ABSTRACT

Tubulointerstitial nephritis and uveitis syndrome is a rarely seen multi-systemic disease with autoimmune features. Renal and ocular involvement generally occurs asynchronously therefore leads to late diagnosis. Renal manifestations generally precede ocular involvement. Eye disease is almost always of recurrent bilateral anterior uveitis. Renal disease is generally mild, self-limited and rarely requires immunosuppression. Definitive diagnosis is based on histopathological evaluation in the presence of clinical features and exclusion of masquerading disorders. Steroid is the most preferred first line agent, usually suggested for at least 3 to 6 months. Here, our objective with this case report is to attract attention to this uncommon entity in the rheumatology literature.

Introduction

The association between tubulointerstitial nephritis and uveitis (TINU) was firstly described by Dobrin et al.^[1] in two cases presented with similar features, including eosinophilic nephritis, bilateral anterior uveitis, increased sedimentation rate and granuloma formation in the bone marrow. Organ involvement may be variable that kidney precedes the eye in 65% of the patients.^[2] Renal involvement mostly has a mild course with spontaneous improvement. Bilateral granulomatous anterior uveitis is the most common eye involvement, seen approximately in 80 to 90% of patients.^[3] Fever, fatigue, arthralgia may accompany. After excluding mimickers such as sarcoidosis, Sjogren’s syndrome, granulomatosis with polyangiitis (GPA), histopathologic evidence of tubulointerstitial nephritis in a patient with compatible clinical features is mandatory for definitive diagnosis. No treatment guidelines are currently available. Steroids are generally recommended, particularly in the presence of active uveitis and/or renal insufficiency.^[4] Our goal with the report of this case is to increase the awareness of this rare entity among rheumatologists.

Case Report

A 20-year-old man with a previous diagnosis of autoimmune hypothyroidism was admitted to an opthalmology clinic with acute vision loss in both eyes. On ocular examination, the best-corrected visual acuity was 8/10 in the right eye and 7/10 in the left eye. Slit-lamp examination of the right eye was remarkable for granulomatous keratic precipitates, 3⁺ cells in the anterior chamber with fibrinoid reaction. In the left eye, there were 2⁺ cells in the anterior chamber, and the posterior synechiae. A dilated fundus examination revealed a fainted optic disk with increased venous fullness. The patient was consulted due to the differential diagnosis of panuveitis. On admission, systemic rheumatologic questionaire was inconclusive. He reported neither history of recurrent oral ulcers, genital ulcer, osteofollicular lesions, thrombosis, hemoptysis, cough, hearing loss nor the recent medication intake or infectious contact. Laboratory investigations showed an erythrocyte sedimentation rate of 80 mm/h (0-10), C-reactive protein (CRP) of 47 mg/dL (0-5), serum creatinine level of 1.63 mg/dL (0.7-1.20), serum glucose of 80 mg/dL (70-126), serum pH of 7.32, serum bicarbonate (HCO₃) level of 20 mEq/L (22-26), serum potassium of 5.0 mEq/L (3.5-5.3), and urine pH of 6. Hematuria, glycosuria, and mild proteinuria (328 mg/g on spot urine protein/creatinine) were found on urinalysis. Microscopic examination of urine showed eosinophiluria and granular cast, but no dysmorphic erythrocytes. His recent serum creatinine level was 0.8 mg/dL two months ago. Serum complement levels were normal, and anti-nuclear antibody and anti-neutrophilic cytoplasmic antibody (ANCA) tests were negative. All possible infectious causes were excluded and the chest X-ray was normal. Serum angiotensin-converting enzyme (ACE) levels were not studied in our clinic. Renal biopsy revealed interstitial lymphocytic infiltration with focal tubular atrophy and interstitial fibrosis, consistent with acute tubulointerstitial nephritis (ATIN) (Figures 1, 2). Based on the clinical features and histopathologic findings, a diagnosis of TINU syndrome was considered. He was started on high dose methylprednisolone (1 mg/kg/day) due to bilateral panuveitis and renal insufficiency. At the first month visit, eye examination was normal, as well, serum creatinine and acute phase parameters returned to normal reference values. At the fourth month, while receiving 4 mg methylprednisolone, the patient presented with an acute panuveitis attack in the left eye. Therefore, azathioprine (AZA) (2.5 mg/kg/day) was added along with escalating steroid dosage. The patient is currently on AZA without any eye attack in the last 11 months.

Figure 1

Figure 2

Discussion

Uveitis is an inflammatory ocular disease that may lead to vision loss if left untreated. It is well-known that nearly 40% of uveitis is associated with a systemic autoimmune disease.^[5] Therefore, all uveitis cases should be evaluated by a rheumatologist especially in terms of Behcet’s syndrome (BS), spondyloarthropathies, sarcoidosis, systemic lupus erythematosus, GPA and relapsing polychondyritis. Despite an extensive investigation, the etiology still may not be well-clarified nearly in half of the patients. To date date, the prevalence of TINU syndrome has not been truly estimated because of its rarity. According to some recent observational studies, 2% of uveitis and 15% of ATIN population were found to fulfill the diagnosis of TINU syndrome.^[6,7]

In an early observational study, TINU syndrome was reported to be more frequent in females (female to male ratio 3:1) with a mean age of 15 years for disease onset, and mostly presenting with anterior uveitis (80%).^[2] However, a recent study has demonstrated that it may not be as common in females (female/male 1.6:1) as previous reports and the disease might be seen more frequently in the adult population (mean age of 46 years) as well.^[8] This change can be explained by the increased disease awareness in the recent years. Our case was of a young man with acute onset bilateral panuveitis. In our region, BS indeed should be placed among differential diagnoses, especially in a young male with panuveitis. The absence of other clinical components of BS, presence of granulomatous inflammation in the eye and negative pathergy test were the elements used for ruling out this possibility.

Based on the analysis of published cases, there is a unique relationship between the time in the emergence of renal and eye disease. The eye is typically involved in a period of 2 months before and 14 months after renal manifestations. As in our case, the synchronous presentation was seen only in 15% of patients.^[2] Interestingly, in a recent study, it has been demonstrated that asymptomatic uveitis may be detected in 50% of cases if ocular examination is performed regularly regardless of the symptoms.^[9] Therefore, all individuals should be investigated attentively in terms of each component of the disease at each outpatient visit. With better understanding of the disease nature in the last decade, prevalence rates have been relatively changed compared to earlier reports. This difference might be explained by the asynchronous pattern of the clinical features, which were not well-known previously. However, subsiding of each component after initiating steroid might be another possible explanation for the diagnostic delays.

Sarcoidosis is of important mimicking clinical condition that should be excluded before diagnosing TINU syndrome. Some experts have speculated that TINU syndrome might be an atypical form of extrapulmonary sarcoidosis according to the described granuloma formation in the kidney, eye and bone marrow in previous reports.^[1] Literature data regarding methods used for excluding sarcoidosis are not homogenous, mainly determined by normal chest X-ray and serum ACE levels. However, it has been well-identified that pulmonary involvement may not be evident in 10% of sarcoidosis and serum ACE levels can be seen normally in nearly half of the patients.^[10] In a study including 45 patients, it was found that combinating high levels of serum creatinine with urinary beta2-microglobulin has a predictive value of 100% for diagnosing TINU syndrome.^[11] We were not able to measure serum ACE and beta2-microglobulin levels in our center. Thus, we excluded sarcoidosis based on normal chest X-ray and serum calcium level, and with no evidence of a granulomatous lesion in the renal specimen. Additionally, ANCA-associated vasculitides should also be considered when a patient manifests with simultaneous eye and renal involvement, but urinalysis and ANCA profile were nonsupporting in this case.

To date, the pathogenesis of TINU syndrome has not been well-addressed. Evidence of infiltration of T-cells and lymphoplasmacytes on renal biopsy, established familial forms of TINU, and case reports seen post infections are some footprints of cellular immunity.^[12-17] On the other hand, IgG antibodies detected against ciliary and tubular cells, high levels of circulating modified CRP (mCRP) in the sera of TINU cases as well as antibodies demonstrated against mCRP in the renal and eye tissue of TINU patients suggest the role of humoral immunity.^[18,19]

No consensus on treatment is currently available. Steroids are the most common preferred first line agent in the setting of acute eye involvement and/or profound renal insufficiency. This recommendation is based on observational experience from the literature of ATIN. Renal prognosis is generally good in contrast to eye disease, which may show high recurrence rates (70%) despite steroid monotherapy.^[20] Therefore, addition of an immunosuppressive agent such azathioprine, mycophenolate mofetil and methotrexate may be considered for favorable long-term outcome.^[21]

Conclusion

TINU syndrome should be considered in the differential diagnosis of a young male with uveitis and renal involvement. Of note, it should not be forgotten that each component of this unusual disease may not be seen simultaneously. Therefore, the clinician should perform a thorough examination of each manifestation at each visit. Data on this issue is insufficient in rheumatology. We believe that this disease deserves more interest than being an “orphan” among rheumatologists.

Ethics

Informed Consent: Written informed consent was obtained from the patient.

Peer-review: Externally and internally peer-reviewed.

Authorship Contributions

Concept: R.Y., N.Ş.Y.B., T.K., Design: R.Y., N.Ş.Y.B., T.K., Data Collection or Processing: R.Y., Analysis or Interpretation: R.Y., N.Ş.Y.B., T.K., Literature Search: R.Y., Writing: R.Y., N.Ş.Y.B., T.K.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declare that they have no relevant financial disclosures.