A 76-year-old Japanese man visited a nephrologist with complaints of edema and dyspnea. He had first been diagnosed with nephrotic syndrome at 38 years old. Nephrotic syndrome had recurred at 57 and 63 years old. With the previous recurrence at 63 years old, he underwent renal biopsy and was diagnosed with MN (Ehrenreich-Churg stage II) with granular deposition of IgG, IgA, and IgM along the capillary wall. After the biopsy, he was treated with oral prednisolone (PSL) at 25 mg/day. Ten days later, the PSL dose was increased to 40 mg/day because urinary protein levels remained elevated. Urinary protein gradually decreased, and the patient achieved remission 3 months later. PSL was tapered and discontinued after 2 years of maintenance treatment. Although immunoglobulin (Ig) levels were not available, the ratio of albumin to globulin was 1.29 (total protein, 7.1 g/dL; albumin, 4.0 g/dL), suggesting that no hyperglobulinemia was present after remission at 65 years old.
During follow-up, edema of the lower extremity and pericardial effusion gradually developed, and he was referred to a cardiologist. Laboratory workup then revealed a recurrence of nephrotic syndrome, and he again consulted a nephrologist. Initially, body temperature was normal with no obvious abnormalities in other vital signs. On physical examination, the patient showed pitting edema of the lower extremities and lymphadenopathy bilaterally in the axillary and inguinal regions. Laboratory data showed massive proteinuria (4.4 g/day) and hypoalbuminemia (1.4 g/day) (Table 1), suggesting nephrotic syndrome without hematuria. Notable findings were newly developed polyclonal gammopathies (IgG, 3,468 mg/dL; IgA, 534 mg/dL; and IgM, 284 mg/dL). Anemia and systemic inflammation were indicated from: hemoglobin, 9.8 g/dL; C-reactive protein, 0.63 mg/dL; and IL-6, 22.1 pg/mL (Reference; <7 pg/mL). Computed tomography (CT) showed multiple lymphadenopathies in the mediastinum, inguinal, and axillary regions. Blood culture, tuberculosis tests, tumor markers, and protein electrophoresis of sera and urine, and autoantibodies all yielded negative results.
 Figure 1 indicates the clinical course of this case. Before administration of PSL to treat nephrotic syndrome, an inguinal lymph node biopsy was performed for a definitive diagnosis. Light microscopy revealed diffuse interfollicular infiltration of plasma cells. Immunohistochemistry revealed CD20-positive lymphocytes in the follicular region and significant CD138-positive plasma cells in the interfollicular region (Figure 2). As hyaline vascular proliferation was not evident, this case presents the plasma cell type of MCD rather than the hyaline-vascular type. Furthermore, additional staining to diagnose malignant lymphoma yielded negative results, and the lack of monoclonality indicated no evidence of deviation in the light chain limitation. Based on polyclonal gammopathy, the pathology of lymphadenopathy, and elevated IL-6, we diagnosed MCD with renal involvement.
Nephrotic syndrome promptly responded to PSL, and proteinuria improved and reached 0.2 g/day by day 14, along with decreases in disease markers of MCD such as IgG, IgA, C-reactive protein, serum IL-6, and plasma vascular endothelial growth factor (VEGF). At the same time, leg edema, and pericardial effusion gradually improved. During the tapering of PSL, proteinuria was transiently elevated, and we performed a renal biopsy to evaluate the activity of renal involvement and the differential diagnosis of primary or secondary MN. The renal specimen contained 12 glomeruli, with global sclerosis in three. No infiltration of inflammatory cells or mesangial cellular proliferation, crescents, or adhesions were noted (Figure 3(a)). Glomerular capillaries were diffusely and globally thickened and periodic acid methenamine silver staining showed spikes and bubbling in basement membranes (Figure 3(b)). Electron microscopy revealed subepithelial and intramembrane deposits of homogenous size estimated as Ehrenreich-Churg stage II late to III, partially with stage IV, and mild subendothelial enlargement (Figure 3(c)). Immunofluorescent investigations showed marked granular deposition of IgG, IgA, and IgM along the glomerular basement membrane, but no staining for complement (Figure 3(d)). We further assessed IgG subclass and revealed positive staining for IgG4, while faintly stained in IgG1 and negatively stained in IgG2 and IgG3 (Figure 3(e)). Regarding antigen-specific antibody staining, deposition of phospholipase A2 receptor (PLA2R) was positive in this case, while any other representative antigen-specific antibodies were not stained (thrombospondin type-1domain-containing 7A, neural epidermal growth factor-like 1 and exostosin-1) (Figure 3(f)). Finally, he was diagnosed with recurrence of primary MN of Ehrenreich-Churg stage II to III coincident with MCD.
At discharge after 6 weeks of hospitalization, we performed a CT to confirm the effect of the lymph node reduction in size throughout the body. The periaortic and lung hilar lymph nodes were reduced in size (Figure 4), as were the lymph nodes in the bilateral axillary and inguinal regions. This case of proteinuria was successfully controlled for 6 months with corticosteroid monotherapy, and proteinuria was kept below 0.5 g/day. However, during the process of tapering PSL to 15 mg/day, the serum IgG titer (bottom; 1,275 mg/dL) began to increase, and at a PSL dose of 7.5 mg/day, urinary protein increased from 0.5 g to 1.9 g, CRP changed from negative to positive (0.33 mg/dL), and polyclonal gammopathy (IgG 2,161 mg/dL, IgA 471 mg/dL, and IgM 445 mg/dL) appeared. The patient was referred to another hospital for induction of anti-IL-6 therapy (Figure 5). Combination therapy with PSL and tocilizumab has successfully decreased concentration of IgG, C-reactive protein, and proteinuria, again.