A 70-year-old man with weight loss, dry mouth and renal insufficiency

Teaching Point (Section Editor: K. Ku hn) Bassam Alchi 2 Tamami Sekiguchi 1 2 Soujirou Ogino 1 Shinichi Nishi 0 Satoshi Ito 2 Honami Mori 2 Mitsuhiro Ueno 2 Fumitake Gejyo 2 0 Blood Purification Center, Niigata University Hospital , Niigata , Japan 1 Niigata Rousai Hospital 2 Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medicine and Dental Sciences Correspondence and offprint requests to: Bassam Alchi, 1-757 Asahimachi-dori, Niigata 951-8510, Japan. Email: Introduction Kidney involvement is a frequent extraglandular manifestation of primary Sjo grens syndrome (SS); however, a clinically significant renal impairment as a result of it is rare [1]. We report a patient with primary SS with renal failure, in whom we encountered diagnostic difficulties in ruling out renal lymphoma. Immunopathologic analysis of renal biopsy specimens from this patient showed polytypic interstitial cell infiltration; and his renal failure, caused by severe tubulointerstitial nephritis, responded favourably to oral prednisolone therapy. Case A 70-year-old Japanese man complained of bilateral cervical masses, dry mouth and weight loss starting in June 2000. His past medical history was unremarkable except for 20 years of well controlled hypertension. In May 2001, he was found to have renal dysfunction (serum creatinine 2 mg/dl) and anaemia, and was therefore admitted to the internal medicine department for further work-up. The patient had anorexia and a substantial weight loss ( 17 kg, from 64 to 47) kg over 1 year. His cervical masses had been present since the onset of the disease, but he had no history of local pain or fever. Enlarged submandibular salivary glands and a blood pressure of 100/60 mmHg were found on physical examination, which was otherwise unremarkable. Laboratory tests revealed: serum creatinine 2.7 mg/dl; blood urea nitrogen 38.0 mg/dl; erythrocyte count 2911044 ml; haemoglobin 9.7 mg/dl, with normocytic normochromic erythrocytes; leukocyte count 4400/ml, with a normal differential; and platelet count 16.1104/ml. Serum electrolytes were: sodium 138 mmol/l; potassium 4.9 mmol/l; calcium 8.8 mmol/l; and inorganic phosphorus 3.9 mg/dl. Serum uric acid was 7.7 mg/dl. Urinalysis revealed a specific gravity of 1.015, a pH of 6, normal urinary sediments, and no sugar. Urinary protein excretion was 0.27 g/24 h and creatinine clearance was estimated to be 33 ml/min. Urine N-acetyl-b-D-glucosaminidase (NAG), and b2-microglobulin (beta 2MG) excretions were 2.8 IU/l (normal range 0.69.4 IU/l), and 13 200 ng/ml (normal range 13301 ng/ml), respectively. Arterial blood gas analysis ruled out metabolic acidosis, and liver and pulmonary function tests were normal. The patients total serum protein was 7.6 g/dl, and gammaglobulin was 31.3%. On immunoglobulin electrophoresis, the following values were found: immunoglobulin G (IgG) 2541 mg/l (normal range 8701700 mg/dl), IgA 371 mg/dl (normal range 110410 mg/dl), and IgM 53 mg/dl (normal range 65135 mg/dl) without a monoclonal component. The C-reactive protein level was 0.2 mg/dl, and the erythrocyte sedimentation rate (ESR) 89 mm/h. The anti-nuclear antibody titre was 1:320; the following antibodies were absent: anti-DNA, anti-Sm, anti-RNP, anti-SCL-70, antiJo-1, anti-neutrophil cytoplasm, anti-hepatitis C and the anti-SSA and -SSB. The levels of C3, C4 and CH50 were 40.8 mg/dl (normal range 65135 mg dl), Fig. 1. Abdominal MRI shows multiple hypo-intense areas within the renal parenchyma on axial T2-weighted imaging. 14.6 mg/ dl (normal 1335 mg/dl) and 27.8 U (normal range 2853 U), respectively; the level of the soluble interleukin receptor (sIL-2R) antibody was elevated at 4590 U/ml (normal range 190650 U/ml). A precontrast computed tomography of his abdomen showed both kidneys to be of normal size. Magnetic resonance images (MRI) revealed loss of the renal cortico-medullary junction on T1-weighted images and multiple hypo-intense areas within the parenchyma on T2-weighted images (Figure 1). A Ga-67 scan showed prominent and diffuse accumulation of Ga-67 citrate in both kidneys. At that time, the diagnosis of malignant lymphoma was entertained. Thoracic and abdominal scans failed to show lymph node enlargement. Bone marrow aspiration revealed a hypocellular bone marrow with a nuclear cell count of 2.7104/ml (megakaryocytic count 1/ml), and the myeloid/erythrocytic ratio increased to 6.28 (normal range 23). Neither malignant cells nor an increase in the ratio of lymphocytes were found. In September 2001, an open renal biopsy was performed. On light microscopy of the specimens, the most prominent feature discovered was massive interstitial infiltration with inflammatory cells, composed almost exclusively of mononuclear lymphocytes. Tubular degeneration and atrophy was marked, but tubulitis was mild. No proliferative glomerular changes were present, although 15 out of the 50 examined glomeruli were globally sclerosed. The glomerular basement membrane was wrinkled and thick. The Bowmans capsule was also thick. The vessels were unremarkable except for mild arteriolar hyaline changes compatible with aging. An immunofluorescence study showed IgG, IgA and C3c deposits on the tubular basement membrane, and electron microscopy confirmed the presence of electron-dense deposits on it. Therefore, the renal biopsy was suggestive of severe tubulointerstitial nephritis. Still, lymphoma remained to be excluded. The immuno-histochemistry of the infiltrating mononuclear cells showed the majority of the inflammatory cells to be T lymphocytes (CD3, CD45RO positive), though some (<10%) were B lymphocytes (CD20, CD79 positive) without features of malignancy. The diagnosis of tubulointerstitial nephritis with renal dysfunction was made based on clinical and histopathological findings. After excluding druginduced interstitial nephritis, we suspected the diagnosis of SS. Schirmers test was positive. Technetium99m pertechnetate (TC-99m) scintigraphy of the salivary glands revealed low uptake in the submandibular glands compared with the parotids. A submandibular gland biopsy showed distortion of the ductal pattern by diffuse inflammatory cells and a marked fibrosis. An immunohistochemical study revealed the slight predominance of T lymphocytes (CD45RO positive) over B lymphocytes (CD20 positive) among the cellular infiltrate. Oral steroid therapy (40 mg/day prednisolone) was initiated in September 2001, because of progressive renal insufficiency and severe tubulointerstitial nephritis. Within 2 months of starting that treatment, the patients laboratory findings showed a dramatic improvement in concert with his subjective improvement. As for his renal function, serum creatinine decreased from 3.3 to 1.5 mg/dl and creatinine clearance improved from 15 to 47 ml/min. Proteinuria decreased from 0.34 to 0.09 g/day. His haemoglobin level increased markedly, from 9.1 to 13.7 g/dl, and the ESR returned to normal. Moreov (...truncated)