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Tubulointerstitial nephritis and uveitis (TINU) syndrome is an entity known mainly to the nephrologists. It has similar features to some of the rheumatic diseases, especially Sjögren’s syndrome and lupus. However, many rheumatologists are not familiar with this entity. TINU syndrome should be considered in the differential diagnosis in patients with renal and/or ocular involvement.
A 56 year old woman was referred to the rheumatologist for the evaluation of musculoskeletal pain, positive antinuclear antibody (ANA), and renal failure. She reported diffuse musculoskeletal pain for the past two months, with worsening of these symptoms during the past week. She denied morning stiffness or swelling of the joints. One month ago she also had sore eyes with some redness and was evaluated by an ophthalmologist, who prescribed “eye drops” with good results. She also had dry cough during the past month. Otherwise she had no chronic health problems. She denied dry mouth, photosensitivity, alopecia, oral or genital ulcers, Raynaud’s phenomenon, or swallowing problems. For the musculoskeletal pain she took simple analgesics only. A physical examination showed blood pressure 110/70 mm Hg, and diffuse trigger points without joint swelling. There was no organomegaly or lymphadenopathy. Skin was normal. Sclera and conjunctiva looked normal. Lungs were clear.
Laboratory studies showed a white cell count of 8.7×109/l, haemoglobin 103 g/l, packed cell volume 0.33, platelets 224×109/l, neutrophils 0.66, lymphocytes 0.22, urea 8.3 mmol/l (normal 2.5–6.0), serum creatinine 140 μmol/l (serum creatinine was normal one year ago), sodium 134 mmol/l, potassium 3.8 mmol/l, calcium 2.3 mmol/l, phosphorus 1.00 mmol/l, total protein 77 g/l, globulins 37 g/l, uric acid 150 μmol/l (normal 140–340), glucose 4.8 mmol/l. Liver function tests, prothrombin time, partial thromboplastin time, and fibrinogen were normal. A Coombs test was negative. Erythrocyte sedimentation rate (ESR) (Westergren) was 85 mm/1st h, C reactive protein 570 mg/l (normal 0–50), ANA positive, antibodies to DNA, SS-A, SS-B, RNP, Sm, Jo-1, Scl70, HIV, HCV, glomerular basement membrane, and cardiolipin were all negative. Antibodies to brucella, chlamydia, Epstein-Barr virus, cytomegalovirus, and toxoplasma were negative for acute infection. Rheumatoid factor (RF), hepatitis B surface antigen, and antineutrophil cytoplasmic antibodies (ANCA) were negative also. C3 was 1.4 g/l (normal 0.9–1.8), C4 0.4 g/l (normal 0.1–0.4), antistreptolysin O antibody titre 98 IU/ml (normal 0–200), serum IgG 20.7 g/l (normal 7.00–15.00), IgA 3.47 g/l (normal 1.30–4.00), IgM 3.34 g/l (normal 0.50–2.00). Immunoelectrophoresis was normal. Angiotensin converting enzyme (ACE) level was normal. Urine analysis showed glucose 5.6 mmol/l, protein 250 mg/l, pH 7.0, specific gravity 1.01, erythrocytes 4–6/high power field (hpf), leucocytes 1–3/hpf, granular casts 2–4/hpf, and few epithelial casts. Twenty four hour urine protein was 1.39 g/day, creatinine clearance 0.52 ml/s, Schirmer test 5 mm (during five minutes). Rose bengal staining was negative. Chest radiographs and electrocardiograms were normal.
Repeated tests a few days later disclosed deterioration of kidney functions (creatinine 190 μmol/l) and the patient was admitted to the nephrology department. The patient had a kidney biopsy that showed dense mononuclear infiltrate in the stroma, mainly lymphocytes and plasma cells. Few eosinophils and neutrophils were also seen. Some of the tubuli were damaged. A non-caseating granuloma was seen. About 25% of the stroma was sclerotic. Glomeruli were normal. Immunofluorescence studies showed minimal granular deposition of C3 in the wall of the tubuli but was otherwise negative. An eye examination showed “snowballs” in the vitreous near the inferoposterior part of the retina consistent with intermediate uveitis. The anterior chamber was normal. There was no evidence of vasculitis. Computed tomography (CT) of the chest and pulmonary function tests were normal. A lip biopsy was normal.
The patient was diagnosed with TINU syndrome and treatment was started with 40 mg/d of prednisone. An ophthalmological evaluation one week later was completely normal and serum creatinine was 140 μmol/l. After two months of systemic corticosteroid treatment prednisone was stopped with serum creatinine 120 μmol/l, creatinine clearance 0.86 ml/s, and 24-hour urine protein 0.59 g/day. Three months later the patient was admitted to the ophthalmology department owing to recurrence of intermediate uveitis with similar findings on ophthalmological evaluation as before. Her symptoms of musculoskeletal pain and cough were much less than before. A Schirmer test 6 mm (during five minutes) and a rose bengal test were negative. Complete blood count was normal, creatinine 110 μmol/l, urea 6.4 mmol/l (normal 2.5–6.0), ESR 10 mm/1st h, C3 1.3 g/l, C4 0.2 g/l, RF negative, ANA positive with negative panel. Repeated chest radiographs and ACE level were normal. Spot urine analysis was negative for glucose, ketones, and leucocytes with a pH of 6.0, specific gravity 1.026, and urine protein 300 mg/l. The patient was treated successfully with topical and subtenon corticosteroids.
The findings for our patient do not satisfy the criteria for the diagnosis of either lupus or Sjögren’s syndrome. Lack of pulmonary findings on CT scan and pulmonary function tests, no lymphadenopathy, and skin involvement with normal ACE levels do not strongly support the diagnosis of sarcoidosis. On the other hand, the findings best fit a diagnosis of TINU syndrome.
TINU syndrome was first reported by Dobrin et al in 1975.1 An excellent major review of world publications on TINU syndrome that was published recently identified 133 cases.2 The female:male ratio is nearly 3:1. Initial symptoms occur mostly in adolescence or adulthood but it has also been reported in the elderly. These symptoms/signs include fever, weight loss, fatigue, malaise, anorexia, weakness, and abdominal or flank pain. Seventeen per cent of the patients had arthralgia or myalgia. The most common ocular symptoms are eye pain and redness, decreased vision, and photophobia. The uveitis is usually anterior and bilateral, but all chambers may be affected. It may precede, follow, or occur concomitantly with the renal disease. Proximal and/or distal tubular dysfunction are the prominent features of the tubulointerstitial component of the disease. These patients may also develop mild to severe renal disease. Histologically, there is evidence of acute interstitial nephritis and tubular lesions with or without eosinophils. Non-caseating granulomata could also be seen. The infiltrate is of mononuclear cells, mainly CD4 positive T cells. The pathogenesis of the disease is unknown. It is believed that T cell mediated immunity has an important role. A recently identified autoantibody directed to renal tubular cells3 and hyperglobulinaemia also support a humoral role. Laboratory features of the disease include anaemia, increased ESR, raised C reactive protein, hypergamaglobulinaemia and increased β2 microglobulin in the urine. Some of the patients had positive serology, including ANA,4,5 anti-DNA antibodies,6 RF,1 anticardiolipin antibodies,7 cANCA,8 and low complement.9 The uveitis usually responds to local or systemic steroids, but recurrence or chronicity is not uncommon. The interstitial nephritis also responds favourably to corticosteroids and it may regress spontaneously.
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