Three cases of tubulointerstitial nephritis and uveitis syndrome with different clinical manifestations

Tubulointerstitial nephritis and uveitis syndrome (TINU) is a disease in which idiopathic acute tubulointerstitial nephritis (TIN) is complicated by uveitis. Since Dobrin et al. [1] first reported 2 cases of acute eosinophilic interstitial nephritis accompanied by anterior uveitis and myeloid sarcoma in 1975, at least several hundred cases have been reported. In Japan, 2 years after the report by Dobrin et al. and Kikkawa et al. [2] reported 2 cases of combined interstitial nephritis and uveitis that were not associated with myeloid sarcoma. The diagnostic criteria of TINU are defined as the presence of histopathologically confirmed acute TIN and uveitis, as well as the absence of systemic diseases (e.g., sarcoidosis) associated with these conditions. Patients who suffer from TINU typically develop acute-onset bilateral uveitis, which commonly becomes chronic or recurrent, and fever is the most common symptom of TINU in Japan [3]. Herein, we report 3 cases of TINU with different clinical manifestations.

We observed 3 cases of TINU with different clinical manifestations (Table 1). Although this disease can occur in all ages and sexes, it is more likely to occur in peripubertal girls (median age, 15 years; male-to-female ratio, 1:3) [3]. TINU reportedly accounts for 1–2% of uveitis cases in children aged ≤15 years [4]. There are also reports of TINU in middle-aged people [5, 6], which are similar to Case 3 herein. Matsumoto et al. summarized the findings from 102 Japanese patients with TINU that were reported between 1977 and 2013 [5]. In their study, TINU showed a female predominance (approximately 2.5:1) and was more likely to develop in younger patients, with a median age of 14 years. Slight fever was the most common general symptom. Similarly, in Case 1, flu-like symptoms were some of the first clinical symptoms.

Uveitis reportedly develops between 2 months prior to 12 months after the onset of TIN, occurring before, simultaneously, and after the diagnosis of TIN in 20, 15, and 65 % of cases, respectively [3]. Although cases of concurrent onset of uveitis/TIN (Case 1) are easy to diagnose, cases in which uveitis occurs after nephritis (Case 3) require differentiation from other diseases [7]. The differential diagnoses of TINU include systemic lupus erythematosus, sarcoidosis, Sjögren’s syndrome, Behcet’s disease, tuberculosis, toxoplasmosis, and infectious mononucleosis. In Case 3, differentiation from sarcoidosis complicated by granulomatous uveitis and renal lesions was important. If the history of TIN had not been confirmed, the diagnosis might not have been established. Importantly, it should be noted that uveitis tends to become chronic in middle-aged patients [8]. Moreover, in cases of uveitis preceding TIN [9], such as Case 2, it is important to repeat whole-body imaging studies in order to differentiate from other diseases. However, in some cases, the nephritis is mild and resolves spontaneously, which makes it difficult to diagnose [10].

In this study, Cases 1 and 2 presented with non-granulomatous uveitis, while Case 3 presented with granulomatous uveitis. Although non-granulomatous anterior uveitis associated with fine keratic precipitates is typically observed in TINU, recurring/prolonged cases may be accompanied by mutton-fat keratic precipitates (granulomatous inflammation), fibrin deposition, posterior synechiae, hypopyon, etc. [11]. The reported features of the fundus in TINU include papilledema, tortuosity, and dilatation of the retinal vessels in the posterior pole, peripheral exudates, chorioretinal scars [3, 12, 13], and concurrent choroidal neovascularization [14]. Moreover, neuroretinitis may be exhibited in TINU [9]. A common FA finding of TINU is the leakage of fluorescent dye from the optic disks and central-to-peripheral microvessels, which was observed in our cases [15].

In Case 2, leakage of fluorescent dye from the optic disk and optic disk edema on optical coherence tomography were observed, and Goldmann perimetry revealed enlargement of Mariotte’s blind spot. Therefore, differential diagnoses of optic neuritis and uveitis with optic disk edema were considered.

However, as RAPD was not recognized, and no swelling of the optic nerve was observed upon computed tomography, we excluded optic neuritis. Moreover, the critical fusion frequency value in both eyes was within the normal range. We also considered the possibility of a disease related to intercurrent optic disk edema and uveitis, such as sarcoidosis, Vogt–Koyanagi–Harada disease, or cat-scratch disease. However, this case exhibited non-granulomatous uveitis, and sarcoidosis and Vogt–Koyanagi–Harada disease are both classified as granulomatous uveitis. Therefore, we considered that these diseases were unlikely in this patient. Moreover, in this case, vasculitis was seen upon FA, while the distinctive periphlebitis with perivascular nodules associated with sarcoidosis was not recognized. In addition, no increase in the angiotensin-converting enzyme level was observed in the biochemical tests, and there was no bilateral hilar lymphadenopathy upon chest X-ray, excluding a diagnosis of sarcoidosis. Concerning the differential diagnosis of Vogt–Koyanagi–Harada disease, a type of optic neuritis that does not exhibit serous retinal detachment, symptoms of meningitis, including headache, were not observed, nor were the prodromes of Vogt–Koyanagi–Harada disease, including ringing in the ears and dizziness. Further, this case showed a self-limiting trend without systemic steroid administration, and ocular depigmentation, nummular chorioretinal scars, and retinal pigment epithelium clumping and migration were not observed, thus ruling out Vogt–Koyanagi–Harada disease. Finally, cat-scratch disease remained as a potential differential diagnosis; however, no anti-Bartonella antibodies were detected and a “star figure” did not appear in the macula even over time, suggesting that this was not the correct diagnosis. Instead, from the above findings, we eventually diagnosed this case as TINU. It should also be noted that the positive predictive value of increased β2M and serum creatinine has been reported to be 100 % for detecting TINU [16]. Additionally, NAG is a good screening marker for detecting renal dysfunction in TINU [17]. However, while Case 1 showed increased urinary β2M and serum creatinine levels, Case 2 showed only increased urinary β2M levels.

Matsumoto et al. [5] reported that, in Japanese patients with TINU, the efficacy of systemic corticosteroids was unclear, while ocular administration of steroids to treat uveitis was effective in 60 % of patients. If systemic administration of steroids shows poor efficacy in the treatment of TINU, administration of an immunosuppressive agent such as methotrexate or cyclophosphamide should be considered. Methotrexate is considered to be very useful in the tapering of steroids; however, it is associated with severe side effects such as bone marrow suppression, interstitial pneumonia, and stomatitis. On the other hand, although cyclosporine is associated with a risk of renal toxicity, it is often used for steroid-resistant cases of non-infectious uveitis in Japan. In Case 1, when the dose of oral prednisolone was tapered, anterior uveitis recurred along with an increase in the urine β2MG and NAG levels. However, although the patient experienced relapse of symptoms during steroid tapering, the efficacy of the steroids at the initial dose was good, and cyclosporine administration was therefore not needed in this case [18, 19]. On the other hand, in Cases 2 and 3, systemic corticosteroids were not needed.

Typical pathological features of TIN include infiltration of inflammatory cells (predominantly lymphocytes along with neutrophils and plasmatocytes) to the tubulointerstitium. Edema and atrophy of tubular epithelial cells may also be observed. Conversely, the normal structure of the glomerular matrix, blood vessels, and the number of mesangial cells are maintained. Lastly, using fluorescent antibodies, deposition of immunoglobulins and complements may be observed. In the present study, the pathological features of Case 1 were consistent with these findings, whereas pathological testing was not performed and was performed at another hospital for Cases 2 and 3, respectively; hence, the pathological features of these patients could not be verified.

Moreover, in our cases, we did not examine the human leukocyte antigen (HLA) types. A genetic background has been suggested in Caucasian patients with TINU (associations of HLA-A2 and -A24 with TINU) [3], but no specific HLA types related to TINU have been identified in Japanese patients [5].

Finally, TINU is known to have a relatively favorable prognosis, while there are some reports of poor visual prognosis, such as in cases with choroidal neovascularization [14]. Thus, early diagnosis and treatment are recommended.

In conclusion, when a diagnosis of TINU is considered, detailed history taking along with whole-body imaging studies and examinations of renal function are important.