Development of IgG4-related disease in a patient diagnosed with idiopathic membranous nephropathy
A 59-year-old male was hospitalized because of edema of the lower extremities. He had previously been well and had no significant medical history. His serum total protein level was 46 g/L (4.6 g/dL), serum albumin 17 g/L (1.7 g/dL), urinary protein excretion 4.3 g/day without occult blood and the 24-h creatinine clearance was normal at 1.51 mL/s (90.5 mL/min) (Table ). The anti-nuclear antibody was negative, and serum immunoglobulins G, A and M were all within normal limits at 11.98 g/L (1198 mg/dL), 11.37 g/L (1137 mg/dL) and 0.48 g/L (48 mg/dL), respectively. Complement levels were also within normal limits: C3 1.12 g/L (112 mg/dL), C4 0.314 g/L (31.4 mg/dL) and CH50 30 U/mL. Hepatitis-B surface antigen, hepatitis C antibody and cryoglobulin were all negative. Contrast-enhanced computed tomography (CT) demonstrated small, non-specific nodules in the right lung, and a hemangioma of the liver.\nPercutaneous kidney biopsy was performed, and the histology revealed diffuse membranous changes on the glomerular basement membrane without tubulointerstitial lesions (A and B). No mesangial hypercellularity, endocapillary proliferation or glomerular basement membrane duplication was observed. An immunofluorescence study showed diffuse, fine-granular staining of IgG, C3, fibrinogen, kappa- and lambda-chain in the glomerular capillary loops. There were no deposits in other areas including mesangeal matrix, subendothelial aspects and tubular basement membrane. An additional immunofluorescence study of IgG subclasses showed predominant positive staining for IgG4 and IgG1 and weak positive staining for IgG2 and IgG3 in the glomeruli (C). An electron microscopy examination revealed diffuse, homogenous, small electron-dense deposits in the subepithelial aspects of the glomerular basement membrane, which corresponded to Ehrenreich and Churg stage 2. Subendothelial deposits were not present, and endothelial cells did not contain any tubuloreticular structure. The mesangial matrix and tubular basement membrane did not contain electron-dense deposits.\nA systemic work-up revealed no other disease or malignancy, and the patient was diagnosed as having idiopathic MN. Prednisolone was administered at 40 mg daily, but the patient suffered repeated cerebral infarction attacks after starting the therapy. Prednisolone was tapered and discontinued 6 months after the start of the therapy, without any significant effect. The patient's proteinuria persisted at around 3 g/day and he was followed up while receiving diuretics and the angiotensin receptor blocker, olmesartan.\nTwo years after discontinuation of glucocorticoid therapy, the patient developed epigastric discomfort and was hospitalized again. Laboratory examinations revealed elevated serum levels of AST, ALT, ALP, total bilirubin and γ-GTP [64 IU/L, 106 IU/L, 1948 IU/L, 111 μmol/L (6.5 mg/dL) and 1544 IU/L, respectively] accompanied by a slight increase in serum creatinine at 100 μmol/L (1.13 mg/dL) and a normal serum amylase level of 111 IU/L. Abdominal CT revealed swelling of the pancreatic head, dilatation of the main pancreatic duct and stenosis of the common bile duct. Tumor markers including CEA and CA19-9 were all within the normal ranges, while hypergammaglobulinemia was observed and the serum IgG level was elevated at 39.21 g/dL (3921 mg/dL) with marked elevation of IgG4 at 19.2 g/L (1920 mg/dL). The patient was transferred to our hospital because of suspected type 1 autoimmune pancreatitis.\nA physical examination demonstrated jaundice and upper abdominal tenderness. Swelling of the bilateral lacrimal and parotid glands was observed. Hypergammaglobulinemia persisted, and serum IgA, IgM and complement studies showed that all were within normal limits. Serum anti-nuclear antibody was negative, whereas the rheumatoid factor was positive at 120.6 IU/mL. Urinary protein excretion was 2.1 g/day without occult blood and 24-h creatinine clearance was mildly deteriorated at 1 mL/s (60.0 mL/min) (Table ). Excretion of urinary β2-microglobulin (β2-MG) and N-acetyl-β-d-glucosaminidase was markedly elevated at 11 636 μg/day and 25.0 IU/day, respectively. Contrast-enhanced CT showed bronchial thickening in the bilateral lungs, pancreatic swelling with stenosis of the main pancreatic duct and bile duct, bilateral swollen kidneys with multiple lesions exhibiting low attenuation, periaortic and periarterial mass lesions, diffuse swelling of the prostate gland and systemic lymphadenopathy, compatible with the radiologic abnormalities characteristic of IgG4-RD ().\nPercutaneous kidney biopsy was not performed since we could not obtain the patient's agreement. Instead, percutaneous needle biopsies from the pancreas and prostate gland were performed to rule out malignancies and confirm the diagnosis. Specimens obtained by biopsy from the prostate gland and pancreas revealed dense lymphoplasmacytic infiltration with storiform fibrosis and infiltration of numerous IgG4-positive plasma cells (IgG4/ IgG-positive plasma cell ratio >50%) without malignancy ().\nBased on these findings, the patient was definitively diagnosed with IgG4-RD []. Western blot analysis of the patient's serum for the detection of serum autoantibodies against the M-type phospholipase A2 receptor (anti-PLA2R) was performed, as described previously [], and was negative. Oral administration of prednisolone was initiated at 40 mg daily, and the patient's clinical symptoms including jaundice and anorexia improved rapidly. The laboratory data and multiple organ lesions also improved, while proteinuria persisted at around 3 g/day.