IgG subclass analysis showing positive linear and granular staining of IgG1 (D) and strong granular staining of IgG4 (E) on capillary loops. F IF staining showing global granular staining of PLA2R on capillary loops

Based on these histological findings, the patient was diagnosed as MN stage II with anti-GBM glomerulonephritis. The patient received 5 plasma exchange treatments and pulse intravenous methylprednisolone 240 mg for 3 days, followed by an oral prednisolone taper regimen (50 mg/day). Her serum creatinine decreased to 2.84 mg/dL. The patient developed chronic kidney disease (CKD) stage 3 without hemodialysis.

The patient was a 53-year-old woman who experienced nausea and vomiting for one week. She had a high fever with no history of underlying disease. On admission, her body temperature was 36.9 °C, her pulse was 76 beats/minute, and her blood pressure was 177/82 mmHg. Urinalysis revealed 4 + for protein with microscopic hematuria in the sediment. Her hemoglobin level was 84 g/L, and her white blood cell count was 14.22 × 109/L, with 89.1% neutrophils, 8.3% lymphocytes, 2.4% monocytes, 0% eosinophils, and 0.2% basophils. Her platelet count was 162 × 109/L. Her serum albumin level was 21 g/L. Her serum creatinine level was 13.57 mg/dL (normal range 0.7–1.4 mg/dL). Anti-GBM was positive, and the titer was > 200 RU/ml (negative range, less than 9 units). Anti-PLA2R was positive (1:32 positive, indirect immunofluorescence assay). C-reactive protein level was 93.67 µg/dl, and the titers of anti-streptolysin-O and anti-streptokinase were within normal ranges. She had no underlying disease. Renal ultrasound revealed that the sizes of both kidneys were normal (right, 10.1 × 5.4 cm; left, 10.5 × 4.7 cm), and the thickness of the cortex in both kidneys was normal (1.0 cm).

Renal biopsy was performed for diagnosis. Light microscopy revealed crescentic glomerulonephritis with cellular crescents involving 24 of 31 glomeruli, 22 of which had fibrinoid necrosis. Light microscopy pathology indicated the presence of crescentic glomerulonephritis as case 1 and case 2. Immunofluorescence demonstrated the coexistence of fine granular and linear depositions of IgG, IgG subclass except IgG4, C3 and κ and λ light chains along the glomerular capillary walls. PLA2R and IgG4 staining was granular along the glomerular capillary walls (Fig. 4). Electron microscopy revealed diffuse podocyte foot-process effacement and microvillous transformation in biopsy specimens. Very few mesangial electron-dense deposits were observed, and subendothelial deposits were absent. There was no evidence of an organized substructure within the deposits, and tubulovesicular inclusions were not present.

A IF staining showing global linear and granular deposition of IgG on capillary loops. B IF staining showing positive for IgG3 (global linear and granular deposition) on capillary loops. C-D IF staining showing strong granular deposition for IgG4 (C) and PLA2R (D) on capillary loops

Based on these histological findings, we diagnosed stage II MN with anti-GBM glomerulonephritis. After diagnosis, the patient received 3 plasma exchange treatments and continuous renal replacement treatment. Pulse intravenous methylprednisolone (500 mg) was administered for 3 days during the early phase of the disease, followed by an oral prednisolone taper regimen (60 mg/day). However, renal function never improved, and serum creatinine decreased to 10.18 mg/dL. The patient died of cerebral infarction one week after renal biopsy.

Table 1, Table 2 and Table 3 list the clinical and pathological features of the 3 patients.