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Nephroquiz
(Section Editor: M. G. Zeier)
A dry mouth and oedematous ankle
1 Department of Rheumatology and Clinical Immunology2 Department of Pathology3 Department of Haematology4 Department of Nephrology University Medical Centre Utrecht PO Box 85500 3508 GA Utrecht The Netherlands
A 59-year-old woman, suffering from primary Sjögren's syndrome (pSS) since the age of 48, was treated symptomatically. In 2003 a marginal zone B-cell lymphoma was diagnosed, localized in the mediastinum, producing IgM 
paraproteins. This type of lymphoma is a low grade lymphoma and observation without treatment is legitimate.
In August 2004 she experienced ankle oedema and foamy urine. Physical examination revealed hypertension (170/95 mmHg) and peripheral leg oedema. Laboratory data showed: haemoglobin 7.3 mmol/l, white cell count 7.3x109/l, thrombocytes 603x109/l, serum sodium 133 mmol/l, potassium 4.6 mmol/l, serum creatinine 165 µmol/l (4 months earlier 104 µmol/l), blood urea nitrogen 10.4 mmol/l, albumin 23.2 g/dl, bicarbonate 19.5 mmol/l, calcium 2.12 mmol/l, phosphate 1.6 mmol/l, total cholesterol 8.4 mmol/l, C4 <0.08 g/l, C3 0.62 g/l. Urinary analysis demonstrated 300 erythrocytes/µl of which 45–60% dysmorphic and 25.2 g protein/24 h. In the serum, free light chain paraproteins were detected as well as cryoglobulines at 4 and 20°C, positive for polyclonal IgG and monoclonal IgM . Renal ultrasonography was unremarkable.
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Clinically, a nephrotic syndrome was present and renal biopsy was performed. On light microscopy, the most prominent feature was infiltration of the interstitium by clusters of small B-lymphoid cells, surrounded by lymphoplasmacytoid cells and plasma cells, which were monoclonal for IgM and
(Figure 1). We concluded that the kidney was infiltrated by the known marginal zone B-cell lymphoma, explaining kidney function deterioration in this patient. However, the nephrotic syndrome is not explained by interstitial damage, but is thought to be due to glomerular changes. In total, 11 glomeruli were present in the biopsy specimen, of which three were sclerotic. In the non-sclerotic glomeruli, extensive endo-capillary proliferation with presence of tram tracks was seen (Figure 2); in two glomeruli extracapillary proliferation was also noted. Glomerular basement membranes (GBM) were irregular and contained vacuoles. Double immunofluorescence staining revealed extensive deposits of monoclonal IgM on the subendothelial side and fine granular deposits of polyclonal IgG on the subepithelial side of the GBM (see insets to Figure 2). In conclusion, we demonstrated a marginal zone B-cell lymphoma localized in the renal interstitium, endocapillary proliferation due to subendothelial deposits of IgM , and in addition features of membranous glomerulopathy due to subepithelial polyclonal IgG deposits.
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Primary Sjögren's syndrome and kidney involvement [1,2]
Interstitial nephritis is the most common renal lesion reported in pSS. The clinical presentation is typically hyposthenuria, overt or latent distal tubular acidosis (RTA type I), and less commonly the Fanconi syndrome (RTA type II). RTA may be present in 22–30% of pSS patients. Many of the cases have been latent, but overt clinical manifestations are present in 3–9%. RTA manifestations in pSS patients are observed mostly in young patients early in the course of the disease.
Glomerulonephritis (GN) is much less often present in pSS patients. Subjective and objective sicca manifestations always precede the appearance of GN for years [3]. Strong predicting factors for the development of GN are cryoglobulinaemia and low C4 levels, factors that are also predictors for the development of lymphoma. The pathogenesis of GN in pSS is most probably attributed to subendothelial deposition of immune complexes, which are formed by cryoprecipitating monoclonal IgM rheumatic factors along with polyclonal IgG and IgA, analogous to that observed in renal involvement of hepatitis C-associated mixed monoclonal cryoglobulinemia [4]. This produces a mesangiocapillary reaction pattern, which may lead to both proteinuria and loss of glomerular filtration rate. In our patient besides subendothelial deposits, we also found polycolonal subepithelial deposits of IgG, indicative of membranous glomerulopathy, which has been reported to occur as a paraneoplastic syndrome in patients with lymphoma [4].
Primary Sjögren's syndrome and lymphoma [5]
After correction for age, sex and race, the relative risk for developing lymphoma is 44 times higher in patients with pSS than in the normal control population. Lymphomas associated with pSS are primarily of B-cell origin, and usually express IgM immunoglobulin in the cytoplasm. The majority of lymphomas are marginal zone B-cell lymphomas. The localization is mostly extranodal, involving the salivary glands in 55% of cases, and are then considered as a mucosa associated lymphoid tissue lymphoma. Survival is closely associated with the histological grade of lymphoma. Low-grade lymphomas may remain localized for many years and undergo spontaneous remission without therapy. On the other hand, patients with high and intermediate grade lymphomas have a worse prognosis.
The outcome of pSS patients with glomerulonephritis is diverse [6]. Beneficial response to immunosuppressants (pulse cyclophosphamide and corticosteroids) has been reported, although some patients may progress to end-stage renal disease.
We decided to treat the lymphoma using chlorambucil 1 dd 6 mg and prednisolon 1 mg/kg. Her proteinuria and creatinine levels improved rapidly. After 3 months of therapy, a second renal biopsy was performed, revealing only one interstitial focus of B-cells, which was too small for further immunohistochemical typing, and minimal residual changes of mesangiocapillary glomerulonephritis and membranous glomerulopathy.
This patient with pSS represents one of the rare cases of glomerulonephritis in combination with a renal localization of marginal zone B-cell lymphoma.
Conflict of interest statement. None declared.
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- Skopouli FN. Kidney injury in Sjogren's syndrome. Nephrol Dial Transplant 2001; 16 [Suppl 6]: 63–64
- Goules A, Masouridi S, Tzioufas AG et al. Clinically significant and biopsy-documented renal involvement in primary Sjogren syndrome. Medicine (Baltimore) 2000; 79: 241–249[CrossRef][Medline]
- Daghestani L, Pomeroy C. Renal manifestations of hepatitis C infection. Am J Med 1999; 106: 347–354[CrossRef][Web of Science][Medline]
- Gagliano RG, Costanzi JJ, Beathard GA, Sarles HE, Bell JD. The nephrotic syndrome associated with neoplasia: an unusual paraneoplastic syndrome. Report of a case and review of the literature. Am J Med 1976; 60: 1026–1031[Medline]
- Voulgarelis M, Dafni UG, Isenberg DA, Moutsopoulos HM. Malignant lymphoma in primary Sjogren's syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjogren's Syndrome. Arthritis Rheum 1999; 42: 1765–1772[CrossRef][Web of Science][Medline]
- Goules A, Masouridi S, Tzioufas AG et al. Clinically significant and biopsy-documented renal involvement in primary Sjogren syndrome. Medicine (Baltimore) 2000; 79: 241–249
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