Inflammation of renal interstitium and uveal tissue establishes the two components of tubulointerstitial nephritis and uveitis (TINU) syndrome. Although believed to occur more frequently in young females, a broad spectrum of patients can be affected. Both renal and eye disease can be asymptomatic and may not manifest simultaneously, having independent progressions. Renal disease manifests as acute kidney injury and may cause permanent renal impairment. Eye inflammation can manifest in different anatomical forms, most commonly as bilateral anterior uveitis and may progress to a chronic course. TINU syndrome accounts for approximately 1%–2% of uveitis in tertiary referral centres. A literature review covering the clinical features, pathogenesis, diagnosis and treatment is presented.
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Definition and epidemiology
In 1975, Dobrin et al described for the first time the concomitant presentation of an acute idiopathic kidney inflammation followed by bilateral anterior uveitis of unknown cause.1 Today, around 300 cases of tubulointerstitial nephritis and uveitis (TINU) syndrome are reported.2
This syndrome was originally believed to have a female predominance (3:1) and a median age of onset of 15 years, with males having an earlier age of onset.3 4 However, this gender effect appears weaker than initially proposed and manifestation in middle-aged people has also been reported.3 5–8 TINU syndrome has been described in most ethnic groups, and no geographic or racial predilection has to date been defined.
Up to 2% of patients attending specialised uveitis centres are diagnosed with TINU, and it accounts for nearly one-third (32%) of children and adolescents under 20 years old with characteristic sudden-onset bilateral anterior uveitis.3 4 9 However, it is deemed to be an under-recognised disorder and the true incidence may be higher.
TINU has been suggested to derive from the interplay of host vulnerability factors and environmental triggers.
Family and HLA
The genetic predisposition of TINU has been highlighted through clinical reports on monozygotic twins, siblings and a mother and her son diagnosed years apart, without a likely common environmental influence.10–15
As with other autoimmune diseases, the investigation for genetic susceptibility markers has centred on human leucocyte antigen (HLA) genes. The first specific HLA associations with TINU was led by Mandeville et al regarding the HLA-A2 and HLA-A24 antigens in Japanese patients (75%), which were later also identified in healthy subjects.3 7 Levinson et al found the link to HLA-DQA1*01, HLA-DQB1*05 and HLA-DRB1*01.16 The strongest association was for the HLA-DRB1*0102 allele (a subtype of HLA-DRB1*01), which was present in 72% (13/18) of patients in a TINU population.16 17 Mackensen et al showed that the HLA-DRB1*0102 allele occurs in increased frequency in one cohort of European patients with isolated sudden-onset bilateral anterior uveitis (typical of TINU), but not in another group with isolated tubulointerstitial nephritis (TIN). This could provide evidence that these risk alleles might be most relevant for the uveitic component of TINU.17
Several other small studies and case reports referring association to different alleles have been published.5 The discrepancy between studies may reflect a regional variation in predisposing alleles. There is as yet no determined susceptibility genotype across populations.
Drugs and infections
In most cases, TINU appears to be an idiopathic immune-mediated process, but it may be precipitated by drugs or infections.3 18 19 Although there is currently limited scientific evidence of a causal relationship between drugs or infections and TINU, the most commonly concomitant infections originate in the respiratory tract.3 Prior infections with agents such as Epstein-Barr virus, Chlamydia trachomatis, Mycoplasma tuberculosis, Toxoplasma gondii and Varicella zoster virus reactivation have been related.20–28 Non-steroidal anti-inflammatory agents and antibiotics have been proposed as precipitating agents, with other less well-known drugs, such as Chinese herbs, also reported.3 4 20 29
Most studies in this field are retrospective, and a substantial proportion of the suggested risk factors are common in the general population and may even coexist.5
To date, the exact pathogenesis of TINU syndrome remains elusive. The current accepted hypothesis proposes that an environmental factor may trigger an immune-mediated cascade in an individual with a particular susceptible genetic background.5 8 16 Both cellular and humoral immunity are thought to be involved in the disease development.3
Cellular immunity is believed to be a key-feature. HLA-class II (such as HLA-DRB1*0102) presents exogenous antigens to CD4 +helper T cells in the early phases of cellular immunity. A specific class II subtype might modify the immunity response, making a subject susceptible to a harmless antigen.17 A shared or similar antigen may explain the involvement of both organs.14 The role of T-cell mediated immunity is supported by kidney histology with tubulointerstitial infiltrates composed primarily of helper/inducer T-cells subset.30–36 FOXP3 +T regulatory lymphocytes (T-reg) are central to the maintenance of self-tolerance and tissue homeostasis, and abnormal T-reg function is implicated in many autoimmune diseases and malignancies.37 T-reg cells were recently found in kidney biopsies from paediatric patients with TINU. In patients with TINU with chronic uveitis, the density of T-regs were lower, implying an autoimmune mechanism to a persistent inflammatory response.38
The role of humoral immunity is suggested by the presence of autoantibodies against modified C reactive protein (mCRP) in renal and ocular tissue.39 40 In comparison with other renal autoimmune diseases and normal controls, a significantly higher prevalence of serum anti-mCRP autoantibodies in TINU syndrome was noted. This suggests that anti-mCRP may have disease-specific relevance.40 It remains unclear whether this autoantibodies are pathogenic, since they could merely be an epiphenomena in chronic inflammation with formation of acute phase reactants, as documented in lupus nephritis.41 Moreover, in patients with acute interstitial nephritis, elevated anti-mCRP antibodies may be predictive of subsequent uveitis development.42 This is consistent with the clinical evidence implying that the kidney may be the primary target of a sequential process, leading to an inflammatory cascade with secondary effects on the eye. The implication of the humoral immunity has also been demonstrated clinically with the recurrence of TINU in a patient following a kidney transplantation.43
The renal and intraocular inflammatory symptoms have often an asynchronous presentation.44 In most cases (65%), the uveitis follows the interstitial nephritis with an average delay of 3 months, although an asynchrony up to 14 months has been reported. In 20% of patients, the eye disease can also precede the kidney illness and, in a minority (15%) both have a concurrent onset.3 45
Renal disease: symptoms and signs
TIN is a frequent cause of acute kidney injury (AKI) and a potentially life-threatening condition. It is characterised by an immune-mediated infiltration of the kidney interstitium with inflammatory cells. Renal involvement is generally mild, resolving sometimes spontaneously.3 45
Patients may be asymptomatic or experience prolonged non-specific constitutional symptoms, typically linked to a hypersensitivity reaction, which can be mistaken for a ‘flu-like syndrome’. These include weight loss, malaise, fever, rash, arthralgia or abdominal pain.45 46
TINU-related uveitis typically develops between 2 months prior up to 14 months after TIN onset, but ocular symptoms may not be always present.3 4 47–49 Asymptomatic uveitis in TINU syndrome was present in up to 50% of patients in prospective studies.2 50 Eye disease may be masked by high dose of corticosteroids initiated for renal disease and occur with systemic corticosteroid taper or withdrawal.
Most patients (80%) experience non-granulomatous anterior uveitis of sudden-onset, presenting with symptoms of redness, pain and photophobia.2 4 Ocular manifestations are bilateral in about 80% of cases.51 52 The uveitis is initially unilateral, with a median time to second eye involvement of 1 week.4
A broad spectrum of manifestations is reported in the literature including posterior uveitis or panuveitis in up to 20% of patients although posterior uveitis is assumed to be underdiagnosed.2 3 There are also a few reports of TINU with granulomatous anterior uveitis and reports of intermediate uveitis and nodular scleritis.53–60
TINU syndrome remains a diagnosis of exclusion. Other disease entities known to simultaneously cause uveitis und nephritis must first be excluded.3 22 TINU is usually diagnosed in either an azotaemia of unknown origin, conceivably related to a flu-like illness, or a spectrum of ophthalmological symptoms, namely visual impairment, burning and/or red eyes.31 This diagnosis should be promptly suspected in young patients presenting with either uveitis or TIN. A definite diagnosis is confirmed through renal histopathology.
Peripheral blood abnormalities such as normochromic, normocytic anaemia, elevated erythrocyte sedimentation rate, hypergammaglobulinaemia and elevated CRP are described in TINU.61
TIN renal disease is difficult to diagnose based on clinical examination alone and the diagnosis may be challenging with reliance on laboratory findings and confirmatory renal biopsy. In patients with unexplained AKI (elevated blood urea nitrogen and/or serum creatinine (SCr)) or progressive reduction in glomerular filtration rate (GFR), TIN should be suspected.5 A hyperkalemic, hyperchloremic metabolic acidosis out of proportion to the renal dysfunction can occur.46
TIN affects primarily the renal interstitium and the tubular wall without prominent glomerular or vascular involvement.34 Urinalysis abnormalities are usually non-specific. Microscopic examination of the urinary sediment may be bland or denote subnephrotic proteinuria, microscopic haematuria, sterile pyuria and aminoaciduria.3 39 As glomerular pathology is not significant, high albuminuria levels are usually not seen, but tubular proteinuria may be detectable.5 Evidence of proximal tubular dysfunction is common, such as normoglycaemic glycosuria and Fanconi syndrome (glycosuria, aminoaciduria, acidosis).3 31 45
Biomarkers of kidney tubular damage, such as β2-microglobulin (β2M), are commonly found in TINU and are helpful. β2M is a small globular protein, filtered at the renal glomeruli and reabsorbed at the proximal tubule, representing a very sensitive marker for tubular damage.4 In patients with uveitis, increased SCr combined with elevated urinary β2M levels showed high positive and negative predictive values in detecting TINU.52 Urinary β2M levels have therefore been proposed as a screening measure for individuals with uveitis to investigate for underlying TINU syndrome.4 A positive correlation between urinary β2M levels and the histological grade of TIN in 10 paediatric patients was reported.34
Identification of typical histopathological findings on renal biopsy is definitive for the diagnosis.8 50 62 TIN is characterised histologically by interstitial oedema with infiltration of inflammatory cell (predominantly T lymphocytes along with neutrophils and plasmatocytes) and tubular damage with tubule oedema, epithelial degeneration and focal necrosis. Granuloma formation is uncommon. Conversely, the normal structure of glomerular matrix, blood vessels and the number of mesangial cells is preserved.6 63
Renal symptomatology is often a cause of late referral to specialised centres. HLA-DRB1*0102 allele might provide a time-independent marker, useful to suggest the diagnosis of TINU. HLA-DR, DQ class II DNA typing may help narrowing the differential diagnosis and defining the need for further medical assessment in both typical TINU syndrome uveitis and in some atypical cases, such as panuveitis.14 17 This may be particularly important in patients without evident renal disease, where the alleles detection could target the patients who would require additional evaluation of renal function. The sensitivity and specificity of this test seem to be relative good in North American and European patients.14
Associated ocular and renal inflammation can occur in other systemic illnesses, notably sarcoidosis, Sjögren’s syndrome, systemic lupus erythematosus, granulomatous polyangiitis, Behçet’s disease, tuberculosis and syphilis.3 5 64 65 The typical uveitis subtypes, median age of onset, and other characteristic systemic symptoms and signs may be promptly distinguishable. In children with anterior simultaneous uveitis, juvenile idiopathic arthritis should be considered, although an absence of renal disease is a feature of this condition.66 In non-granulomatous anterior uveitis, the clinical examination may be insufficient to distinguish between underlying causes. A complete review of clinical history, risk factors and clinical examination should guide the investigation for these conditions.55 65
Sarcoidosis can be similar to TINU syndrome, with Ali et al even hypothesising about a common pathogenesis.67 The distinction may be challenging in the paediatric population where the typical pulmonary manifestations may not arise.65 Sarcoidosis is a prolonged systemic granulomatous disease. The eye is commonly implicated, with a spectrum of uveitis manifestations including anterior, intermediate, posterior or panuveitis with granulomatous or non-granulomatous features. Kidney involvement is less frequent, with 20% having granulomatous interstitial nephritis, also with elevated urinary β2M levels.54 68 69 Granulomas are the exception in TINU disease. In challenging cases, such as in granulomatous uveitis, a renal biopsy may clarify the diagnosis. However, even the histological findings may be inconclusive. It is important to keep in mind that TINU is a diagnosis of exclusion.3 46 65
Criteria and problems in diagnosis
Mandeville and associates described in 2001 the evaluation criteria for TINU syndrome.3 The typical uveitis is bilateral anterior and has an onset less than 2 months before or less than 12 months after the onset of nephritis. Renal involvement is confirmed either on histopathological examination or clinically, by the presence of the three components listed in Box 1.3 TINU can be categorised as definite, probable or possible on the basis of the diagnostic criteria for TIN and the clinical characteristics of uveitis (table 1).3
Clinical criteria of acute tubulointerstitial nephritis3
Abnormal serum renal function
Increased serum creatinine or decreased creatinine clearance.
Increased urinary β2-microglobulin, low-grade proteinuria, presence of urinary eosinophils, pyuria or haematuria without infection, urinary white cell casts or normoglycaemic glycosuria.
Systemic illness lasting ≥2 weeks
Signs and symptoms: Fever, weight loss, anorexia, malaise, fatigue, rash, abdominal or flank pain, arthralgia or myalgia.
Laboratory findings: Anaemia, eosinophilia, abnormal liver function or erythrocyte sedimentation rate >40 mm/hour.
TINU is thought to be an under-recognised syndrome due to an absence and/or asynchrony of the ocular and renal symptomatology. Renal symptoms arise commonly first, and kidney function tests may be altered before the ocular inflammation, which can be difficult to diagnose and treat in the early stages. The subsequent uveitis may cause few or no symptoms and/or have a late onset, and the link with the renal disease may be missed. The natural history of associated uveitis may be influenced by systemic corticosteroids initiated for renal disease. Corticosteroids may prevent, mask or delay onset of uveitis, and ocular inflammation may develop during tapering or following discontinuation of therapy. The diagnostic of ‘idiopathic’ TIN may thus be incorrectly established.
TINU syndrome is presumably an uncommon cause of TIN.39 The highest prevalence of uveitis related with TIN in a retrospective case study was 46%, reaching 84% in a prospective study conducted in the same population submitted to regular slit-lamp examination and may be higher with longer follow-up time, due to late-onset presentation of ocular inflammation.2 18 19 50
On the other hand, mild renal disease may also be hard to detect, since it can exhibit very mild and nonspecific symptoms. Diagnostic tests regarding renal involvement are therefore either not obtained or not performed at the time of presentation of uveitis.3 58 Renal investigations may already be normalised when assessed, being responsible for cases labelled as ‘idiopathic’ uveitis. Even when both diseases cause symptoms, they may not be synchronous, and the connection between them may be missed.5
Treatment and prognosis
Long-term follow-up in TINU syndrome is still insufficiently studied. Outcomes with treatment are generally favourable for both the eyes and kidneys, but TIN and uveitis appear to have independent courses and severities.3 48 55 70 71 As a rare disease, treatment is not standardised. During the active phase, both ocular inflammation and renal function respond to corticosteroid treatment but controlling the eye-disease can be more challenging. The uveitis may persist or relapse even after 10 years, whereas renal disease carries a better prognosis.4 44 72
Topical corticosteroids and cycloplegic agents are the first-line treatment for anterior uveitis. However, in the acute phase of anterior uveitis in TINU, up to 80% of patients will require systemic corticosteroid therapy.3 54 In non-anterior uveitis, systemic steroid therapy may be necessary treatment.3 54 65 Earlier short follow-up publications reported high rates of spontaneous resolution with systemic corticosteroids, with only 10% of refractory patients.3 More recently, it has been shown that in 70% of patients with TINU, systemic corticosteroid therapy does not seem to be sufficient to prevent recurrences of uveitis.54 55 Younger age has been identified as a risk factor for developing chronic uveitis lasting >3 months. Ocular inflammation recurs in up to 50% of patients after corticosteroid withdrawal and relapses are generally often more severe than the initial event.3 34 54 72 Immunomodulation therapy (IMT) with methotrexate (MTX), azathioprine (AZA) or mycophenolate mofetil (MMF) is reported for refractory disease and/or corticosteroid sparing effect.22 There is no reported significant difference in terms of therapeutic effectiveness of the different IMTs. The selection of the IMT must follow a sequential stepladder approach, with low-dose, once-weekly MTX generally being the first choice. AZA or MMF are preferred in kidney involvement.22 34 54
In the series of Sobolewska et al, with adequate prolonged IMT treatment the control of the ocular disease was achieved with improved recurrence-free period.22 54 They reported a median treatment duration of 29.5 months (range: 13–40 months) in most patients (70%, 6/9) over a follow-up period of 4.5 years (range: 24–133 months).54 IMT therapy should seek to maintain quiescence for at least 12–24 months before withdrawal.65 Conventional IMT is usually enough to control the disease and the use of biologics (adalimumab, an antitumour necrosis-alpha blocking agent) in this condition has been reported in one patient due to recurrences and increased liver enzymes on MTX therapy and in another refractory case in combination with MTX.65 73
Despite the difficult control, uveitis in TINU carries a good prognosis for visual acuity.2 4 Ocular complications occur in up to 20% and include posterior synechiae (the most common), optic disc oedema, cystoid macular oedema or chorioretinal scarring.3 4 8 54 55
Most patients with TINU require systemic therapy for renal disease.55 Prompt initiation of systemic corticosteroids is the mainstay of TIN treatment, although it may not prevent the occurrence of late-onset uveitis.2 75 76 Corticosteroids reduce interstitial inflammation and subsequent fibrosis, promoting a more rapid recovery from renal symptoms and a greater improvement in GFR as compared with no treatment.77 With steroids, renal relapses are much less frequent than uveitis relapses but reactivation of nephritis is documented with steroid tapering.50 71 78 In one series, even with corticosteroid therapy, progression to chronic disease was described in 70% and moderate to severe chronic kidney disease in 30% of patients at 1 year of follow-up.71
Evidence for IMT in TIN is limited to a small number of retrospective series in severe renal disease and steroid-resistant cases.71 76–78 In one series of nine patients, two benefited from MMF added to corticosteroids for control of nephritis.77 To date, there are no studies comparing renal function outcomes with corticosteroid-therapy alone and combined corticosteroid plus IMT.
Follow-up and screening for TINU
Management of TINU has not yet been sufficiently researched, due to the rarity of this disorder and variabilities regarding primary endpoints and patient age group.65
Along with an important role as a diagnostic tool, β2M has been suggested as a marker of inflammatory anterior uveal activity. A prospective study comprising nine patients showed a strong correlation between high levels of urinary β2M and anterior chamber cells and flare.78 Traditional laboratory tests of renal function, including SCr tend to normalise rapidly in TINU, whereas urinary β2M levels decrease over the course of disease.34 78 As a possible predictor of ongoing subclinical systemic inflammation, urinary β2M levels may help in therapeutic decisions.77 78
Ophthalmological screening has been suggested by some authors, for all patients with isolated TIN for at least 1 year after the diagnosis, starting with 3-month intervals.2 50 In all patients with uveitis, renal function should be included within standard investigations. The possibility of renal disease should be considered, particularly in bilateral simultaneous anterior uveitis. However, by the time of presentation with uveitis renal findings may have normalised. Urinary β2M levels and SCr have been proposed as important investigations to assess renal function.2–4 52
The pathophysiological and epidemiological features of the TINU syndrome remain poorly understood, and most of the conducted clinical studies are retrospective and small in size.
TINU syndrome is probably underdiagnosed and high-grade clinical suspicion is crucial, with important attention to the cases ‘labelled’ as idiopathic TIN or idiopathic uveitis. These patients and/or their parents should be counselled on the association with eye or renal disease, respectively.
Disease relapses may be underestimated due to the short follow-up time in most studies. Even under systemic corticosteroid therapy, long-term reports show a significant proportion of patients exhibiting refractory uveitis. Further prospective studies with large cohorts may help to understand the disease and efficacy of treatments, especially emerging biological therapy in this condition.
Contributors IL and CMN devised the project. DA collected information and participated in drafting the manuscript with IL. All authors revised critically the article for important clinical content and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.