Membranoproliferative glomerulonephritis with predominant IgG2 and IgG3 deposition in a patient with IgG4-related disease

A 70-year-old Japanese woman with a past history of bronchial asthma and paroxysmal atrial fibrillation was transferred to Kyushu University Hospital because of leg edema and insidious onset of proteinuria and microhematuria. She had presented with mild leg edema 8 months before, and was admitted to another hospital because of pneumonia. Then heavy proteinuria was identified. She had a history of polyarthralgia, although other symptoms such as skin rash, hair loss, oral ulcers, and Sicca syndrome were not evident.

On admission, the patient’s characteristics were: height 144 cm, body weight 38.7 kg, body temperature 36.9 °C, and blood pressure 120/46 mmHg. Physical examination revealed normal breath sounds, heart sounds, abdomen and nervous system, but signs of anemia in the palpebral conjunctiva and bilateral leg edema were found. Urinalysis revealed proteinuria (2+), and occult blood (2+). Urinary protein excretion was 2.3 g/day. Complete blood counts revealed: white blood cells 3050/μL, red blood cells 252 × 10⁴/μL, hemoglobin 8.2 g/dL, hematocrit 24.3 %, and platelets, 12.9 × 10⁴/μL, with no atypical leukocytes. Serum biochemical analyses revealed: total protein 6.9 g/dL, serum albumin 3.0 g/dL, blood urea nitrogen 33.0 mg/dL, serum creatinine 1.09 mg/dL (eGFR 43.2 mL/min/1.73 m²), sodium 141 mmol/L, potassium 5.1 mmol/L, chloride 115 mmol/L, calcium 8.3 mg/dL, phosphate 4.9 mg/dL, and C-reactive protein 0.21 mg/dL. Quantitative immunoglobulin analysis showed: IgG 2407 mg/dL (normal, 872–1815 mg/dL), IgA 114 mg/dL and IgM 53 mg/dL (59–269 mg/dL), and the additional measurement of IgG subclasses revealed IgG1 564 mg/dL (320–748 mg/dL), IgG2 1650 mg/dL (208–754 mg/dL), IgG3 214 mg/dL (6.6-88.3 mg/dL), and IgG4 1110 mg/dL (4.8–105 mg/dL). Serum levels of C3, C4 and total serum hemolytic activity (CH₅₀) were 58 mg/dL (71–135 mg/dL), 9 mg/dL (11–34 mg/dL), and 32 U/mL (31.6–57.6 U/mL), respectively. Although rheumatoid factor was increased to 133 IU/mL (<15 IU/mL), antinuclear antibodies, anti-double-stranded DNA antibodies, anti-U1-ribonucleoprotein antibodies, myeloperoxidase anti-neutrophil cytoplasmic antibodies (ANCA), proteinase 3 ANCA, anti-glomerular basement membrane (GBM) antibodies, anti-Sjögren syndrome related antigen (SS)-A antibodies, anti-SS-B antibodies, circulating immune complexes, and cryoglobulins were all negative. Hepatitis B virus surface antigen, hepatitis C virus antibodies, and human T-lymphotropic virus 1 antibodies were negative. T-SPOT.TB assays for the diagnosis of latent tuberculosis was also negative. Abdominal ultrasonography and computed tomography scanning revealed the absence of systemic lymphadenopathy, and no abnormal findings in the pancreas, salivary glands, and thyroid gland, although ultrasonography showed mild enlargement of bilateral kidneys (right 10.3 × 4.4 cm, and left 10.8 × 4.1 cm).

Percutaneous kidney biopsy was performed on the 12th hospital day to determine the cause of the urinary abnormalities and kidney dysfunction. Light microscopic observation revealed global glomerulosclerosis in 1 of 13 glomeruli with mild interstitial edema and inflammation (Fig. 1a). The infiltrating cells were mainly mononuclear cells, but occasional eosinophils and a number of plasma cells were also noted. Storiform interstitial fibrosis was not evident (Fig. 1b). Twelve non-sclerotic glomeruli showed uniform changes; moderate to severe mesangial proliferation, increased mesangial matrix, and mild to moderate endocapillary hypercellularity. Subendothelial deposits (Fig. 1c), and double contours of the glomerular capillaries were also observed (Fig. 1d). No glomerular crescent was found. Immunofluorescence studies showed “full-house” staining for IgG (3+), IgA (1+), IgM (1+), C3 (2+), C1q (3+), and fibrinogen (1+) in the glomerular mesangium and the capillary wall (Fig. 2). Ultrastructural examination showed focal foot process effacement of the glomerular epithelial cells, mesangial and subendothelial electron-dense deposits, and mesangial interposition (Fig. 3). According to these findings, we confirmed the pathological diagnosis of MPGN type 1.

Because the patient showed extremely high serum IgG4, we performed a lip biopsy and found the diffuse infiltration of IgG4 positive plasma cell in the glandular area (Fig. 4a and b); thus, the diagnosis of IgG4-RD was confirmed. Kidney-infiltrating plasma cells also produced IgG4, suggesting focal and early stage IgG4-related kidney disease (IgG4-RKD) (Fig. 4c and d). However, additional immunofluorescence studies revealed predominant deposition of IgG2 and IgG3, negative IgG1, and minimal IgG4 deposition in the glomeruli (Fig. 4e–h).

Although we found discrepancies in IgG subclass among the glomeruli and kidney interstitium, we treated this patient as IgG4-RD. Oral prednisolone administration (initial dose 30 mg/day) was started. The patient showed decreased urinary protein, and increased serum albumin and complement levels. In examinations conducted in our outpatient clinic 8 months later, the patient showed proteinuria (±), hematuria (3+), white blood cell count 9690/μL, hemoglobin 11.4 g/dL, platelet count 32.5 × 10⁴/μL, serum albumin 3.9 g/dL, serum creatinine 0.96 mg/dL, C3 99 mg/dL, C4 23 mg/dL, IgG 1002 mg/dL and IgG4 200 mg/dL (Fig. 5).

Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.