Tubulointerstitial nephritis and uveitis (TINU) syndrome is an under-diagnosed entity that may in fact be more frequent than originally appreciated. The clinical picture combines features of tubulointerstitial damage and uveitis in the absence of other diseases that may account for these findings. Diagnosing TINU syndrome may be challenging due to the fact that the renal and ocular findings do not necessarily occur concurrently. In addition, the renal disease can be mild and self-limited, so the syndrome might remain unnoticed. On the other hand, the uveitis may be initially mild and asymptomatic. In any event, a high index of suspicion and a close cooperation between nephrologists and ophthalmologists is warranted to prevent potentially serious renal and ophthalmic complications.
Although the association of TINU syndrome with several autoimmune disorders has been recognized, the concurrence with Hashimoto’s thyroiditis has barely been noted in the existing literature. This report describes such a case and may contribute toward a better characterization of the association between TINU syndrome and other autoimmune conditions.
A 16-year-old boy was admitted to the Pediatrics Clinic of the University Hospital of Ioannina, Greece, because of fatigue, anorexia, paleness, fever up to 38.5°C, and weight loss of 6 kg within 3 weeks. His clinical history was only significant for Hashimoto’s thyroiditis, for which he had been treated with thyroxin (175 μg daily) for the past 8 years. He denied medication use other than thyroxin, recent infectious or flu-like diseases, alcohol consumption, smoking, and illicit substance use. His family history included psoriasis in his father and hypothyroidism in his mother and sister.
The patient had a normal build (weight: 60 kg, height: 173 cm) but appeared pale, with normal body temperature and blood pressure of 110/80 mm Hg. Physical examination of the other systems was unremarkable.
The laboratory examination revealed normocytic normochromic anemia with hematocrit 36% (normal: 36% to 43%), hemoglobin 12.1 g/dL (normal: 13 to 14.5 g/dL), 12,380 white blood cells/μL (normal: 4,500 to 13,500/μL), 448,000 platelets/μL (normal: 150,000 to 350,000/μL), high erythrocyte sedimentation rate (85 mm/hour; normal: < 20 mm), and high C-reactive protein (116 mg/dL; normal: < 0.5 mg/dL). High urea (55 mg/dL; normal: 6 to 20 mg/dL) and serum creatinine (1.8 mg/dL; normal: 0.5 to 1.0 mg/dL) levels revealed renal insufficiency. The patient’s thyroid hormone levels were normal because he had been treated with thyroxin, but levels of antithyroid peroxidase antibodies were elevated (> 1,000 IU/mL; normal: < 9 IU/mL). Anti-thyroglobulin antibodies were negative. Urinalysis suggested tubular dysfunction because it revealed aminoaciduria, proteinuria, severe glycosuria with normal blood glucose, and elevated urinary beta-2 microglobulin (9,040 μg/L; normal: 700 to 3,400 μg/dL). Urine cultures were repeatedly negative. Autoimmune markers such as antinuclear antibody, anti-neutrophil cytoplasmic antibody, and rheumatoid factor were negative. Serology for Toxoplasma gondii and hepatitis A, B, and C were negative. IgG and IgM antibodies for herpes virus, Epstein–Barr virus, cytomegalovirus, echo virus, and coxsackie virus were also negative.
Computed tomography of the chest and abdomen ruled out masses and lymph node enlargement. Ultrasound examination of the kidneys documented increased echogenicity of the renal parenchyma with an indistinct cortico-medullary junction in both kidneys.
Because the patient’s clinical and laboratory findings could be attributed to several systemic inflammatory conditions, an ophthalmic evaluation was requested by the attending pediatrician to rule out ocular involvement, despite the fact that the patient denied complaints such as blurring of vision, pain, or ocular hyperemia. Snellen uncorrected visual acuity was 1.25 in both eyes. Slit-lamp examination revealed mild, non-granulomatous anterior uveitis (cells +1) with fine keratic precipitates in the left eye. The intraocular pressure was normal and funduscopy was unremarkable in both eyes. However, at a follow-up visit 2 weeks after admission, anterior non-granulomatous uveitis (cells +1) was also found in the right eye. Funduscopy of both eyes was again unremarkable. At this time, renal biopsy results confirmed the clinical picture of acute interstitial nephritis. The combination of uveitis and interstitial nephritis posed the diagnosis of TINU syndrome.
The patient was given 60 mg/day prednisolone orally with tapering over 4 months and dexamethasone eye drops four times a day. His renal function recovered and remains normal after 2 years of follow-up. A bilateral severe relapse of the anterior uveitis appeared 4 months after the initial attack, while the steroids were being tapered and the patient was receiving a dose of prednisolone 10 mg/day. A less severe relapse occurred 9 months after the initial attack. All recurrences were managed successfully with topical steroids. At the last follow-up visit 2 years following the initial event, both eyes were quiet, with no sign of the preceding uveitis attacks, and visual acuity remained 1.25 in both eyes.
TINU syndrome is a rare clinical entity with approximately 200 reported cases so far.1 Both a male1 and a female2 preponderance has been described. The mean age of presentation is 15 years (range: 9 to 74 years).2,3 The pathophysiology of the syndrome is uncertain but prior infection or the use of medications such as antibiotics or non-steroidal anti-inflammatory drugs have been linked to TINU syndrome.3 Diseases potentially linked to altered autoimmunity such as rheumatoid arthritis, hyperthyroidism, and primary hypoparathyroidism have been reported to occur more frequently in patients with TINU syndrome.4–6 Strong associations with HLA-DRB1*0102, HLA-DRB1*01, HLA-DQA1*01, and HLA-DQB1*05 have also been found.7 HLA-DQB1*05 was identified in our patient.
Our patient had Hashimoto’s thyroiditis and the typical laboratory feature of high anti-thyroid antibody titers (> 1,000 IU/mL). Because the existing literature does not support the association of Hashimoto’s thyroiditis with uveitis, the diagnosis of TINU syndrome is proposed. To our knowledge, this is only the second report in which the TINU syndrome is associated with Hashimoto’s thyroiditis.6 However, cases with TINU syndrome and hyperthyroidism have been described.4
The pathomechanism explaining the concurrence of TINU syndrome with Hashimoto’s thyroiditis is unclear to us. The fact that both the parents and the sister had autoimmune diseases might imply a genetic predisposition for a common immune-related link between nephritis, uveitis, and thyroiditis. On the other hand, the recently described IgG4-related disease could represent a link between certain cases of Hashimoto’s thyroiditis and tubulointerstitial nephritis.8–10 This disease is characterized by lymphoplasmacytic inflammation with IgG4-positive cells and fibrosis in several organs and sites, such as the thyroid, liver, pancreas, and retroperitoneum.8–10 However, our patient did not have IgG4-related disease; this may indicate that although this entity can be implicated in some cases of Hashimoto’s thyroiditis and nephritis, as yet un-identified mechanisms may be responsible in other cases with TINU syndrome or nephritis.
The most common initial symptoms of the TINU syndrome are fever, anorexia, weight loss, fatigue, arthralgias, myalgias, and abdominal pain.11 Our patient had typical laboratory findings indicating tubular renal damage, such as increased urinary beta-2 microglobulin,12 glycosuria with normal blood glucose levels, and aminoaciduria. Renal biopsy confirmed our clinical suspicion of tubulointerstitial nephritis.
The interstitial nephritis usually responds well to steroids and resolves without recurrences. Rarely, immunosuppressive agents such as cyclosporine, methotrexate or azathioprine are needed.3,13 In a few patients, the nephritis may be so difficult to manage that dialysis is needed. The uveitis tends to affect both eyes and usually occurs after the onset of the renal disease, but it can manifest up to 1 month before or up to 14 months after the onset of the renal disease.3 Although the uveitis is typically of the anterior non-granulomatous type, few patients have been reported to have panuveitis with reduction of visual acuity.11 The ocular inflammation usually responds well to topical steroids. If the response to topical therapy is unsatisfactory, oral steroids should be considered. Uveitis tends to relapse in 50% of patients.3,12 The recurrence is usually noted 2 to 3 months after the discontinuation of steroids but it may occur up to 2 years after the initial bout. Importantly, the recurrence tends to be more severe than the initial bout.12 In general, the course of the ophthalmic disease is independent from that of the renal disease. In our case, uveitis developed 2 months after the onset of the systemic symptoms and the first recurrence occurred 4 months later. Notably, the relapse occurred during tapering and before discontinuation of the oral steroids.
The diagnosis of TINU syndrome is one of exclusion because it is based on the presence of both uveitis and acute interstitial nephritis in the absence of other diseases that may cause such ophthalmic and renal manifestations. Clinicians need be aware that TINU syndrome may be under-diagnosed for many reasons.1,3 First, the renal disease is often mild and self-limited and the syndrome may remain unnoticed unless a high index of suspicion is maintained. Moreover, uveitis may not occur simultaneously with the renal disease. Finally, the ophthalmic manifestations of TINU syndrome may be initially mild. For example, our patient did not have any symptoms that would prompt him to visit the ophthalmologist. Had he presented at a later stage, however, the complications of anterior uveitis could have adversely affected his prognosis. Cooperation between ophthalmologists and nephrologists or pediatricians is therefore crucial for early diagnosis and treatment. In addition, because of the frequent recurrences of uveitis, patients with TINU syndrome should be carefully followed up by ophthalmologists. Conversely, ophthalmologists need be reminded that in cases of acute anterior uveitis, urinalysis, and laboratory examination of serum creatinine may reveal renal dysfunction and raise the suspicion of the TINU syndrome.
Our report constitutes the second described case of the concurrence of Hashimoto’s thyroiditis with TINU syndrome. As a consequence, it may contribute to the better characterization and heightened awareness of the association between TINU syndrome and other autoimmune diseases.
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- Paul E, Van Why S, Carpenter TO. Hyperthyroidism: a novel feature of the tubulointerstitial nephritis and uveitis syndrome. Pediatrics. 1999;104:314–317. doi:10.1542/peds.104.2.314 [CrossRef]
- Catalano C, Harris PE, Enia G, Postorino M, Martorano C, Maggiore Q. Acute interstitial nephritis associated with uveitis and primary hypoparathyroidism. Am J Kidney Dis. 1989;14:317–318.
- Hudde T, Heinz C, Neudorf U, Hoeft S, Heiligenhaus A, Steuhl KP. Tubulointerstitial nephritis and uveitis (TINU syndrome): comorbidity and complications in four patients [article in German]. Klin Monbl Augenheilkd. 2002;219:528–532. doi:10.1055/s-2002-33583 [CrossRef]
- Levinson RD, Park MS, Rikkers SM, et al. Strong associations between specific HLA-DQ and HLA-DR alleles and the tubulointerstitial nephritis and uveitis syndrome. Invest Ophthalmol Vis Sci. 2003;44:653–657. doi:10.1167/iovs.02-0376 [CrossRef]
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- Sugimoto T, Tanaka Y, Morita Y, Kume S, Uzu T, Kashiwagi A. Is tubulointerstitial nephritis and uveitis syndrome associated with IgG4-related systemic disease?Nephrology (Carlton). 2008;13:89. doi:10.1111/j.1440-1797.2007.00870.x [CrossRef]
- Weinstein O, Tovbin D, Rogachev B, et al. Clinical manifestations of adult tubulointerstitial nephritis and uveitis (TINU) syndrome. Int Ophthalmol. 2010;30:621–628. doi:10.1007/s10792-010-9369-9 [CrossRef]
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