Immunohistochemical Characteristics of IgG4-Related Tubulointerstitial Nephritis: Detailed Analysis of 20 Japanese Cases

Abstract

Although tubulointerstitial nephritis with IgG4+ plasma cell (PC) infiltration is a hallmark of IgG4-related kidney disease (IgG4-RKD), only a few studies are available about the minimum number of IgG4+ PC needed for diagnosis along with IgG4+/IgG+ PC ratio in the kidney. In addition, the significance of the deposition of IgG or complement as a reflection of humoral immunity involvement is still uncertain. In this study, we analyzed 20 Japanese patients with IgG4-RKD to evaluate the number of IgG4+ PCs along with IgG4+/IgG+ PC ratio and involvement of humoral immunity. The average number of IgG4+ PCs was 43.8/hpf and the average IgG4+/IgG+ or IgG4+/CD138+ ratio was 53%. IgG and C3 granular deposits on the tubular basement membrane (TBM) were detected by immunofluorescence microscopy in 13% and 47% of patients, respectively. Nine patients had a variety of glomerular lesions, and 7 of them had immunoglobulin or complement deposition in the glomerulus. In conclusion, we confirmed that infiltrating IgG4+ PCs > 10/hpf and/or IgG4/IgG (CD138)+ PCs > 40% was appropriate as an item of the diagnostic criteria for IgG4-RKD. A relatively high frequency of diverse glomerular lesions with immunoglobulin or complement deposits and deposits in TBM may be evidence of immune complex involvement in IgG4-related disease.

Figure 1

IgG4-related tubulointerstitial nephritis with membranous glomerulonephritis. (a) Periodic acid methenamine silver (PAM) staining reveals spike and bubbling formation (PAM ×400). (b) Immunofluorescence staining for IgG reveals granular deposits along the glomerular capillary walls (×400). (c) Many IgG4+ plasma cells are seen in the interstitium (IgG4 ×400). (d) Electron microscopy (EM) shows subepithelial deposits and variable reabsorption of these deposits with thickened glomerular basement membrane. (Ehrenreich-Churg stage II–IV).

Figure 2

IgG4-related tubulointerstitial nephritis with Henoch-Schönlein purpura nephritis. (a) Periodic acid-Schiff (PAS) staining reveals severe tubulointerstitial nephritis (PAS ×100). (b) Global endocapillary proliferation is evident (PAS ×400). (c) Immunofluorescence staining for C3 reveals mesangial and capillary wall deposits (×400). (d) Many IgG4+ plasma cells are seen in the interstitium (IgG4 ×400).

Figure 3

IgG4-related tubulointerstitial nephritis with IgA nephropathy. (a) Periodic acid-Schiff (PAS) staining reveals severe tubulointerstitial nephritis (PAS x100). Regional lesion distribution is evident. (b) Segmental mesangial proliferation is seen (PAS ×400). (c) Immunofluorescence staining for IgA reveals bright mesangial deposits (×400). (d) Immunofluorescence staining for C3 reveals weak mesangial staining for C3 (×400).

Figure 4

Anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis. (a) IgG4+ plasma cells surround a glomerulus (IgG4 immunostaining ×400). (b) Accumulation of many IgG4+ plasma cells is seen in the interstitium (IgG4 immunostaining ×400). (c) Many CD138+ cells are seen in the interstitium (CD138 immunostaining ×400). (d) These plasma cells are IgG4 negative (IgG4 immunostaining x400).