Membranoproliferative glomerulonephritis with predominant IgG2 and IgG3 deposition in a patient with IgG4-related disease

Background IgG4-related disease is a novel disease entity characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. Typical renal pathology is tubulointerstitial nephritis with storiform fibrosis, although the co-existence of various glomerular lesions has been described. Here, we present the first report of a case of IgG4-related kidney disease and membranoproliferative glomerulonephritis showing the discrepancy in IgG subclasses between the kidney interstitium and glomeruli. Case presentation A 70-year-old Japanese woman was diagnosed with membranoproliferative glomerulonephritis and focal tubulointerstitial nephritis with IgG4-positive plasma cells. Immunofluorescence studies revealed predominant deposition of IgG3 and IgG2, but not IgG4 in the glomeruli. We administered oral prednisolone at 30 mg/day, and the abnormalities in urine and blood tests gradually resolved. Conclusion In this case, different patterns of IgG subclasses detected in the glomeruli and interstitial plasma cells suggest overlapping immunologic abnormalities. The favorable clinical course in our patient suggests that steroid therapy is promising in cases of IgG4-related kidney disease accompanied by glomerulonephritis.


Background
IgG4-related disease (IgG4-RD) is a novel disease entity characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. Renal involvement is often observed in this disease, and the typical histopathological findings are tubulointerstitial nephritis with abundant IgG4-positive plasma cells and storiform fibrosis and sclerosis [1]. With regard to the glomerular lesions, membranous nephropathy is the most common type, and can develop with and without tubulointerstitial nephritis [2][3][4]. However, some other forms of glomerulonephritis, such as mesangial proliferative glomerulonephritis, IgA nephropathy, Henoch-Schönlein purpura nephritis (IgA vasculitis), endocapillary proliferative glomerulonephritis, and membranoproliferative glomerulonephritis (MPGN) have also been reported [3][4][5][6][7][8]. In the cases with membranous nephropathy, IgG4 deposition along the glomerular capillaries was demonstrated [8], suggesting that membranous nephropathy shares the same pathogenesis as systemic serological abnormalities and other types of organ involvement. However, the interpretation of the pathogenesis of other types of glomerulonephritis is still unclear.
Here, we report the case of a patient diagnosed with IgG4-RD, complicated with MPGN and accompanied by focal tubulointerstitial nephritis with IgG4-positive plasma cells. We also investigated IgG subclasses in the glomeruli, and found predominant deposition of IgG3 and IgG2, but not IgG4.

Case presentation
A 70-year-old Japanese woman with a past history of bronchial asthma and paroxysmal atrial fibrillation was transferred to Kyushu University Hospital because of leg edema and insidious onset of proteinuria and microhematuria. She had presented with mild leg edema 8 months before, and was admitted to another hospital because of pneumonia. Then heavy proteinuria was identified. She had a history of polyarthralgia, although other symptoms such as skin rash, hair loss, oral ulcers, and Sicca syndrome were not evident.
Percutaneous kidney biopsy was performed on the 12th hospital day to determine the cause of the urinary abnormalities and kidney dysfunction. Light microscopic observation revealed global glomerulosclerosis in 1 of 13 glomeruli with mild interstitial edema and inflammation (Fig. 1a). The infiltrating cells were mainly mononuclear cells, but occasional eosinophils and a number of plasma cells were also noted. Storiform interstitial fibrosis was not evident (Fig. 1b). Twelve non-sclerotic glomeruli showed uniform changes; moderate to severe mesangial proliferation, increased mesangial matrix, and mild to moderate endocapillary hypercellularity. Subendothelial deposits (Fig. 1c), and double contours of the glomerular capillaries were also observed (Fig. 1d). No glomerular crescent was found. Immunofluorescence studies showed "full-house" staining for IgG (3+), IgA (1+), IgM (1+), C3 (2+), C1q (3+), and fibrinogen (1+) in the glomerular mesangium and the capillary wall (Fig. 2). Ultrastructural examination showed focal foot process effacement of the glomerular epithelial cells, mesangial and subendothelial electron-dense deposits, and mesangial interposition (Fig. 3). According to these findings, we confirmed the pathological diagnosis of MPGN type 1.
Because the patient showed extremely high serum IgG4, we performed a lip biopsy and found the diffuse infiltration of IgG4 positive plasma cell in the glandular area ( Fig. 4a and b); thus, the diagnosis of IgG4-RD was confirmed. Kidney-infiltrating plasma cells also produced IgG4, suggesting focal and early stage IgG4-related kidney disease (IgG4-RKD) ( Fig. 4c and d). However, additional immunofluorescence studies revealed predominant deposition of IgG2 and IgG3, negative IgG1, and minimal IgG4 deposition in the glomeruli (Fig. 4e-h).

Discussion
Here, we report the case of a patient diagnosed as IgG4-RD accompanied by MPGN type 1 with "full-house immunofluorescence". We confirmed the diagnosis of IgG4-RD with serological tests and a lip biopsy showing significant infiltration of the glandular area by IgG4positive plasma cells. IgG4-positive plasma cells with little fibrosis were also found in the kidney interstitium,  and the IgG4/IgG ratio exceeded 40 %. We then diagnosed IgG4-RKD equivalent to stage A tubulointerstitial nephritis according to the schema suggested by Yamaguchi et al. [9]. However, the predominant IgG2/IgG3 deposition and minimal IgG4 deposition in the glomeruli conflicted with the systemic serological status, and the pathology of minor salivary glands and kidney interstitium. In this case, the most important differential diagnosis was a proliferative form of lupus nephritis because the patient developed hypocomplementemia and pancytopenia. However, her extrarenal symptoms did not suggest systemic lupus erythematosus (SLE), and laboratory data revealed that she was negative for antinuclear antibodies and anti-DNA antibodies; thus, ultimately, the patient did not fulfill the criteria of SLE.
Renal involvement in IgG4-RD, designated IgG4-RKD, is characterized by increased IgG4-positive plasma cells in the kidney interstitium, and various degrees of storiform fibrosis that can be recognized with methenamine silver and trichrome stains. Several forms of concurrent glomerulonephritis have been reported in IgG4-RKD [3][4][5][6][7][8]. Membranous nephropathy is the most common, and predominant IgG4 deposition along the glomerular capillary has been demonstrated [8], suggesting a common pathophysiology with systemic IgG4 overexpression and related cytokine production. However, in patients with IgG4-RD with other forms of glomerulonephritis, the common pathophysiology between systemic abnormalities and glomerular lesions is less apparent. One case of IgG4-RD and MPGN has been reported previously, but unfortunately, immunofluorescence analysis of IgG subclasses in the glomeruli was not included [5]. Thus, this is the first report of a case of IgG4-RKD and MPGN showing the discrepancy in IgG subclasses between the kidney interstitium and glomeruli.
The immunological abnormalities associated with IgG4-RD have been extensively investigated, and recent studies  [11]. In the present case, predominant deposition of IgG2 and IgG3, but not IgG4 was found in the glomeruli, and immunofluorescence analysis showed that IgG3 deposition predominated. IgG3 is well-known as the typical "Th1 subclass IgG" and associated with primary MPGN [12,13]. In general, Th1 and Th2 cells suppress each other, and polarization toward a Th1 nephritogenic immune response is associated with proliferative, crescentic forms of glomerulonephritis such as MPGN, ANCA-associated glomerulonephritis, and anti-GBM antibody glomerulonephritis, whereas Th2 activation is found in membranous nephropathy [12,14,15]. The renal pathology of the present case revealed co-existence of a Th1associated pro-inflammatory response in the glomeruli, and Th2/Treg-associated changes in the interstitium. Similar phenomena of overlapping different pathologies can be found in the exceptional cases of crescentic membranous nephropathy with or without ANCA [16,17]. Furthermore, in lupus nephritis, co-incidence of class IV and class V glomerular lesions are often found [18]. Further investigations are required to clarify the detailed mechanisms of the co-existence of two different immune responses in the same patient.
With regard to the treatment, we initially started lowdose oral prednisolone (30 mg/day) which was previously reported for the treatment of IgG4-RKD [3,8], Fig. 3 Electron microscopic findings. a Mesangial cell proliferation, mesangial matrix increase and mesangial electron dense deposit, and mesangial interposition (arrow) are noted. Subepithelial deposits were not found in the sampled glomeruli. b Diffuse foot process effacement and subendothelial electron dense deposit (arrowhead) are noted after we had carefully excluded SLE, cryoglobulinemic vasculitis, and monoclonal immunoglobulin deposition disease. Although low-dose steroid monotherapy is not sufficient for primary MPGN type 1, the patient's urinary protein immediately decreased, kidney function was preserved, and serum IgG4 levels showed a gradual decline.
The complement levels and complete blood cell counts also returned to the normal range. In the previous report of MPGN and IgG4-RKD reported by Morimoto et al. [5], the patient died of mycoplasma pneumonia and congestive heart failure a few months after the biopsy confirmation and without receiving corticosteroids. Thus, the favorable clinical course in our case is promising, and it is important to collect information on more cases of IgG4-RKD accompanied by glomerulonephritis to determine the response of such patients to steroid therapy.

Conclusions
We have described the case of a patient with IgG4-RD accompanied by IgG4-related tubulointerstitial nephritis and MPGN with predominant IgG2 and IgG3 deposition. Different patterns of IgG subclasses detected in the glomeruli and interstitial plasma cells suggest overlapping immunologic abnormalities. IgG4-RD is a novel disease entity and the detailed pathophysiology is still unknown; thus, this emphasizes the need to accumulate the details of more cases of IgG4-RKD, and perform IgG subclass staining extensively if glomerular lesions are found in IgG4-RKDs to clarify the nature of this disease.

Consent
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