Excellent Outcome of Tubulointerstitial Nephritis and Uveitis: Case Report and Five-Year Follow-Up

Abstract

Acute tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease usually having a good prognosis. But the recurrence of uveitis and the chronic progression of kidney injury are still main problems. We report a 15-year-old girl with TINU who showed proteinuria, pathological renal change, multiple organ dysfunction, and immune disorders. After 2 months of 1 mg/kg/day corticosteroid therapy, 24-h urine protein, liver function tests, and creatine kinase returned to normal level. In spite of this, steroid was tapered off slowly and small dose of steroid maintenance therapy lasted for 1 year. Her kidney and ocular symptoms did not recur during 5 years of follow-up. We suggest low-dose steroid maintenance therapy to decrease the recurrence of the TINU syndrome.

• tubulointerstitial nephritis and uveitis (TINU)
• uveitis
• recurrence
• steroid maintenance therapy
• follow-up

INTRODUCTION

Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare condition characterized by the concurrence of TINU. It was first described in two patients by Dobrin et al.¹ in 1975 and approximately 200 more cases have been published since then.² As we reviewed, a few reports provide effective protection from recurrence of this disease in eyes and kidneys. This article reports an adolescent girl with TINU who was successfully treated with long-term steroid maintenance therapy.

CASE REPORT

A 15-year-old girl was admitted to our department because of a 4-week history of fatigue, low-grade fever, increased nocturia, and weight loss of 10 kg in 4 weeks. Four weeks before admission, she suffered from an upper respiratory infection that was treated with penicillin. She denied photosensitivity, alopecia, oral or genital ulcers, Raynaud’s phenomenon, arthralgia, or swallowing problems. Her past medical history was unremarkable and recent medical history was negative for toxic agents and other drugs.

On admission, she was 162 cm in height and weighed 54 kg. Her temperature was 37.1°C, pulse rate was 82/min, and her blood pressure was 115/70 mm Hg. The remainder of the physical examination was unremarkable. Laboratory studies showed a white cell count of 14.7 × 10⁹/L, hemoglobin 103 g/L, platelets 326 × 10⁹/L, neutrophils 0.86, lymphocytes 0.11, sodium 141.0 mmol/L, potassium 2.47 mmol/L, calcium 2.02 mmol/L, phosphorus 1.08 mmol/L, total protein 82.3 g/L, globulins 42.5 g/L, glucose 4.56 mmol/L, ALT 124.3 U/L (normal <40), AST 61.9 U/L (normal <37), creatine kinase 536.6 U/L (normal <195), MB isoenzyme creatine kinase 26.8 U/L (normal <24), serum creatinine 130.6 μmol/L (normal <133), and urea nitrogen 5.12 mmol/L (normal <7.14). The patient was breathing ambient air PaO₂ 87.1 mmHg, PaCO₂ 32.5 mmHg, pH 7.385, HCO₃ 19 mmol/L, and BE 6 mmol/L. Erythrocyte sedimentation rate was 55 mm/h and C-reactive protein level was 14.26 mg/L (normal <3). Antinuclear antibody (ANA) 1:40, antineutrophil cytoplasmic antibodies (ANCA), and antibodies to Sm, Ro-52 were positive. Antibodies to SS-A, SS-B, RNP, Jo-1, Scl70, anticardiolipin, HCV, brucella, Chlamydia, Epstein–Barr virus, cytomegalovirus, and toxoplasma were all negative. Rheumatoid factor and hepatitis B surface antigen were also negative. C3 was 0.65 g/L (normal 0.85–1.93), C4 0.18 g/L (normal 0.16–1.47), antistreptolysin O antibody normal, serum IgG 12.7 g/L, IgA 3.24 g/L, and IgM 2.43 g/L. Urinalysis showed specific gravity 1.005, glucose 2.8 mmol/L, protein positive, pH 7.00, erythrocytes 0/high power field (HPF), leukocytes 2-5/HPF. Urinary beta-2-microglobulin was 25.73 mg/L (normal <0.3), N-acetyl glucosamine 28.5 U/L (normal <18.5), 24 h urine protein was 1.34 g/day, and creatinine clearance 58.8 mL/min. Renal sonogram showed normal size kidneys and chest radiographs were normal.

A renal percutaneous biopsy (Figure 1) was performed and acute tubulointerstitial nephritis was demonstrated. The renal interstitium was infiltrated by a significant number of monocytes, lymphocytes and a few plasma cells, and eosinophils. The tubular epithelial cells showed signs of degeneration and regeneration. The changes of the vessels and glomeruli were unremarkable. Immunofluorescence was negative for fibrinogen, immunoglobulins, and complement components on glomerular as well as on tubular structures.

Figure 1.  Renal biopsy with histological staining [(A) hematoxylin–eosin, ×200; (B) periodic acid-Schiff, ×400] revealed massive interstitial infiltration by inflammatory cells mainly composed of lymphocytes and plasma cells. The glomeruli showed a mild mesangial hypercellularity.

Five days after her admission her right eye became red and she complained of discomfort and photophobia. This episode was diagnosed as conjunctivitis. Despite an initial improvement with local antibiotic eye drops, she continued complaining of itching, redness, and decreased vision. Ophthalmological consultation documented the presence of right anterior uveitis.

The patient was therefore diagnosed with TINU syndrome, and the treatment was started with 55 mg/day oral prednisone and prednisone eye drops. She responded very well, and 1 week later an ophthalmological evaluation was completely normal; 24-h urine protein was 0.535 g/day and liver function tests and creatine kinase returned to normal level. After 2 months of 55 mg/day oral prednisone treatment, the results of follow-up urine examinations progressively returned to normal level. The serum creatinine decreased to 72.3 μmol/L and the creatinine clearance increased to 96.8 mL/min. Subsequently, prednisone was reduced by 5 mg every 2 weeks. At 6-month follow-up there was no sign of relapse in the uveitis and ANA, ANCA, and antibodies to Sm, Ro-52 became too negative. Thereafter, oral 5 mg prednisone was continued for the next year and then discontinued. The urinalysis and blood tests were done every 3 months and revealed a normal level.

DISCUSSION

There are no standard diagnostic criteria for TINU so far. Mandeville et al.³ pointed out that a definite diagnosis of TINU syndrome requires histological confirmation or extensive clinical evidence of acute interstitial nephritis and the presence of an anterior uveitis, as evidenced by cell and flare in the anterior chamber on ophthalmologic examination. Our patient has marked clinical features of TIN associated with uveitis; therefore, the diagnosis of TINU syndrome was established. As TINU syndrome is a diagnosis of exclusion, some systemic diseases that can also cause both AIN and uveitis must be ruled out first.⁴ Although our patient showed many immunological abnormalities, such as positive ANA, ANCA, antibodies to Sm, Ro-52, and low complement 3, these findings do not satisfy the criteria for the diagnosis of either lupus or Sjögren’s syndrome. Moreover, all these immunological tests became normal after therapy and remained negative during the 5-year follow-up. Lack of pulmonary findings on chest radiographs and lack of lymphadenopathy do not strongly support the diagnosis of sarcoidosis and Wegener’s granulomatosis.

Early diagnosis of TINU syndrome is challenging because patients with this syndrome present with nonspecific symptoms (such as fever, weight loss, and fatigue) and laboratory findings (elevated erythrocyte sedimentation rate, elevated urinary beta-2-microglobulin, normochromic/normocytic anemia, elevated serum creatinine, and elevated immunoglobulins). Moreover, TIN and uveitis usually do not present at the same time. It has been reported that the uveitis occurs 2 months before the presentation for TIN in approximately one-fifth of the patients, and may occur 8 or more months after the TIN in about 5% of the patients.³ Furthermore, in the early stage of TINU the curative effect with treatment of steroid is usually good, but the prognosis is dissatisfying if the renal pathology progresses to tubulointerstitial fibrosis, so early diagnosis and treatment for patients with TINU is important. It should be emphasized that for a physician, it is important to pay attention to ocular signs in patients with a history of TIN. In our patient, the outcome was excellent for both renal and visual functions.

In many reports, TINU is steroid-responsive but the recurrence is still a prominent problem. Uveitis recurred or followed a chronic course in 56% of patients. Persistent renal dysfunction was reported in 11% of cases and a few patients required renal dialysis.³ Immunotherapy with methotrexate, cyclosporine A, and azathioprine was suggested for the frequent recurrence of ocular involvement.⁵ In another study, cyclophosphamide therapy was used in a patient with TINU syndrome to reduce its recurrence.⁶ In our patient, though proteinuria and all blood tests had already recovered to normal level, 5 mg/day prednisone was continued for the next year. She had no sign of relapse during the following 5 years. For young female, cytotoxic agents are limited because of their impairment of fertility. Long-term oral steroid maintenance therapy may be a choice to reduce the relapse of this sort of patients with TINU. However, it needs further evaluation before it is recommended as a standard therapy for TINU syndrome.