PMC6336600_01
Clinical course. The dotted line indicates serum ALT levels, and the bars indicate the daily urinary protein excretion (g/gCr). Abbreviations: ALT = alanine aminotransferase, HBV = hepatitis B virus, PSL = prednisolone, UP = urinary protein.
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At the time she visited our hospital, laboratory findings were as follows: proteinuria (urinary protein: 8.1 g/gCr), microscopic hematuria (urinary occult blood: 3+, 30 to 49 urinary sediment red blood cells per high-power field [HPF]), and hypoproteinemia (serum total protein: 5.3 g/dL; serum albumin: 2.7 g/dL) (Fig. 1, Table 1). After starting PSL treatment, proteinuria improved to 0.1 g/gCr within 3 months and serum albumin remained normal thereafter (Table 1, Fig. 1). Although HBV DNA in her serum was detected again in 2011 (3.3 Log copies/mL, TaqMan), her urine protein was maintained at <1 g/d for >8 years (Table 1, Fig. 1).
Light microscopy: (upper side, PAS stain; lower side, PAM stain) RBx1: first renal biopsy specimens (A). The glomeruli show large renal corpuscles and MPGN accompanied with PAS-positive deposits, thickening of the glomerular capillary walls, mild increase in mesangial matrix, and mild-to-moderate mesangial hypercellularity. A majority of the glomerular capillary loops demonstrates double contours. PAS stain, x400; PAM stain, x400. RBx2: Second renal biopsy specimens (B). The glomeruli show large renal corpuscles and MPGN accompanied with PAS-positive deposits, thickening of the glomerular capillary walls, moderate increase in mesangial matrix, and mild mesangial hypercellularity. A majority of the glomerular capillary loops demonstrates double contours. PAS stain, x400; PAM stain, x400. RBX3: Third renal biopsy specimens (C). The glomeruli show MPGN without obvious PAS-positive deposits, thickening of the glomerular capillary walls, increase in mesangial matrix, and mesangial hypercellularity. The glomerular capillary loops demonstrate focal double contours. PAS stain, x400; PAM stain, x400. MPGN = membranoproliferative glomerulonephritis, PAM = periodic acid-methenamine-silver, PAS = periodic acid-Schiff, RBx = renal biopsy.
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The first renal biopsy that was performed in March 2008 revealed large renal corpuscles, glomerular hypertrophy and MPGN (Fig. 2A), which was accompanied by focal deposits of HBsAg in the glomerular capillary wall (Fig. 3, bottom left A). LGE/mL), and urinary protein excretion (3.4 g/gCr). Light microscopy showed large renal corpuscles, glomerular hypertrophy, and MPGN accompanied by periodic acid-Schiff (PAS)-positive deposits (Fig. 2B). The third renal biopsy showed remarkable decrease in the activity of HBV-MPGN with a significant decrease in mesangial proliferation and immune complex deposition compared with previous biopsies (Figs. 2-5). On light microscopy, no obvious PAS-positive deposits and no mesangial hypercellularity were observed (Fig. 2C).
Immunofluorescence microscopy: RBx1: First renal biopsy specimens (A). IgM is positive along the capillary loops in a granular pattern (top right, represented by 2+). IgG and IgA are also present but to a lesser intensity (top left, represented by +--1+; top middle, represented by 1+). Moderate glomerular C4d staining is observed along the glomerular capillary loops, represented by +2 (middle right). C3c is weakly present (dead center, represented by +--1+). No C1q is observed in the glomeruli (middle left). Double staining with anti-HBs reagent and IgG showed that the vascular deposits of HBsAg were an integral part of the immunoglobulin and complement deposits (bottom right). These orange-yellow mixtures were resolved into the green fluorescence of HBsAg and the red fluorescence of IgG (bottom left, bottom middle). x400. RBX3: Third renal biopsy specimens (B). No IgM and IgA depositions are observed in the glomeruli (top right and top middle). Weak and granular pattern of IgG deposition is present (top left, represented by +-). Moderate glomerular C4d staining is observed along the glomerular capillary loops, represented by +2 (middle right). Weak and granular pattern of C3c deposition is present (dead center, represented by +--1+). No C1q is observed in the glomeruli (middle left). HBsAg was not detected (bottom left). x400. RBx = renal biopsy.
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IgM, IgA, and C4d were detected along the capillary loops in a granular pattern. IgG and C3c were also present but to a lesser extent (Fig. 3). On immunostaining, the deposition of HBsAg and the corresponding immune complexes in the glomeruli were observed (Fig. 3, bottom side A); HBcAg was not detected. The third renal biopsy showed remarkable decrease in the activity of HBV-MPGN with a significant decrease in mesangial proliferation and immune complex deposition compared with previous biopsies (Figs. 2-5). IgM and IgA in the glomeruli (Fig. 3, top right, and top middle). Immunohistochemical staining with Papanicolaou staining revealed resolution of C5b-9 deposition in the glomeruli (Fig. 4B).
Immunohistochemical staining with Papanicolaou staining: RBx1: First renal biopsy specimens (A). Mild-to-moderate glomerular C5b-9 staining is observed along the glomerular capillary loops (anti-C5b-9). x400. RBX3: Third renal biopsy specimens (B). No C5b-9 staining is observed (anti-C5b-9). x400.
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Immunohistochemical staining with Papanicolaou staining showed mild-to-moderate glomerular C5b-9 expression along the glomerular capillary loops (Fig. 4A). The third renal biopsy showed remarkable decrease in the activity of HBV-MPGN with a significant decrease in mesangial proliferation and immune complex deposition compared with previous biopsies (Figs. 2-5). IgM and IgA in the glomeruli (Fig. 3, top right, and top middle). Immunohistochemical staining with Papanicolaou staining revealed resolution of C5b-9 deposition in the glomeruli (Fig. 4B).
Electron microscopy. RBx1: First renal biopsy specimens (A). The glomeruli show mild foot process fusion of the epithelial cells (represented by 1+). Mesangial interposition is frequently noticed with a marked degree of mesangial proliferation (represented by 3+). Subepithelial (represented by 1+), intramembranous (represented by 2+), and subendothelial (represented by 3+) electron-dense deposits are frequently confirmed, compatible with active MPGN type III. x2500. RBX3: Third renal biopsy specimens (B). The glomeruli show moderate foot process fusion of the epithelial cells (represented by 2+). Old mesangial interposition is noticed with no mesangial proliferation. Subepithelial (represented by 1+), intramembranous (represented by 2+), and subendothelial (represented by 1+) electron lucent-dense deposits are sparsely confirmed, compatible with inactive MPGN type III. x2500.
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MPGN type III (Fig. 5A). Mesangial interposition was frequently observed with a marked degree of mesangial proliferation (3+). The third renal biopsy showed remarkable decrease in the activity of HBV-MPGN with a significant decrease in mesangial proliferation and immune complex deposition compared with previous biopsies (Figs. 2-5). It was compatible with inactive MPGN type III, which showed electron lucent-dense deposits (Fig. 5B).
Liver biopsy. The photomicrographs represent liver tissue stained with hematoxylin-eosin stains. There was slight inflammation and lymphocyte invasion in the portal region. The diagnosis was chronic B-type hepatitis and the grade of severity was A1F0. x100.
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A subsequent liver biopsy demonstrated portal inflammation and changes consistent with mild chronic hepatitis (A1, F0) (Fig. 6).