Epidemiology

TINU accounts for 0.2% to 2% of cases of uveitis presenting to tertiary uveitis centers [ , , ]. Initially perceived as predominantly affecting females (3:1) at a median onset age of 15 years, more recent observations suggest a different demographic makeup, spanning individuals of all ages with a less pronounced gender bias [ , ]. A recent systematic review, which included almost 600 cases conducted by Regusci and colleagues, supported this new notion, with reports of an overall median onset age of 17 years (range: 13–46 years) and a female-to-male ratio of 1.8:1, with a higher female preponderance in adult age [ ]. Recent reports have suggested there may be a bimodal age distribution for TINU [ , , ]. Cao and colleagues identified one cohort between 10 and 46 years of age and another between 77 and 83 years [ ]. Other studies have suggested that this bimodal distribution is associated with sex, with evidence that males (median age 15 [ ]; median age 13.5 [ ]; mean age 29.4 [ ]) have a lower age at onset than females (median age 26 [ ], median age 34 [ ], mean age 49 [ ]).

The literature suggests that regional and ethnic variability occurs in the demographics of TINU, though it has not been shown to adhere to defined geographic or racial biases. In China, a systematic review of 71 cases reported a median age at onset of 42 years [ ]. Pichi and colleagues reported a male predominance in a population of Middle Eastern patients [ ].

TINU often is considered an underdiagnosed syndrome. It is postulated that this may be because both the ocular and renal disease can be asymptomatic, or that the lag time between the onset of renal and ocular disease may make it easy to overlook this connection [ ]. Mandeville and colleagues demonstrated that many patients with TINU were initially mislabeled as “idiopathic,” leading to an underestimation of TINU`s prevalence [ ]. The apparent lack of widespread recognition within the medical community suggests a potentially higher prevalence rate than is currently reported.

Interestingly, an increased number of TINU cases were reported during the COVID-19 pandemic. A retrospective study by Huang and colleagues found a statistically significant increase in TINU during the pandemic at a single tertiary referral center: they reported an increase from 1/561 (0.18%) new patient diagnoses between 2017 and 2019 to 15/581 (2.58%) new patient diagnoses between 2020 and 2022 ( P = .0005) [ ]. The causality of that increase is still uncertain. It could be the heightened awareness of the variable clinical presentation of TINU leading to higher rates of diagnosis during the pandemic, or an actual increase in incidence due to either the disease itself, as suggested by Sakhinia and colleagues [ ], or to vaccination against COVID infection. Some reports have similarly described a temporal association between COVID-19 infection and sarcoid-like uveitis, COVID-19 infection and acute TIN, and COVID-19 vaccination and uveitis [ ]. These studies suggest that TINU should be considered in the differential diagnosis of patients with a recent COVID-19 vaccination or infection.

Pathophysiology

TINU is currently believed to be an auto-immune condition that may be triggered by an environmental factor in patients with certain genetic predispositions [ , ].

Although the majority of TINU cases are idiopathic, the 2 main environmental factors that may trigger TINU are infections and drugs [ , , ]. It is important to note that limited evidence supports a causal relationship between these factors and TINU because of the small size and retrospective nature of many of the studies available and the commonality of these factors in the general population. The drugs most associated with TINU include antibiotics and nonsteroidal antiinflammatory drugs (NSAIDs), while some less common agents reported to be associated with TINU have included proton pump inhibitors, supplements, and Chinese herbs [ , , , , , ]. Regusci and colleagues systematic review sought to identify triggers for 352 cases: drugs and toxic agents accounted for 28% of cases, and infection accounted for 6% of cases; no identifiable trigger occurred in 63% of cases [ ]. Although infection is a rare risk factor, different infectious agents have been associated with TINU and tend to originate in the respiratory tract. Mandeville and colleagues reported that 15 of 122 (12%) patients with TINU had a respiratory tract infection, which was the most common type of infection in their cohort [ ]. The infectious etiologies reported in association with TINU have included streptococcus species, Campylobacter jejuni , Chlamydia trachomatis , Epstein-Barr virus, human T-cell leukemia virus type 1, rhinovirus, hepatitis C, varicella-zoster virus, tuberculosis, other nonspecified respiratory viruses, and, more recently, SARS-CoV-2 virus [ , , ].

Genetic predispositions in TINU were introduced with cases of familial clustering and then further investigated with susceptibility studies around human leukocyte antigen (HLA) gene markers [ , ]. In 2001, Mandeville and colleagues initially reported that 75% of Japanese patients with TINU had HLA-A2 and HLA-A24 [ ]. However, Matsumoto and colleagues later demonstrated no significant correlation between those HLA antigens and TINU when comparing it to a group of healthy Japanese patients [ ]. More recently, in Spain and Portugal, a strong prevalence of HLA-DQB1∗05 was identified among patients with TINU who underwent HLA phenotyping [ ]. In American cohorts, a study demonstrated a strong association between TINU and HLA-DQA1∗01, HLA-DQB1∗05, and HLA-DRB1∗01, while another study showed strong associations between HLA-DRB1∗01/HLA-DQB1∗05 and idiopathic pediatric panuveitis [ , ]. Mackensen and colleagues later added to that knowledge by demonstrating an increased incidence of HLA-DRB1∗0102 in sudden onset bilateral patients with anterior uveitis, but not in patients with isolated TIN, suggesting that this allele may be more associated with the ocular manifestation of TINU [ ]. To date, the strongest correlation in Western populations appears to be with HLA-DRB1∗01.

While the pathophysiology of TINU is still not fully understood, evidence exists that points to both humoral and cell-mediated immunity involvement in the development of the disease. Studies suggest that cellular immunity is the main driving force of disease onset, while humoral immunity may be more associated with the chronicity of disease [ , , ]. The different HLA-class II genotypes associated with TINU and multiple accounts of predominantly T-cell and monocytic interstitial infiltration in renal biopsy serve as evidence for cell-mediated immunity as a major pathogenic mechanism [ , ]. Evidence of autoantibodies against C-reactive protein (mCRP) in both the kidney and eye samples of patients with TINU supports humoral immunity involvement in its pathogenesis [ , ]. Tan and colleagues hypothesized that mCRP could be a target autoantigen in TINU and showed that mCRP antibodies were significantly more prevalent in patients with TINU when compared with controls and other patients with other autoimmune diseases such as autoimmune neutropenia, IgA nephropathy, minimal change disease, antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis, Sjogren syndrome, and amyloidosis [ ]. Li and colleagues demonstrated a correlation between abnormally high levels of mCRP antibodies and late-onset TINU in Chinese adults. Palamaris and colleagues suggested that patients with more prolonged renal disease and higher chronicity indices had immune complex deposition, suggesting a higher degree of humoral involvement in the later stages of disease progression [ , ]. Reports of TINU recurrence in patients with kidney transplant further support humoral immunity involvement [ , ].

Renal

Acute TIN is a relatively common form of acute kidney injury (AKI) that can lead to serious complications such as chronic kidney disease (CKD) and renal failure requiring dialysis, especially in older age groups [ , , ]. Although TIN can be asymptomatic in many cases, there are a variety of systemic, nonspecific symptoms that have been reported [ ]. These include fatigue, weight loss, anorexia, low-grade fever, arterial hypertension, maculopapular rash, arthralgia, nausea, and abdominal pain [ , , , ]. In the less common cases whereby uveitis precedes the onset of TIN, the renal disease can present up to 2 months after uveitis onset [ ].

Ocular

Similar to TIN, the uveitic component of TINU may be asymptomatic in up to 50% of patients in prospective studies [ , ]. Those who are symptomatic may present with ocular pain, conjunctival injection, blurred vision, visual loss, and photophobia [ , ]. Another important consideration is that the absence of ocular symptoms in TINU may be secondary to the use of corticosteroids initiated for renal disease. In this case, patients may become symptomatic later in the disease course with the reduction or cessation of systemic corticosteroid treatment.

Although the majority of TINU cases described in the literature present with sudden-onset nongranulomatous, bilateral (88%) anterior uveitis (65%), there is increasing prevalence and awareness of cases presenting with intermediate, pan-, and posterior uveitis [ , ]. In addition, while TINU typically is nongranulomatous, rarely it may present with granulomatous disease [ ].

Posterior segment manifestations are more common than initially postulated and can be present in the absence of anterior involvement [ ]. Findings may include vascular sheathing, chorioretinal scars, neuroretinitis, acute posterior multifocal placoid pigment epitheliopathy, multifocal choroiditis, choroidal neovascularization, and retinal pigment epithelium detachments. Posterior segment imaging with fluorescein angiography (FA), ultra-wide fluorescein angiography (UWFA), and optical coherence tomography (OCT) can reveal subclinical vascular leakage, cystoid macular edema, peripheral nonperfusion, and optic nerve edema [ ]. Additional complications associated with TINU that have been shown to affect up to 20% of patients include posterior synechiae, ocular hypertension or glaucoma, and cataracts [ , , , ].