A 72-year-old man presented with cervical, axillary, left subclavian, and inguinal lymph nodes (LNs) swelling. The LNs gradually increased in size for 1 month. During this period, the patient often had a low-grade fever and arthralgia. He also experienced a marked weight loss of 7 kg in 3 months. In June 2009, he developed an erythematous rash predominantly on his lower legs and was admitted to the hospital. In 2005, he had developed similar erythematous rashes in the lower extremities several times. In 2006, the patient was diagnosed with Henoch-Schönlein purpura (HSP) on the basis of histological examination of skin biopsy samples, which showed leukocytoclastic vasculitis. Immunohistochemical study with anti-IgA antibody was not performed. A treatment with prednisolone (PSL; 25 mg) had been effective (Figure ). He had no history of allergic diseases such as bronchial asthma, atopic dermatitis, and allergic rhinitis. In 2002, he underwent gastrectomy for gastric cancer.
Figure 1 Clinical course of the patient. Purplish-red spot in the lower extremities as a picture had been developed 3 times in 6 years (downward bald arrow). Hematoproteinuria has been detected since 2006. TP; serum total protein, Alb; serum albumin, PSL; prednisolone. (more ...)
On admission, he was febrile, and the rash was palpable and purpuric in nature. A physical examination showed no abnormalities in the lungs, heart, abdomen, and central nervous system. Laboratory findings showed an increased erythrocyte sedimentation rate (73 mm/h) and the value of C-reactive protein was 0.22 mg/dL. The hemoglobin concentration was 11.0 g/dL, the white blood cell count was 8,900/mm3 (neutrophils 66.8%, lymphocytes 21.5%, monocytes 4.1%, eosinophils 7.0%, and basophils 0.6%), and the platelet count was 45.1 × 104/mm3. Hematuria and proteinuria with granular cast were detected. The results of the serum chemistry analyses are as follows: serum creatinine, 0.96 mg/dL (normal, 0.4-1.2 mg/dL); blood urea nitrogen, 16.7 mg/dL; total serum protein 8.6 mg/dL (normal, 6.5-8.2 g/dL); and serum albumin 3.6 g/dL (normal, 3.7-5.2 g/dL). Serum transaminase, amylase, and lactate dehydrogenase (LDH) levels were within normal limits. The immunological tests were positive for antinuclear antibody at a titer of 80 dil, and the immunofluorescence patterns were speckled and homogeneous. Anti-double-stranded DNA antibody, rheumatoid factor, anti-Sjögren's syndrome A (anti-SS-A), anti-SS-B antibodies, anti-Sm antibody, anti-Jo-1 antibody, and anti-RNP antibody were all absent. The serum level of immunoglobulin G (IgG) was abnormally high, but IgA and IgM were within normal limits (4,359 mg/dL, 242 mg/dL, and 64 mg/dL, respectively). The serum IgE level was elevated (537 U/mL). Molecules of the subclass IgG4 accounted for 25% (1,100 mg/dL) of the IgG molecules. Serum protein electrophoresis revealed polyclonal hypergammaglobulinemia. Serum levels of C3, C4, and total complement hemolytic activity (CH50) were 55 mg/dL (normal, 86-160 mg/dL), 3 mg/dL (normal, 17-45 mg/dL), and less than 12.0 U/mL (normal, 25-48 U/mL), respectively. Myeloperoxidase antineutrophil-cytoplasmic antibody (MPO-ANCA) was detected at a titer 22 EU (normal, <10EU), but proteinase-3 antineutrophil cytoplasmic antibody was not detected. Serologic specimens also tested negative for cytomegalovirus, herpes simplex virus, Epstein-Barr virus, mycoplasma, hepatitis C virus (HCV) antibody, and hepatitis B virus surface (HBs) antigen. The tuberculin skin test was negative for the purified protein derivative. Although several small LNs swelling in the para-aortic and bilateral renal artery branching area were detected in an abdominal CT scan, any abnormal finding was not confirmed in FDG-PET. Chest CT showed no finding such as interstitial pneumonia. Systemic lymphadenopathy, polyclonal hypergammaglobulinemia associated with IgE and IgG4 elevation, hypocomplementemia, and renal dysfunction reminded us of development of IgG4 related disease, and echo-guided percutaneous kidney biopsy was performed on the 7th hospital day. Four out of 28 glomeruli showed global sclerosis, and 2 glomeruli collapsed with periglomerular fibrosis. The other glomeruli showed mild or no mesangial proliferative change. The biopsy revealed interstitial inflammatory cell infiltration, including infiltration of lymphocytes and plasma cells, and concurrent segmental glomerulonephritis (Figure and ). Direct immunofluorescence microscopy revealed apparent positive staining with anti-human IgA (Figure and anti-human IgG antibodies in the mesangium, Complement 3 deposition was also recognized. Anti-human IgG4 antibody staining revealed many positive plasma cells in the interstitium (Figure . The ratio of IgG4-positive plasma cells to IgG-positive plasma cells was more than 50% (data not shown). Electron micrograph revealed numerous electron-dense deposits in the mesangium. Subepithelial electron-dense deposit in the capillary wall was not detected (Figure .
Figure 2 Representative images of the renal biopsy samples. A. Mild mesangial proliferation is observed. (PAS ×200) B. Obvious inflammatory cell infiltration including lymphocytes, plasma cells and eosinophils are found in the interstitium. (PAS ×200) (more ...)
The patient was diagnosed with HSP nephritis that was complicated by IgG4-related TIN. The patient was treated with PSL (30 mg/day) for 14 days, followed by tapering of PSL. As a result of the treatment, the swelling of the LNs decreased, but the patient continued to have persistent hematoproteinuria.