Glomerulonephritis with severe nephrotic syndrome induced by immune complexes composed of galactose-deficient IgA1 in primary Sjögren’s syndrome: a case report

Background Primary Sjögren’s syndrome (pSS) is an auto-immune disease characterized by sialadenitis and dacryoadenitis with lymphoplasmacytic cell infiltration. In pSS, not only sicca symptoms, but also extra-glandular involvement induced by immune abnormalities based on pSS occurs. Renal involvement is one such important life-threatening extra-glandular involvement. Although the aberrant glycosylated IgA in pSS as a product of over-activated B cells is a risk factor of renal involvement, its association has not been clarified. Here we report a case of glomerulonephritis (GN) induced by immune complexes (IC) composed of galactose-deficient IgA1 (Gd-IgA1) in a patient with pSS. Case presentation A 48-year-old Japanese woman with pSS was admitted to our hospital because of a two-month history of nephrotic syndrome. Seven years before she had been diagnosed with pSS from keratoconjunctivitis sicca, elevation of serum anti-Ro/SSA antibody titer and lymphoplasmacytic cell infiltration around salivary ducts of the small salivary glands. Renal biopsy revealed diffuse bubbling appearance in glomerular basement membrane (GBM) with scarce mesangial proliferation. Immunofluorescence showed granular IgA, C3 and Gd-IgA1 staining of GBM. Light chain staining showed no monoclonality. Electron microscopy showed electron dense deposits mainly in the intra-membranous and paramesangial areas and slightly in the subepithelial area. Additional serum analysis confirmed elevation of Gd-IgA1 (13.5 μg/mL), which was comparable with that seen in IgA nephropathy, and qualitative enzyme-linked immunosorbent assay of IgA-containing circulating immune complex (IgA-CIC) was positive. Thus, we diagnosed GN induced by IC composed of Gd-IgA1. Furthermore, retrospectively performed immunofluorescence of the small salivary gland evaluated at the diagnosis of pSS showed positive Gd-IgA1 staining of infiltrating lymphoplasmacytic cells. Therefore, we concluded that Gd-IgA1 produced by over-activated B cells in pSS formed circulating IC and thereby induced GN. After induction therapy with high dose prednisolone and mycophenolate mofetil, the nephrotic syndrome remitted within 3 weeks, the serum Gd-IgA1 level decreased to the normal range (3.8 μg/mL), and serum IgA-CIC disappeared in the 6th month after induction therapy. Conclusions Our findings clearly demonstrate an association between aberrant glycosylated IgA and the renal involvement seen in pSS, thereby helping to clarify the renal significance of aberrant glycosylated IgA in pSS.


Background
Primary Sjögren's syndrome (pSS) is an auto-immune disease characterized by sialadenitis and dacryoadenitis with lymphoplasmacytic cell infiltration. The appearance of aberrant glycosylated immunoglobulins based on B cell over-activation in pSS patients has been described, [1] but the nature of its pathogenic role and association with extra-glandular involvement have not yet been fully determined.
Renal involvement is one of the life-threatening extraglandular manifestations and presents various forms such as tubulointerstitial nephritis, membranoproliferative glomerulonephritis (GN), mesangial proliferative GN, membranous nephropathy (MN) and rarely IgA nephropathy (IgAN) [2]. Glomerular lesions in particular are often associated with cryoglobulinemia and a worse prognosis.
We report here one pSS patient with GN induced by immune complexes (IC) composed of galactose-deficient IgA1 (Gd-IgA1) presenting nephrotic syndrome (NS). Additional investigation of Gd-IgA1 revealed both its origin in a glandular lymphoplasmacytic lesion associated with pSS and its pathogenicity as a component of circulating IC which contributed to the activity of NS. In addition, the atypical form of Gd-IgA1 deposition encountered here highlights the possibility that the Gd-IgA1 of pSS and IgAN may exhibit some clinically significant differences.

Case presentation
A 48-year-old Japanese woman was admitted to hospital because of a two-month history of NS. Seven years before admission, she had been diagnosed with pSS from keratoconjunctivitis sicca, elevated serum anti-Ro/SSA antibody titer and lymphoplasmacytic cell infiltration around salivary ducts of the small salivary glands. At no time had she developed any extra-glandular manifestations. Although anti-nuclear antibodies were positive with a speckled pattern, no signs/symptoms satisfied the classification criteria of systemic lupus erythematous. Although a persistently elevated serum IgA level (400-500 mg/dL) was noted, she had no history of macrohematuria accompanied by upper-airway infection. In addition, there was no evidence of hypocomplementemia, cryoglobulinemia or M-protein. She had no pertinent family history, medication use, smoking or alcohol consumption habit, or occupational history.
Two months before admission, she noticed gradually appearing symmetric pedal edema. Urinalysis revealed 6.7 g/day urinary protein but no glomerular hematuria or cellular casts. On admission, her general appearance and vital signs were stable. She had no fever or malaise, and a good appetite. Her height was 152.6 cm, and weight was 45.9 kg, representing a gain of 5 kg from baseline. Physical examination showed no significant findings except for pitting edema in the bilateral lower limbs. Blood tests showed hypoalbuminemia (2.2 mg/dL) with normal kidney function (serum creatinine 0.64 mg/ dL). No electrolyte imbalance was noted.
Renal biopsy showed 11 glomeruli, one of which showed global sclerosis. In the other glomeruli, diffuse bubbling appearance in the glomerular basement membrane (GBM) and slight mesangial proliferation were confirmed (Fig. 1a). There were no crescents, endocapillary proliferation, double contour of GBM, interstitial nephritis or vasculitis. Immunofluorescence (IF) revealed granular IgA and C3 deposition in GBM ( Fig. 1b and c) but was negative for IgG. Light chain staining indicated no monoclonality. Anti-human Gd-IgA1 antibody (KM55) (Immuno-Biological Laboratories, Cat. No.:10777) staining was significantly positive in GBM with a granular pattern (Fig. 1d). In electron microscopy, a few electron dense deposits located in the subepithelial area, and more so in intra-membranous and paramesangial lesions accompanied diffuse GBM thickening ( Fig. 1e and f). Diffuse podocyte foot process effacement was also observed. Screening for secondary MN showed no evidence of neoplasms or infection of hepatitis B virus, hepatitis C virus or human immunodeficiency virus. Additional serum analysis confirmed an elevated Gd-IgA1 level (13.5 μg/mL), comparable to that seen in IgAN, [3] and qualitative enzyme-linked immunosorbent assay (ProGen Biologics, Cat. No.:IC-003) of IgA-containing circulating immune complex (IgA-CIC) was positive. Thus, we diagnosed GN induced by IC composed of Gd-IgA1. Furthermore, retrospectively performed immunofluorescence of the small salivary gland evaluated at the diagnosis of pSS showed positive Gd-IgA1 staining of infiltrating lymphoplasmacytic cells (Fig. 2). Therefore, we concluded that Gd-IgA1 produced by over-activated B cells in pSS formed circulating IC and GN.
NS deteriorated rapidly, with the urinary protein elevated to 12 g/day by the 10th day after admission which resulted in nephrotic crisis requiring hemodialysis for 1 week (Fig. 3). Induction therapy with high dose prednisolone (PSL) (1 mg/kg/day) and 1 g/day of mycophenolate mofetil (MMF) were administered on the 17th day, after which the amount of urinary protein reduced dramatically. NS remitted on the 24th day and she recovered baseline renal function by discharge. Five months after discharge, the remission was maintained with 1 g/day of MMF and PSL tapered to 9 mg/day. Moreover, in the 6th month after induction therapy, the serum Gd-IgA1 level decreased to the normal range (3.8 μg/mL), [3] and serum IgA-CIC disappeared.

Discussion and conclusions
Our findings clearly demonstrate an association in pSS between aberrant glycosylated IgA and renal involvement. Although the appearance of aberrant glycosylated immunoglobulin based on B cell over-activation in pSS has been reported, [1,4] its significance remains unclear. The present case may be of help in clarifying the clinical significance of aberrant glycosylated IgA in pSS.
The first salient point of the present case is that IC composed of Gd-IgA1 induced GN in this patient with pSS. Although the pathogenicity of aberrant glycosylated immunoglobulin in pSS has not been clarified as well as Gd-IgA1 has been in IgAN, a few past reports indicate that aberrant glycosylated IgA in pSS is correlated with elevation of serum IgA, existence of circulating IgA-CIC, and renal involvement [1,5,6]. The present case likewise showed a persistently elevated serum IgA and the existence of circulating IgA-CIC, in addition to Gd-IgA1 comparable with IgAN. Gd-IgA1 has been extensively investigated as a specific pathogen inducing IgAN and IgA vasculitis, [3] while some recent reports have documented that other kidney diseases also often show IC composed of Gd-IgA1 in the glomeruli such as lupus nephritis and primary MN [7,8]. Although the frequency and pathogenicity of Gd-IgA1 in pSS are unknown, aberrant IgA in pSS has been reported to be associated with augmentation of sialylated IgA1 and IgA2, as well as reduction of galactosylated IgA1 and IgA2 [4]. In the present case at least, the detection of Gd-IgA1 in lymphoplasmacytic infiltrates implies a causal relation between Gd-IgA1 and pSS, while the rapid remission accompanying reduction of serum Gd-IgA1 level and disappearance of IgA-CIC also imply the pathogenicity of circulating IC composed of Gd-IgA1. In addition, the detection of Gd-IgA1 in glandular lymphoplasmacytic infiltration associated with pSS indicates that various lesions have the possibility to produce Gd-IgA1. In fact, a recent case report of multicentric Castleman's disease with Gd-IgA1 dominant GN supports our contention [9]. In that report, Gd-IgA1 producing plasma cells were detected by anti-Gd-IgA1 staining of lymph nodes. Taken together, glandular Gd-IgA1 secreted by infiltrating lymphoplasmacytes could form IgA-CIC and thereby induce GN in the kidney.
The second noteworthy point is rapid resolution of NS with high dose PSL plus MMF. The treatment of GN as a renal involvement of pSS has not been established and   [13]. They tend to have NS, serum Gd-IgA1 level comparable with IgAN, and a lower frequency of gross hematuria than IgAN. Although these clinical features are similar to those of the present case, our case is quite different because of the scarce mesangial proliferation and granular IgA deposition along the GBM seen. In addition, our case is also different from two previous ones of MN with solitary polyclonal IgA deposits [14,15]. Although they are different from our case in terms of lacking C3 deposition and subepithelialdominant electron dense deposition, it should be noted that polyclonal IgA can pass through GBM and deposit at subepithelial sites.
In conclusion, aberrant glycosylated IgA as a product of immune abnormality in pSS has the potential to induce IC-mediated GN causing severe NS. More reports on similar cases will be required to validate this conclusion.